V 78 no 3 by Joanne Paterson

Volume 78 Number 3

UWOMJ

Ge n e ti cs

CONTENTS EDITORIAL Editori a l

Wendy Ng and Amber Menezes

A Bump in th e Road for the UWOMJ

Wenc6•Ng

DEPARTMENTAL ARTICLES Clinical Procedures N a ilfold Capill aroscopy and H e redita~y Di ea e: C urrent Appli cati ons and Future Prospects Edward We iss and Paul Lau

Interdisciplinary Collaboration Multidi sc iplinary M anage ment at Key Stage in th e Huntington's Di sease N eurodegenerati ve Process Abhijat Kitchlu and Allanah Li

Diagnostic Review 0 teoarthritis: An Old Di sease Cast in a N ew Li ght through Greater Understandin g o f th e Human Ge no me Rachel Bevan and Jason Essue

Medicine and the Law Who' in Yo ur Ge nes: A Ph ys ic ian ' " Duty to Warn" Pati ents' Re lati ves about Geneti c Ri k Colin Meyer-MacA ulay

Ethics Ethi ca l Impli cati ons of Ge rm Line Geneti c Eng ineerin g Hassan Mir and Christina Mo rgan

Medicine and Technology Persona lized Cancer M anagement Jenny Shu and Pencil/a Lang

Thinking on Your Feet M arfa n Syndrome Kalpa Shah and Aim an A fak

Zebra Files Human Statue : C ha llenge in Manage me nt o f Pati ent w ith Fibrodys pla ia Oss ifi cans Progres iva Anna Burianova. A ·hfey Brown. and Jenna Ashkana e

N ucha l Translucency and Prenata l Di agnos i o f Congenita l Hea t1 Disease: Progress and Future Directi on

Health Promotion The Bla meworthy Gene Jennifer N. Bondy and Laura Hinz

History of Medicine Vampire Proj ects or Long Ago Person Found? A Hi to ry of Ge ne ti c Researc h in First Nations Communiti es Kate MacKeracher and Michael Livinoston

FEATURE ARTICLES Quality of Life Consequence o f Long QT Syndrome !. hvinder Chattha and Caleb Zelenietz

X iangning Fan Genetic Susceptibility in Rh eum ato id Arthritis Kimberley Colangelo and Caleb Zeleniet::

58 The Legacy of a Life L ived : TransGenerati ona l Epi ge neti c a nd Cancer Deve lopment

Mark Kirchhof

UWOMJ, Vol 78, Issue 3

Page

CONTENTS FEATURE ARTICLES Ami sh, M enno nite and Hutterite Geneti c Di order Database Michael Payne

Hemochro mato is- Scree ning fo r a Comm on Condition N ick Sunderland

A mni ocentes is: Safety, Re li ability and Altem ati ves Caleb Zelenietz. Kimberley Colangelo, and Ishvinder Chattha

CASE REPORT Ducta l Carci noma in si tu in a 25-Yea r-O ld Ma le with Unil ateral Gyneco ma ti a Christopher J. Coroneo

COVER ART Front: Edward Wei , M eds 201 2. In ho nour of UWOMJ's inaugural geneti cs issue, 1 thought it would be interestin g to juxtapose the old and the new -- the x-ray and th e mi croarray. Eac h represents an attempt to peer inside the inner workings of the human mac hine and di vine its mysteri es. Of course, whil e th e Roe ntgenesque head ca n be ea il y identifi ed as such, the radi ograph gives us little info rmation about th e hea lth and fun ction of what li e benea th . The microarray, on the other hand, resembles nothing human at a ll, yet provides more informati on than we can rea lly handle all at o nce. The chall enge fo r medica l geneti cs in th e future w ill be tb e integration of th ese multiple moda lities -- th e shaping and moulding of mountains of data into findin gs we can see, feel, and hear. Back: Juli e Huang, Meds 201 2 . Mi che langelo's Tbe Creati on of M an, found o n the ceiling of th e Si tine C hape l depi ct the hand of Adam reachin g o ut to the hand o f God. The cover re ferences thi s ico ni c wo rk, and brings into question th e ways in w hi ch science and medicin e use ge neti cs as determin ants of human creati o n.

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EDITORIAL STAFF EDITORIAL BOARD AND SUPPORT Editors-in-Chief

Amber M enezes and Wendy Ng, Meds 2009

Managerial Stream Manag ing Editor Senior Associate Editor Junior Associate Editor

Wendy Ng, Meds 2009 Tiffany K wo k, Meds 20 10 Laura Hinz, Med 20 11

Contracts and Awards Stream Executive A sociate Editor Senior Associate Editor

Renata Villela, Meds 2009 Jean Chen, Med 2010

Junior Associate Editor

Pasquale Montaleone, Meds 20 11

IT Director

Tshvinder Chattha, Meds 20 11

Layout Editor

Wang Xi, Meds 20 11

DEPARTMENTAL EDITORS Clinical Procedures

Diagnostic Review

Ethics

Sr: Paul Lau, M eds 2011 Jr: Edward Weiss, Med 2012

Sr: Jaso n E ue, Meds 20 11 Jr: Rachel Bevan, Med 20 12

Sr: Chri stina Morgan, Meds 20 11 Jr: Hassa n Mir, Meds 20 12

Health Promotion

History of Medicine

Interdisciplinary Collaboration

Sr: Laura Hinz, Meds 2011 Jr: Jennifer N. Bondy, Meds 2012

Sr: Michael Li vingston , Med 20 11 Jr: Kate MacKerac her, Meds 20 12

Sr: Abhijat Kitchlu, Meds 20 11 Jr: Allanah Li , Meds 20 12

Medicine and Technology

Medicine and the Law

Profiles

Sr: Penci lla Lang, Meds 20 11 Jr: Jenny Shu, M eds 2012

Sr: Abdullah Alabousi , Med 20 11 Jr: Co lin Meyer-MacA ulay, Meds 2012

Sr: Emma Love, Meds 20 11 Jr: Juli e Hughes, Meds 20 12

Thinking on your Feet

Zebra Files

Sr: Aiman Alak, Meds 20 11 Jr: Kalpa Shah, Meds 20 12

Sr: Jenna Ash kan a e, M eds 20 11 Ashley Brown, M eds 20 ll Jr: Anna Burianova, Meds 20 12

UWOMJ ADVISORY BOARD Dr. Dr. Dr. Dr. Dr.

Lois Champion David Co lby Kellie Leitch Jeffrey Ni sker Douglas Quan

Dr. Dr. Dr. Dr. Dr.

Faisal Rehman Michael Rieder Jim Silcox Wayne Weston Ron Wexler

PRINTER InPrint Design: University Students' Council, University of Western Ontario

UWOMJ, Vol 78, Issue 3

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EDITORIAL The mapping of human genes has been an important step in the deve lopment of medicines and other aspects of hea lth care, emphasized by the wo rldwide interest in the Human Genome Proj ect that began in 1990 in the United States at the Nationa l Institutes of Health . It is with thi s deep respect for the profound importance of genetics that we are proud to present our newest issue of the Uni versity of Western Ontari o Medical Journal. Case reports, reviews, and indepth di scuss ions cover a vari ety of topi cs on thi s fasc in ating theme. Maj or impli cations for the future, present and pas t underli e each of these arti c les. The future is a fo cal point of both specul ati on and hope w hen it comes to the detection of blood vessel anomalies and microvascular di sease, as described in an enli ghtening article w ithin the Clinical Procedures departmental section here in. Prenatal geneti c di agnos is helps us predi ct the future of an unborn child, as hi ghli ghted in a feature arti cle in thi s issue. M eanwhile, on a broader sca le, th e endl ess possibiliti es behind the cuttin g edge tec hnology in personali zed cancer management are also explored in the Medi cine and Technology departmenta l secti on. A feature arti cle di scu sse how our seeming ly innocuous current environmental exposures can even affect our future generati ons! And yet, despite all its predi cti ve powe r, geneti c di seases continue to burden oc iety in the present time. What are the impli cati ons of long QT syndrome on quali ty of life? Wh at rol e does geneti cs pl ay for pati ents di agnosed w ith rheumato id arthriti s? How should we sc reen for he mochro matos is? Our authors address these issues. Far more un common conditi ons, such as

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fibrodysplasia oss ificans progressa, can be detected early with genetic screening today, as described in the Zebra Files. Our Interdisciplinary Coll aboration authors weigh in on the necessity of support when it comes to Huntington ' s Disease. But the folli es of genetics are al so addressed what does it mea n to label one another as ill or health y, parti cul arl y when it comes to alcoho li sm? Thi s dil emma is eloquently outlined in our Hea lth Promotion departmental article. is a lso essential to look back in time . Our contributors do not forget to take an in depth look at the past. As our History of Medicine departmenta l arti c le demonstrates, genetic research has affected indi genous peoples, and ethi ca l considerati ons have ari sen from hi torical cha ll enges, leading to stricter implementation of inforn1ed consent princ iples today. [t

Genetics connects all of humanity, from past to present to future, and underscores the simil ariti es and di fferences between us all. Understanding our pas t allows us to plan for the future. The recent period of volatility for the Uni vers ity of We tern Ontari o Medical Journal is hi ghli ghted in thi s i ue, w ith a reflection piece th at addresses the maj or changes that have occurred within the journal 's structure, operations, and content, ultimate ly producing the impre ive coll ecti on of quality articles that you see now. We hope that you find thi s issue re levant in looking toward the future, keeping up with the present, and under tanding the pas t when it comes to genetics and its wide-ranging impacts. Enjoy! -Wendy N g and Amber M enezes Editors-in-chief

HISTORY OF THE UWO MJ A Bump in the Road for the UWOMJ In 2005, the University of Western Ontario Medical Journal had not printed an actual issue in two years, despite its long, successful history as Canada's second oldest medical student journal. At that point, the only printed issue that had been distributed in recent memory was the Obstetrics and Gynecology issue. Meanwhile, the Pediatrics issue had been laid out in full - with cover art, student articles and advertisements included - but there were no funds for printing, nor a printing service set up. However, there were still bills to be paid for the layout of the Pediatrics issue. At the same time, some articles had already been collected for the History of Medicine issue, but there was no realistic plan in place for the issue to go forward. My four years as the managing editor of the UWOMJ have been exteremely rewarding. When 1 both started medical school and joined the UWOMJ in 2005 , the position of " Managing Editor" was newly created and loosely defined my original job description was merely to implement a peer or faculty review process for student articles - but I learned quickly there was so much more to be done, and l vastly expanded my role. The company that had taken care of UWOMJ's layout, printing and distribution in previous years reportedly went bankrupt and fled North America. My phone calls and emails were not returned. The UWOMJ was caught unprepared in a confusing state of affairs. Many students were frequently asking me when their articles would be printed and questioning when the next issues would be coming out. Multiple advisors recommended to me that I should simply put a stop to printing the journal at all, and that I resort to online copies only. But this was not an acceptable answer to me - it was of utmost importance that the UWOMJ remain in print.

UWOMJ, Vol 78, lssue 3

It was with thi s realization that I began to seek out alternatives for both advertising and printing. Individually so liciting advertisements for the journal was not at all an easy task - I came to thi s discovery through trial and error. I contacted CU Advertising, and with the help of my colleague Renata Villela, we signed our first contract with them for the Oncology iss ue. At the same time, I looked for a new printing company. I visited several, collecting proofs and comparing prices, before I finally decided to work with Imprint. I was confident that their staff would ensure that the journal was printed to our high standards.

The Oncology issue was the first edition of the UWOMJ to accept only articles reviewed and approved by faculty at UWO. Recruiting contributors was a challenge in itself, and I designed an original new layout for the issue. I contacted dozens of faculty in 2005, asking them to join our faculty review board. Articles that did not meet rigorous review standards were rejected. I designed and sent out a peer review form to reviewers and requested countless revisions from authors. I acted as a mediator between all authors and reviewers to maintain absolute anonymity in the process. Finally, 1 needed a new process for distribution of the journal. I put together a long I ist of mailing addresses, and we had our first '' mailing label sticker party" in the UWOMJ office. Amber and I carried the journals down to the mailroom, and the bulk of our very first new journals were on their way! However, a sustainable structure for the UWOMJ was sorely needed. Renata offered to take care of the contracts, while I worked on the journal itself. This was how the two divisions of the Editorial Board of the journal were born: Renata took charge of the Contracts and Awards

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Division, while I headed up the Managerial stream. The backlogged Pediatrics and History of Medicine issues were published online.

provided much-appreciated encouragement for this first generously funded the awards.

When Amber Menezes helped collect articles for the subsequent Family Medicine issue, authors were responsible for ensuring that their articles were indeed reviewed and approved by UWO physician faculty members before submission. This process has proven sustainable and has maintained the high quality of articles appearing in the UWOMJ.

We are incredibly lucky to have a remarkable editorial team taking on the immensely rewarding and challenging experience of running the UWOMJ. Laura Hinz organized our first Awards Ceremony, where plaques were presented to very deserving winning contributors. She also initiated the creation of the new Interdisciplinary Collaboration department of the journal, reflecting the growing medical multidisciplinary nature of health care today.

The first online summer supp lement of the UWOMJ was put together by Stephen Chihrin in 2005. This has become an annual tradition. Tiffany Kwok continued to produce the summer supplement and put together the Cardiovascular issue, our first alternatively funded issue. She also ensured that the UWOMJ office was clean and in a functional state for our editoria l staff - a massive task, given the mess that it was in before! Renata instituted some amazing new changes for the UWOMJ. Recently, she has spearheaded the process for the UWOMJ to be catalogued by PubMed. Notab ly, she suggested that we recognize our writers' and artists' talents and hard work with departmental and feature article awards, as well as cover art awards. We had our first Awards meeting in the early summer of 2008 . Dr. Fai sal Rehman, who has been our most active facu lty supporter from our rocky start,

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food meeting,

and and

It has been unmistakably clear that the transition into sustainable operations has progressed pectacularly. We are fortunate to have an extraordinary group working on ensuring that the UWOMJ continues its high-quality publishing and distribution, whi le consistently exceeding our readership's expectations. The graduatin g students of the UWO Medicine C lass of 2009 have seen our medical journal recover dramatically over the past few years from its lowest point in 2005 . I eagerly look forward to following the journal as a UWO alumnus, with such a capable new editoria l team at the lead! WendyNg Managing Editor-in-chief

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CLINICAL PROCEDURES Nailfold Capillaroscopy and Hereditary Disease: Current Applications and Future Prospects Edward Weiss (Meds 2012) a nd Paul Lau (Meds 2011) Fa culty Reviewer: Dr. janet Pope Nail fo ld capillaroscopy is a proven non-invasive method of examining the peripheral microvasculature. Primaril y u ed to a e s rheumato logica l di sease, it is being increasingly recogni zed as a versatile tool that can detect blood vesse l abnorma liti es in a wide range of conditi ons, including a number of hereditary di seases. As a compl ement to geneti c testing and other clini ca l examinati ons, capill aroscopy can often yield important diagnos tic clues, and has the potentia l to aid research in hereditary conditi ons as disparate as te langiectas ia, glaucoma, and schi zophreni a.

Introduction At an estimated length of between 50,000 and I 00,000 miles, th e vasc ul ar system of the human body holds th e distincti on of being longer than the road networks of many sma ll countri es. As a conduit fo r metabo lites, hom1ones, e lectrolytes, and drugs , it excels in its fun cti on and is exquisitely sensiti ve to constant changes in suppl y and demand. Its very pervas iveness can, however, act as a doubl e-edged sword patho logies that affect one area of the vasculature, such as atherosclerosis or Marfan 's synd rome, are likely to affect other areas as we ll. As a di agnostic too l, the ti ght integrati on of the vascul ature with all oth er body orga ns and systems can often be used to the c lini c ian and pati ent ' s advantage , since signs observed at one po int in th e vessel netwo rk ca n indi cate patho logy at a di stant site. T he presence of caput medusa around the umbili cus, fo r exa mpl e, is useful in di agnos ing portal hypertension and inferi or vena cava o bstructi on. Often, however, abnorma liti es in the vascul ar system are more subtl e and require suita bl e clini ca l skill to ascertain them. Na il fo ld capill aroscopy (NC) is the in vivo mi croscopi c examinati on of the capill ari es found in the skin just prox ima l to the na il. T he capill ari es in thi s area run para ll e l to th e surface of the skin , and can be eas il y visuali zed w ith Page

appro pri ate li ghting and magnifi cation . U sing onl y a magni fy ing g lass, the 19th century Italian phys ician Gi ovanni Ra or1 was able to describe abnorma l capillarosco pi c findings and re lated th em to conjuncti val inflammation.' In the twenti eth century, the practi ce of N C was refin ed and now it is used most prominently to detect markers of rheumatologica l di sease, such as systemi c sclerosis. However, there are indi cations that NC may a lso be he lpful in the diagnosis and progno is of vari ou hereditary conditions that invo lve the mi crova cul ature. In thi s articl e, we hope to illustrate a genera l approac h to NC as a too l in assess ing rh eumato logica l patho log ies as we ll as its potenti a l utility in the context of geneti c di sease.

Procedure T raditi onall y, NC has been performed w ith a li ght mi cro cope. The pati ent is seated a nd acclimati zed to the ambi ent temperature of the examining room. lmmer ion oil or c lear gel i appli ed to the nailfold area to enhance transparency of th e skin and make the capillaries more visibl e, and the li ght source is positioned at a 45 degree ang le to the nailfold . A green L ED or green-filtered li ght is often used to furth er enhance visibili ty, as li ght in th e blue-green part of the spectrum is preferenti a lly absorbed by hemoglo bin. A w ide view of the termina l capill ari es can be obta ined with a 1Ox-60x

magnification, and more detailed views can easily be achieved with higher magnification (250x2 1000x). Photomicrographs can be taken at the time of examination for further study or archival purposes. The capillaries can also be examined with hand-held instruments, such as an ophthalmoscope or a dermatoscope, although these often make it more difficult to spot areas of diminished vascularity. 3 More recently, specialized videocapillaroscopic systems have been developed to facilitate the analysis of capillary abnormalities, although the expen e of these systems may be prohibitive for some clinicians. The more common findings in patients with microvascular abnormalities include the of large or giant capillaries, presence disorganization of the vascular array, tortuous vessels, microhemorrhage, loss of capillaries, and 4 ramified, or "bushy," capillaries.

Rheumatological Findings Classically, nailfold capillaroscopy has been utilized to differentiate patients presenting with isolated Raynaud's phenomenon (RP) from those who may have underlying connective tissue disorders causing secondary RP. The nailfold capillaries of healthy patients and isolated RP patients appear as parallel hairpin loops with visible afferent, transitional and efferent portions (Figure 1). In contrast, secondary RP patients may possess deviatory capillary patterns directing the clinician to investigate for certain connective 5 tissue or autoimmune rheumatic diseases. The scleroderma pattern has been extensively characterized and represents a multitude of nailfold capillary changes seen in 6 Three patients with systemic scleroderma. variations of the scleroderma pattern have led to the categorization into early, active and late phases (Figure 2). Specific findings that have been described include giant capillaries proposed to be a result of an autoregulatory response to tissue hypoxia, capillary microhemorrhages due to early vascular damage, avascular fields due to UWOMJ, Vol 78, Issue 3

increasing hypoxia and architectural di sruption of capillaries. Similar to systemic sclerosis, variations of the sclerodem1a pattern are also seen in patients with other connective tissue diseases such as dermatomyositis , systemic lupus erythramatosus, antiphospholipid syndrome, Sjogren' syndrome 7 and occasionally rheumatoid arthritis.

Figure I. Normal nailfold capillaries. (Courte y of Dr. Joerg Piper)

N ailfold Capillaroscopy Hemorrhagic Telangiectasia

Hereditary

An autosomal dominant disorder characterized by easily bleeding telangiectases on the skin and mucosal surfaces, hereditary hemorrhagic teleangiectasia (HHT; OMIM 187300) can lead to arteriovenous malformations in many organs and paradoxical septic emboli .8 Therefore, early diagnosis is important for better prognosis. Currently, three typical teleangiectases are required to make the diagnosis of HHT, with genetic testing only positive for a small subset of families. If not diagnosed, arteriovenous malformations and septic emboli may be missed. One study demonstrated that over 80 percent of patients with HHT show enlarged afferent portions of the capillary loop, a finding that was not evident in matched patients without HHT. 8 More importantly, five of nine patients without visible macroscopic cutaneous telangiectases but having a clinical diagnosis of HHT showed enlarged afferent capillary loops. Although further studies are needed to validate this , nailfold capillaroscopy appears promising as a diagnostic aid when a definitive diagnosis of HHT can ' t be Page

0 Fi gure 2. Ca pillaroscopy findin gs in systemi c scleros i . (A) No rma l na il fo ld pattern . (B) Early sclerodetma pattern , w ith dil ated and giant ca pillari es . (C) Ac ti ve sc lerodem1a pa tt em hows frequent g iant capill ari es and hemorrhages . (D) La te sclerodc1111a pattem shows severe capill ary architec ture di orga ni za ti on. (Co urte y of Dr. Soumya C hatterjee)

made based on clini ca l in fo m1ati o n alone (for exampl e, if it is suspected but not yet proven).

Capillary Blood Glaucoma

Flow

Measurements

and

As one of th e leading cau es of blindn ess in the world , g laucoma represents a s ignifi cant threat to ocul ar hea lth and day- to-day fun cti on. One of th e most co mmon sub ty pes, primary open-angle glaucoma (POAG; OMIM 1377 60), is known to have a signifi cant geneti c compo nent, as the preva lence of POAG amo ng those with a pos iti ve fa mil y hi story is 5- to 20-fo ld g reater than th e 9 no m1al po pul ati o n. T he progress ion of POAG is often in sidio us, and it is estim ated that more than half of those w ith th e di ease re main unaware of the ir conditi on until their vis ion begins to

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deteri orate. Thu , screening measures fo r those w ho have a famil y hi story of POAG and o thers at increased ri k have an important role in preventing the progress io n of glaucoma to v isua l damage and blindne s. Unfortunate ly, the class ic sig n of deve lo ping g laucoma, a hig h intra-oc ular pressure, i onl y detectabl e in about half of those w ith the di sease. 11 A ltho ug h the precise patho phys iology of POAG is compl ex and still not complete ly understood, it has been noted that abeiTation s in systemi c bl ood fl ow are often cone lated w ith th e 12 incidence of glaucoma. One such abnorma lity is the degree of periphera l capillary vasospasti c ity after a peri od of coo ling. Usin g capill aroscopy, it is poss ibl e to mea ure blood flo w in the na ilfo ld vesse ls and estimate the extent to whi ch flow

stops in response to cold. Patients with POAG often show an exaggerated vasospastic response relative to normal controls, which may indicate a systemic abnormality of blood flow regulation . 12 Thus, capillaroscopic examination in patients with ri sk factors for POAG may be useful in research and eventually in screening for thi s di sease, especially when an elevated intra-ocular pressure is not detectable.

possibly enab le families with a hi story of schi zophreni a to be mindful of early manifestations of mental illness and seek appropri ate treatment. Active research in thi s area is underway, and it is hoped that being ab le to identify a distinct subc lass of people with schi zophreni a may assist in future genetic studies aimed at di scoverin g the underlying etio logy for a truly debilitating disease.

Capillary Abnormalities and Psychiatry One of the more intriguing domains of medicine that can be examined with capillaroscopy relates to hereditary mental illness, namely schizophrenia. As early as 1939, researchers discovered that a disproportionate number of patients with schizophrenia exhibited abnom1alities of the nailfold capillaries and increased visibility of the nailfold plexus, the dense subcutaneous network of capillaries found prox imally adjacent to the fingernail , which is 13 generally not visible past puberty. Typical findings upon examination of the nailfold include a highly visible capillary plexus (Figure 3), and oddly-patterned individual capillaries with 14 numerous horizontal anastamoses. Subsequent studies in the 1960's and onwards aimed to establish an objective scale for measuring visibility of the plexus and concurrently found evidence that the endophenotype of high plexus visibility was positi ve ly correlated with familial , rather than 14 sporadic, schizophrenia, as well as more severe and more negative symptoms. 15 Conversely, it is estimated that 70% of patients with familiar schizophrenia have an elevated plexus 16 visibility. Thi s demonstrates that schi zophrenia is a more complex disease, with abnormalities that extend beyond the brain in many patients.

Figure 3. Nailfold venous pl ex us images w ith associated Maricq plexus visibility score (0 = no visib le plexus, 4 = high ly visib le plexus) . (A) Nom1al, 0/4 on Maricq scale. (B) Ab normal, 4/4 on Maricq sca le. (Courtesy of Dr. John Vuketich)

Conclusion Taken together, these data suggest that an elevated plexus visibility has the potential to be a suitable non-invasive biomarker for those at ri sk of developing hereditary schizophrenia or 17 schizotypic personality features. Given the young age at which many patients with schizophrenia begin to show symptoms, the ability to screen for nailfold abnormalities could UWOMJ, Vol 78, Issue 3

Nailfold capillaroscopy i a tried and true clinical method that has app lications to many di sparate pathologies. While the usual investigation s th at comprise genetic workups cannot be rep laced by a simple observation of nailfold capillaries, a thorough examination of the microvasculature can often yie ld clues that aid in Page I l l

diagnosis and prognosi路s, wi.th a mm1mum o f expense and invasiveness. It is important to be aware that capillary abnormalities and other vascular signs can be missed if not sought and that magnification of the nailbeds in patients with m~ny di seases can be a useful and relatively easy skill to acquire.

Acknowledgements I 0.

We thank Drs. Piper Joerg (http ://www.joerg-piper.com), Soumya Chatterjee, and John Vuketich for contributing helpful images of nailfold findings.

11.

References I.

Cuto lo M, Grassi W, Matucci Cerini c M. Raynaud 's Phenomenon and the Rol e of Capillaroscopy. Arthritis Rh eum 2003;48( II ):3023 -3030. Bar~er JH,. Anderson GL, Menger MD. Clinica ll y app lied microcirculation resea rch Boca Raton . ' FL: CRC Press, 1995:325. Baro n M , Be ll M, Boo kman A, et al. Office cap illaroscopy in systemi c sclerosis. C lin Rheumatol 2007 ;26: 1268- 1274. Cutolo M, Pi zzorni C, Sulli A. Cap illaro copy. Best Pract Res C lin Rheum atol 2005; 19(3):437452 . Bl ockmans D, Beyens G, Verhaeghe R. Pred icti ve va lue of na il fold ca pillaroscopy in th e diagnosis of conn ective ti ss ue di sease. C lin Rh eumatol. 1996; 15(2) : 148-53. Cutolo M, S ulli A, Secchi ME Olivieri M Pi zzorni C. The co ntribution of ca;illaroscopy t~ th e differential diagnosis of co nnec ti ve autoi mmune di sease . Best Pract Rc C lin Rheumatol. 2007;2 1(6): I 093-1 I 08. C utolo M, Sulli A, Secchi ME, Pao lino S, Pi zzorni C. Nailfold capillaroscopy is use ful fo r th e diagnosis and fo llow up of autoimmune

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rheumati c diseases. A future tool for the analysis of mi crovascular heart involvement? Rheumatology (Oxford). 2006 ;45 Suppl4:iv43-6. Mager JJ, Westermann CJ. Value of capillary microscopy in th e diagnosis of hereditary hemonhagic te langiectasia . Arch Dermatol. 2000; 136:732-4. Tsai JC, Forbes M . Medical Management of Glaucoma . West Islip, NY: Professional Communications, 2008:18 . Lieberman MF. Glaucoma in the World : The e lusive cha llenges of a major cause of blindness. Cataract and Refracti ve Surgery Today . 2005 Oct:62-63 . Hara ymowycz P, Fansi AK, Papamatheakis D. Screening for primary open-angle glaucoma in the developed world : are we there yet? Can J Ophthalmol2005 ;40:477-486. Pac he M , Dubl er B, Flammer J. Peripheral vasospasm and nocturnal blood pressure dipping-two di stinct ri sk factors for g laucomatous damage? Eur J Ophthalmol. 2003; 13(3):260-5. Olkon D . Capillary structure in patients with schi zophrenia. Arch Neurol and Psyc biat 1939;42:652. Maricq HR. Capillary Pattern in Familial Schizophrenics: A Study of Nailfold Capillaries. C ircul ation 1963; 27:406-4 13. Poo le JH, Maricq HR, Alson E, Willerman L. Negative sy mptom in schi zo phrenia and nailfold plex us vi ibility. Bi o l P yc hiatry 1991 ;29(8):75773. Maricq HR ..Familial sc hi zophrenia a de fin ed by na1.l fold cap1llary pattern and selected psyc hiatri c trmt . J Nerv Ment Di 1963; 136:2 16-26. Vuchetic~ JP, Li ka JL, Dio ni io DP, Stanwyck JJ, McGu1re KA , Sponheim SR. Eleva ted na ilfold pl ex us visibility aggrega te in famili e and is assoc iated w ith a specifi c negative sy mptom pattcm in sc hi zop hreni a. Psyc hiatry Res 2008; 160( I ):3 0-7 .

DIAGNOSTIC REVIEW Osteoarthritis: An Old Disease Cast in a New Light through Greater Understanding of the Human Genome Rachel Bevan (Meds 2012) and jason Essue (Meds 2011) Faculty Reviewer: Dr. Andrew Leask The successful mapping of the human genome offers the potential to greatly advance our understanding of various disease processes. Osteoarthritis is a disease of particular interest because there is ignificant morbidity and societal burden associated with this condition . Furthermore, the prevalence of this disease is expected to rise dramatically with the aging of the baby-boomer generation (individuals born between 1946 and 1964), with a concomitant elevation in health care costs in Canada and abroad. Osteoarthritis was previously viewed as a commonp lace disease resulting from environmental 'wear and tear' , that was an inevitable part of aging. However, new advances have demonstrated that osteoarthritis is a surprising ly comp lex multi-factorial disease that is affected by both environmental and genetic variables. This review discusses some of the environmenta l and genetic factors that influence the progression of osteoarthritis. Recent advances in biomarkers that are associated with increased disease risk are also discussed. Finally, the potential impact of genetics on both early diagnosis of disease, and prediction of how a patient will respond to a particular pharmacological treatment is presented.

Introduction Ever since the discovery of the three1 dimensional structure of DNA the field of genetics has intrigued both sc ientists and the general public alike for its potential impact on disease diagnosis. Indeed, the concept of genetics as a primary player in the role of diseases is assumed by most of the lay public today. One of the goals of understanding genetic influences in the disease process is to aid in treatment of patients through the development of a personalized medical approach. Predictive genetic testing is one area that has garnered great interest in the past decade, especia lly since the sequencing of the human genome. 2 The goal of predictive genetic testing is to determine if an individual is likely to develop a disease state based upon the presence/absence of particular genes or biomarkers. Although c hallenging, determining how best to treat a patient based on their genetic make-up is simplified in the cases where a particular gene or mutation is the direct cause of particular disease. For examp le, cystic fibrosis is

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an autosomal recessive disease; for the disease to occur, each copy of the CFTR gene must have a mutation that renders the resultant protein non. I .3'4 fu nct10na However, in many cases the disease process is not straightforward; the pre ence of a particular genetic variant doesn ' t necessarily lead to the disease. Instead, diseases, espec ially those of a chronic nature, are multi-fact01ial, resulting from a complex set of interactions among many different genetic and environmenta l factors. In general, there is no single gene that causes the disease, but genetic factors are likely to contribute to an increased probability of developing the condition. Thus, it is imperative to develop methods to identify individuals at risk. Osteoarthritis (OA) is one example of a multi-factorial disease that is influenced by genetic and environmental variab les. OA was previously viewed as a commonplace disease resulting from environmental 'wear and tear ' that was an inevitable part of aging. 5 However, new

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advances have demonstrated that OA is a surpri sing ly complex multi-factorial di sease that is affected by both env ironmenta l and genetic 56 vari ables. • Thi s rev iew di scusses some of the environmental and geneti c fac tors th at influence the progress ion of OA. Recent advances in biomarkers that increase di sease ri sk are also discussed. Finally, the potenti a l impact of geneti cs on both earl y di agnos is of di sease, and predi ction of how a pati ent will respond to a parti cular pharmaco logica l treatment are presented.

susceptibility. 13 Th e intrinsic local-mechanica l ri sk factors fo r OA include joint. ali gnment, . 5, 13 muscle weakness, and propnoceptwn . Extrinsic loca l-mechani ca l ri sk factors include phys ical acti vity, occupations involving strenuous . . . . s 13 A repetiti ve motions, obes ity, and JOint lllJUry. ' number of systemi c risk factors have been reported, including age, sex, et~icity , b~ne density, nutriti ona l fac tors, and genetic factors .

Disease Burden of Osteoarthritis

At present, the best way to characterize O A invo lves measuring j oint space narrowing on radi ographs, evaluating clinical symptoms suggesti ve of O A (i. e. pa in), and direct arthroscopi c visuali zati on of the articular surfaces w ithin the joint capsul e (parti cularly in the case of knee OA) . 10 • 14 However, these methods are often onl y abl e to detect OA after irreparable joint damage has occurred. T hus, there is a need to identi fy more sensiti ve methods to detect OA prior to irreversible j oint damage, in order to improve morbidi ty outcomes. In parti cular, there is great interest in identi fy ing specific biological markers that w ill refl ect the biological changes that occur w ithin the j o int during the earl y phases the A di sease process. S ince OA primarily affects bone, cartilage, and synovial ti ssue, it is logica l to co n ider the structural molecules deri ved fro m th e e tis ue a potenti a l biolog ica l 14 markers of OA. Notabl e candidate biolog ical markers inc lude:

OA affects 10- 12% of the adult popul ati on in North America and is a leading cau e of pain, phys ica l di sability, and use of hea lth care 7 serv ices. •8 OA is a degenerati ve di sease characteri zed by the earl y deteri orati on of arti cular cartil age from w ithin the j o int, and later by compl ete loss of arti cular cartil age, damage to the subchondral bone, severe deformiti es, and 10 di sabling pain.5·9• The consequences of disease 11 are detrimental to overall qua li ty of life in many ways, inc luding fa ti gue, reduced income due to impa ired labour force engagement, hospitali zati on, surgery, medi cati on side effects, fa mil y instabili ty, and decreased socia l 8 parti c ipati on. A larmingly, th e number of peopl e affected by OA is ex pected to increase dramati call y as the baby-boomer generati on ages. For in stance, in Canada approx imately 3 milli on people are currentl y li vin g with OA. T hi fi gure is ex pected to rise to 5 milli on by the yea r 2026. 11 Unl ess better methods are deve loped to di ag nose and treat OA, the direct and indirect costs associated w ith caring fo r such indi vidua l will ri se substanti a ll y w ith broader impli ca ti ons for the overa ll eco nomi c burde n.

Risk Factors for Osteoarthritis The ri sk fac tors fo r OA can be class ifi ed 13 as e ither systemi c or loca l-mechani cal. Th e loca l-mechanica l ri sk fac tor are then further cia sift ed a intrin sic or extrin sic to th e j oint in questi on. In acco rdance w ith thi s model, OA is w ide ly be li eved to be th e result of loca l ri sk fac tors acting within the context of systemi c

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Biomarkers in Osteoarthritis: Personalized Medicine

Targets for

l. N-termin al cross- linked telopeptide of ty pe l coll age n (NTX- l) as a marker of bone degradati on; 2. C- termina l cross- linked telopeptide of ty pe II coll agen (CTX- II) as a marker of carti Iage degradati on; 3. G lucosy l-ga lactosy l-pyridinoline (GicGal-P YD) as a marker of syno vium degradation. 14 • 15 It should also be noted that the biomarkers described above represent the net outcome of di sease and do not indicate how the di sease ? ri ginate? , n ~ r do they represent targets for drug mtervent1 on m OA . However, these biomarker

are useful to clinicians to stage the disease process in patient . Furthermore, biological markers may enable clinicians to differentiate patients based on risk of experiencing rapid progression of OA as these individuals will be in greatest need of targeted early intervention . 16 Biomarkers are also expected to advance the process of drug development by providing costeffective and sensitive indicators of a drug ' s 15 Unfortunately, a single specific effectiveness. biological marker has yet to emerge to fulfill these lofty objectives, and it seems likely that it will be nece ary to u e a combination of markers in order to adequately characterize OA. Additionally, practical issues such as tissue specificity, clearance rates, potential circadian 14 and differences due to gender, variations, ethnicity, and age need to be resolved prior to widespread acceptance of candidate biological markers . It is also important to highlight that recent genome-wide linkage studies have identified several gene variants that appear to predi pose to OA. 14• 17 In these studies, researchers relied upon microarrays capable of assessing 300,000 or more single-nucleotide polymorphisms (SNPs) in a given DNA sample. These microarrays examined interpersonal differences in inherited genetic variability by comparing the prevalence of gene variants among patients who have a given disea e 1 with controls who do not have the disease. Several chromosome regions and genes have been identified that are associated with OA prevalence (FRZB, BMP2, CD36, PTGS2, and NCOR2) or OA progression (CILP, TNFRSFllB, and ESRl ; ADAM12 is associated with both . ) 14 17 prevalence and progressiOn . ' Most o f t he genes identified encode proteins that are involved 14 in signal-transduction pathways. This work should help to clarify the relationship between genetic susceptibility, the genomic expression of aberrant genes that predispose to OA via biological markers, and the actual manifestation and rate of onset of the disease process. More significantly, further clarification of such pathways in preclinical and clinical models of OA will lead not only to the identification of new clinically relevant biological markers, but help

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achieve the ultimate goal of OA researchers in both academia and industry, which is to de velop novel drug targets and therapies to combat thi s .. . d. · 14 I S 17 de b 11ttatmg con ttiOn . · ·

Predictive Genetic Testing OA is a good example of a multi -factorial disease with a large societal burden for which predictive genetic testing could play a role in the future. In general, the goal of predictive genetic testing is to identify asymptomatic individuals at ri k for di ea e ba ed on particular biomarkers and/or genes that have been linked to predisposition to a particular disease. This differs from the majority of current medical tests, which are diagnostic, and thus seek to determine the etiology of a patient's current disease state . Thus, there is a fundamental uncertainty as to whether or not the di ease state will develop and how severe the disease will manifest if it does in fact develop . This is especially true in complex multifactorial diseases such as OA where it is difficult to make accurate predictions due to the influence of environmental factors ?

Pharmacogenomics Genetic diagnosis and biomarker testing is important not only for current and future disease states, but also in predicting how an individual might respond to particular medications. The study of the genetic basis of differential drug response has been termed 'pharmacogenomics' . ln general, many genes play a role tn phannacokinetics and pharmacodynamics of various drug responses. Pharmacogenomics research eeks to elucidate the genetic basis of how individuals or sub-populations respond to different drugs in terms of side-effects, toxicity, and drug efficacy. Such knowledge can lead to the development of biomarker tests to predict which individuals will respond well to particular . h t a lso he Ip .m targetmg . d rugs. 19·20 It mtg drug development to specific sup-populations that may be more likely to respond to a patiicular 21 therapy. In general, knowledge of the genetic factors that relate to drug response will provide a powerful tool for treatment in the future . 19•20

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However, the deve lopment of detail ed geneti c test that can be linked to a populationspec ifi c drug response is quite complex. A number of teps are invol ved, including: 1. ldentifi cati on of genes that are in vol ved in the drug response (e.g. pharmaco kineti cs and pharmacodynami c of the drug); 2. Determining differing variants of these gene ; 3. Determining whether or not these di ffe rent geneti c va ri ants corre late w ith a di ffere nti al drug respon e. One recent success of the fi eld is the drug warfa rin , whereby spec ifi c variants of parti cul ar genes were found to corre late w ith response to warfa rin at parti cul ar doses. n As of A ugust 2007, the FDA has updated prescribing informati on fo r warfa rin to incl ude th e in formati on that th e geneti c make-up of a patient may influence how they respond to wa rfarin .23 However, it i not clear that the benefits out- we igh the costs. In a recent study on non- va lvular atrial fibrill ation , it was determined th at there is little benefit to geneti c testing for warfarin do ing, based on an estimated cost of $400 (US) per ge neti c te t, except in pati ents at the hi ghe t ri sk for 24 hemorrage. Thi s is like ly to change as th e cost of ge neti c testing decrea e w ith th e advancement 25 o f sequencing techno log ies , however it does ca ll into questi on the cost-effecti ve ness of personali zed medi cin e. 26

compl ete human haplotype mapping proj ect (the HapMap proj ect which provides a compl ete 27 30 li sting of human SNPs) â&#x20AC;˘ will he lp . in t~e acqui sition of know ledge about the genettc basts for human disease. However, even these advanced techniques are not sufficient to deal with probl ems like incompl ete penetrance, whereby presence of the di sease allele(s) does not . necessaril y mean that that d tsease wt"11 occur. 31 Furthermore, mode ls for the genetic basis of di sease should account for the effect of epigenetic 24 control of gene express ion. Epigenetic control of gene express ion (and problems w ith epi genetic control) have been hown to play a fundamental role in both Prader-Willi and Angelman di seases 33 , and is th ought to be implicated in the di sea e proces for many di seases, including auto34 immun e di seases and p yc hiatric di sorders . Rea li zing the full benefits of personalized medic ine and predi cti ve genetic testing i till far 29 in the future. Nonethe less, it i important to be awa re of these rapidl y evo lving fields as they hold the potenti a l to revo luti oni ze medicine.

References I.

Personalized Medicine: Is it Realistic? The goa l of per ona li zed medi c in e is to prov ide indi vidua li zed treatment to pati ent , based parti a lly on the kn ow ledge of th e ge neti c profil e of an indi vidua l (including genes/biomarkers of di sea estate) and lmow ledge of how pati ents mi ght respond to di ffe rent 27 28 medi ca l treatments. Âˇ The complex itie of mov ing towards a persona li zed medi cine approach are immen e. 25 Co t-effecti ve genome equenc ing techniques , methods for ana lyzing genome-wide gene/prote in/mRNA ex press ion profiles and 23 interac ti on related to di sease tates , and th e

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Watson JD, rick FH . The stmcture of DNA . o ld Spring Harbor ympo ium on Q uantitati ve Bio logy 1953 : 18: I :?3-31. E ans JP, krzy ni a and Burke Wyli e. The compl exit ie of predi cti ve geneti c testing. Briti h Medi ca l Joum a l. 200 I :322 : I 052- 1056. Kerem 8 , Rommens JM , Buc hanan JA, Marki ew icz D, Cox TK. C hakrava11i A. Buc hwa ld M and Tsui LC. Ident ifica tio n of the cysti c fibro is gene: geneti c ana lys is. c ience. 1989 :245 : I 073 -1 080. ene Ga teway - Ex plo ring Genes and Geneti c Disorder . A web compani on to the human genome landm ark po te r. http://www.oml. gov/ c i/techresources/Human Gen o me/po ters/chromo o me/c ftr. shtml. Felson DT , Law rence RC, Dieppe PA , Hir c h R, He lmi ck CG, Jo rdan JM, et al. 0 teoarthriti : N ew in ig hts. part I : The di sea e and it ri k fac tor . Ann a ls of Intern a l Medi c ine 2000; 133(8):635-646. ndriacchi TP, M undem1ann A, mith RL , Alexander EJ, Dyrby 0, K oo S. A framework fo r the in vivo patho mec hani cs of o teoa rthriti s at th e kn ee. Annals of Bio medi ca l Eng ineerin g 2004;32(3 ):44 7-457 . Ctmnin gham LS, Ke lsey JL. E pidemi o logy of musc ul oske leta l impa im1ents and assoc iated

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di sability. American Journal of Public Health 1984 ;74(6):5 74-579. H ealth Canada. Arthritis in canada: An ongo mg c hallenge No. Cat. #H39-4/1 4-2003E). Ottawa: Health Canada 2003. Brage ME, Draganich LF, Pottenger LA , C urran JJ. Knee laxity in symptomati c osteoarthritis. C linical Orthopaedics & Related Research 1994;304: 184189. Di eppe PA. Recommended methodology for assessing the progress ion of osteoarthritis of the hip and knee joint . Osteoarthritis & Ca rtil age 1995 ;3(2):73-77. Marks PH, Droll KP , Ca meron M . Does ACL reconstruction prevent articular dege neration? The ACL ri k eq uat ion. In R. J. Williams, & D . P. Johnson (Eds.), Controversies in knee surgery (pp. 15-36). Oxford: Oxford University Pre s 2004. Canadian Orthopaedics As ociation . Canada in motion : Mobilizing access to orthopaedic ca re. 2005. Retrieved June/06, 2007 , from http ://www.coaaco.org/library/health _policy/canada_ in _ motion.ht ml Sharma L. Local factors in osteoarthritis. Current opinion in rheumatology 2001; 13(5):441-446. Rousseau J, Delmas PD. Biological markers in osteoarthritis. Nature clinical practice rheumatology June 2007;3(6):346-356. Kraus VB. Biomarkers in osteoarthritis. C urr Opin Rheumatol 2005; 17 :641-646 . Lohmander LS , Felson D . Can we identify a ' hi gh ri sk ' patient profile to determine who will experience rapid progress ion of osteoarthritis? OsteoArthritis and Carti lage 2004; 12 :S49-S52 . Slag boom E, Meulenbelt I. Genetics of osteoarthritis: early deve lopmental clues to an old di sease. Nature Clinical Practice Rheumatology November 2008;4(11) :563. Hunter, OJ, Khoury MJ, Drazen JM. Letting the genome out of the bottle - Will we get our wish? New England Journal of Medicin e. 2008:358(2); 105-107. Evans WE and Johnson JA. Pharmacogenomics: The Inherited Basis for Interindi vidual Differen ces in Drug Response. Annual Review of Genomics and Human Genetics. 2001 : 2: 9-39. Evans WE and Relling MR. Pharmacogenornic : Translating Functional Genomics into Rational Therapeutics. Science. 1999:286 : 487 - 491 An audience with: Jonathan K. C. Knowles di sc usses the impact of pharmacoge nornics on

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market segmentation. Nature Revie ws Drug Discovery . 2004: 3:822 Sang-Seop L and Jae-Gook S. Current warfarin pharmacogenomics researc h for per ona li zed medicine: statu and perspectives. Perona! ized Medicine. 2009 :6:13- 14 . US Food and Drug Admini stration . FDA Appro ves Updated Warfarin (Coumad in ) Prescribi ng In formation . http ://www.fda .gov/bbs/topics/news/2007 /newO 168 4 .html. Eckman MH. , Rosand J, Greenberg SM, and Gage BF. Cost- Effectivene s of Using Pharmacogenetic Informati on in Warfarin Dosing for Patients With Non va lvular Atri al Fibrillation. Ann als of Inte rn al Medicine. 2009: 150:73-83. Wheeler DA, Maithreyan S, Egho lm M, Shen Y, Che L, McGuire A et a/. The compl ete geno me of an indi vidual by massive ly parallel DNA sequencing. Nature. 2008:452: 872 -876. Joannidi s JPA. Personali zed Geneti c Predi ction: Too Limited, Too Ex pensive, or Too Soon? Anna ls of Internal Medicine. 2009 :150: 139- 141. The [nternati onal HapMap Consortium . A hapl otype map of the human genome. Nature. 2005:43 7: 1299-1 320. Weston AD and Hood L. Systems biology, proteo mics and th e future of hea lth ca re : toward predi cti ve, preventati ve and perso nali zed medicine. Journal ofProteome Research. 2004 :3; 179-1 96 . Gomez A. and Inge lman-Sundberg M. Phannacoepigeneti cs: Its role in interindi vidual differences in drug response. C linical Pharmacology & Therapeutics. Advance Online Publication February 25 , 2009. The International HapMap Consortium . A second generation human haploty pe map of over 3. 1 million SNPs. Nature. 2007:449 :85 1-86 1. Holtzman NA. and Marteau TM . Will genetics revo lutioni ze medi ci ne. New England Journal of Medi cine. 2000 :343:141-144. Lesko LJ. Personali zed Medicine : E lus ive Drea m or Imminent Rea lity? C linical Pharmaco logy & Therapeuti cs. 2007:8 1: 807- 8 16. Adams J. Imprinting and genetic di sease : An ge lman , Prader-Willi and Beckw ith-Weide mann sy ndromes. N ature Educati on 2008 :1( I). Rodenhiser D and Mann M . Epigeneti cs and human di ease : translating basic biology into clinical applications. Canadian Medical As ociat ion Journal. 2006 : 174 :341-347 .

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ETHICS Ethical Implications of Germ Line Genetic Engineering Ha ssan Mir (Meds 2012) and Christina Morgan (Meds 2011) Fa culty Reviewer: Dr. Lois Champion Following the recent decision by th e Obama admini stration to li ft strict limi tati ons on embryonic stem cell research, geneti c engineering has once again come to the forefro nt of scientifi c di scuss ion. An upcoming FDA-approved tria l using human embryoni c stem cell s in recentl y para lyzed indiv iduals has further pro mpted an ana lys is of the lega l and ethi ca l issues surrounding the use of germ line geneti c engineering. Though prohibited g loba ll y due to inadequate safety and effecti veness, it is inev itable that these concerns w ill one-day be met by continua l techno logica l advancements. Neverthe less, there remains a plethora of issues such as equal access ibility for all soc ioeconomi c groups, autonomy of descendents, and effect on the human gene poo l to name a few. In thi s di sc uss ion, it is important to make the di stinction between germ line geneti c eng ineering used fo r therapeutic purposes (a ltering DNA to correct a geneti c defect before it manifests itse lf as a di sease) and enhancement purposes (a ltering DNA to improve an indi v idual above " norma l" fun cti oning) . A lth ough the use of thi s technology could be justifi ed fo r therapeuti c purposes, it is very di ffi cult, if not imposs ible, to mora lly defend interventions fo r enh ancement purposes.

Introduction Geneti c engin eering has once again come to the fo refront of scientifi c di scuss ion foll owing President Obama 's recent dec ision to lift stri ct limitati ons on human emb ryo ni c stem cell research set by the prev ious admini strati on in Ameri ca. Co inc iding w ith thi s was th e approva l of a phase I stem ce ll tri al by the Food & Drug Admini strati on a imed primaril y at testing the safety of thi s therapy in e ight to ten compl ete ly para lyzed pati ents with severe pina l injuri es. 1 T he stem cell s, whi ch were obtained from emb ryos that wo uld have otherw ise been di scarded, w ill a lso be used to test for any s igns 1 of fun ctiona l recovery in these pati ents. A lot of controver y has surrounded a lterati ons made spec ifi ca ll y in the germ line (s perm or egg), s ince they affect every ce ll in the child and would be transmitted to all future 2 descendants. It is important to make the di stincti on between germ line geneti c engineering used for th erapeuti c purposes (a ltering DNA to correct a geneti c defect before it manifests itself as a di sease) and enhancement purpo es (a ltering

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DNA to improve an indi vidual above " normal" average func ti o ning). ~ C urrentl y, many laws around the world prohibit th e u e of germ line genetic eng ineering due to safety concern and the poss ible impli cati ons for future generations. In addition , th e fo ur prin cipl es of bi oethi cs, 3 - beneficence , non-ma lefi cence, autonomy, and justice influence the debate regarding the future use of thi s tec hno logy. Thi s arti c le eva luates some re leva nt lega l and ethi ca l arguments that are important in determinin g w hether gern1 line geneti c eng ineering should be utilized in humans in the future.

Current Legislation There are well defin ed Can adian and internati onal laws governing the use of germ line geneti c engineering. Canada 's Ass isted Human Reproduction Act (2004) prohibits the alteration of " the genome of a ce ll of a human being or in vitro embryo uch that the alteration is capable of be ing transmitted to descendants. " 4 The prohibition is large ly due to the question abl e

nature of the safety, effectiveness, appropriateness and efficiency of the technology. 5 This view is shared intemationally, 6â&#x20AC;˘ 7 and thus there are currently no legal cases pertaining to this topic around the world. While the law dictates what can and cannot be done, the technology 's controversial nature makes it necessary to assess the many ethical issues involved. Laws often reflect changing societal values, and therefore are constantly evolving. As a result, ethical analysis becomes invaluable for future policy development.

The Costs and Benefits of Germ Line Genetic Engineering The principles of beneficence and nonbackbone of maleficence constitute the 89 bioethics. â&#x20AC;˘ Beneficence asserts that there is an obligation to treat and improve the condition of others when it is possible to do so. Hence, altering the genome for therapeutic purposes on a permanent and heritable basis to prevent future genetic diseases becomes an obligation. This suggests that even within our limited capabilities, it is our duty to prevent any unnecessary harm and suffering and to improve the quality of life for future generations. The promise of enhancement to increase human functioning to above normal levels may seem very alluring and advantageous. Potentially favourable outcomes include a dramatic increase in life expectancy, a delay in the natural aging process, and increased tolerance and functioning of our immune system. 10 â&#x20AC;˘ 11 It is also fair to argue in favour of enhancements that improve health and mental acuity in general. Such enhancements will increase survivorship, quality of life as well as the c fu . 12 life expectancy 10r ture generatiOns. Nevertheless, the majority of techniques involved in this technology are in their early testing stages. This imposes numerous technical barriers that jeopardize the effectiveness and safety of such procedures, hence challenging the principle of non-maleficence; this principle states that a therapy should have a net benefit, loosely 9 translating to "do no harm". Additionally, germ UWOMJ, Vol 78, Issue 3

line genetic engineering experiments invol ving animal model s are hi gh ly inefficient and produce greatly variabl e offspring. The process requires breedin g to be repeated through several generations until it results in a stable and pem1anent animal line with the desired properties. Not only would this be highl y dangerous in humans, but because of the threat this presents to human dignity, it would also be impossible to justify morally. 10 Insertion or modification of certain genes may also have unknown and potentially harmful interactions with other genes in the recipient genome. Similarly, the removal of disease- linked genes may remove the beneficial effects of those genes. 10 Due to the unpredictable and largely unknown hazards of such procedures in humans, taking such risks is difficult to justify despite the potential benefits .

Respecting the Right to Self-Governance Autonomy is the right to se lfdetermination , which embodies freedom and the 10 ability to determine one ' s own future. In germ line genetic engineering, one must consider autonomy of the parent, the child, and his or her progeny. According to the principle of reproductive autonomy, parents have the right to use whatever therapeutic means available to ensure that they have a normal pregnancy and a healthy baby. However, this principle excludes the parents ' attempts to enhance the traits of their genetically normal offspring. Similar to situations where parental autonomy can be taken away in cases of soc ial concern (such as child neglect) , the American Association for the Advancement of Science has argued that strict legislation should regulate and differentiate between germ line genetic engineering for therapeutic versus enhancement applications. 10 The autonomy of the child and subsequent progeny must also be considered. Upon reaching adulthood, a child is considered a rational agent and it is therefore safe to assume that he or she would consent to most genetic augmentations . 13 While this argument may apply for therapeutic purposes, autonomy for enhancement ordeals is more complicated. Traits that a parent may choose to Improve (such as improved Page 119

mathematica l versus phys ical abilities) may not be what the child or their progeny would have chosen to enhance if given the choice as rational adults. In such instances, issues of informed consent and violati on of autonomy ari se, leading to the poss ibili ty of lega l cases that cha llenge the reproducti ve autonomy of the parents versus the autonomy of the c hild .

The Role of Justice Justi ce is another fu ndamenta l ethical concept and requires that harms and benefits be di stributed equall y among the who le popul ati on. 3 If certain procedures become cl ass ifi ed as therapeuti c, it is reaso nabl e fo r indi vidua ls to ask that such services be made uni versa ll y ava il abl e. It can be argued that getm line therapy is ana logo u to large ly access ibl e publi c hea lth initi ati ves aimed at preventing heart di sease and the refore should a lso be access ibl e to the maj ority of th e po pul ati on. Neverthe less, even if th erapeutic germ line geneti c engineering becomes covered under a uni versal health plan, such as Medi care in Canada, long wa itin g li sts w ill like ly pose a myri ad of probl ems. O n the other hand, th e prospect of germ line geneti c engineering for enhancement purposes becomin g covered under public hea lth 10 in surance is hi ghl y unlikely. Thus, the wea lth y wo uld have greater access to thi s techno logy, furth er expanding the di vide between different soc ioeconomi c group in soc iety. Thi s skewed access ra ises a few criti ca l concem s. Those unabl e to affo rd thi s procedure wo uld likely have some undes irabl e traits and co uld be viewed as 14 abnonnal. In co ntras t, those abl e to afford it wo uld have greater contro l over shaping the human gene poo l by remov ing undes irabl e traits w hil e enhancing benefi c ia l ones, leading to a form of e ugeni cs within ociety. Additiona ll y, a lterati ons in the germ lin e wo uld be carri ed on throughout the progeny of an indi vidua l, mainta ining thi s inequa li ty th ro ughout future generati ons.

Conclusions As we venture into the twenty-first century, technological advancements continue to expand the hori zons of human potential, while a lso ra isin g important ethical issues; germ line genetic engineering is one such advancement. Although these procedures are legally prohibited due to their lack of safety and effecti veness, it is important to develop an understanding of the implicati ons on soc iety to he lp make more informed decisions about their future uses. Though by no means exhausti ve, thi s paper aimed to ana lyze and di scuss the four major principles of bi oethi cs benefi cence, non-maleficence, autonomy, and justi ce - as related to germ line geneti c eng ineering. Through thi s analysis, it seems that thou gh the use of thi s technology could be j ustifi ed for therapeutic purposes, it is very difficult, if not imposs ibl e to defend mora lly fo r enh ancement purpo es. A mong other concerns, the ava ilability of thi s therapy to the publi c would require extreme ly c lose monitoring of its hea lth effects (harms and benefits in both th e short and long term), as we ll as ensuring equa l access for everyone in a time ly manner regardless of their soc ioeconomic status. Fa ilure to do so could result in de leterious situati ons from dire hea lth effects for pati ents and their progeny to di criminati on based on ones genetic make-up. Though there are e ndless po sibiliti es in improv ing both the qua lity and quantity of human life, it is criti ca l to ensure that geneti c eng ineering i safe, effecti ve, reasonabl e for future generations, and equall y access ibl e before it can become a viable component of both th e sc ienti fic and g loba l community.

References I.

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Fa lco, M . FDA approve human embryonic stem ce ll stud y [Intern et]. 2009 [cited 2009 Ma r 0 7]. Availabl e from: http ://www.cnn. com/2009/HEALTH/Ol/23 /stem . ce llli ndex. html. G lann on, W . Ge nes, Embryos, and Future Peopl e. Bi oethi cs. 1998; 12(3): 187-2 1 L.

Hebert, P.C. Doing Ri ght: A Practical Guide to Ethics for Medical Trainees and Phys ic ians. Brett Miller, eds. Don Mill , Ontario: Oxford University Press ; 1995 . 5-13 p. Depat1ment of Justice, Canada. As isted Human Reproduction Act [Internet]. 2004 [cited 2009 Mar 15]. Available from: http ://laws.j ustice.gc.ca/en/ A- 13.4/2389.html. Berni er, L. and Gregorie, D. R eproduction and therapeutic cloning, germline therapy, and purchase of ga metes and embryos: comments on Canadian legislation governing reproduction technologies . Journal of Medical Ethic . 2004; 30(6): 527-532. Institute on Biotechnology and the Human Future. National Legislation Concernin g Human Cloning and Germline Manipulation [Internet]. No date [cited 2009 Mar 05]. Available from: www. thehumanfuture.org/documents/I ntl_ Legis_ clon_germline_text.pdf. The Council of Europe. About the Council of Europe [Internet]. 2006 [cited 2009 Mar 13]. Available from : http ://www .coe. int/T /e/Com/about_ coe/. Rancich, A.M., Perezm, M.L. , Moral es, C. , and Gelpi, R.J. Beneficence, Justice, and Lifelong

10.

I L.

12.

13.

14.

Learning Expressed in Medical Oath s. Journal of Continuing Education in the Health Profess ions. 2005 ; 25(3): 2 11-220. McCormack, P. Q uali ty of Life and the Ri ght to Di e: an Ethica l Dilemma . Journal of Advanced Nursing. 1998 ; 28( I): 63-69. Frankel, M .S. , and Chapman , A.R. Human Inheritabl e GeneticModification : Assess ing Scientific, Ethical, Religious, and Policy Is ues. The American Association for Advancement of Science [Internet]. 2000 [cited 2009 Mar 05] Available from: http ://www .aaas .org/spp/s frllproj ects/ germ li ne/re port. pdf . Loftis, J.R. Germ-Line Enhancement of Humans and Nonhumans. Kennedy In titute of Ethi cs Journal. 2005 ; 15(1): 57-76. Mwase, I.M .T. Genetic Enhancement and the In stitute of Fate of the Wor e Off. Kennedy Ethics Journal. 2005 ; 15(1 ): 83 -89. Farrelly, C.P. Justice in a Genetically Tran formed Society . Kennedy In stitute of E thics Journal. 2005 ; 15( 1): 9 I-99. Grey , W. L. The Ethi cs of Human Genetic Engineerin g. Australian Biologist. 1996; 9( I): 5056.

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HEALTH PROMOTION The Blameworthy Gene j ennifer N. Bondy (Meds 2012) a nd Laura Hin z (Meds 2011} Faculty Reviewer: Dr. Raj Harricharan W ith improved techniques of genetic ana lysis, medici ne is becomi ng increas ingly re liant on genes to di agnose and treat di sease. However, a geneti c diagnos is is a value-laden enti ty w ith s ignificant potentia l to change the way we categorize peopl e as ill or hea lthy, fl awed or norma l, and responsible for or a hapless victim of d isease. Nowhere are these va lue j udgements more preva lent than the fie ld of mental hea lth. T hi s article w ill exami ne the meaning and impli cati ons of genetic di agnoses, and appl y the theories to the example of alcoho li sm .

"Genetic Diagnosis" Defined and Clarified ''He lp us fin d the gene fo r in ert disease here." Slogans such as thi s have become increas ingly common s ince the human genome was sequenced. T hese s logans seem to impl y that once we have fo und the gene, the cure w ill natura ll y fo ll ow. They also imply that we cannot be truly certain of a diagnos is until it is proven by geneti c techn ology. These attitudes have the potential to mod ify the way we conceptua li ze both the di sease and the patient. Is a person w ith a genetic diagnos is but no symptoms a patient? ls a patient w ith sympto ms but no gene defect si mply a ma lingerer? The answe rs to these que ti ons have the potenti a l to change the way the person (or pati ent, depend in g on the in te rpretation) ts categori zed, pa lli ated, and sti gmati zed . T he term ' geneti c di ag nosis ' i oft u ed in the li terature, but req uires evera l clarifi ca ti ons. T he fi rst is the timin g of the di agnos is. One may have a di sease and later d iscover that it has a geneti c component. Thi s impac ts th e patient by a process that has been termed 'genetic izati on ' : the patients are re li eved of blame fo r the ir conditi ons, 18 they are s impl y victims of fa ul ty genes. Such a di agnos is, however, does not prevent susceptibl e indi vidua ls from looking ahead ; there are impli cati ons fo r fa mil y pl anning as the conditi on 13 14 could potentiall y be passed on to offspring. â&#x20AC;˘ In contrast, one may receive genetic testing befo re the onset of symptoms. When the geneti c

Page I 2 2

precedes the cli ni ca l di agnosis, the indiv idual 14 may be prematurely thrust into the sick role . Thi s broadened defi nition of the sick ro le carri es with it soc ieta l repercussions, a it increases the 14 number of pati ents requiring interventi on . A geneti c di agno is can carry permanent tigma and 13 14 may damage one ' s fee ling of personal controi. â&#x20AC;˘ Secondl y, it is important to keep in mind whi ch di sease is be ing examin ed w ith the 'geneti c diagnos is' . Certa in di eases have more ignifi cant geneti c contributions, thus affecting the potenti al 14 fo r remedy. For instance, a geneti c di agnosis of Huntington ' s di ease corre lates we ll w ith clini cal progress ion to the di sorder wherea depress ion has approx imately 40% heritability. 14 M enta l illne ses carry both a hi gh ocia l stig mati zation and a low geneti c determinati on, two conditi ons that Spri ggs el a / all eged require strin gent j ustifi cati on for geneti c te ting. 14 However, the low geneti c detem1in ati on means that identifi cati on of a gene carri er need not be a di agnos is, rather it may be an opportunity for proph ylacti c intervention. 14 T hi s ha been termed the 'geneti c w indow ' . 17 The fi na l c larifi cation is the di stincti on between patho logy and vari ation. T here w ill naturally be vari ati ons in genes, but these di ffe rences need not be COITe lated w ith di sea e. 12 Therefore, a geneti c di agnos is may inappropri ate ly labe l an indi v idual as "ill. " The anti thes is of patho logizing the hea lth y 1s

legitimizing the plight of the ill. Mental health is often viewed as a di sorder, something that is the responsibility of the affected person or the consequence of poor moral fibre. 14 Once there is a genetic diagnosis, the disorder may qualify as a legitimate di sease, one that is now the responsibility of the health care system. 14 â&#x20AC;˘ 16 Thus, genetic diagnoses must be approached with caution: they have equal potential to inappropriate ly or appropriately cast individuals in the sick role.

Nature Versus Nurture The distinction between a clinical and genetic diagnosis hinges on the multi-factorial nature of di sease. Specifically, the express ion of genes can be influenced by the indi vidua l's environment. In a document classic in the rea lm of health promotion, Hancock summarized these multiple influences in the Mandala of Health (F igure 1). The individual is viewed as the centre

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of a web of influence, with each spoke having the 15 potential to create or treat disease. Therefore, wh il e genes themselves cannot be altered by promoting healthy li vi ng, there is the potential to mitigate disease through environmenta l and 12 14 lifestyle interventions. '

Reactions to a Genetic Diagnosis Wi th the meaning of "genetic diagnosi s" clarifi ed, the reaction to uch diagnoses can be examined. A genetic diagnosi s can decrease 12 blame and stigma as oc iated with disease. In an of preventi ve hea lth and personal era responsibility , Minkler summarized these va lue judgements as "when ill is redefined as being 16 guilty". In the past, sufferers of mental illness were the victims of soc ieta l sti gma large ly because mental patho logy does not fit into the class ic Western biophys ica l approach as there is often not one eas ily delin eated causal mechanism . If there is a causal gene identified, however, the di sorder becomes a biophysica l di sease and the

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THE MANDALA OF HEALTH Figure 1. Hancock 's Mandala of Health . The individual is viewed as the centre of a series of spheres of influence, each providing an opportunity for hea lth promotion interventsions. 15

UWOMJ, Vol 78, Issue 3

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person now has legitimate claim to the sick role . Notw ithstanding thi s pos itive reacti on to a genetic diagnos is, there can also be negati ve 13 ramifi cations. Whil e there was nothing yo u could have done to prevent the di sease, there is nothing yo u can do now. M inkl er wa rns that a geneti c diagnos is may be the same as labellin g someone as fa tall y fl awed. 14 However, thi s fa talistic approach di sregards the multi -factorial nature of most mental di seases. 13 The same argument appli es to those who rece ive their geneti c di agnos is before the onset of clini ca l symptoms - th e optimi m of environmental modifi cati on should temper the doom of one's bi ologica l lot. G iven thi s spectrum of poss ible reactions, the impact of a genetic diagnosis must be conside red at three leve ls: the pati ent, the hea lth care sy tern, and soc iety. An indiv idual rece iving a genetic di agnos is is now a candidate fo r earl y interventi on and a legitimate actor in the sick ro le. Converse ly, the geneti c di agnosis may tum a hea lthy indi vidual into a ti cking time bomb , wa iting anxiously fo r the onset of symptoms that 14 now seems inev itabl e. Thi s emphas izes the importance of not viewing a geneti c di agnos is as a label of defecti veness nor as an immutabl e entity. These issues can now be considered in the contex t of a spec ifi c illn ess- alcoholi sm. Genetic Diagnoses in Practice: Alcoholism

A number of studi es demonstrate that children of alcoholi cs suffe r fro m a vari ety of behav ioural and psychopatho logica l prob lems, such as substance abuse, anxiety, depress ion, conduct di sorde rs and delinquency. 10 Thi s type of behav iour, however, is not consistent across all childre n of alcoho li cs. By deve loping a better understanding of these vari ati ons, clini cians ca n attempt to ensure that children of alcoho li cs will not succumb to potenti all y avo idabl e hea lth probl ems. The mode of inheritance of an alcoho lic "gene" is fa r from esta blished, yet there is ev idence to sugge t that alcoholi sm is indeed a di sease of both geneti c and enviro nmental etio logy.' Past research ha demon trated an Page I 24

increased ri sk of alcohol abuse in the children of al coholics. 2 ' 3 ' 4 It is poss ible that thi s is due to 5 "verti cal cultural transmi ss ion" . This theory describes the transmi ssion of disorders, or traits which lead to increased susceptibility to a disease, through parental-offspring learned behaviour. However, studi es have demonstrated that behav ioural transmi ss ion IS not the only contributing fac tor w hen the children of alcoho lics develop drinking problems of their own. For exampl e, a twin-family study by Ke ndl er et al examined the mode by which alcoho lism was passed from parents to daughters .6 The results indi cated that a solely environmental etio logy was insufficient to explain alcoho li sm. Furthermore, the researchers found th at in the best-fitting model, usceptibility to alcoholi sm was due in large part to a geneti c predi spos iti on. In a cohort study by Goodw in et al, the preva lence of alcoholi sm was compared in two group of adoptees: a group w hose biol ogical parents were alcoho li cs, and a contro l group whose bi o logica l parents were not alcoholi cs. 7 The researchers fo und that 18% of those adoptees whose bi o logica l parents were alcoho li cs suffered from the same di sease; nearly four times the preva lence found in th e control group . These fi ndings offer further evidence of a genetic co mponent of alcoho li sm . As th ere has not yet been a sing le c ulpable gene identifi ed, one canno t be "diagnosed" with the potenti al fo r deve loping a lcoho li sm. Notwithstanding, fa mil y hi story may be utili zed as a proxy by which to identi fy targets for hea lth promoti on intervention . For exampl e, in a study of co ll ege students in th e U.S., the children of probl em drinker (COPDs) were identifi ed and compared to a contro l group, and COPDs were 17% more likely to engage in heavy epi odi c drinking tha.n non-COPDs.8 Additi onall y, they were approx imately three times more likely than non-COPDs w ith simil ar drinking habits to eek help for their drinking probl ems. Thi s was parti cularl y true of students who had prev iously consumed a lcoho li c beverages but had abstained

from drinking in the past year. In light of these results , it stands to reason that when possible, COPDs, particularly those who have recently attempted to curtail their own drinking, should be targeted for counselling and treatment in order to prevent future alcohol dependency. Walker and Lee, however, caution that clinicians should not pathologize the children of alcoholics (COAs). 9 They indicate that COAs who come from "famil[ies] with strong emotional bonds and ... warm, supportive environment[s]", are able to maintain caring and empathetic interpersonal relationships , and will not necessarily develop psychiatric disorders , as has been suggested to be typical of COAs. The authors elaborate, explaining that alcoholic families may have " reservoirs of strength", which can come in a variety of forms , which clinicians should seek out and draw on in order to provide treatment. For example, sibling-sibling relationships within alcoholic families may be the only instance in which a family member is consistently emotionally available, and thus these relationships should be encouraged in an effort to promote healthy living and an avoidance of alcohol dependency . Walker and Lee emphasize the plasticity of human development and the fact that it can drastically influence the qualities exhibited by COAs; specifically, the exhibition of resilient or maladaptive behaviours. 9 The key to this process is to determine which relationships (i .e. marital , parent-child, sibling-sibling) within the family are resilient, and then encourage the fostering of these relationships, the affirmation of belief systems, and the improvement of communication. Resilient relationships within families may be the counterbalance to genetic predisposition. Wemer 11 adds that COAs who do not develop serious problems tend to have good communication skills, are goal-oriented, have a positive concept of self, and believe in self-help. While these determinants may possess a somewhat innate component, they are also qualities which can be addressed in counselling. By encouraging the development of the aforementioned attributes, it is poss ible that UWOMJ, Vol 78, Issue 3

susceptible individuals may alter their envi ronments in such a way as to not fa ll victim to a genetic predisposition to alcoholi sm.

Impact of a Genetic Diagnosis - Conclusions Genetic diagnosis can be costly not only in terms of the gene test itself, but in terms of treating the pati ents we have created. Before the advent of gene testing, these asymptomatic indi viduals did not cons ume health care resources. Ethical and politica l consideration s arise of whether we have an obligation to treat those that we have identified as be ing ill or at risk, regardless of a lack of clinically recogn izab le di sease. An additional societal consideration is the creation of the "other" - a group of genetically di stinct indi vi duals, almost a separate spec ies. This us-versus-them attitude sterns from the view of a genetic diagnosis as a fatal flaw and has the potential to perpetuate rather than reduce stigrna. 13 ' 14 On the other hand, early identification of at-risk individuals opens the poss ibility of hea lth promotion and disease prevention interventions. Alcoholism is but one example of di seases which are all too frequently attributed to a lack of "will power" on the part of the ilL By acknowledging the sc ientifically demonstrated genetic component of thi s disease we can play a dec isive role in the prevention of alcoholism in those who are most susceptible to the disease. Being cognizant of the issues discussed in this article is an important step in improving our understanding of the individual and soc ietal implications of genetic testing. Furthermore, recognition that phenotypic expression of genotype is environmentally mediated prov ides an opportunity for health promotion interventions.

References l.

Ferguson RA, Goldberg DM. Genetic markers of alco hol abu e. Clinica Chimica Ac ta . 1997;257: 199-250. Cotton NS. The familial incidence of alcoholi sm: a review. J Stud Alcohol. 1979;40:89-11 6.

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Merikangas KR. The genetic epidem iology of alcoholism. Psycho! M ed . 1990;20: ll-22. 4. Pollock VE, Schneider LS, Gabrielli WF, Goodwin DW. Sex of parent and offspring in the transmission of alcoho lism: a meta-analys is. J Nerv Ment Dis. 1987; 175:668-673. cu ltura l 5. Kendl er KS . Indirect ve rti cal transmi s ion : A model for nongenetic parental influences on th e liability to psychiatric illness . The American Journal of Psychiatry. 1988; 145(6):657 -665. 6. Kendler KS , Nea le MC, Heathe AC, Kessler RC, Eaves LJ . A population-based twin study of alcoholism in women. J Am Med A oc. l 994 ; 15 I ( 5): 70 7-7 I 5. 7. Goodwin DW, Schulsingcr F, Hermansen L, Guze SB , Winokur G. A lcoho l problems in adoptees rasied apa rt from a lco holic biologica l parents. Arch Gen P ychi atry. 1973;28 :238-243 . 8. Weitzman E, Wechsler H. Alcoho l use, abu e, and re lated problems among chi ldren of problem drinkers : Findings from a national urvey of co ll ege a lcohol use . The Journal of Nervous and Mental Illness. 2000 ; 188(3 ): 148- 154. 9. Walker JP, Lee RE. Uncovering strengths of children of alcoholic parents. Co ntemporary Family Therapy. 1998;20(4) :52 1-538. 10. Steinhausen HC. Children of alcoho li c parents. A rev1ew. European C hild and Ado lescent P yc biatry . 1995 ;4(3): 143-1 52. 1 1. Werner EE. Res ilient offspring of alcoholi cs - A longitudinal study from birth to age 18. Journal of Studies on A lco hol. 1986;4 7:34-40 .

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12 . Castiel LD, Guilam MCR, Vasconcellos-Silva PR Sanz-Valero J. Genomic risk and personal res~onsibility in health. Panamerican Journal of Public Health. 2006; 19(3): 189-197. 13. Phe lan JC . Genetic bases for mental illness- a cure for sti gma? Trends in Neurosciences . 2002 ; 25(8): 430-431. 14. Spriggs M, O lsson CA, Ha~l w_. How will information about the geneti C nsk of mental di sorders impact on stigma? Australian and New Zealand Journal of Psychiatry. 2008; 42(3): 214220 . 15 . Schatz P, Dzv imbo KP. The adolescent sexual world and AIDS prevention: a democratic approach to programme design in Zimbabwe. Hea lth Promotion International. 200 1; 16(2): 127-1 36. 16. Minkler M . Personal respon sibility for health? A rev iew of the arguments and the evidence at century's end. Health Ed uc Beha v. 1999 ; 26: 121-141. 17. Hood KK, Johnson SB , Carmichael SK, Laffel LMB , She JX, Schatz DA. Depress ive symptoms in mothers of infant identified as genetically at ri sk for Type I Diabetes . Diabetes Care. 2005; 28: 1898 -1903. 18. Arribas-Ayllon M , Sarangi S, C larke A. Manag ing e1f-re ponsibility through otheroriented blame: Family accounts of genetic testin g. Social Science and Medici ne. 2008 ; 66: 152 1- 1532 .

HISTORY OF MEDICINE Vampire Projects or Long Ago Person Found? A History of Genetic Research in First Nations Communities Kate MacKeracher (Meds 2012) and Michael Livingston (Meds 2011) Faculty Reviewer: Dr. Michelle Hamilton Genetic research of Indigenous populations has been fruitful for scientists and the wider public, but has it benefited Indigenous communities themselves? We explore past (ab)uses of genetic research in Canadian First Nations communities through case studies. Although early projects were largely research er-driven, the Human Genome Diversity Project of the 1990s catalysed a change towards participatory, communitycontrolled genetic research in Canadian Aboriginal communities.

Introduction Indigenous* peoples have often been subjects for biomedical research , and the benefits to mainstream society include improved vaccines and better understanding of type 2 diabetes pathophysiology.' Genetic studies of Aboriginal populations have yielded dissertations and scholarly artic les on subjects ranging from rheumatoid arthritis, 2 to breast cancer,3 to evolution and migration of human populations. But to what extent have Indigenous communities themselves benefited from this research? Through selected case studies, we exp lore the history of genetic research in Canadian First Nations communities, with a particular emphasis on the degree of community control.

Why Community Control? In the late 1960s, Vine Deloria (Standing Rock Sioux) drew attention to research in Aboriginal communities that was driven more by researchers ' interests than by " the needs of the people."4 Given that these communities are often struggling for survival against the political , economic, and social consequences of colonialism, Deloria condemns " pure research" of Indigenous peoples that benefits only the

researcher: "We should not be objects of 4 observation for those who do nothing to help us." Indeed, power disparities between a community and outside researchers can make the research process into a form of exploitation,5 undermining Aboriginal knowledge and overeignty : "The Indian explanation is always cast aside as a superstition," Deloria observes, " Indians must simp ly take whatever status they have been granted by scientists." 6 Furthermore, research ethics in North America have traditionally focussed on individual rights , neglecting co llective rights of groups. 7•8 •9 Yet many Indigenous communities consider infom1ation about the group to be communal 10 property. Even something considered so individualistic, at least in mainstream Canadian society, a DNA may be seen as a common resource, as Debra Han-y (Northern Paiute) describes: " We ' re talking about something that has existed co ll ective ly. It doesn't belong to the present generation." 7 Outsider researchers may lack the lmowl edge to negotiate these political, cultural, and ethical complexities, and so the long-term distribution of benefits and harms from a project will be influenced by the degree of community controiY· ''

• We use " Indigenous" and " Aborigina l" interchangeab ly. In a Canadian context, " Aborigina l peoples" include First Nations, Metis, and Inuit populations.

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" He Used Us like Guinea Pigs" : Two Cases of Genetic Research In 1989, the Havas upa i people of A ri zona gave blood to researchers from Ari zona State U ni versity, seeking to understand the hi gh preva lence of di abetes in their communi ty. In the earl y 2000s they rea li sed the bl ood had also been used fo r unrelated studi es by severa l 11 researchers. Of parti cular concern to some donors was the use of their DNA in popul ation evo lution stud ies that contradicted the ir oral hi story; Havasupai Cha irwoman Carletta T ilousi expl ains, "They chall enged our identity and our origins wi th our own bl ood without te lling us what we were doi ng." 7 Ani shinaabeg scho lar W inona LaDuke argues that such stud ies have po liti ca l, as we ll as cultura l, signi fica nce. Governments or others w ith interest in Abori g ina l peop les' trad itional lands, she suggests, may use the authori ty of "genetic evidence" to portray Indi genous groups a mi gratory "settlers" w ith no 7 higher claim to land ri ghts. T he Havasupai T ribal Council and several co mmuni ty members have fi led multi-milli on-do ll ar laws uits against 12 the researchers and the ir uni versity. Members of N uu-chah-nulth First Nati ons in Bri tish Co lumbi a gave their blood to Ryk W ard, a genetic ist at the U ni versity of British Co lumbi a (U BC), in the mid- 1980s, hoping to uncover the rea on fo r th eir community's hi gh 13 rates of infl amm atory arthriti s. They heard nothing more until 2000, w hen the N uu-chahnulth learned that W ard fa il ed to find signifi cant res ults in his arthriti s stud y and had taken the ir blood w ith him to new a ppo intments at Utah State Uni versity and Ox ford Uni ve rsity. He and coll eagues rece ived fundin g fo r fu rther, unre lated analyse of th e blood, inc luding popul ati on 13 evoluti on studi e . N uu-chah-nulth peopl e, led by Larry Baird, one of the blood donors, have successfully lobb ied for the return of the bl ood, 14 and it i now stored at UBC. Baird ex plained hi s efforts to retri eve th e bl ood fro m Ward in a Nuu-chah-nult-run newspaper: " He profited at our ex pense. He published over 200 papers and became top guru in hi s fi e ld because he was carryin g our bl ood around w ith him . He used us 14 like cheap guin ea pi gs. " Page

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Note the di versity of communities' responses. Baird obj ected to a researcher ~rofit~ng from his community w ithout rectproctty; Havasupai donors protest the use of their DNA in populati on studi es that contradict their oral hi story ; others, such as members of the Amazo nian Yanomami peopl e, have cultural 15 be li efs aga inst the preservation of blood; and di ffe rent groups w ithin communities may have con fli cting responses to the secondary use of their sa mples. 9 What these cases have in common are researchers who stored, shared, and re-used geneti c sa mples w ithout donors' knowledge. Geneti c ists treated the samples much as biologists treat bacteri al cultures: as scientific resources to be tudi ed and bared. But indi vidua l donors did not consent to these uses; and since genetici sts were naming a specifi c Indigenous community in their ana lyses, research was a lso being done on the communi ty as a who le, without its consent. Perhap fo r the e researcher , operating re lati ve ly early in the genetic era, complex ethi cal reasoning had not yet caught up w ith scientific technique and curi osity. In an interv iew w ith Nature, W ard implie hi s secondary use of N uu-chah-nulth sampl es was simply the "way peopl e operated at the time ... it didn ' t cross anyone's mind -- we didn ' t mean to be ev il , and we are more careful ,., 13 now.

" The Vampire Project" T he increas ing vig il ance of Indi genous communiti es , and corTesponding tendency of genetic ists to be " more careful now," deve loped over the 1990s in th e context of the Human Genome Di vers ity Proj ect (HGDP) controversy. Conce ived as a supplement to the Human Genome Proj ect, the not-for-profit HGDP a imed to co ll ect samples fro m geneti ca lly iso lated Indi genous communiti es around the world, create immorta li zed cell lines, and make the DNA avail abl e to not-for-profit scienti sts. T he initi a l goa l was to facilitate study of popul ati on 16 evo luti on and mi gration , although later representati ons of the proj ect empha ised potenti a l hea lth research. 17

An Indigenous resistance movement to the project developed very quickly . By 1993, the World Council of Indigenous Peoples had christened it "The Vampire Project" for the emphasis on retrieving blood, and the tenn stuck in North American Aboriginal newspapers . 18-20 HGDP organizers attempted to mitigate criticism by forming a North American Regional Committee with two Aboriginal members, and by drafting a Model Ethical Protocol for collecting 21 samples. Nevertheless, Canadian and American government agencies ultimately declined to fund the project, and it has stalled in North America. 22 Why did a project considered innocuous 22 by its originators generate such resistance? Representatives of Indigenous organizations from the Americas outlined common problems with the HGDP in 1995 , including spiritual objections to immortalized cell lines, potential military or commercial abuses, and objectification of Indigenous peoples " to satisfy scientific curiosity" without benefit to the peoples themselves ? 3 Was true informed consent from individuals and communities possible, given 24 linguistic and cultural barriers? Would genetic research support population migration theories that dismissed community origin stories and undermined struggles for land and sovereignty 25 rights? One of the most frequent objections stemmed from the language of the HGDP's draft project proposal; genetically distinctive Indigenous populations are refen-ed to as "isolates of historical interest" whose genetic resources need to be collected immediately, before the . d.1e out or d.1sappear. 1s'25-27 .L a D u ke popu 1at10ns explains many Aboriginal individuals' outrage at the idea of salvaging genes instead of saving people: " Why would so many resources be involved in collecting the genetic materials from 'vanishing populations ' rather than working to 7 preserve those peoples and their cultures?" As evidenced by the presence of lawyer Catherine Twinn (Sawridge First Nation) and anthropologist Russell Thornton (Cherokee) on the HGDP's North American Regional UWOMJ, Vol 78, Issue 3

Committee, Indigenous opposition to the proj ect has not been universal. Defences from A bori g inal persons in scholarly literature or the popular press, however, are difficult to find. Th e most prolific Indigenous writer on the HGDP in academia has been Frank Dukepoo, a Hopi/Lacuna genetici st. Citing the moral naivete of the project 's ori g inators, th e real ri sks and uncertain benefits to Indigenous peoples, and the lack of community control inherent in open-ended gifts of genetic resources, he has generally argued 28 against the project. Yet he asserts that not all Indigenous individuals and communities rej ct genetic research per se; the HGDP 's mistake, he suggests, is its " paternalistic" approach to conducting " research on rather than with .m d.1genous peop Ie.,29

Participatory Research Early in the 1990s, the people of Oji-Cree Sandy Lake First Nation (Ontario/Manitoba border) decided to address their community's high prevalence of type 2 diabetes. They formed a partnership with two physician-researchers that "incorporates the principles of participatory research," according to the project website.30 Community leaders and researchers established goals determining community-specific prevalence and risk factors , implementing primary and secondary prevention programmes and continue to discuss all aspects of the project, from protocol designs to dissemination of 30 results . Protocols must be approved by the Band Council, and research is conducted by trained 30 community members. Preyalence of type 2 diabetes was found to be five times the Canadian average, and a range of environmental and lifestyle risk factors were isolated; based on these findings , the project partners began to develop community-run, culturally-specific intervention programmes in 1995 .31 The following year, the project organizers invited researchers from Robarts Research Institute at UWO to seek possible genetic components to diabetes in Sandy Lake First 32 Nation. Analysis of DNA from 728 community members showed that a mutation unique to this community in gene HNF JA increased the risk of Page I 29

deve loping type 2 di abetes by up to 15 times in homozygous indi viduals, compared with communi ty members hom ozygous for the normal 32 a ll ele. The clini ca l appli cability of testing for thi s mutati on was examined as a means for directing enhanced prevention support to genetica lly susceptibl e indi vidua ls.33 The re lati ve importance of geneti c and env ironmental ri sk factors for earl y onset type 2 di abetes in communi ty members was quantitati ve ly assessed, w ith the conclusion that "changes in environment, at the leve l of li fes ty le, could overturn geneti c susceptibility, probably rapidly, and in a ' lowtech ' manner. " 32 The e genet ic studi e have not occurred in reductioni st iso lati on, as a ll too often happens in bas ic science research, but rather are embedded in a communi ty-contro lled research proj ect that inc ludes probl em , causes, and communityspec ific so luti ons in its scope of inqui ry, and that requires results to be relevant and meaningful for a ll parti es. Canadi an Mohawk scholar Marl ene Brant Caste llano observes that thi s sort of coll aborati on makes fo r more effecti ve research, and cites th e Sand y Lake First Nation di abetes proj ect as ev idence that " Ho li stic awa reness and hi ghl y foc ussed analysis are compl ementary, not . , JO contra d 1ctory. Long Ago Person Found In 1999, th e body of a youn g man who di ed hund reds of yea rs ago was fo und pre erved in a g lac ier on traditi ona l Champagne Aishihi k 34 First Nati ons (CAFN) land (BC/Yukon border). T he F irst Nati ons assumed respons ibility fo r the rema ins, in keeping w ith a 1995 treaty affim1in g the ir contro l over cultura l resources on the ir land.34 CAFN E lders named th e rema ins Kwad'!Y Dan Ts' inchj (Long Ago Person Found ), 35 and togeth er w ith the Band Counc il and oth er community members, dec ided to in vestigate hi s 34 on g ms. After consulting w ith ne ighbouring First Nati ons, th e CAFN Ba nd Counc il signed a manage ment agreement with th e BC government 34 to a llow fo r research on the rema in . Researchers wo uld not be abl e to own geneti c or Page I 3 0

other materials gathered at the discovery site and 34 would return all samples after analys is. T~e research included a compari son of mitochondnal DNA (mtDNA) in the remains to nearly 250 35 Th. Abori ginal volunteers from the area. IS geneti c test suggested Long Ago Per~on Fo~nd has li ving re lati ves in CAFN and ne1 ghbou~mg 35 Abori g inal communities. Since the relat1 ves identifi ed by materna lly-inherited mtDNA are all members of the W olf/Eagle clan, Elders concluded the ir ancestor like ly was as well, given 35 the matrilineal c lan structure of their nations . Th is identifi cation a llowed for a memorial potl atch to be planned by E lders of the correct c lan. 35 Sympos ia at the Royal BC Museum and th e CAFN reserve in 2008 and 2009 made info rmati on gathered about the remains accessible to loca l Indigenous people and the genera l publi c. Thi s inc luded sc ientifi c and cultural talks, traditi onal accounts of lost travellers and trade routes to complement forensic ana lyses of cl othing materi al and stomach conte nts, and local genea logies to fill m the gaps of hi gh 35 spec ifi c ity/low sens1t1v1ty mtDN A testing. Requested by the communi ty and contextualized with oral hi story and other studi es, thi s DNA ana lysis demonstrates th at community-controlled geneti c research can sometimes support Abori g ina l peopl es' psycho oc ia l, as well as bi omedi ca l, we ll-being. Jn thi s case, the community ' desire to know more about the ir ancestor coinc ided w ith outside researchers' curios ity , and DNA testing was deemed acceptabl e by Band Counc il, E lders, and bl ood donors. Not a ll Abori gina l peoples w ill make s imil ar decision about rema ins found in the ir land, however, and interested genetic ists must not suppose that DNA ana lys i w ill a lways be we lcomed or acceptable in these situations. 36 Conclusions In response to the increasing power and voi ce Indi genous peopl es have negoti ated for themse lves about re earch in the ir communities Canadi an government funding age ncies hav~ begun requiring spec ial ethi ca l conside ration , in

addition to usual practices, from those seeking grants for research with Aboriginal peoples. 8â&#x20AC;˘9 For examp le, the 2007 CIHR Guidelines for Health Research Involving Aboriginal People emphasises community/group con ent, participatory research , ownership of biological pecimens and data by the community, and new informed consent before any secondary use of amples and data, among other requirements.9 Although these regulations apply only to CIHR-funded resea rchers, Canadian First Nations communities are beginning to establish their own codes of conduct and research ethics boards. 10 These efforts flow from Canadian Aboriginal peoples ' constitutional right to se lf-government, according to a report by the National Aboriginal Health Organization (NAHO), and reflect the principles of "OCAP": community ownership, control, access, and possess ion of research and 37 biological samp les. When they learned how Ward had used their samp le , the Nuu-chah-nulth Tribal Council formed a Research Ethics Committee chaired by Larry Baird, the community member most active in repatriating the blood. " We ' re not c losing the door on research ," Baird exp lains, noting that some Nuu-chah-nulth people are interested in renewing inquiry into the arthritis that still 14 plagues their communities. But the "way people operated" when Ward took their blood in the 1980s will not be tolerated , Baird warns: " From now on our eyes are w1'de open. '14 '

References 1.

Rhoades ER, Rhoades DA, Freeman W. Research Ethics and th e American Indian. In: American Indian Health . Ed Rhoades ER . Baltimore: John Hopkins Univer ity Press; 2000. 426-33. Oen K , El-Gabalawy HS , Canvin JM, Hitchon C, Cha lmer IM, Schroeder M, Jacobso n K, Reed M , WoodS, and Cheang M . HLA associations of seropositive rheumatoid ar1hritis in a Cree and Ojibwe population. Journal of Rheumatology. 1998 25( 12): 2319-23 . Liede A, Jack E, Hegele RA, Narod SA. A BRCAl mutation in Nati ve North American famjlies. Human Mutation . 2002 19(4):460.

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Deloria V . Custer died for yo ur sin . London : Macmillan Company ; 1969. 5. Schn arc h B. Owners hip, control, access, and possess ion (OCAP) or self-determination applied to research. Journal of Aboriginal Health . 2004 Jan ; I (l ):80-95 . 6. De loria V. Red ea rth , wh ite li e : Native Americans a nd the myth of scientific fact. Toronto : Scribner; 1995. 7. LaDuke, W. Recovering th e sac red : The power of naming a nd claiming. Cambridge, MA : South End Pre ; 2005 . 8. Ca nad ian Institute of Health Research , Nat ional Sciences and Engineerin g Research Co unc il of Canada, Social Sciences and Humanities Resea rch Counc il of Canada. Tri-council policy statemen t: Ethical conduct for re ear-ch involving humans: Re earch in vo lvi ng Aboriginal P eop les [Internet]. 2005 [cited 7 March 2009]. Available from: http ://www.pre.ethics .gc.ca/eng li hlpo li cystateme nt. 9. C IHR (Canadian In titute of Health Research). Guidelines for Health Research In vo lving Aboriginal People [Internet]. Ottawa 2007 [cited 7 March 2009]. Available from : http ://www.ci hrirsc.gc.ca/e/doc uments/ethi cs_aboriginal _g uid elin es_e.pdf. I 0. Castellano, MB. Ethics of Aboriginal research. Journal of Aboriginal Health. 2004 Jan ; 1( I ):98 114. 11. Noe TD, Manson SM, C roy C D, McGough H, Henderson JA, Buchwald OS. In their own vo ices: American Indian decis ions to par1icipate in hea lth researc h. In: The handbook of ethi ca l resea rc h with ethnocultura l populations and co mmunrtres. Eds Trimble JE and Fisher CB. Thousand Oaks, CA: Sage Publi cations; 2006.

77-92 . 12. Shaffer M. Havasupai blood amp les mi sused. Indian Co untry Today. 2004 May I 0 23(39):8 l. 13. Dalton R. Tribe blast 'exploitation of blood sa mples. Nature. 2002 Nov ; 420: Ill. 14. Wiwchar D . Nuu-chah-nulth blood returns to we t coast. Ha-Shilth-Sa. Ahousaht ; 2004 Dec 16 3 1(25): 1,3. 15 . Martin LL. Yanomani blood sa mples: A question of ethi c . Native Americas. 200 I Dec 13 8(3/4 ):6. 16. Marks J. The trouble with the Human Genome Diversity Proj ect. Molecu lar Medicine Today. 1998 4(6):243 . 17. Cavalli-Sforza LL. The Human Genome Di vers ity Proj ect: Past, pre ent, and future.

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Nature Reviews: Genetics . 2005 6:335-40. 18. ' Vampire Proj ect' draws fire from Indigenous groups. C herokee Observer. Parkhill , Oklahoma; 1995 April20 3(4): 17. 19. Smoke-Asayenes D . The conunodification of life: The Human Genome Diversity Project. News from Indi an Country. Hayward, Wi consin; 2001 Aug 15 15(15):4A. 20 . Wendell J. Tracking the Vampire Bri gade. Akwesane Notes. Roo seve ltown ; 1996 M arch 31 2(1 ): 73 . 21 . Morrison Institute for Population a nd Resource Studies . Human Genome Diver ity Proj ect [Internet]. Stanford University; 1999 [cited 5 March 2009]. Avai lab le from : http://www. tanford .edu/g roup/morrin t/hgdp. ht ml. MS , Goodm a n A H, Hea th D. 22 . Lindee Introduction . In : Ge netic Nature/C ulture . Ed . AH Goodman AH, Heath D, Lindee MS . B e rke ley, CA : Uni vers ity of California Pre s; 2003 . 1-1 9. 23 . Indi an leader from North, Centra l, and South America meet to decla re opposition aga inst genetic manipulation a nd the Human Genome Di versity Proj ect. News from Indi an Country . Hayward, Wi consi n; 1995 April 30 9(8) :6 . 24. Oros T , G ray S. Blood mon ey . The Ci rc le: News from an American Indian Perspecti ve. Minneapolis ; 1994 Nov 30 15( 11 ):7. India ns, ge ne a nd 25 . Harry D, Dukepoo FC. ge ne tic s: What Indi ans should know about th e new bi otec hn o logy [Internet]. Nixon, Nevada : Indi genou Peop les Coa liti on Again t Biopiracy ; 1998 [ci ted 9 March 2009]. Available from : http :1/www . ipc b.org/ pd (_ fi Ies/pri mer. pdf. 26. Indi geno us Peop le Co unc il o n Bioco loni a lis m. Dec la ration of Indi genou s Peoples of th e westem hem i phere regarding th e Huma n Ge no me Di vers ity Proj ect [Internet]. Phoe ni x, Ari zona ; 1995 Feb 19 rcited 9 March 20091. Available from: http ://www.ipcb .org/reso lutio n /htmls/dec_phx .ht

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ml. Whose genes are they? The 27. Lone Dog L. Human Genome Diversity Project. Journal of Health & Social Policy. 1999; 10(4): 51-66. The trouble with the H~~an 28 . Dukepoo FC. Genome Dive rsity Project. Molecular Med1cme Today. 1998; 4(6):242-3 . 29. Dukepoo FC. It's more than the Human Genome Di vers ity Proj ect. Politics and the Life Sciences. 1999; 18(2) :293-7 . Sandy Lake Health and Diabetes Project 30. [Intern et]. 2006 [cited 5 March 2009]. Available from: http: //www .sa ndy lak diabetes.corn/?q=node/1 . 3 1. Black J. Scientists find diabetes link in Oji-Cree. Windspeaker. Ed monton, Alberta; 1999 Apr; 16( 12) : l. 32. Hegele RA, Zinman B, H enley AJG , Harris SB, B arrett PH, a nd Cao H. Gene , environment, and Oji-Cree type 2 di abetes. Clinical Biochemistry. 2003 ; 36 : 163 -70 . 33 . Hegele RA , Cao H, Hanley AJG, Zinman 8 , Harris SB, Anderson CM. Clinical utility of HNF 1A ge notypin g for di abetes in Aboriginal Canadi ans. Diabete Ca re. 2000; 23(6): 775-8 . 34. Hunter T . Di covery: They ca ll him Long Ago P erson Found. Raven ' s Eye. Edmonton ; 31 Dec 2000 ; 4(8): 2. 35 . McKinnon A . CAF ev s letter [Intemet]. 2008 June-Jul y [cited 7 March 2009] Available from : http ://www.cafn .ca/pdfs/JuneJul y_ 2008 _ Newsletter_ 144_ dpi .pdf. 36. Weaver J. Indian pre e nce with no Indians prese nt: NAGPRA and its di sco ntents. Wicazo Sa R e iew . 1997 ; 12(2) : 13-30. 37. Fir t Nations Centre, AHO (National Aboriginal Hea lth Organi zatio n). First Nation Conceptual Framework and Applied Mode ls on Ethics, Pri vacy, a nd onse nt in Hea lth R esea rc h a nd Info rmation : umma ry Report [Inte rnet]. 2006 November [cited 23 March 2009] Available from: http ://www. naho. ca/e ng l ish/ pub _ resea rch . php. .

INTERDISCIPLINARY COLLABORATION Multidisciplinary Management at Key Stages in the Huntington's Disease Neurodegenerative Process Abhijat Kitchlu (Meds 2011) and Allanah Li (Meds 2012) Faculty Reviewers: Dr. Shannon Vena nee and Dr. Christopher Hyson

Introduction Huntington's Disease (HD) is an adultonset neurodegenerative disorder with significant motor, cognitive, and psychiatric manifestations. Symptoms are progressive, with no effective treatments currently available and death occurring 15-20 years after onset. 1 HD is inh erited in an autosomal dominant manner. Affected individuals display an expanded CAG trinucleotide repeat in 1 the HD gene on chromosome 4 . Given the devastating natural history of the disease and its hereditary basis, HD can present many challenges for patients, their families, and healthcare providers. In this article, we describe some of the complex issues that arise during key stages of the HD neurodegenerative process and emphasize the importance of comprehensive, interdisciplinary team management at each stage.

Predictive Testing for HD Predictive testing for HD based on trinucleotide repeats has been available since 1993, with a less definitive linkage ana lysis test avai lable in the mid-1980s. While some argue that the test can relieve uncertainty and enable planning for the future, only 4-24% of those at 2 risk for HD go through with testing. Decisions regarding testing have many ethical, legal, and psychosocial implications and at-risk patients must find a way to navigate through these concerns. Patients must consider the psychosocial effects of declining or postponing testing, as well as the effects of undergoing testing and receiving either a positive or negative result. Moreover, the results of testing can have a significant effect on the patient's family, who may become future

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caregivers or future patients due to their at-risk status. 3 Patients also face the possibility of discrimination based on genetic information, particularly regarding eligibility for disability or life insurance and obtaining employment. While there are only anecdota l reports of genetic discrimination in Canada, the fear of discrimination remains a very powerful influence 4 on patients and physicians. â&#x20AC;˘ 5 The healthcare team at this stage takes a primarily counselling and supportive role. Genetic counse lling, often done by genetic counsellors or medical geneticists, is particularly important during this time. Counse lling provides patients with disease information, takes them through the impli cations of testing, and offers psychosocial support. 6 Counse lling must provide the patient with all necessary and relevant information, because the far-reaching consequences of testing neces itate truly infom1ed consent for the procedure. Genetic counsellors must present information regarding HD and predictive testing in a balanced and non-directive manner, ultimately respecting the patient's autonomy. 5 Patients must be assured of privacy and confidentiality. In order to support the patient through their decision of whether or not to undergo testing, other services that may become involved at this stage include social work, family support and counselling, psychology, psychiatry, neurology, and family medicine. Management should be specific to the individual patient, while taking the family and cultural contexts into account.

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After Undergoing Testing for HD - Living with the Results The results of predictive testing for HD can have a profound impact on patients and their families. A Canadian study examining the p ychological consequences of predictive testing found that although psychological well-being was ignificantly improved for the majority of participants, 6.9% experi enced clinically s ignificant adverse psychological events, including di agnosed clinical depre s ion and 7 suic ide attempts. The e adverse events occurred in individual g ive n po iti ve and negative te t re ults. The paradoxical reaction of some pati ents with a nega ti ve test res ult (noncarriers of the HD gene) has been ca ll ed "survi vo r's guilt" and involve psychological distress from be ing spared 1 from HD. Patients receiving a po iti ve te t result (carriers of the HD gene) must come to tern1s with the meaning for their own health , as well as implication for their family, career, and life plans. Although fear, anxiety, and depression may be understandable responses to a positive test result, these are also poss ible psychiatric manifestation of HD and pati ents must be followed for earl y onset of symptom s. 3 A pos itive result can a lso ha ve a tremendous impact on family dynamics, with studies showing hi gher di vo rce rate among carri ers than noncarri ers in the 6 month following test results, and parents poss ibly experi encing guilt for ha ving tran ferred 2 ri sk tatus to their offspring. Thu for HD and other geneti c disease , the unit of care is often the family rath er than the patient. 3 Following predictive testing for HD , patients are faced with new chall enges that may require multidi sciplinary in vo lvement. It is c lear that psychologica l counse lling and follow-up mu t be available to all patients undergoing predictive testing rega rdl ess of test result, and psychiatric care may also be required at thi s stage. Support and education hould be offered to th e patient's family and may require the he lp of soc ial workers, nurses, psyc hologists, and therapi st . Early collaboration between the family doctor and a spec iali t in HD can monitor for onset of di sease symptoms. Physician s must also formulate a plan with the pati ent for future

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management. 3 In addition to the formal healthcare team, patients and their families may benefi~ from joining a support network like the Huntmgton Society of Canada.

Reproductive Decisions HD presents complex dilemmas for patients and their families with respect to reproductive decision-making. Although HD follows autosomal dominant inheritance, the penetrance of the disease varies with the extent of the CAG triplet expansion. Triplet repeats of 40 or more are fully penetrant, those 36 - 39 are thought to be variably penetrant and those less than 35 repeats do not typically manifest as disease. The expansion (and, in some cases, contraction) of the repeats during gametogene is further complicates reproductive choices and can pre ent a challenge for health care professionals when communicating risk . Qualitative research has identified several difficult deci sion s facing patient and their healthcare team : whether to have children at all, whether to undergo prenatal testing or preimplantation genetic diagno is, and whether to abort gene-po itive fetuses. Many patients who wish to have children expre s opposition to giving birth without attempting to prevent pa ing on the di ease; how ver, thi concern is often superseded by patient ' fears of their illness preventing them from providing for and rai s ing children. 8 For this rea on, pati ents must be coun elled with con ideration and potenti al involvement of their partn ers, families, and wider social support networks. Thi in tum can be a concern for pati ent , as many report the influence of others a a major factor in deci ion-making .9 Thi includes the influence (whether or not intentional) of the healthcare team , which is an important con ideration in light of a recent tudy which indicated that 38% of Mexican neurolo a ists 0 ' psychologi sts and psychiatri sts felt that those with the HD mutation should not have off: pring. 10 Prenatal testing for HD currently exists via amniocentesis . or chorionic villu sampling. However, testmg rates for those at risk for HD remain low; within the United Kingdom and

Australia only 5 - 25% of at ri sk populations undergo prenatal testi ng.8 Within Canada, a survey exa mining 15 of the 22 centres offering testing found that onl y 15 prenatal tests were completed between 198 7 and 2000. T he 12 fa mili es w ho underwent these tests were estimated to represent approximately 0. L% of the 11 at-ri sk popul ati on. W o men were shown to be more like ly to request prenatal testing as we ll as predicti ve testing for themse lves. 11 More recently, pre-implantati on geneti c di agnos is has become ava ilable to ensure only mutati on-negati ve embryos are implanted. Thi s process, however, can be di ffi cult fo r many couples and may not be an option for many due to personal beli efs and 12 preferences. Pre-implantation genetic di agnos is is now also offered without infom1ing the parents of their own HD gene status, whi ch is preferabl e to some pati ents who des ire certainty th at they are not pass ing on the di sease to their children, but do not want to detem1ine their own gene status. Despite these difficulti es, many HD pati ents and carri ers do opt to have children. A European study demonstrated that L4% of HD carriers had subsequent pregnancies following predi cti ve testing, compared to 28% of noncarriers. 12 Furthermore, many pati ents consider adoption as a potential a lternati ve depending on their expectati ons of di sease onset. 8

Interdisciplinary Care of the Symptomatic HD Patient The management of symptomati c HD patients is a broad topi c, and in its entirety is beyond the scope of this overv iew; instead, a brief outline of the interdi sc iplinary nature of HD care is presented here. The nature of HD requires a team-based approach to symptom management. An optimal healthcare team includes leadership not onl y from a neurologist or psychi atrist spec ia lizing in HD, but also a family physician to monitor 3 compli cations in the late stages of the di sease. Allied health care profess ionals, including nurses, dentists, di eticians, physica l, occ upational and speech therapists, psychologists, and social workers also play maJor rol es. Advance care UWOMJ, Vol 78, Issue 3

plann ing is also extremely important in establishing quality of life goa ls and end-of- life care di rec ti ves. The stages of symptomatic HD d ictate the need fo r each of these team-members. The Shoul son-Fahn sca le, origina lly designed for research, has become usefu l in eva luating the severi ty of HD . The fi ve stage scale is based on a Tota l Functiona l Capac ity (TFC) score fro m 0 to 13 that assesses the pa ti ent's fu ncti onal skill s and ability to carry o ut activities of da ily li vi ng. In stages I through 3, the focus of care inc lude treatment of chorea, sleep d isturbance, depress ion, anxiety, impulsivity, irri ta bili ty a nd o ther psychiatric symptoms. 3' 13 In these tages the phys ician members of the team are fo remost. However, the ro le of psycho logists and social workers may be crucial in the transiti on fro m working li fe to di sability status for some patients and their fa mili es. It has been suggested that one of the most preva lent deficiencies in HD treatment i di sproporti onate foc us on mi nor findings of chorea, without proper management of depress ion and deteri orati on of fa mil y re lati onships. 13 Medica l therapy including anti depressants and mood stabili zers may be of va lue and neuro lepti cs may be warranted in cases of . b e l1avwur. . 13 more aggress1ve Mid- to late-ph ase HD requires fo llow-up v1s1ts to phys icians to assess fo r compli cati ons, but also increased invo lvement of other hea lthcare profes ionals. Occupati onal therapi sts may be invo lved in assess ing driving ability and determining necessary restricti ons. Pati ents often have large appetites, and may have di ffi c ul ty meeting nutriti ona l requirements g iven increas ing dysph agia and lack of coordinati on (aspirati on and subsequent pneumonia are often the terminal events for HD pa ti ents). For thi s reason, d ieticians' expertise and nursing or persona l support worker ass istance w ith feeding can be of great benefit. Phys icia n fo ll ow-up may invo lve the reduction of medi cation for chorea, w hi ch paradox ica lly decreases in the late stages and is suppl anted by rigidity and dystonia. These symptoms are often worsened by excess pharmacotherapy for chorea, whi ch must become 13 more judicious. Ph ys ic ians must a lso he lp Page I 35

patients and familie deal with increasing cognitive impairment and mood a lterations, and a such, behavioural coun e lling is often 3 required. In the end stage of the disease, hospice nursing and palliative care specialists ensure patients are as comfortab le as possible and assist familie with the patients ' death .

Conclusion Huntington 's di sease pre ents significant challenges for the hea lthcare tea m. Despite the paucity of treatment ava ilable to delay di sease progre ion , a well-coordinated, multidi sc iplinary team can as ist pati ents and the ir famili es with manag ing the evolving nature of their illness and he lp them make informed dec isions. Through appropriate co llaboration, care can be optimized and th e burden of thi multi-faceted di sease can be reduced.

I 0.

References I.

2. 3.

Wahlin T-BR. To know or not to know: A review of behaviour and ui cida l ideation in precl ini ca l Huntington's disea e. Pati ent Edu cation and Coun e llin g. 2007 ;65:279-87 . Tibben A . Predictive te tin g for Huntington' di ease. Brain Re earch Bulletin 2007;72 : 165-7 1. Nance MA . Comprchen ive care in Huntington' di case: A phy ic ian' per pective. Brai n Rc carch Bulletin . 2007;72 : 175- . Harper P , Gevers S, de Wert G, re ig hton Bombard Y, Hayde n MR. Genetic testing and Huntingto n's di sca : iss ue o f empl oy ment. TH E LAN CET Ne urol ogy. 2004;3:249-52 . En cnaucr RE, Miche l VV, Rei nke SS. Ge neti c Te tin g: Practi ca l, Ethi ca l, and Co un c ling

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II .

12.

13.

Cons iderations. Mayo Clinic Proceedings . 2005 ;80( I ):63-73. Mularczy k M , Decruyenaere M , Denayer . L, Evers-Kiebooms G. A Theoretical Psychologica l Perspecti ve on Predi cti ve Testing for Late O~set Hereditary Diseases. Genetic Counselmg. 2007; 18(4):367-7 8. Almqvi st E, Brinkman R , Wiggins S, Hayden M . Psychological consequences and predictors of adverse events in th e first 5 years after predictive te tin g for Huntington's disea e. C linical Genetics . 2003;64:300-9. Klitzman R , Thome D, Williamson J, Chung W, Marder K. Decision-making about reproductive choi ce among indi viduals at-ri sk for Journal of Genetic Huntington' di sease. Counselling. 2007; 16(3):347-62 . Klitzman R, Thome 0 , Williamson J, Chung W, Marder K. Di c lo ures of Huntington di sease risk w ithin families: patterns of dec ision-making and implication . American Journal of Medical Genetic Part A. 2007; 143A( 16): 1835 -49. Vilatela M, Morale A, de Ia Cadena C, Lopez I, Aranda C, Villa A. Predictive and prenatal diagno i of Huntington ' di ease: Attitudes of Mexican neurologists, psychi atri t , and psyc hologist . Archive of M edical Research . 1999;30( 4 ):320-4. Creighton lmq vi t E, MacGregor 0 , et a/. Predi cti ve, prenatal and diagnostic genetic testing for Hunting! n' di ea e: The ex perience in Ca nada from 19 7 to 2000. Clinica l Genetics. 2003;63:462-75 . Evers-Kicboom , Ny K, Harper P, et a/. Predi cti ve ONA-te tin g for Huntington's disea e and reproductive dec ision making: a Europea n co llaborati ve tudy. Europea n Journa l of Human Genetic . 2002; l 0(3 ): 167-76. Walker F. Huntington ' Di ease. Semi nars in Neurology. 2007;27(2): 143-50.

MEDICINE AND THE LAW Who's in Your Genes: A Physician's "Duty to Warn" Patients' Relatives about Genetic Risk Colin Meyer- MacAulay [Meds 2012) Faculty Reviewer: Dr. Victoria Siu The genetic information of a patient as it relates to disease risk may prove invaluabl e to blood relati ves who may wish to use it to make informed decisions about health care or reproduction. On the other hand, diagnosis of a genetic disorder may carry with it a certain social stigma , as well as concerns about discrimination with regards to employment and life insurance. Furthermore, genetic risk cannot be altered nor is it caused by the actions of the patient. A physician 's "d uty to warn" individuals who may be put at risk by the actions of a patient has been recognized in the context of both infectious disease and psychiatric illness. However, it is unclear whether these same precedents may apply in the context of genetic information. Nonetheless, a number of lawsuits in the United States have been brought against physicians for their alleged failure to warn relatives of genetic risk. Canadian Policy deci sions on thi s issue must be made based on an understanding the benefits and limitations of genetic medicine, as well as a clear appreciation of the physician's dual duties to maintain confidentiality and prevent harm . In light of this, this article reviews the available literature to address legal and ethical issues as well as potential policy directions surrounding a physician 's "duty to warn" patients ' relatives about genetic risk.

Introduction Recently, well-known Harvard professor and bestselling author of The Stuff of Thought, Steven Pinker, allowed his entire genome not only to be sequenced, but also to be posted on the 1 Internet for the world to see. In so doing he has given celebrity status to key questions in the era of personalized genomics. These include whether one has a responsibility to disclose the results of genetic tests to family members who might likewise be affected, 2 and who should protect the consumers of the health care system from what 3 has become known as "genetic discrimination". To date, instances of so-called genetic discrimination have been scarce in the United States 3 and nearly unheard of in Canada, aside from the odd account of discrimination with respect to life insurance. Furthermore, this topic has been well covered by this publication in a previous article and will not be expanded upon further. 4 However, an issue that does warrant further investigation is whether physicians have

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an ethical and legal obligation to warn the relatives of patients with a positive genetic test if that information may benefit them . A thorough understanding of the theoretical benefits and limitations of genetic testing, as well as how these translate to our patients in practice, will ultimately have to guide policy in this matter.

Genetic Testing According to Knoppers et a!. (2004), genetic tests can be defined in a legal sense as either those tests that are based on "the presence or absence of pecific genetic abnormalities" or more broadly, those that include " tests based on the end products of most genes." Knoppers et a!. argues that in the latter case, genetic risk factors amount to nothing more than probabilities, and thus are difficult to distinguish from other routine predictive tests performed by a family physician. 5 Some diseases can be conferred by a single gene mutation, or the inheritance of two mutated genes at the same genetic locus. In contrast, many

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common diseases such as diabetes, cancer, and heart di sease have a multifactorial etiology, invo lving the interacti on between genes and the environment. U p to now, most genetic tests have been a imed at detecting s ingle gene di sorders, and often prov ided definiti ve di agnoses when the clini ca l pi cture was suggesti ve of genetic di sease . With the advent of whole genome sequencin g, tests that enabl e clini cians to assess geneti c ri sk in much the same way as a fa mil y history are increa ing ly ava il abl e. 6

Genetic Medicine Med ica l uses of geneti c in fo rmati on are nearly as di verse as th e defi niti on of genetic testing is broad. Phys ician ca n use geneti c in fo m1ation to make diagnoses in newborn s (e.g. pheny lketonuria, PKU), to ide nti fy future hea lth ri sks (e.g. BRCA l and 2 mutati on ), and to pred ict drug respon es or even to predict hea lth ri k to children not ye t bom .6 Most pertinent to the current di scuss ion are th ose geneti c di agnoses or predi cti ve genetic te ts that may indi cate a fa mili a l ri k of di sease. Often so me of thi s ri sk can be mi tigated through ea rl y recogniti on of a geneti c risk fac tor. Converse ly however, there are geneti c di eases w here pre-symptomatic di agnos is confe r no progno ti c advantage, but whi ch may carry a ignifi cant assoc iated burden of di sease, such a Huntington di ease (HD).6 Centra l to the ethi ca l dilemm a of predi cti ve geneti c tes ing i w hat the infonnati on w ill actua ll y mean to th e pati ent in terms of hea lth care o pti ons. ln fac t, acco rd ing to Wyli e Burke onl y about 20% of th o e at ri sk fo r deve lopment of HD in the UK had o pted for predi cti ve testing as of 2002. 6 T hi s reluctance to pur ue predi cti ve tes tin g fo r an incurable di ease may li e in the p yc hosoc ia l consequence of an unfavo rabl e result. O ne study by Gi argiul o et a/. found th at of I 19 pati ents who underwe nt predi cti ve testing for HD, a s ignifi cantly greater number of presymptomati c carri e rs ex perienced depres ive 7 epi ode than those fo und to be non-carri ers. Those peopl e w ho do choose to pursue predicti ve te ting often do so in order to make informed dec isions about reprodu cti on, rather than for th e 78 ho pe of treatment. â&#x20AC;˘ ln thi s se nse, predi cti ve

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genetic testing can be used to make deci s!ons t~at limit the poss ibility of birthing a chtld wtth significant ri sk of di sease deve lopment. On the other hand, many geneti c di sorders show incomplete penetrance, w ith some indi_v iduals having an a ltered genotype but showmg no 6 ev idence of di sease.

Confidentiality and the Duty to Warn Phys icians have a duty to protect the genetic info rmati on of a pati ent from unauthorized disc losure to any third party. However, under certa in circumstances confidenti ality may be justifi abl y breac hed, as is the case when legis lati on mandates it, or w hen it is breached 9 w ith th e aim of preventing harm to a third party. N umerous lega l precedents, including Tarasoflv. Regents of the University of California 10 and Pitman Estate vs. Bain 11 recognize a phy ician 's " du ty to warn " under circumstances where " di sclosure is essenti al to ave rt danger to others". 9 Furthermore, the Per onal Health lnfom1ation Protecti on Act provide that physicians or other hea lth care wo rker " may di close persona l hea lth info rmati on if th ere are reasonable grounds to be lieve that the di c losure i necessary to e liminate or reduce a ignifi cant ri k of serio us bodil y harm to a pe rson or a group of persons." 12 It is important to understand thi di tinction when con id ring w hether or not a family member may be entitl ed to know about a pati ent' s geneti c infom1a ti on. An excu abl e breach of confidenti a li ty i techni ca ll y ill ega l, though the court may c hoo e not to mandate compensation or puni shment ba ed on well-intentioned 9 moti ves. Thu , a pati ent ' ri ght to confidenti a lity is lega ll y protected in genera l, though th e courts recogni ze that under ce rta in c ircum tance it may be ethi ca ll y nece sary for a physician to breach thi s confidenti ality. By contrast, a phys ic ia n ' "duty to wam " refer to a lega l obli gation to inform a third party of imminent ri sk to the ir we ll -be ing, regardl e s of a patient' s ri ght to . 1' 'l 9 13 con fid 1 entr a rty. ~ Âˇ Âˇ Wh ether or not uch a breach of confidenti ality mi ght be ju tified in the case where di sc losure of geneti c informati on to famil y members may enabl e them to decrease the ir ri sk of di sease deve lopment remains to be determined

by the courts. ' On the other hand where genetics is concerned, physicians become pri vy to information that has implications to both the patient and their relatives. In thi s sense, the calculation of genetic risk in one person may violate another's right to personal autonomy where health care decisions are concerned .9 Thus Dickens et a/. argue that health care profess ionals may take on a new and very real set of duti es as it pertains to sensitive information that may be very beneficial to individuals who may in fact not be their actual pati ents. 9 While a "duty to warn" has been recognized in the context of both psychiatric 10 illness and infectious disease, 11 Canadian courts have yet to set similar legal precedents where genetic information is concerned. 2 Wh ether or not the aforementioned precedents mi ght apply to cases where di sclosure of genetic information may benefit a third party is questionable. Disease ri sk conferred by your genotype is not preventable, nor can relati ves be viewed as potential victims of the patient (i.e. the patient 2 does not directly cause the risk). ' 9 Finally, less than 1% of physicians surveyed in the US believed a " duty to warn" was reasonable in instance where no valid medical therapy exists. 13 Notwithstanding, as of 2004 failure to warn a relati ve of genetic risk had already resulted in 3 lawsuits against physicians in the 13 United States. In all three of these cases, State Appellate courts ruled in fa vor of the plaintiffs, asserting that physicians must ensure that immediate family members are warned of impending genetic ri sk (though in one case the actual jury eventually decided in favor of the physician). 13 Currently in Canada there is no obligation to warn family members of genetic ri sk, and disclosure could even potentiall y be punishable by courts or profess ional regulatory bodies.2 Some strategies aimed at reso lving this issue include: strict confidentiality, a universal duty to warn, and informed consent or as Offit et . M.Iran d a warnmg. · , 2' t3 a!. would say a " genetic This third strategy involves physicians informing their patients of the circumstances under which they would be obliged to disclose information prior to genetic testing. While the first strategy UWOMJ, Vol 78, Issue 3

does not adequately protect the interests of the family members, the latter two strategies are coercive and do not respect the patient 's ri ght to make a utonomous deci ions about health care. In addition, it is like ly that they wo uld adverse ly affect patient utilization of predictive testing 2 13 beca use of perce ived genetic discrimination . ' Thus, the cun·entl y accepted strategy is to adopt an " intermediate position" whereby confidentiality is respected as a rul e, but it is recogni zed that circumstances exist in wh ic h di sc losure of genetic informati on may be justifiable?· 9 Conclusion While no formal lega l duty to warn currently exists in Canada, there is a general consensus that phys ici ans should make a va li ant effort to inforn1 their patients that genetic information may prove inva luable or even life sav mg to th eir relatives. In cases where penetrance is hi gh, ri sk of imminent and severe harm is great, and viab le treatme nt option s do ex ist, th e benefits of di sclosure to a third party may so far outweigh the potential harm to the patient as to make it justifiable in a court of 2 13 Iaw . •9• Thus the phys ician 's dual duti es to maintain confidentiality while simultaneously acting in a spirit of beneficence continue to be at odds in thi s matter. Unfortunately it is likel y that they will remain so until more is known about the circumstances under which knowledge of their relative's genetic risk mi ght actually prove beneficial to an indi vidua l. References I.

3. 4.

My Genome, My Self. Steven Pinker. New York, USA : New York Times. January 11 , 2009. MM24 (Accessed at http ://www.nytimes .com/2009/0 1/ 11 Genomet.html?pagewa nted=a ll on March 23, 2009). Lacroix M , Nycum G, Godard B, Knoppers BM. Should phys icians warn patients' relati ves of genetic risks? CMAJ. 2008 ; 178:503-5 . Geely, H. Banning Genetic discrimination. N Eng J Med . 2005 ;353:865-7 . Slatnik M, Fot1in C. BRCA Genetic Testing: Ethi ca l, Legal and Policy Con siderations. UWOMJ 2007;76:26-29.

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6. 7.

Knoppers et a/. Genet ics and Life Insurance in Canda: Points to Consider. CMAJ. 2004; 170( online): 1-3. Burke W. Genetic testing. 2002 . N Eng! J Med . 2002 ;34 7:1867-75 . Garg iulo M, Lej eun e S, Tanguy M-L, LahlouLafon~t K, Faudet A, Cohen D, Feingold J, Durr A. Long-term outcome of pre ymptomatic testin g in Huntington di ease. Eur J Hum Genet. 2009 ; 17 :165- 171. Dec ruyenae re M, Evers-Ki ebooms G, Boogaerts A, Philippe K, Dcmyttenaerc K, Dom R, Vandenberghe W, Fryn J-P. The compl ex ity of rep rod ucti ve deci ion-making in a ymptomati c carriers of the Huntington mutati on. Eur J Hum Genet. 2007; 15:453-462.

I 0. II.

12.

13.

Dickens B, Pei N , Taylor K. Lega l and ethical is ues in Genetic Testing and counseling for susceptibility to Breast, Ovarian and Colon Cancer. CMAJ. 1996; 154:68 13-1 8. Tarasoff v. Regents of California ( 1976), 551 P 2nd 334 (sup ct) . . th Pitmann Estate v. Bam (1994), 11 2 DLR (4 ) 257 (O nt Gen Di v). Cavouki an A. A Guide to the Personal Hea lth Information Protection Act. Information and Pri vacy Commis ioner/Ontario. 2004. Offit K, Groeger E, Turner S, Wadsworth E, Weiser M. The " Duty To Warn" a Patient 's Famil y M embers About Hereditary Di ase Ri sks. JAMA . 2004;292: 1469-73.

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MEDICINE AND TECHNOLOGY Personalized Cancer Management j enny Shu (Meds 2 01 2) a nd Pencil/a Lang (Meds 2 011) Fa culty Reviewer: Dr. Robert Hegele The aggression of cancer is characteri zed by its multi geni c and heterogeneous nature. With the com plet ion of the Human Genome Projec t in 2003, there has been growin g interest in the fie ld of persona lized medic ine fo r cancer management, using an indi vi dual's geneti c compos iti on to d irect prevention, detection, prognosti c, and therapeutic efforts. Thi s rev iew w ill prov ide an overview of so me of th e mo lecul ar profi ling techniques that are cutTentl y in use, in clud ing transcrip to mi cs, proteomi cs, and genom ics usin g asse ment of sing le nucleotide po lymorphi sms (SNPs), copy number vari ati on (CNV) and hi gh- throughout gene sequencing. Some recent exa mpl es of persona li zed medi c in e appli cat ions in the screening, d iagnos is, tumor class ificati on, and targeted therapy of vari ous ty pes of ca ncer wi ll a lso be discussed. A lthough mo re va lidati on and con o lidati on of these research studi es is req uired before personalized med icine is w ide ly used for cancer management, its potenti a l benefits ho ld impli cati ons fo r ph armace utica l companies, di agnosti c agencies, hea lthcare providers, and most importantl y, pati ents .

Introduction A di agnos is of 'cancer' is a life-chang in g event for pati ents. An es timate of over I 0 milli on peopl e g loball y w ill di e annua ll y as a result of 1 cancer in the year 2020. It is not surpri sing that there is a dri ve to furth er our understanding of the disease mechani sms, pathophys iol ogy, and treatment of cancer. The multi geni c and heterogenous nature of cancer has long been recogni zed, and thi s hete rogeneity can determine the aggress iveness of cancer in an indi vidua l patient. 2â&#x20AC;˘3 The compl etion of the Huma n Genome 4 Proj ect in 2003 ' 5 has brought forth the hope of advancing medi ca l practi ce into a "genomi c era" that w ill identi fy key therapeutic targets and disease biomarkers for cancer. Despite these advancements, much of the systemi c therapy fo r 6 cancer pati ents is still empiri cal and two pati ents who may be at apparentl y 'identica l' stages of cancer and harbor the 'same' tumor type w ill exhibit significantly di ffe rent clini ca l outcomes as 7 measured by survi va l and therapy response. Instead of continuing to progress down th e traditional ' trial and error' method of testing for new therapeutic agents, the personali zed medi cine model has been proposed because of its

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theo retica l appea l: in thi s mode l, an indi vidua l's geneti c compos iti on he lps foc us and d irect prevention, de tecti on, prognosti c, and therapeutic efforts .7 Thi s article w ill provide an overv iew of th e current status of mo lecula r profiling techno logies and their current appli cati ons in persona li zed medi cine, fro m the initi al stages of identi fy ing signifi cant ca usati ve and modul a ting genes to the integrati on of multiple genes w ithin a personalized profil e that w ill direct th erapy in the sub-population of cancer pati ents.

Molecular Profiling Techniques Th e main mo lec ul ar pl atfo m1s cunÂˇe ntl y w ide ly used in persona li zed medi cin e are tran criptomi cs, proteomi cs and genomi cs, w hi ch ing le nucleotide in cludes th e ana lys is of po lymorphi sms (SNPs), copy number vari ati ons (CNV s) and hi gh-throughput gene sequencing.7 O f course, these are often not mutua lly exc lusive and one of the current goa ls in persona lized medi cine is to deve lop an approac h to utili ze a nd the info m1a ti on fro m d iffere nt integrate techniques.

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Transcriptomics, the study of altered express ion of the leve ls of messenger RNA (mRN A) w ithin cancer ti ssue samples or biopsies, has led to the deve lopment of Internet-based resources such as Oncomine Research Pl atform 8 that ma intains a cata logue of published transcriptome profi les so th at clini cians and sc ienti sts can eas ily access the informati on. A lthough mi croarray techno logy, the main means of transcriptome profilin g, is cost-effecti ve and accurate, it is till inhibited by sampl e heterogene ity and the absence of a hi gh-quality multi-institu tional tumor ti ssue library that would be necessary to cater to a large po pulati on. Proteom ics also expl ores genetic express ion, but at th e leve l of tra nslated pro tein quantity, structure and fun cti on w ithin cancer tissue sampl es . While techni ca ll y more d iffi cul t th an transcription profi ling, p roteo mi c ana lys is has th e adva ntage of more di rec tly examining mo lecul ar mac hinery of ce ll physio logy, posttranslati ona l modifi cati ons, and pro tein-protein compl exe .9 Mass spectro metry and protein mi croarrays have also been used to target spec ific bi omarker in s igna ling cascades, a lthough there are some limitations with respect to di ffi culti es in large-sca le ta rget identi fica ti on as the exact number of polypeptides produced 1s still uncertain . 10 F inally, there is a w ide range of genomi c DNA vari ati ons that predi spose or propagate the development of ca ncer. Exa mpl es inc lude ing le nuc leoti de polymorphi sms (SNPs), whi ch are geneti c va ri ati ons in th e DNA sequence due to the di ffe rence of one nucl eotide a mong indi vidua ls. Copy number vari ati on (CNV ) refer to largersca le changes, in c luding gene dupli cati on, de leti on, in vers ion or trans locati on events. Both SNPs and CNVs have been linked to a w ide range of di fferent ph ysio logica l ph enotypes and di seases. However, thi s is onl y an initi a l step; the examin ati on of genomi c DNA in a pati ent 's germlin e or in somati c ce lls taken from ca ncerous ti ssue can strati fy ri sk and identi fy new ca usati ve gene and path ways, but thi s infom1ati on a lone is not suffi c ient to defin e mec hani sms of di sease or therape uti c approaches.

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The ultimate genomic assessment is whole-genome sequence analysis, in which all 3 billion nucleotides of genomic DNA from an indi vidual pati ent or the cancer tissue sample are analyzed using automated nuc leotide sequencers to determine potenti al fun cti ona l changes from a norma l reference sequence. T here ha ve been many initi atives such as the Human Cancer Genome Proj ect and Cancer Genome Anatomy Proj ect to use hi gh throughput gene sequencing to identi fy nove l di sease-associated mutations at a . has genome-w ide leve l. I I Much of the attentiOn shifted from mastering the technologies th emselves to extracting biologically relevant in fo m1ati on - a fi e ld call ed " bioinfom1atics" such as pairing screen results with fun ctional 7 assess ments of a specifi c neoplastic process. Despi te the more comprehensive sequence in fo rmati on at the expense of a hi gher cost, there have been some appli cati ons of genomic and 12 bioin fo rmati c ana ly i in tumor c lass ifi cati on.

Screening and Diagnostics Preventi ve measures taken aga inst cancer can u e per ona lized medi cine to screen for one's predi spos ition to cancer, which is important in prov id ing a w ider range of therapeuti c options for the pati ent and guiding in clini cal deci ion ma king. Geneti c screening is parti cularl y useful for indi vidua ls w ith a fa mil y hi story of can cer, where the presence of oncogenic mutations such as APC (adenomatous po lypos is co li ), BRCA J (breast ca ncer l , early onset), and BRCA2 (breast cancer 2, earl y onse t) can be used as ri sk fa ctors before any ymptoms or even ce llul ar dyspl a ia 13 occur . Ce lecox ib, the current chemopreventi ve agent of cho ice for co lorecta l can cer, is only recommended for hi gh-ri sk pati ents w ith famlial adenomatous po lypo is linked to the APC 13 oncogene mutati on. There is a lso a dri ve to utili ze persona li zed medicin e m c linical di agnosti cs. Although the pro tate-spec ifi c anti gen (PSA) is th e go ld-standard for detecting prostate cancer, greater diagnosti c acc uracy m unscreened popul ati ons can be achi eved if biologicall y-based prediction mode ls are used to link biom a r~e r leve ls to other indi v idua l fac tor such as age.

Prognosis and Tumor Classification Another important goal in personalized medicine is to consolidate infonnation from traditional prognostic factors and genetic profiles in order to optimize treatment for patients. An important prognostic biomarker for breast cancer is the human epidermal growth factor receptor 2 (Her2), which encodes a transmembrane receptor protein that is overexpressed in breast cancer 15 cells. Specifically, these levels can be used to predict clinical outcomes; serial changes in the circulating Her2 extracellular domain (ECD) levels have paralleled the clinical course of disease regardless of the treatment. Specifically, higher ECD levels have been corre lated with earlier recurrence of breast cancer. 15 There is also a 186-gene "invasiveness" gene signature (IGS) generated from differentially expressed genes that has been found to be strongly associated with metastasis-free survival and overall survival of medulloblastoma, lung cancer, prostate cancer, 16 and especially breast cancer. Hence, bioinformatics-centric prediction models have been gaining ground in predicting the therapeutic response of common tumors based on their gene expression profiles.

Targeted Therapy Current research has been progressmg towards a consolidation of our current knowledge on diseases, genetic alterations, and drug responses, allowing both the creation of new chemotherapeutic drugs and expanding existing ones on the market. For instance, imatinib meyslate (Gleevec) is a drug that was initially approved by the Food and Drug Administration in 2001 to treat chronic myelogenous leukemia 17 (CML) by targeting the BCR-ABL protein. Later, G leevec became the first specific effective treatment against advanced gastrointestinal stromal tumors (GISTs) after researchers found that the link between the mutant KIT protein, which shows similarities to the BCR-ABL 1 protein, and GIST aggression. However, researchers are still looking into ways to probe into individual resistance mechanisms to combat . . . 19 the issue of Gleevec res1stance m patients. Gefitnib (Iressa) is another anticancer drug that

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targets the epidermal growth factor receptor (EGFR), an important component leading to lung cancer aggression. The concept of personalized medicine may explain why there were largely negative results of clinical trials as only 10-15% of the test patient population carried the EGFR 20 gene mutation or gene amplification. Hence, clinicians are looking into the possibility of conducting more targeted trials that restrict e li gibility of subjects to those whose molecular profile predicts a better re ponse to a particular chemotherapeutic agent.

Challenges and the Future of Personalized Medicine Although there is much hope regarding the potential of personalized medicine, there are still many barriers preventing its widespread usage. Duffy et a/. 6 illustrate some of the key challenges in the field, including underpowered studies, invalidated results from independent patient populations or prospective trials , multiple end points and subsets of patients used, and poor quality of design and unreliable data. These problems can be addressed in part by better coordinated multi-centered prospective studies using much larger patient cohorts than have been studied to this point. Nonetheless, the potential benefits of personalized medicine - with respect to improving positive outcomes and minimizing side effects and costs of treatment - are worth taking the time and effort to pursue. This holds implications for pharmaceutical companies, diagnostic agencies, members of the healthcare profession, and most importantly, patients. Indeed, there is a movement towards focus on the individual and not just the disease- what has been a barrier to treatment in the past may very well be the key to unlocking mechanism of di ease to combat cancer in the future.

References I.

Parkin OM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin . 2005 ; 55 : 74-108. Kopnin BP. Targets of oncogenes and tumor suppressors: key for understanding basic

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mechanisms of carcinogenesis. Biochemistry (Mosc). 2000; 65:2- 27 . 3. Croce CM. Oncogenes and cancer. N Eng! J Med 2008 ; 358:502- 5 11 . 4. Duffy MG . Role of tumor markers in pati ents with so lid cancers : a critical review. Eur J Intern M ed . 2007 May; l 8(3): 175-184. 5. [no authors li sted]. International Germ Cell Consen us C lass ification : a prognostic factorbased staging system for metastatic germ cell cancers. Intem ati onal Germ Ce ll Cancer Co llaborati ve Group. J C lin Oncol. 1997 Feb; 15(2):594-603. 6. Duffy MJ, Crown J. A per ona li zed approach to cancer treatment: how bi omarkers can he lp . C lin C hern . 2008 Nov;54( II ): 1770-9 . Epub 2008 Sep 18. 7. O ve rdeve t JB, Theodoresc u D, Lee JK. Utilizing mo lec ul ar ga teway : th e pathway to personalized cancer manage ment. C lin Chern. 2009 Feb 26. [Epub ahead of print]\ 8. Compendia Bioscience. Cancer Pro filin g Database [Intemet]. Oncomine Re earch ; 2007 . [ci ted 2009 March 20]. Avai lable from : www.o nco mine.o rg/. 9. Koomen JM, Ha ura E B, Bepl er G , Sutphen R, Remil y-Wood ER, Ben on K, Husse in M , Hazlehurst LA, Yeatm an TJ , Hildreth L T, Se ll ers T A, Jaco bsen PB , Fen stermac her DA, Da lton WS . Proteomi c contributi ons to perso na li zed cancer care. Mol Ce ll Protcomi c . 2008 Oct;7( l 0): 1780-94 . Ep ub 2008 Jul 29 . I 0 . Aeber o ld R, Mann M . Mass spectrometry-based proteo mi cs . Nature. 2003 Mar 13;422(6928): 198207 . ll. Stra usberg RL, Simp on AJG , Wostcr R. Sequence-ba ed cancer gcnomi cs ; progress, lesion and oppo rtuniti e . Nat Rev Genet. 2003; 4; 409-1 8. 12. Ley TJ , Minx PJ , Wa lter MJ , Ri c RE, Sun H, Mcle ll an M, et a /. A pilot tudy of hi gh

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throughput sequence-based mutational pr?filing of primary human acute myeloid leukemia cell genomes . Proc Nat! Acad Sci USA. 2003 ; 10014275 -1 80. Ponder B. Genetic testing for cancer risk. Science. 1997 ; 27 8: 1050-4. Shariat SF, Scardino PT, Lilja H. Screening for prostate cancer: an update . Can J Urol. 2008 Dec; 15(6):4363 -74. Carney WP, Neumann R, Lipton A, Leitzel K, Ali S, Price CP . Monitoring the c irculating leve ls of the HER2/neu oncoprotein in breast cancer. C lin Breast Cancer. 2004 Jun ;5(2) : 105-16. Liu R, Wang X, Chen GY , Dalerba P, Gurney A, Hoey T, Sherlock G , Lewicki J, Shedden K, C larke MF. The Prognostic Ro le of a Gene Signature from Tumorigenic Breast-Cancer Cells. N Eng! J Med. 2007 Jan 18;356(3):2 17-26. Wei G et a /. Gene ex pression-based chemical Optimi zing Imatinib M esy late Treatment in Ga trointestina l Stromal Tumors . Gastrointest Cancer Re . 2008 Sep;2(5) :245-50. Paez JG , Janne PA, Lee JC, et a!. EGFR mutat ion in lung cancer: Correlation with c linica l response to gefitinib the rapy. Science 2004; 304: l 497-500genomics identifies rapamyc in as a modulator of MCL1 and g lucocorti coid resi tance. Cancer Cell. 2006 Oct; I 0( 4 ):33 1-42. O'Brien G, Guilhot F, Lar on RA el a/. Imatinib compared w ith Inte rferon a nd low-dose cytarablne for new ly dia gnosed chronic-phase chronic mye loid leukemi a. N Eng! J Med . 2003 Mar 13;348( II ):994- l 004 . Pacz JG , Janne PA, Lee JC, et a /. EG FR mutations in lung cancer: Cone lat ion w ith c lini ca l rc ponse to gefitinib th erapy. Sci ence. 2004; 304: 1497-500.

THINKING ON YOUR FEET Marfan Syndrome Kalpa Shah (Meds 2012) and Aiman Alak (Meds 2011) Faculty Reviewer: Dr. Victoria Siu Marfan syndrome was first described in 1896 by Antonine-Bernard Marfan, Professor of Pediatrics in Pari s. It is a relatively common inherited connective tissue disorder with an incidence of 1 in 10,000 individuals. The condition is inherited in an autosomal dominant pattern , with an equal di tribution in males and females.

Case The following case is meant to serve as a prompt to guide the discussion on the clinical aspect of Marfan Syndrome. An 18 year old man develops sudden chest pain while playing basketball. He is noted to be quite tall at 6'5" and has long fingers and toes. Does he have Marfan syndrome? What are the diagno tic criteria? If he has Marfan syndrome, what are 3 possible causes of his chest pain? It wou ld be relevant to note whether the patient wears contact lenses as individuals w ith Marfan syndrome are often near- or far-sighted and/or have other eye abnorma liti es.

Clinical Presentation Most patients who have Marfan syndrome are usua ll y diagnosed incidenta lly. Typically, patients with Marfan syndrome present with tall stature, lens dislocation (ectopia len ti s), aortic root dilatation and a positive family history . Less common presentations include: • Dominant ectopia lentis with variab le ske letal and negligible cardiac involvement • Mitral valve prolapse without ske letal features • Dominant aortic aneurysm without ske leta l and ocular features

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• Presentation at birth, rapid aortic dilatation, deformities (such as pectus deformities, where the breastbone protrudes inward or outward), and death 1 • Sudden death

Pathogenesis The genetic basis for Marfan syndrome is a mutation in the gene encoding fibrillin-1 (FBN1) found on chromosome 15 . Fibrillin is a g lycoprotein that is an integral part of microfibril s found in the connective ti ssue of the body. Microfibrils function as the main component of elastic fibres, anchoring fibres between the dermis and epidermis, as we ll as in the lens of the eye. C lassically, it was thought that the ubiquitous features of Marfan syndrome could be attributed . . ., to weak or deformed connective tissue.- However, recent re earch sugge t that a defect in the fibrillin-1 structure reduces its abi lity to bind to the cytokine TGF-8 , which results in increased ex pres ion of TGF-8. 1n mouse model s, increased TGF-B signaling was associated with myxomatous mitral va lve leaflets and aortic dilatation, both feature of Marfan syndrome. Furthermore, by admini tering an antibody that binds TGF-8, it was shown that these common features cou ld be prevented. 3 Thus, it IS now thought that it is the over-expres ion of the cytokine TGF-B , due to the inability of the defective fibrillin-1 that would m norn1al circumstances bind TGF-8 , that results in the features of Marfan syndrome.

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Marfa n syndrome has di verse m anifesta ti ons that can affect many organ systems such as the skeleta l, ocular, cardiovascular systems and can a lso invo lve the skin, lungs and musc le ti ssue - an exampl e of pl e io tropy.

Clinical Diagnosis The d iagnosis of Marfa n syndro me (MFS) is usua ll y ba ed on cl ini ca l fea tures and fa mil y 4 hi story. The fea tu res of M arfa n syndrome may overlap w ith other connecti ve ti ssue di sorders and the presentati on of Marfan synd rome vari es w idely, even among fa mil y member . Nonethe less, the deve lopment of a set of guide lin es, known as the Ghent cri teri a, has 4 bro ught c larity to the issue. •

If an ind ividua l has a fi rst-degree relative affected by Marfan syndrome, a diagnos is of Marfa n syndrome req uires maJor invo lvement in one organ system (ske leta l, cardi ovasc ul ar, o r oc ul ar) and minor invo lve ment of a second organ system. • In the ab ence of a fa mil y hi story fo r Marfa n syndro me (or ambi g uous famil y hi story), a di agnosi of Ma rfa n syndrome require maj or criteri a in two di ffe rent organ systems and min or in vo lvement of a third . Pl ease refer to Tab le I attached at th e end of the arti cle for more deta il s on the c lini ca l fea tures that wo uld constitute majo r o r mm or in vo lvements in di ffe rent organ systems. As a s implifi ed g uide lin e, fo r a pati ent suspected of hav ing Ma rfa n sy nd ro me orne in vestigati ons that are he lpful in making a c lini ca l di ag nos is inc lude: •

Examin ati on by an an ophtha lmolog ist to look fo r lens di slocati o n o r sublu xati on; often pati ents with Marfa n ynd ro me are near-sig hted (myopi a) and at increased ri sk fo r deve lopin g catarac ts and g laucoma

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• Referral to a cardiologist for an echocardiogram to assess if there are any cardiovascular abnormaliti es su ch as mitra l valve prolapse, aortic root dila tation or a011ic dissection • Phys ica l exam to assess ske leta l fea~re~ : rati o of arm span-to-he ight ratio w hich IS cons idered sig nifi cant if it is greater than 1.05, or wrist and thumb sig ns. (A pos iti ve w ri st sign is present if the thumb and fifth fin ger overlap w hen encircling the opposite w ri st. A pos itive thumb sign is present if the entire thumbnail protrudes beyond ulnar border of hand w hen the thumb is adducted across the pa lm .)

Differential Diagnosis The di fferenti al di agnosis for MFS incl udes ho mocystinuria, congenita l contractura l arac hnodacty ly, mild ao rti c root dilatati o nske leta l-skin (MASS) syndrome, E hlers-Danlos syndro me, Sti ckler synd ro me, congenita l bic uspid aorti c va lve di sease, ao rti c coarctation, LoeysDi etz yndro me, and fa mili al th oracic aortic aneury m wi th aortopath y. T he most s imilar di ffe renti a l i homocystinuri a as the two di seases share a imil ar phenotype. Fea tures that overlap between Marfa n syndro me and homocystinuria inc lude ecto pi c lenti s, severe myopi a, mitra l va lve pro lapse, and ke leta l abno m1a liti es, such as body habitus, c hest defo rmiti e , and spine defom1iti es. Pati ents w ith homocys ti nuri a are at an increased risk for th ro mboembo lic events, but many pati ents w ith thi s co nditi on are respo n ive to pyridox in e. T hus, it is impo rtant to screen for homocystinuri a w ith meas urement of urinary amin o ac ids, as th ere are impli cati ons for rna nage men t. 5

Management O verall, the prognos is for M arfan syndro me is re lati ve ly favo rabl e. Acti v ity restri cti o ns, medi cati ons, monitoring, and e lecti ve surgica l interventi on we re associated w ith an improved life span for M FS patients fro m 4 1 years in 1993 to 6 1 years in 1996 .6•7

Aortic disease is the most significant source of morbidity and mortality for patients with MFS. Untreated MFS can be associated with an aortic dissection spanning the entire length of the aorta. Aortic dissection occurs earlier among patients with MFS compared to the other cases of aortic dissection. Assessment for aortic root

dilatation and regurgitation can be performed by thorac ic echocardiography; however, if that yie lds incompl ete or insufficient information, transesophagea l echocardi ography can be used. Routine measurements ca n be performed annua lly as long as th e aortic root diameter increases proportional to increases in body surface area. If

Table l. Ghent Criteria for Diagnos is ofMarfan Syndrome* System Majo r Family/genetic history

• •

Skeletal

• • • • • • • •

Ocular

• •

Cardiovascular

•

Minor

Hav ing a first-degree relati ve who meets these diagnostic criteria Presence of a mutation in FBN I known to cause Marfan syndrome

•

None

Presence of at least 4 of the following manifestations: Pectus carinatum Pectus excavatum requiring surgery Reduced upper-to-lower segment ratio or arm span-to-height ratio > 1.05 Wrist and thumb sign Scoliosis > 20 degrees or spondylolisthe is Reduced extension at elbows (< 170 de grees) M edial di splacement of medial malleolus causing pes planus Protrusio acetubu lare of any degree Ectopia lenti (dislocated lens)

• • •

Pectus excavatum of moderate severity Joint hyperrnobility Highly arched palate with crowdin g of teeth Facial appea rance (do lichocephaly, malar hypoplasia, enophthalmos, retrognathia, down-slanting pa lpebral fi ss ures)

Dilatation of ascending aorta with or without aortic regurgitation and in volving at least the sinuses of Valsalva or di ssection of ascending a011a

•

• •

Abnormally flat corn ea Increased axial length of globe

•

Mitral va lve prolapse with or without mitral va lve regurgi tati on Dilatation ofthe main pulmonary a11ery, in the absence of valvular or peripheral pulmonic tenosis or any other obvious cause in patients < 40 year Calcification of mitral annulus in patients <40 yea r Dilatation or di ssection of the descending thoracic or abdominal a01ta in pati ents < 50 years Spontaneous pneumothorax Apical blebs

•

• •

Pulmonary

•

None

• •

Skin and integument

•

None

•

Dura

•

Lumbosacral dural ectasia (by CT or MRI)

•

Stretch marks not assoc iated with weight changes , repetitive stress Rec unent incisio na l herni as

•

None

*Adapted from Rangasetty UC, Karnath BM. (2006) 1

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the increase is di sproportiona l, or if the aorti c root diameter is greater than 4 5 mm, bi annual measurements should be performed. The European Soc iety of Cardi ology has publi shed recommendations for the treatment of 8 pati ents with M F S. The standard of care in vo lves beta bl ockers whi ch can de lay the progress ion to aorti c di ssection . Beta blockers decrease myocardia l contractili ty and pul se pressure and may a lso improve the e lasti c properti es of the aorta, parti cul arly in pati ents w ith an aortic roo t 10 diameter <40 mm .9路 In a randomi zed tri a l, treatment w ith pro pranolo l was as oc iated with de layed prog ress ion of aortic dil atati on, and hi gher surv iva l at approx imate ly fi ve years. Longer term surv ival di ffe rences between proprano lo l and pl acebo were Ies c lear. 11 No randomi zed tria ls have been done to establish the 12 efficacy of beta blockers in children. However, many c li nic ians wo uld give beta bl ockers to a ll childre n with MFS . In the fu tu re, therapy di rec ted at the renin-ang ioten in -a ldosterone system may prove benefi cia l, but th e ro le of these drugs in MFS ha not ye t been e tabli h ed . 13 ' 1 ~ Pati ent w ith MFS may parti cipate in low to moderate in te nsity, non-competiti ve exercise uch a bow lin g, go lf, tati onary bike, or modest hikin g. Strong ly di couraged acti vities inc lude: weight li ft ing, ice hockey, rock c limbing and surfing. 15 The cho ice of permi ss ibl e acti viti e requi res indi vidua l assess ment. For chil dren to comply w ith th ese actj vity re tri cti ons, there mu st be coordinati on between parents, schoo l offic ials, and ph ysical ed ucators. Electi ve surgica l repair fo r an aorti c dil atati on is assoc iated w ith reduced mortality compa red to urgent or emergent repa irs. For adults and children, surgica l repair should be cons idered at an ao rti c root di ameter of 2': 50 mm. 16 Uncertainti es ex ist regarding the root di ameter fo r perfo rming e lecti ve surgery. The 2006 A meri ca n Co ll ege of Cardi o logy/A meri can Heart Assoc iati on (ACC/ AHA) guide lines recommend e lecti ve surgery for an ao rti c root di ameter 2':50 mm , w hil e European Soc iety of Ca rdi o logy (ESC) recommends surgery fo r an 17 . .on to aorti c root di ameter of 2':4 5 mm . I n a dd 1t1

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the absolute size of the aortic root di ameter, other considerations are a famil y history of aortic di ssection or a rapid increase in aortic size (i.~ ., . 2': 5 mm per year). 18 Some suggest usmg ao rt tc root dimensions re lati ve to body surface area. This factor is parti cularl y important for children. For children, the o nl y clear indi cations for surgica l intervention are: an aortic root diameter of 2':4 5 mm ("giant aneurysm"), rapid enlargement of > l 0 mm/year, or progress ive aortic in suffi c iency. Other cut-offs for aortic root di ameter are less clear. A few opti ons exist regarding the surg ical technique and the cho ice depends on patient factors. O ne approach in vo lves tota l replacement of the ao rtic roo t. 19 A lternati vely, for patients with structura ll y norma l va lves th e nati ve aortic va lve may be reta ined using remodeling and 20 2 1 I . Iantat10n . . re1mp tee hmques. 路 n th.IS Iatter opti on, li fe -long anti-coagulati on is not required; however, repeat operati ons may be necessary . An tibi otic prophy lax is hould be indi vidua lized. As other sites throughout the aorta maybe in vo lved, fo llow- up radiography using MRI or CT angiography is requi red inde finite ly.~ 2 Ocular and mu ke loske le ta l problems also require attenti on. Eyeg lasses can correct myopi a, whil e arti fic ia l lens inserti on should onl y be undertaken w hen growth of th e eye is compl ete . Furth er, ph otocoagulati on can correct retina l tears and detac hment. If interventi on w ith phys ical th erapy and brac ing fa il s, sco li os is may require urgica l tabili zation of the spine. Orth o ics can correc t fl at foot, whi ch i as oc iated w ith musc le cramps and leg fa ti gue.

Answers to Case Di agno is wo uld be made based on Ghent criteri a. Poss ibl e causes of che t pa in are : musc le/li gament tra in , aorti c root di section , and pn eumothorax .

Glossary pectus carinatum : deformity of the chest characterized by protrusion of ribs and temum

pectus excavatum: deformity in which several ribs and the ste rnum g row abnormally, producing a concave appea rance in a nte rior ches t wall protusio acetabulare: protrus ion of the acetabulum (socket that r eceives fe moral head to make the hip joint) pes planus: flat foot dolichocephaly: elong ated s kull enophthalmos: rece ss ion of eye ba ll within the orbit sinuses of Valsalva: al so known as a orti c s inus; the space be tween each se milunar v a lve a nd th e w a ll of th e aorta

References Rangasetty UC, Kam a th BM. C linical ign o f Marfan sy ndrome. Hosp Ph ys. 2006: 33-38. 2. Dietz HC, C uttin g GR, Pye ritz RE, et a!. Marfan syndrome caused by a recurrent de novo missense mutati on in the fibrillin ge ne. Nature. 199 1; 352 : 339-10. 3. Pyeritz RE . A small mo lec ul e for a large di ease . N Eng! J Med. 2008;358: 2829-283 1. 4. Rangasetty UC, Karnath BM. C lini cal signs of Marfa n syndrome. Hosp Phys. 2006: 33-38. 5. Fowler B, Jakobs C. Post- and prenatal di agno ti c methods for the homocystinuri as. Eur J Pedi atr. 1998; 157 Suppl 2: S88. 6. Finkbohner R, John ston D, Crawford S, et a /. Marfan sy ndrome: Long-term surv iva l and compli cati ons after aorti c aneurysm repair. C irculati on. 1995; 9 1: 728. 7. Silvem1an Dl, Burton KJ, G ray J, et a/. Life expectancy in th e M arfa n syndrome. Am J Cardi ol. 1995; 75: 157. 8. Erbel R, A lfon so F, Bo il ea u C, et a!. Diagnos i and management of aorti c di ssection . Eur Heart J. 2001 ; 22 :1 642. 9. Groenink M, de Roos A, Mulder BJ, et a!. Change in aorti c di stensibili ty and pul se wave veloc ity assessed w ith magneti c resonance imag ing follo w ing be ta-blocker therapy in th e Marfan syndrome. Am J Cardio l. 1998; 82 :203 10. Rios AS, Silber EN, Bavishi N, et a!. E ffect o f long-term 13-blockade on aorti c root compli ance in patients with Marfa n syndrome. Am Heart J . 1999; 137:1057 11. Shores J, Berger KR, Murphy E, et a!. Progression o f aortic dilatation and the benefit o f

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13.

14.

15.

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17 .

18.

19.

20 .

2 1.

long-term beta-ad renergic blockade in Ma rfa n's synd rome. N E ng! J Med. 1994; 330: 1335. Ahimastos AA, Aggarwa l A, D'O rsa K.M, et al. Effect of perindopriI o n large arte ry ti ffne and ao rti c root d ia meter in patients w ith Marfan yndrome: a ra nd omi zed contro ll ed tri a l. JAMA. 2007; 298: 15 39. Brooke BS, Habas hi JP, Judge DP, et a!. Ang iotensin II blockade and aortic-root dil ati on in Ma rfa n's syndrome. N Eng l J Med. 2008; 358 :2787 . Maron BJ, C haitman BR, Ackerman MJ, et a/. Recommendati ons fo r ph ys ical acti vity a nd recreati onal spott parti c ipati on for youn g pati ents with geneti c cardi ovascul ar disease . Circul ati on. 2004; 109 :2807. Erbel R, Alfonso F , Boi lea u C, et a /. Di agnos is and manageme nt of aorti c di ssection. Eur Hea rt J. 200 1; 22: 1642. Va hani an A, Baumgartn er H, Bax J, et a/. Guidelines on th e management of valvular heart di sease: The Tas k Force on the Ma nagement o f Va lvular Heart Di ease o f th e Europea n Society of Cardi o logy. Eur Heatt J. 2007; 28:230. Bonow RO, Carabell o BA, Chatterjee K, et a/. ACC/A HA 2006 guid e lines fo r the manage ment of pati ents with val vul a r heart disease. A report of th e Ameri can College of Cardi o logy/ Ameri can Heart Associati on Tas k Force on Practi ce G uidelines (Writing committee to rev i e th e 1998 guidelines for th e management of patients w ith va lvular heart di sease). J Am Co li Cardi o l. 2006; 48:e l. Ka rck M, Kallenbac h K, Hag l C, et a!. Aortic root surgery in Marfa n synd rome: Compari son o f ao rti c va lve-sparin g re implantati on ve rsus compos ite graftin g. J Thorac Cardi ovasc Surg. 2004; 127:39 1 Ka ll enbac h K , Ka rck M , Pak D, et a /. Decade of aorti c va lve sparin g reimplantati on: are we pu hin g th e limits too fa r? C irculati on. 2005; 11 2:1253 Sil verman DI , G ray J, Roman MJ, et a /. Fa mily hi tory of severe cardi ovascul ar di ease in Marfa n sy ndrome i as oc iated w ith increased aorti c di ameter and dec reased surviva l. J Am Coli Cardi ol. 199 5; 26 : 1062 Di etz H. M a rfa n Syndrome [Internet]. Seattle, : Uni ve rsity of Wa hin g ton; 200 5 Oct 26 [C ited 2009 A pr 3]. Availabl e fro m: http ://www .nc bi .n I m.ni h.gov/bookshel f/b r. fcgi?b ook=gene& pa rt=marfa n.

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ZEBRA FILES Human Statues: Challenges in Management of Patients with Fibrodysplasia Ossificans Progressiva Anna Burianova (Meds 2 01 2J Ashley Brown (Meds 2011J andjenna Ashkanase (Meds 2011) Fa culty Reviewer: Dr. Kathleen Hill Fibrodys pl as ia oss ifi cans progress iva (FO P) is a rare geneti c di sorder in whi ch soft tissues transform into bone, caus ing pati ents to gradua lly become entombed in th eir own bodi es. Earl y symptoms ty pically invo lve infl ammatory les ions that are often confused with a va ri ety of tumours and other conditions, leading to delays in d iagnos is and medi ca l procedures that may ca use significant detriment. The recent di scovery of th e FOP gene may he lp to all ev iate thi s issue, as DNA testing can allow for earlier identi fica ti on of the condition. A case study is presented to exempli fy the challenges faced when treating a pati ent w ith FOP, and po sibl e compli cati ons are detail ed to emphasize the consequences if precautions are not taken. W ith a spec ifi c gene target in sight, it is hoped th at treatments can extend beyond supportive care and be abl e to prevent or ha lt thi debilitating conditi on.

Introduction Metamorphos is IS defin ed as the transformati on of one norma l ti ssue or orga n system in to anoth er through a patho logica l 1 process. W ithin its rea lm , heterotopi c oss ifi cati on (HO) describes the abn orma l formati on of true bone within ex traske leta l soft tissues. Fibrodys pl as ia oss ifi cans prog ress iva (FOP) is an exceeding ly rare geneti c di sorder whi ch has , until rece ntl y, been one of medi c in e' most e lusive mysteri es and the most di sabling conditi on of extras keleta l os ifi cati on kn own in humans.2 Âˇ3

Genetics FOP is an ex treme ly rare conditi on, occulTing at a popul ati on frequency of about I per 2 milli on w ith no ethni c, rac ial, gender or 12 geographi c predi spos iti on. ' Th e severe di sability of FOP results in low reproducti ve fitn ess and fewer th an ten multi generati onal fa mili es are 1 known wo rldw ide. Most cases of FOP are sporadi c w ith onl y one affected indi vidua l in a famil y, though when ob erved, geneti c 1 2 transmi ss ion is autosoma l dominant. â&#x20AC;˘

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A rece nt breakthrough in the study of FOP was attained with th e identification of a recurrent s ing le nuc leotide mi ssense mutation in activin receptor INacti v in-like kinase 2 1 (ACV R l/ A LK2). Thi bone morphogenic protein (BMP) type I receptor ca uses ske letal morph ogene is, and is therefore the fir t identifi ed human metamo rphogene. u The mutati on ha been reported in a ll sporadic and fa mili a l case of cl ass ic FOP wo rld w ide, making it one of the mo t hi ghl y spec ifi c di sease-ca using mutati ons in the human genome .3

Clinical Features The c lass ic presentati on of FOP is defin ed by two clini ca l features: conge nital ma lformation of the great toes and progress ive H0.3 Congenital ma lfonnati on of the great toe i the earli est phenotypi c fea ture present in a ll class ically affected individua ls, w ho appea r otherwi se 1 2 unremarkable at birth . â&#x20AC;˘ Other ke leta l anomali es often associated with FOP inc lude deve lopmental anoma li es of the cervica l spine, short ma lfonned thumbs, clinodacty ly, hort broad femora l necks and proximal medi a l tibi a l osteochondromas. 1

During the first decade of life, children with FOP deve lop painful and highl y inflammatory soft ti ssue swellin gs (or flare-ups) that progress ive ly and permanently transform 13 connective ti ssues into heterotopic bone. ' The ossification in FOP progresses in characteri sti c patterns that mimic normal embryonic skeleta l development, with the first episodes typi ca lly 12 occurring along the upper back and neck. • However, several musc les including the diaphragm, tongue, extraocular and cardi ac as well as smooth muscle are eni gmatically spared 1 from the FOP process. Interestingly, the clinical features of earl y involvement in the ax ia l regions differ from those seen in the appendicular regions. 1' 3 Even though swelling appears more rapidly than typically seen with neoplasms, the bulbous les ions which appear on the neck and back are often mistaken for tumours. 1,3 In the limbs, on the other hand , the swelling is often diffuse and may be mi staken for 13 acute thrombophlebitis. • The natural progress ion of the di sease can al so be altered by environmental factors, as any trauma leading to ti ssue injury has the potenti al to induce HO. Thi s leads to epi sodes of explosive and painful new bone growth, with cumulati ve immobility. 1'2

Case Report An 18-month-old boy from Brita in presented w ith a brainstem les io n in need of neurosurgery. He had recently been diagnosed with FOP, and physical exam prior to surgery revealed heterotopic ossifi cation of the dorsal a nd lumbar paravertebral muscles, the left sternocl eidomastoid, and fu sion of the C4-C6 vertebrae. Although the brainste m lesion was in this case unrelated to hi s FOP, hi s condition nonetheless complicated the procedure to remove it. His montelukast was switched to predni sone to prevent inflammation 24 hours before surgery and Direct continued until four days post-op . laryngoscopy was not possible due to the fu sion of his cervical vertebrae, therefore fiberoptic broncoscopy via the nostril was necessary to intubate him . Traumatic injury was avoided by UWOMJ, Vol 78, Issue 3

using sili con carpets and a headrest, as we ll as by padding every po int of contact w ith cotton woo l. Because hi s FOP was recogni zed and attended to properl y, the procedure produced a favo urable outcome and the c hild had no signs of progress ion of the di sease at two months post-op.-1

Complications of FOP The case repo rt above illustrates some of the diffi culti es in managing pati ents with FOP. Since it is cruci al to prevent exacerbati ons, one of the mainstays of proper care is to avo id the associated w ith certain medi ca l trauma procedures . Surgeri es in parti cula r pose di ffi culti es for pati ents if, as in the case report, fu sion of the cervi cal vertebrae has occurred and impedes intubation . Anesthes ia in an FOP pati ent can also be extremely di ffi cult if anky los is of the jaw is present, w hi ch could be tri ggered by something as simpl e as minor dental 45 procedures. • Biopsies are also contraindi cated, but since they are the investigation of cho ice for most tumours, they are often performed before a diagnosis is made. One of the most severe compli cati ons of FOP is cardiopulmonary compromi se. FOP can lead to ankylosis of the costovertebra l j oints, oss ifi cati on of the intercostal and paravertebral musc les, and progress ive spina l deformity such as kyphosco liosis or thorac ic lordos is. Chest expansion is drasti ca ll y limited, resulting in reduced vital capacity and restri cti ve lung di sease. Ri ght ventricular hypertro phy can also occur due to th e thoraci c insuffi c iency.5•7 Pati ents w ith FOP are also more prone th an th e general population to kidney stones as well as conducti ve hearing loss due to fusion of th e bones of the middl e ear. They are also prone to fracture of heterotopi c bone, whi ch requires closed reduction and splinting, as we ll as analges ia, as in fracture of normotopi c bone in 5 any patient. Thus, pati ents should be educated about ri sk factors for fa ll s to avoid precipitati on of a cyc le in w hi ch a fa ll leads to furth er ossification and joint anky losis, whi ch in tum increases the ri sk of future falls. 5 ·6

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Discussion FOP is an extremely debilitating di sease. Most affected peopl e are wheel chair-bound by the ir 20s and life expectancy is less than 40, as thoracic insuffi ciency usua lly occurs by thi s . 4 . pomt. Pat1 ents must li ve w ith th e constant know ledge that they have a progress ive di sease. As more and more j oints and musc les become permanentl y oss ifi ed over time, pati ents with FOP are essenti all y trapped in ide the ir own bodi es until they can no longer move or even brea the. T he recent breakthro ugh di scovery of the FOP gene has ide nti fie d a spec ifi c target fo r pharmaco logic therapy and a ll owed for th e deve lopment of a DNA di agnosti c test w hi ch expedites di agno is . and limits ham1ful 2 interventi ons. However, the opportuniti es fo r in sight prov ided by stud ying the FOP gene extend fa r beyond thi s rare di sorder a lone. That is, characteri zati on of the underl yin g mec hani sm

causing HO in FOP has much broader impli cati ons fo r pati ents with more common forms of HO and fo r deve loping tissue engineering strategies for ske leta l bone and cartil age repair. 2.3 Conclusions Due to th e rarity, variabl e severity and epi sodi c c lini ca l course of FO P, clini cians often fail to assoc iate the rapidl y deve loping ax ia l soft ti ss ue swe llings witb the di stincti ve ma lformed g reat toes. 3 When such assoc iati ons are not made, FOP is comm onl y mi staken for other conditi ons, 1 de lay ing pro per trea tment. ' 3 Not surpri sing ly, mi sdi agnosed indi vidua ls often undergo a battery of unnecessary bi opsies and tests th at exacerbate progress ion of th e conditi on. Earl y di agnos is and cauti ous manage ment of pati ents w ith suspected

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FOP are therefore very important. Finally, although the current medi cal management of FOP is largel y supportive, the goal of research continues to be the deve lopment of treatments that will prevent, halt or even reverse progressiOn 3 of the di sease.

References l.

Kaplan FS, Shen Q, Lounev Y, Seemann P, G roppe J, Katag iri T, Pigno lo RJ, Shore EM. Skeletal metamorphosis in fibrodysplasia oss ifica ns progress iva (FOP). J Bone Miner Metab. 2008;26(6):52 1-30 . Shore EM , Kapl an FS. Insights from a rare geneti c di sorder of extra-skeletal bone formation , fib rody pl asia ossifica ns progress iva (FOP). Bone. 2008 Sep;43(3):427-33. Kaplan FS, Le Me rrer M , G lase r DL, Pignolo RJ, Go ldsby RE, Ki tterman JA, Groppe J, Shore EM. Fibrodysplas ia o ificans progressiva. Best Pract Re Clin Rh eum ato l. 2008 Mar;22( 1): l 9 l-205 . Tumo lo M, Mo catelli A, S ilve triG . Anaesth eti c manage ment of a child w ith fibrodysplas ia os ifica ns progress iva. Br J Anaesth . 2006;97(5) :70 1-3. The Internati onal lin ical Consortium on FOP. T he medica l manage ments of fibrodys plas ia progress iva : current treatment os ifi cans con iderati on . Clio Proc Inti C lin Consort FOP. 2008;3(2): 1-85 . La nchoney TF, Cohen RB , Rocke DM, Zasloff MA, Kaplan FS . Pem1anent heterotopic o ification at the injection si te after diphth eri atetanus-pertus is immuniza ti on in children who have fi brody pia ia oss ificans progressiva. J Pedi atr. 1995 ;1 26 :762-4. K u smaul WG , Esmail AN, Sagar Y, Ross J, Gregory S, Kaplan FS . Pulmonary and cardi ac fun cti on in adva nced fib rodysplas ia ossificans progressiva . C lin Orthop Re lat Res . 1998;346 : 104-9.

FEATURE Quality of Life Consequences of Long QT Syndrome lshvinder Chattha (Meds 2011) and Caleb Zeleniel::: (Meds 201 1) Faculty Reviewers: Dr. Raymond Sy and Dr. Andrew Krahn Long QT syndrome (LQTS) is a genetic condition characterized by abnormal repolarization of cardiac ventricular myocytes predisposing the individual to ventricular tachyarrhythmias. The first manifestation of LQTS is typically syncope and less frequently cardiac arrest or sudden cardiac death. This article examines the effect of LQTS on patients' quality of life. This includes the psychosocial and physical consequences that may result from both the diagnosis of a potentially lethal genetic disease and its subsequent management. Current guidelines are based on expert consensus and recommend moderate and at times strict exercise restriction, even in asymptomatic patients. Broad exercise restriction affects the social development of children and also removes the protective effect that exercise has against developing both psychological and physical health problems related to inactivity. Due to the potential decline in a patient's quality of life resulting from strict exercise restriction, future research should focus on determining the effectiveness of exercise restriction in the prevention of ventricular arrhythmias.

Introduction

Long QT Syndrome

Genetic disorders are unique in their impact on patients. Often incurable, patients not only need to deal with the wide array of feelings surrounding the initial diagnosis, but there is often guilt related to the possibility of passing the disorder onto their children. 1 Given the implications for family members, genetic testing and resultant therapy is offered to relatives. The diagnosis can also influence family planning. These consequences are in addition to the effects of the disease itself.

The QT interval, seen on the electrocardiogram, is a measure of ventricular depolarization and subsequent repolarization. LQTS is characterized by abnormally delayed repolarization of ventricular myocytes. Lt is caused by abnormalities of cardiac ion channels which result in abnormal amounts of sodium or potassium moving across the cell membrane, interfering with the normal action potential. At least 12 ubtypes of congenital type long QT syndrome have been described resulting from mutations in any one of nearly a dozen genes controlling the expre sion, regulation , or assembly of cell membrane ion channels.3 Subtypes are classified based on the gene affected, with LQTL (KVLQTI mutation) accounting for approximately 50% of cases, LQT2 (HERG mutation) nearly 40% , and LQT3 (SCNSA) about 5% .3

This is the reality for patients diagnosed with congenital long QT syndrome (LQTS). In addition to the difficulties related to the acceptance of a lifelong and incurable disorder, LQTS management imposes a potentially significant decline in quality of life. Severe exercise restriction is currently recommended in patients with LQTS to prevent symptoms from arising. 2 This sudden change in lifestyle can be especially devastating for children, as it can leave them feeling like outcasts (Figure 1). This article examines the impact of LQTS on the quality of life of patients and their families.

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Although most patients remam asymptomatic, the first manifestation of LQTS may be syncope, cardiac arrest or sudden cardiac death. Specific actlvtttes or triggers can precipitate cardiac events in LQTS patients these include startling auditory stimuli such as an Page I 53

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Figure l . Pi cture drawn by a young ma le di agnosed w ith LQTS . The patient experi enced yncope during an ice hockey game w hi ch led to the subsequent di agnos is of LQT S. A a result of the di agnos is and res ultant exercise restri cti o n, th e pati ent quit hi s ice hockey team and abandoned hi s dream of play ing profess ional hockey. Pati ent identifi ers have bee n removed fro m th e drawin g. a lann c lock o r lo ud door be ll , emoti o na ll y charged events, o r even ph ys ical exerti o n as bri ef 4 as running to catch th e bus. Commonl y presc ribed med icati ons in c ludin g certa in antibi otics, bro nchod il ato rs, hypertens io n medi cations, and antidepressa nts can ca use furth er pro longati on of the QT interva l and increase the ri sk of cardi ac atThythmi a in susceptibl e pati ent . Whil e 50% of pati ents rema in asy mpto mati c th ro ug ho ut their lifetime, th e severi ty of th e sympto ms has crea ted a foc u o n preventati ve med icine as an important as pect of manage ment.

Quality of Life lssues- Impact on Patients and Families

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The di agnos i of LQT S can be quite devastating to indi vidua ls. Th e impli cati o ns that it has o n longev ity, menta l state, and day to day life are immense. Fam sworth et a /. (2 006) conducted a eri es of interview w ith parents w ith LQT S, and o ne pati ent 's descripti o n was: "your w ho le li fe is shattered . Yo u fee l w hammi ed off thi 4 earth ." Another parent described the chanoes in 0 her son after being di agnosed : " He is spo rt o ri ented, oc ia l, and wa nts to fl y for the A ir Force. He can ' t pl ay hockey now .. .. H e can ' t fl y. He is on ho ld, hoping thi w ill a ll go away." 4 Sudden cardi ac death ts th e first manife tin g symptom in a lmost 12% of cases. Because of thi s, pati ents constantl y li ve w ith the uncerta inty of the ir own future a we ll a the

future of their loved ones in the context of a genetic disorder. 4 Two thirds of parents interviewed by Farnsworth et a!. (2006) expressed fear of their children dying. For example, one interviewee said, "When I walk into their rooms in the morning to wake them I am always aware 4 in the back of my mind ... will they be cold?" The management of unrelated medical conditions such as infections may also create anxiety because certain prescribed medications may prolong cardiac repolarisation as a sideeffect. There are over 130 recognized drugs, ranging from anti-hypertensives, to antibiotics, heartburn aids, and antidepressants, that should be avoided by LQT patients as they have been shown to further prolong the QT interval, thus increasing the risk of a cardiac arrhythmia. Furthermore, cardiac events may be precipitated by dehydration and inadequate nutrition, which are commonly seen in many disease states. The fear of precipitating a cardiac event is always present: "Anytime she gets sick it is a big deal. It is a totally different ballgame. Medications are a big deal.. ..We do flu shots every year. I am more 4 worried, it is always in the back of your mind."

Quality of Life Issues -Impact of Treatment Once diagnosed, a management strategy focusing on prevention of LQTS related cardiac events is implemented. Management is multimodal, combining lifestyle modification, medication or even surgical options. Lifelong beta blocker therapy is the mainstay of medical 2 treatment for LQT1 and LQT2 subtypes. Trigger avoidance is also important for successful prevention. The most common trigger is physical exertion. As a result, the American Heart Association guidelines recommend severe exercise restriction for LQT patients (Table 1). These restrictions may range from withdrawal from all competitive sports to students potentially sitting out of physical education class. Such broad exercise restriction may impair physical as well as psychological wellbeing. Individuals that are physically active are less likely to suffer from mental health problems.

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Physical activity improves se lf-esteem, can foster identification with peers, red uces stress, and is 5 inverse ly rel ated to adolescent depress ion. Exercise deprivation has been shown to lead to increased symptoms of pain , fatigue , cognitive 6 problems, and negative mood. With children there is added danger beca use proper soc ial development requires common identification with peers, and thus this targeted exclusion from team activities can have a significant negati ve 7 psychological impact (Figure 1). The elderly are also at particular risk from exercise restriction as exercise has been shown to reduce CNS dysfunctions such as cognitive decline. 8 With the rising prevalence of obesity, the physical health benefits of exercise have been given increased attention. Physical activity is unanimously recognized as an essential element in combating the obesity epidemic.9 Resea rch has repeatedly shown regular exercise decreases lipid profiles, obesity, hypertension , and development of some cancers and cardiova cular diseases, and it increases bone mineral density. Physical activity is also used in the management of 10 numerous chronic diseases. Physical activity rates are decreasing in Western populations. Numerous community interventions are being implemented to promote regular exercise to achieve the recognized benefits . The diagnosis of LQTS presents another road block in achieving a healthy lifestyle. Participation in competitive sports as a child, an activity shown to be predictive of physical activity levels in adulthood, is not permitted in patients with LQTS. 5 Participation in sports is an enjoyable method of physical activity. Participants repot1 enjoyment stemming from affiliation with peers, competitive excitement, gaining competency, and 11 12 a source of psychosocial support. ' On the field people can learn sportsmanship, fair play, personal responsibility, and moral reasoning. 13 Because LQTS patients are not permitted to participate in popular sports such as basketball , hockey, soccer and football, these key elements of personal development are potentially missed.

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Table l . Permissibility of common physical activities for LQTS patients Guidelines

Activity HIGH INTENSITY

Basketball Body building Ice hockey Racquetball/squash Rock Climbing Running Skiing Soccer Tennis (singles) Touch football Windsurfing MODERATE INTENSITY

Baseball/softball Biking Motorcycling Jogging Sailing Surfing Swimming Treadmill Weightlifting Hiking LOW INTENSITY

Bowling Golf Horse back riding Scu ba diving Skating Snorke lling Brisk Walking

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Not Permitted

Maybe Permitted

Permitted

Conclusions

References

Long QT syndrome has a large impact on patients and their families on multipl e leve ls. Physicians need to understand the psychologi ca l stress of parents facing the poss ibility of cardiac arrest or sudden cardiac death in the ir children. Physicians should educate patients and their familie on the genotype-specific triggers and encourage them to take an active part in managing this disease. Patients also need to be aware that certain prescribed medications prolong the QT interval putting them at increased risk for cardiac events, and they should be instructed to screen all their future medications against a list of known QT-prolonging drugs (www.qtdmgs.org).

The American Heart Association (AHA) has published recommendations for the management of LQTS. They call for severe exercise restriction as a preventative measure. The premise is based on athletes not using proper judgement in extracting themselves immediately from the physical activity, even upon realization that medical attention may be needed. Due to the unique nature of sports, the AHA consensus statement asserts that cardiac symptoms such as palpitations, fatigue, and dizziness can incorrectly be attributed to the sensations which accompany . . ? mtense exerc1se.-

3. 4.

The AHA recommendations are based on the experience and insights of a panel of experts and by their own admission, are not specifically from scientific evidence. With the negative psychological and physical health effects that exercise restriction can have on patients, it is important for future research to focus on this area, which might serve as a basis for validating or amending the current recommendations. Important areas of research include determining the effectiveness of exercise restriction on the prevention of cardiac events in each LQTS subtype, as well as classifying the degree of QT prolongation that occurs while participating in different sports. This will assist in developing more comprehensive and genotype specific recommendations which may limit the negative iatrogenic effects of LQTS management.

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I 0.

11 .

12.

13.

McAlli ster M, Davies L, Payne K , Nicholls S, Donnai D , MacLeod R. The emotional effects of genetic di seases: Implications for clinical genetics. American Journal of Medical Genetics Part A. 2007; 143A(22):2651-2661. Maron BJ, Chaitman BR, Ackerman MJ et a/. Recommendations for phys ical activity and recreational sports participation for young patients with genetic ca rdi ovascu lar di seases . Circu lat ion. 2004; I 09(22) :2807-2816 . Vohra J. The long QT yndrome. Heart, Lung Circ. 2007; 16:S5-S 12. Farnsworth MM, Fosyth D, Haglund C, Ackerman MJ. When l go in to wake them ... I wonder: Parental perception about congenital long QT syndrome. Journal of the American Academy of Nurse Pract itioners. 2006; 18(6):284-290. Hallal PC , Victora CG, Azevedo MR, Well JCK. Ado lescent physical activity and health - A systema ti c review. Sp011s Medicine. 2006 ;36( 12): l 019-1030. Glass JM, Lyden AK, Byrne-Dugan CJ et a/. Increased symptoms of pain, fatigue, cognitive problems and negative mood after exercise deprivation and sleep restriction are predicted by baseline a utonomic and HP A function . Arthriti s and Rh eumat ism. 2006;54(9):S828. Ussher MH, Owen CG, Cook DG , Whincup PH. The relationship between physical act ivity, sedentary behaviour and psychological we llbei ng adole cents. Social Psychiatry and among Psychiatric Epide mi o logy. 2007;42( I 0):85 1-856. Adlard PA, Cotma n CW. Voluntary exercise protects aga inst stress-induced decreased in brainderived neurotrophi c factor protein expres ion . Neuroscience. 2004; 124( 4 ):985-992. Duche P . Phy ical activ ity and infantile obesity: Tracking, prevention a nd treatment. Science & Spoi1s . 2008;23(6):278-282. Biddle SJH, Gorely T, Sten e l DJ. Healthenhanc ing physica l acti ity and sedentary behaviour in childre n and adol escents. Journal of ports Sciences. 2004;22(8):679-70 I . Me arthy PJ, Jones MY, C lark-Carter D. Understanding enj oyme nt in youth sp011: A deve lopme nta l perspective. Psychology of Sport and Exercise. 2008;9(2): 142- 156. McCai1hy PJ, Jone MY. A qualitative study of sport enj oyment in the sampling years. Sp011 Psyc holog ist. 2007;21 (4 ):400-4 16. Bailey R . Physical ed ucation a nd spot1 in chools: A review of benefi ts and outcomes . Journal of School Health. 2006;76(8):397-40 I .

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FEATURE Genetic Susceptibility in Rheumatoid Arthritis Kimberley Colangelo (Meds 2011) a nd Caleb Zelenietz (Meds 2011) Faculty Reviewer: Dr. j anet Pope Rheumatoid arthritis is a cond ition that causes chroni c infl ammatory arthritis. It has been linked to multiple etio logies; the cause is thought to be a combinati on of the environment, infec ti o n, ho rmones and a genetic component. T he prec ise contri buti on of geneti cs to the deve lopment and course of rheumatoid arthriti s is curren tl y under investigati on , and numerous gene candidates have been identified . The HLA-DR gene has been wide ly studied and numerous a lle les have been identifi ed that correlate to the development of rheum ato id arthritis . The role of geneti cs in rhe umato id arthriti s is expl ored in thi s article.

Background Rheumatoi d arthriti s (RA) is a chro ni c auto immune d isorder w hi ch causes infl ammatory arthritis and occurs in approx imate ly l % of the 1 popul ati on. It freq uentl y presents as periphera l polyarti cul ar arthri ti s, is symmetri ca l, and often progresses wi th j oint damage and loss of fun cti on. T here may be periods of remi ss ion, altho ug h vari ations on this pattern occur. In addition, the extra-arti cular mani festat ion s vary greatly among pati ents . W itho ut treatm ent, it leads to signifi cant defo rmiti es as cartil age and bone are destroyed, so ca ll ed erosive d isease. T he prec ise cause is unknow n, but geneti c pred ispos iti on, the enviro nment, infec ti ons, and ho rmones (potential prec ipitators) are th oug ht to a ll pl ay a ro le. The geneti c component has been the subj ect of much research in recent decades, as RA has been fo und to c luster in fa mili es and occurs more frequentl y in fa mili es with o ther auto immune di so rders. The heritability of RA is estimated to be approx imately 60%, w ith a 122 15% concordance rate amo ng tw ins. Severa l key genes have been targeted as th ey are impli cated in the deve lopment of RA and the course of the di sease. The group of human leukocyte antigen (HLA) genes o n chromosome 6 has been at the fo refront of geneti c research in RA. Certa in a ll e les have been associated w ith an in creased ri k of deve lopin g the di sease and Page I 5 8

predicting its severi ty, and others are invo lved in protecti on fro m RA. The HLA gene products are invo lved in immune fu ncti on, particul arl y coding fo r anti gens expressed on the surface of w hite bl ood ce lls. Many genes as ide fro m the HLA group have been li nked to RA.

Current Research T he HLA regio n in the human genome is one of the most heterogeneou and is frequently in vo lv ing di sease targeted fo r tudies susceptibili ty . For RA , th e HLA-DR fa mily has bee n studied extensive ly. Severa l theori es exist fo r how the HLA mo lecul e could influence the immune ys tem. HLA m o lecul e bind peptides and present th em to receptors on the C D4+ T lymphocyte , so the epito pe assoc iated w ith RA could determine w hi ch peptides bind uccessfull y, th e affinity w ith w hi ch they bind, th e epitope itse lf could be anti geni c, or the epito pe could influence w hi ch T lymphocytes surv ive in the th ymus (i.e. g iving a pro pensity fo r autoreacti ve lymphocytes to surv ive). 1 In the maj o rity of genetica lly -linked cases of RA , a shared epitope at amino ac id pos iti ons 67-74 of HLA-DRB 1 (the beta l subunit of the HLA-DR mo lecul e) has been fo und. H LA-DR4 , one of th e most we ll studi ed s~ems to be assoc iated w ith bo th hi g her ri sk of d1 sease and wo rse prognos i , parti cularl y certain hapl o type w ithin HLA-DR4 such as 0401 .3

Interestingly, some HLA-DR alleles are associated with protection from RA, even counteracting the increased susceptibility when the sister allele was associated with an increased 4 RA risk. These protective HLA-DR all eles have a different conserved seq uence than the so-called shared epitope associated with an increased risk. A well known example is HLA-DRB 1 with the conserved epitope DERAA at positions 70-74 of the amino acid sequence. This allele was not only correlated with a lesser risk of developing RA, but was also linked to a less severe form in people with RA.5 The presence of the HLA alleles with the shared epitope has also been shown to have a high concurrence with the presence of anti-cyclic citrullinated peptide antibodies (anti-CCP), which are used in diagnosing RA. One theory is that the citrullinated peptide binds the HLA shared epitope resulting in activation of T lymphocytes. This may in tum lead to increased autoantibody production that results in the formation of anti-CCP antibodies.6 Anti-CCP is a stronger predictor of radiographic damage in early inflammatory arthritis than Rheumatoid Factor (RF) and is especially useful as a marker in those with negative RF who have RA. However, anti CCP is not sufficiently sensitive to identify all those who will have radiological damage in early inflammatory arthritis. Some important discoveries related to the 7 HLA susceptibi lity region include :

• • •

• •

Having two copies of a susceptibility allele makes a person even more like ly to deve lop RA compared to hav ing on ly one copy Havin g one or two copies of a susceptibility allele makes a person more likely to have severe di sease The combination of alleles present alters th e relative ri sk (i.e DR4/ DR I vs. DR4/X) Presence of the allele may also influence if a person will have extra-articular manifestations The timeline of progress ion of RA is influenced by the alleles present

The HLA-DR genes cannot be the only genetic contribution though, as not all RA patients have the implicated alleles and there is still a wide clinical heterogeneity amongst those that do . It has been estimated through sibship studies that HLA linked genes contribute about 8 30-40% of the genetic component in RA. Numerous other genes have been identified, and the more popular ones are summarized in Table 1. The products of these genes are proteins or molecules that are invo lved in the immune response; as an intracellular signalling molecule, in the fom1ation of antibodies, or in carrier molecules. A physiologic mechani sm through which they contribute to the deve lopment of RA has been postulated for each one. Currently, screening of who le genomes of families where RA is preva lent is being undertaken to poss ibly di scover other genes and better characterize the genes that have been discovered .

Table 1. Summary of genes that confer susceptibility to rheumatoid arthriti Gene Product 9 HLA-DR Encodes cell surface antigens that present protein to the T ly mphocytes STAT4 10 PAD14

Encodes a transcription factor for signals from ce11ain cytokines

Encodes an enzyme that catalyzes peptidyl arg inine to peptidyl ci trulline

N22/PTPN22 II SLC22A4 FCRL3

Encodes intracellul ar tyrosine phosphata e in T and B cells

Encodes for an organic cation transporter

CTLA4/CD 152

Encodes a B-lymphocyte specific membrane molecule 1

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Encodes a protein produced by activated T ce ll s

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The presence and implications of these genes vary widely by ethnic population with respect to rheumatoid arthritis. The prevalence of RA itself differs by ethnic group, for example Native Americans have been reported to have a prevalence as high as 2% whereas Asian 14 populations as low as 0.3 %. In addition, the polymorph isms of the human genome sequence in the alleles that are related to RA vary by ethnic populations, wi th hi gher concordance amongst 15 more close ly rel ated popul ations.

Relevance The key question regarding thi s research is whether it is limited to being an expensive research too l or if it will become relevant to patients and physic ians. Given that many of these alleles are common in the general population, gene screening will not be useful as a screening tool to di scover asymptomatic patients that will develop RA . However, since HLA alleles remain constant over a lifetime, typing may be useful as a predictor of the course of di sease in patients already diagnosed with RA, it can be used to decide which patients will have more severe di sease and who will progress quickly so that aggressive therapy can be initiated. Whether thi s will change outcomes needs to be studied . For now, its value seems limited to research where family members at ri sk for RA are being prospecti ve ly studi ed, particularly those who have already developed anti-CCP or RF .

Conclusions It cannot yet be said what interaction and combination of alleles is neces ary for th e development of RA and for the specifi c phenotypes that are expressed. RF testin g is done to determine who with early inflammatory arthritis will deve lop erosions, but combining RF and HLA may increase the sensitivity and specificity so that early aggressive treatment can be implemented. Since anti-CCP antibodies may have hi gher specificity for the development of RA, the combination of these two components could poss ibly increase the ability to predict the

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development and course of progression of the disease.

References 1.

Harney S, and Woodsworth BP. Genetic epidemiology of rheumatoid arthritis. Tissue Antigens. 2002 D ec;60(6):465-73. 2. MacGregor AJ, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000 Jan ;43( 1):30-7 . 3 . Taneja V, et al. De lineating the role of th e HLADR4 "shared epitope" in su sceptibility versus resistance to deve lop arthritis. 2008 Aug; 18 1(4 ):2869-77 . 4 . van der Helm-va n Mil AH, Hui zinga TW, Schreuder GM, Breed ve ld FC, de Vries RR, Toes RE. An independent role of protective HLA class II alle les in rheumatoid arthritis severity and susceptibility . Arthritis Rheum . 2005 Sep ;52(2);263 7-44. 5 . Carrier N, et al. The DERAA HLA-DR alleles in patients with ea rly polyarthritis. Arthritis Rheum. 2009 Mar;60(3) :698-707. 6 . Auger I, et al. Influe nce of HLA-DR genes on the producti on of rheumatoid arthritis-specific autoantibodies to c itrullinated fibrinogen . Arthritis Rhe um. 2005 Nov ;52( 11 ):3424-32 . 7. Olsen NJ, et al. A sociations of HLA-DR4 with rhe umatoid factor and radiographic severity in arthritis. Am J M ed . 1988 rhe umatoid Feb ;84(2):257 -64. 8. De ig hton CM, Kelly PJ, Walker DJ. Linkage of rh eumatoid arthriti s with HLA. Ann Rhe um Dis. 1993 Sep;52(9) :638-42. 9 . Fries JF, eta/. HLA-DRB l genotype associations in 793 white pa ti e nts from a rhe umatoid arthritis inception co hort: frequency, severity , and trea tme nt bias. Arthritis Rheum . 2002 Sep ;46(9):2320-9 . I 0 . Re mm ers EF, et al. Stat4 and the risk of rh e umatoid arthritis and systemic lupus e1ythema to sus. N E ng l J Med. 2007 Sep;357( l 0):977 -86 . 11 . Pl en~e RM, et al. Re plication of putative ca nd1date-gene associations with rh e uma toid at1hritis in >4000 sa mples from North America and Sweden : as ociation of susceptibility with PTPN22 , CTLA4, and PAD14. Am J Hum Genet. 2005 Dec;77(6): 1044-60. 12 . Tokuhiro S, eta!. An intronic SNP in a RUNX 1 binding site of SLC22A4, encodin g an organic

cation transporter, is as ociated with rh eumato id atihriti s. Na t Genet. 2003 Dec;35(4) :34l-8. 13. Kochi Y, et a!. A fun ctiona l va ri ant in FC RL3 , encodin g Fe recepto r-li ke 3, i a oc iated with rh eumato id arthritis and cveral auto immuniti es. 2005 May;37(5):478-85.

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14. Yamada R, Yamamoto K. M echani ms of di sease: geneti c o f rh eumatoid arthriti s - eth nic difference in di ea e-assoc iated ge nes . Na t C lin Pract Rh eumato l. 2007 Nov;3( I l ):644-50. 15. Mori M, et a/. Ethnic difference in all ele freque ncy of auto imm un e-d isease-as oc iated SN Ps. J Hum Genet. 2005 May ;50(5 ):264-6.

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FEATURE Nuchal Translucency and Prenatal Diagnosis of Congenital Heart Disease: Progress and Future Directions Xiangning Fan (Meds 2010) Fa culty Reviewer: Dr. Eva Welisch N ucha l tran lucency thi cknes is an important compo nent of prenata l screening prog rams, w hi ch ex ist to he lp quanti fy the ri sk of certa in chromosomal and anato mi ca l abnorma liti e in a fetus in utero . Abnormally increased nucha l trans lucency thi ckness has been used as a oft marke r fo r Down's Syndrome and other aneupl oidi es fo r more than a decade. Recentl y, an as oc iati o n has been identifi ed between increased nucha l translucency thi cknes and congenita l heart di sease, rais in g the possi bili ty that nuchal trans lucency thi ckne s may he lp identi fy affec ted fe tuses as earl y as 11-1 4 wee ks gestati on. However, the pathophys iologica l mechani sm whi ch produces an abnorma l nu cha l tran lucency thi ckness in the fetus is no t we ll understood and an abnorma l measurement is not spec ifi ca ll y a oc iated w ith any one type of le ion. Therefore, nucha l trans lucency thi ckness cannot be used for di agno i of congenital heart di ea e in utero, but may be very he lpfu l in identi fy ing fe tuses at ri sk, w hi ch may he lp improve diagnosti c accuracy and direct resource-effi c ient u e of diagnosti c meth od such as fetal echocardi ography.

Introduction A lthough it has lo ng been the ho ly grail of prenata l care to be abl e to ass ure every woman a hea lthy in fa nt at term, 2-3% of infa nts are born w ith at lea t o ne anatom ica l deformi ty. The congenital heart di sease are co ll ecti ve ly the most comm on congenita l defects, with a combin ed inc idence estimated at app rox imate ly l/ 100 at term, and hi g her in th e prenatal popul ati on. 1 Ca rdi ac les ions may occur in iso latio n, or altern ate ly a part of a ge neti c yndro me. Even in iso lated cases, th ere appea r to be a genetic, likely multi fac tori a l, compo nent to the ir eti o logy. They range from inc identa l findin gs of no g rea t fun ctional signifi cance (e.g. small atri a l septal defect ) to les io ns w hi c h, if left untreated, are immedi ate ly life-threatening to the neonate (e.g. transpos iti o n of the great arteri es). Stru ctural hea rt defects a re tho ught to contribute to up to 20% of a ll neonata l death s and up to 50% of all 2 in fa nt dea th . Recentl y, attenti o n has foc used on th e utili ty of ultraso und mea urement of the free fluid behind th e neck of the fe tus- te rmed the " nucha l

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trans lucency" (NT)- in predi cting congenital heart di ea e in th e fe tu . It has been suggested that the ub et of fe tuse w ith abno rmal N T measurement i at increased ri sk for congenital hea rt defect ; therefore the N T thi ckness may be of u e in prenata l di agno is of congenita l heart di ea e.

What is Nuchal Translucency? The NT mea urement is a measure ment of the thi cknes of th e free fluid layer behind the feta l neck. Thi is meas ured by ultrasonography between I I and 14 weeks gestati o n. There are stri ct cri te ri a to establi h an ultra ound imaae a 0 adequate fo r the assess ment of nuc ha l tran lu cency and the no rma l limit to the measurement is dependent upon gestationa l age. The NT measurement was first suggested as a soft marker for feta l aneupl o idy by Ni co la ides and co ll eagues in 1994, and thi s assoc iati o n wa la ter confim1ed by o ther researchers. 3-6 It is now known that the nucha l trans lucency mea urement i 77% ensiti ve and 95% specifi c for D ow n ' Syndrome/Tri o my 2 1, the most common of the

three autosom al aneuplo idies that are compatible with li fe. 4 However, the NT measurement is also assoc iated w ith a host of other abnormaliti es in the fe tus. Even in chromo omall y normal fetuses, increas ing NT is associated with adverse fe tal outcome .7•8 Bila rdo and co ll eagues report that up to 20% of chromosomall y normal fe tuses with increased NT experi enced an adverse outcome, defin ed as mi carri age, intrauter1ne death , parental cho ice to terminate the pregnancy, or one or mo re structura l or geneti c di sorders in the fe tus. Of the 86 adverse outcomes, 14 (1 6% ) were pregnancy termina ti ons. The likelihood of adverse outcome appeared to correlate w ith increasing degrees of NT abnormality.8

Nuchal Translucency and Congenital Heart Disease Recently, in both euploid 9 - 12 and aneupl oid 13- 16 fe tuses, an abnonna ll y elevated NT measurement has been described in assoc iati on with congenita l heart di sea e in th e fetus. There is increas ing ri sk of cardi ac les ions as the NT 12 become progress ive ly more abn ormal. Ghi and co lleague report the overa ll incidence of major cardiac defects to be 4.5% in fe tuses with NT above 2.5 mm , w ith 7% incidence in fetuses w ith nuchal translucency thi c kness equal to or greater than 3.5 mm. 12 They s uggest that abnorma l NT may be more of a ri sk fac tor for maj or congenita l cardi ac le ions than maternal di abetes, pos iti ve fa mil y hi story of congenital hea rt di sease o r exposure to teratogeni c agents, and that therefore fe tal echocardi ography is indi ca ted fo r all fe tuses At a NT with elevated NT mea urements. 111 thi ckne s at or above 3.5 mm (roughly th e 99 percentile), maj or cardiac anomali es appea r to be present in 5-10% of screen-pos iti ve fe tuses. 12• 17- 19 11 Hyett and colleagues propose a cutoff of 111 111 between the 95 -99 percentil e as the optimum point to 1mt1ate referra l fo r fe ta l echocardiography. Hyett suggests the nucha l translucency measurement could contribute to the detection of approximately 30% of all cases of 19 congenital heart defects.

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Prev io usly, Hyett and co ll eagu es have suggested that th e nuchal tran lucency measuremen t may be related to fai lure of the feta l heart ra ther than to the d irect effects of ane uploidy. As card iac lesions are seen in many of the genetic syndro mes, this is certainly a pl a usibl e expl anatio n for the close assoc iati o n seen between in creased nuchal translucency, a neuplo id conditi ons and congenital heart d isease . However, thi s interpre tation is by no means 20 2 1 unanimou ly accepted, and mu ltipl e authors • report that the degree of NT abnorma lity is not spec ifica ll y assoc iated w ith any parti cul ar heart 21 report that les ion. Makrydima a nd co lleague there is consid erabl e overl ap between th e average NT measure ment fo r di ffe rent ca rdi ac le ions and the identity of the les ion; thus, the NT measurement is not helpfu l fo r the specific di agnos is of fe tal congenital heart di sease except to indi cate th at a cardi ac lesion may be present. T he unde rl ying path ophys iology remain unclear, and alternate expl anati ons for th e elevated NT in ca es of congenital heart di sease include venous congesti on in th e head and neck of th e fe tu s, abn orn1ali ties of lymphatic drainage , altered of subcutaneo us ti ssue, d istr1buti on g lycosaminoglyca n and proteoglycan accumul ati on, fe ta l anemi a and/or decrea ed fe ta l ..,.., 23 c . movement.--· T heretore, the NT may mdeed identi fy fe tuse w ho are at increased r1 sk of congenital heart defects so that these can be referred on fo r more spec ia li zed di agnostic testing However, in (e.g. fe ta l echocardi ography) . iso lati on, it doe not appear to be sen itive or pec ific eno ugh to be a d iagnosti c te t fo r . I heart d.1sease. 17 congemta 24

Mo f has uggested that relying on nuchal translucency to identi fy fe tuses w ith Down' s Syndrome may in fact preferentially identi fy fe tuses in w hom there is an as oc iated cardiac defect. G iven the re lati ve incidence of congenital heart d isease ( l/ 100) and Down's syndrome ( l/800-l 000 overa ll ) 25.26 , the NT measurement may in fact pi ck up more babi es w ith congenital heart d isease w ho incidenta ll y have Down's syndro me th an bab ies wi th Down' s syndrome w ho have an assoc iated cardi ac defect.

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The clinical implications of this finding are less clear. It could be argued that, even if increased NT is a marker for congenital heart disease in the fetus, it is not useful clinically as it is a standa rd of care to offer all pregnant women (regardl ess of NT meas urement) a morphological ultrasound scan at L8-20 weeks during which structu ral cardiac les ions can be identified. The current recommendation is a four-chamber view of the heart and imaging of the ve ntri cular outflow tracts in an attempt to identify major 27 anomalies. However, it has been previous ly noted in population studi es of prenata l patients that morphological echocardiograph y JS dependent upon the ex perti se of th e ultraso nographer and consequentl y an inexperienced one may mi ss a signifi cant proportion of major cardiac defects .28 路29 In their tudy, Hyett and co lleagues'' report abnormal NT mea urement in 55 % of fetuses w ith major congenital heart disease, compared to an ab no rma l four chamber view on prenata l ultrasound in 26% of those same babies. The 26% detection rate in that study was consistent 2 w ith pri or estimates. Wald and colleagues have suggested, based on a meta-ana ly is of studies of the utility of nuchal trans lucency measurements and congen ita l heart disea e, a detection rate of 52% and a fa lse- po itive rate of 5% us ing a screenin g cutoff of L. 7 multipl es of the median .30 This is greater than that ac hi eved using a four chamber view alone, and, therefore, the nucha l trans lucency shows great pro mi se as a potenti al screen in g tool for congenita l heart di sease which can he lp direct ap propri ate and resource-effi c ient use of fetal echocardi ograp hy.

normal chromosomes. Routine measurement of the nuchal translucency shows great promise in helping to identify fetuses at increased risk of congenital heart disease, and therefore may help direct resource-efficient use of fetal echocardiography. However, by itself, i~crease_d nuchal translucency does not predict the d~agnos1s of a specific type of cardiac defect in the fetus .

References l.

Summary N uchal trans lucency is typically mea ured at LL-14 weeks as part of prenata l screening programs in order to he lp estimate materna l ri sk of bearing a child with aneuploid y or neura l tube defects. In recent years, an assoc iati on has been demonstrated between abnormally e levated nuchal translucency and a gro up of structura l, geneti c and chromosomal abnormaliti es in the deve lo ping fetus, including the congenital heart di seases, as well as poorer pregnancy outcomes for the fetus, and thi s is een even in fetu ses with

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Hoffman JI. Inc idence of congenital hea11 disease: II . Prenata l incid nee. Pediatr Cardiol. 1995; 16: 155-1 65. Yogel S, Cohen SM, Achiron R. Examination of th e fetal heart by five short-axis views: a proposed screening method for comprehensive cardi ac eva luat ion. Ultrasound Obstet G ynecol. 200 1;17:367-369 . Nicolaides KH, Brizot ML, Snijders RJM. Fetal nuchal tran slucency: ultra ound screening for fetal tri omy in the first trimester of pregnancy. Br J Obstet Gynaecol. 1994; 101 :782-7 86. Pandya PP, Snijders RJM, Johnson SP, De Lourdes Brizot M, Nicolaide KH. Screening for fetal tri omie by maternal age and fetal nuchal at 10- 14 weeks of tran lucency thickne gesta ti on. Br J Obstet Gynaeco l. 1995 ; 102:957962 . Hack haw K, Wa ld J, Haddow JE. Down 's sy ndrome creening wit h nu chal tran lucency. Lancet. 1996;34 : I 740. Snijders RIM, Noble P, Seb ire N, Souka A, Nicolaide KH . UK multicentre proj ect on th e a sessment of ri k of tri omy 2 1 by maternal age and fetal nucha l-tran luce ncy thickness at l 0-14 week of gesta ti on. Lancet. 1998;35 1:343 -346. ouka AP, Kramp) E, Bakali S, Heath V, Nico laide KH. O utcome of pregnancy in c hromosoma ly norma l fetu es with increased nuchal translucency in the first trimester. Ultrasound Ob tet Gy neco l. 200 1;18:9-17. Bil ardo CM, Muller MA, Pajk11 E, C lur SA, va n Zalen MM, Bijlsma EK. Increased nuchal t~ans lu ce ncy thi ck11e s and nonnal karyotype : ttme for parental reass urance. Ultrasound Obstet Gynecol. 2007 ;30: 11 - 18. Hyett _JA, Mosco o G, Papapa nag iotou G, Perdu M , Ntcolatde KH . Ab norm alities of the heat1 and great arterie in c hromoso mall y normal fe~ es with increa ed nuchal translucency thtckn ess at I 1- 13 weeks of gestation . Ultrasound Ob tet Gynecol. 1996;7:245-250.

10. Hafner E, Schuchter K, Li ebhart E, Philipp K. Res ults of routine fetal nuchal translucency mea urement at weeks 10- 13 in 4233 unse lected pregnant women. Prenat Diagn. 1998; 18:29-34. 11 . Hyett 1, Perdu M , Sharland G, Snijders R, Nicolaides KH. Using fetal nuchal translucency to screen for major congenital cardiac defects at 10-14 weeks o f ges tation : a population based cohort study. BMJ. 1999;3 18:8 1-85. 12. Ghi T, Huggon IC, Zosmer N, Nicolaides KH. Incidence of major structural ca rdiac defects associated with increased nuchal trans luency but normal karyotype. Ultrasound Obstet Gynecol. 2002; 18: 610-614. 13. Hyett 1, Moscoso G , Nicolaides KH. Increased nuchal translucency m trisomy 2 1 fetuses: relationship to natTow ing of the aortic isthmus. Hum Rep rod . 1995 ; 10:3049-3051. 14. Hyett 1A, Moscoso G , Nicolaides KH. Cardi ac defects in l s1-trimeste r fetu es w ith trisomy 18. Fetal Diagn Ther. 1995 ; 10:38 1-386. 15 . Hyett 1A, Moscoso G , Nicolaides KH. First trimester nuchal trans lucency and cardi ac defects in fetuses with tri somy 2 1. Am J Obstet Gynecol. 199 5; 172: 1411-141 3. 16. Hyett 1, Moscoso G , Nicolaides KH . Abnormalities of th e heart and great arteri es in first trimester chromsomally abnormal fetuses. Am 1 M ed G enet. 1997; 172 : 1411-141 3. 17. Macrides E, Cobi a n-Sanchez F, Tekay A, Moscoso G , Campbell S, Thilaganathan B, Carvalho JS . Limitations of using first-trimester nuchal translucency meas urements m routin e screemng for IJlaJor congenital heart defects. Ultrasound Obstet Gy necol. 2001 ; 17: 106-110. 18. Galindo A, Comas C , M artinez JM, Guti errezLarraya F, Carrera JM, Puerto B, Borrell A, Mmtera C, de la Fuente P . Cardiac defects in chromosomally norma l fetuses with increa ed nuchal translucency a t I 0-14 weeks o f gestation . 1 Matern Feta l Neonatal Med. 2003; 13: 163 -1 70. 19. Hyett 1A. Does nuchal translucency have a ro le m fetal cardiac screenin g? Prenat Diagn. 2004;24 :1130-11 35. 20. Simpson JM, Sharland GK. Nuchal translucency and congenital heart di sease: heart failure or not? Ultrasound Obstet Gynecol. 2000 ; 16:30-26.

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2 1. Makrydimas G , Sotiriadi A, Huggon IC, Simpson J, Sharl and G , Ca rva lho JS , Da ube ney PE, Joa nnidis JP A. N ucha l tra ns lucency a nd fetal cardi ac defects: a poo led a naly is of maj o r fe ta l echoca rdi ograph y centers. A m J O bstet Gyneco l. 2005; 192 :89-95. 22 . Nicola ides KH, Heath Y, C icero S. Inc reased fetal nucha l translucency at ll - 14 weeks. Prenat Di agn. 2002;22:3 08- 15. 23 . von Ka isenberg CS, Prols F, Nico laides KH, Maass N , Meinho ld-Heerlein I, Brand-Saberi B. G lycosa minog lycans and proteoglycans 111 the skin of a neupl oi d fetuses w ith increased nuchal Huma n Reprod . 2003; 18:2544translucency . 256 1. 24 . Mol BWJ . Down's syndrome, cardi ac anoma li es and nucha l translucency. BMJ. 1999;3 18: 70- 7 1. 25 . Weij erman M E, van Furth AM, Yonk Noordegraaf A, va n Wouwe JP, Broers C1, Gemke R1. Preva lence, neonatal characteri sti cs and first-yea r mmtali ty of Dow n syndrome : a nation al study. J Pedi atr. 2008; 152: 15-1 9. 26 . Collins VR, Muggli EE, Riley M , Palma S, Halliday JL. Is Dow n syndrome a disappearing birth defect? J Pedi atr. 2008; 152:20-24. 27. ACOG Practice Bulletin No. 98 . Ultrasonograph y in pregnancy . Obstet Gynecol. 2008; 1 12:95 1-96 1. 28. Tegnander E, Eik-Ness SH, Jo hansen OJ, Linker DT. Prenatal detection of heat1 defects at th e routine fetal examination at 18 weeks in a nonselected population. U ltrasound Obstet Gy neco l. 1995 ;5:372 -380. 29 . C hew C , Halliday JL, Ril ey MM, Penny OJ. Popula tion-based study of antenatal detecti on of congenital heart di sea e by ultrasound examinati on. Ultrasound Obstet Gynecol. 2007 ;29:6 19-624 . 30. Wald NJ , Morri s JK, Walker K, Simpson JM. Prenata l screenin g fo r se ri ous congenital heart defects usmg nucha l tran lucency : a metaanalys is. Prenat Diagn. 2008;28: 1094-1104.

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FEATURE The Legacy of a Life Lived: Trans-Generational Epigenetics and Cancer Development Mark Kirchhof(Meds 2 00 9) Fa culty Reviewer: Departm ent of Pathology, UWO Your grandfa ther smoked everyday, your mother was stressed w hil e pregna nt, your fa ther w orked in the petroc hemi ca l industry, sho ul d any of thi s matter to yo u? Ev ide nce is emerg ing that the li ves we li ve affect us fa r beyond the boundaries of our own body and can reach we ll into the li ves of fu ture gene rations. T hese lingeri ng traces of li ves li ved mani fes t themse lves in changes to the D NA of o ur cells, commonly referred to as epi geneti cs. E pi geneti cs is defi ned as inheritabl e changes in gene express ion that don ' t a lter the ac tual DNA equence itse lf, most commonl y mediated by DNA meth ylation and/o r hi stone m ethy lation o r acetylati on. In thi s paper, we w ill di scuss some of the epi geneti c changes that have been associated with the deve lopment of di sease w ith spec ifi c foc us on the deve lo pment of cancer. Moreover, we w ill look at environmental ex posures in current generati ons that may affect ca ncer developme nt in future generati o ns. We may mere ly be guardi ans of our DNA fo r future generati ons, and perhaps the impact of the way we treat our bodies should now be examined in thi s new li ght. M y parents are childre n of World War ll. Th ey grew up a mongst the bo mbings, death and destructi on. T heir li ves were foreve r changed by these experi ences at a leve l far deeper than one would expect. Beyond the psycho logica l, emoti onal or physica l impact of th ose ex peri ences, those mo me nts wo uld fo rever c hange th eir DNA . Such are the findin gs of Dr. Yehuda, who fo und that traumati c events ca n permane ntl y alter the ex press ion of th e tres 1 ho rmone, corti so l. Yehuda fo und that childre n of mothers who suffe red psycho log ica l trauma from th e events of WWll had children who had lower leve ls of corti sol producti o n.:! T hi s change in the offspring re lated to mate rn a l be hav iour or ex pe ri ences has been linked to changes w ithin the D NA of th e child ren. T hese changes are refenÂˇed to as e pigene ti cs, w hi c h is defin ed as inheritabl e c hanges in gene express io n th at do n ' t alte r the ac tua l DN A seque nce itse lr_3 ln thi s arti cle, we w ill expl ore th e re lati o n hip between the environment, epi geneti cs a nd cancer. Th ere are two maj o r moda liti es by whi c h DNA can be altered to change the expres ion of a pa rti cul ar gene: th e meth y lati on of DNA a nd Page I 66

modifi cation of hi stones . T he me thy lation of DNA invo lve the additi on of methy l groups to the cytos ine bases in the C pG do ma ins.4 Âˇ5 The modifi cati on of hi stones is the o ther major epige neti c regulatory mechani sm . T he more tightly the DNA is wrapped around the hi stone compl ex, th e lower th e ex press io n of th e genes coded on that p1 ece of DNA . Hi stone modi fica ti on invo lves th e meth y lati o n o r acety lati on of amin o ac id suc h as lys ine, a rg inine and serin e. Hi tone ace ty la ti o n gene rally results in the loosening of the a soc iati on be twee n the DN A a nd th e hi tone, a ll ow ing fo r increased gene 67 expre sion. ; T he effects of hi sto ne me th y lati on are mo re va ri abl e and can res ults in the increase or decrease in gene ex pre sio n de pe nding on whi c h res idues are modi fie d a nd w here w ithin the hi sto ne protein the modifi cati on ta kes place .6 â&#x20AC;˘7 Epi geneti c changes have lon o been assoc iated w ith cancer. T he fi rst maj o rb findin g was that the DNA of cancerous ce lls wa g loba lly 8 hypo me th ylated . In additi on, the degree of hypo meth y lati on of the DN A seem ed to corre la te with th e aggress ivene s a nd prognos i of a 49 parti c ul ar cancer. ' There is some debate a to the

effects of DNA hypomethylation, but several theories have garnered attention. These include the idea that hypomethylated DNA is more unstable and thus leads to deletion s and translocations, potentially creating truncated genes or genes that have different promoter 10 elements. Other theories are based on the observation that imprinted DNA, that is selective DNA methylation to inactivate the expression of either a maternal or paternal allele, is di srupted in 3 11 cancer cells. ' Therefore, hypomethylated DNA may correspond to the disruption of genomic imprinting. As an example, it is known that the loss of imprinting of the insulin-like growth factor . a ns . k 1actor c. c. gene IS 10r co Iorecta I cancer. 1 2- 1 c~ The other major epigenetic mechanism that has been found to be prevalent in cancer cells is the inactivation of tumour-suppressor genes. 6 Tumour-suppressor genes prevent the progression of cancerous cells and some of their functions have been related to the inhibition of cell di vision, the initiation of apoptosis and the mediation of cell adhesion. 4 -6 Hypermethylation in the promoter regions of tumour-suppressor genes is one of the major steps required for the transformation from benign to malignant Two well known genes, the retionoblastoma tumoursuppressor gene (Rb) and the breast cancer susceptibility gene 1 (BRCAl) are examples of genes that have hypermethylated promoter 15 16 regions in cancerous cells. • The inactivation of tumour-suppressor genes by hypoacetylation and hypermethylation of hi stones have been associated with colon cancer, prostate cancer, 12 17 liver and breast cancer. 6 ' ' The question now concerns why these changes arise and how they result in cancer. W e are all familiar with the concepts of nature and nuture intersecting to result in the genetic changes required to initiate the transformation into For example, lung cancer cancerous cells. requires a genetic predisposition on top of an environmental factor, commonly smoking. Research has shown that exposure to cigarette smoke can induce the hypermethylation of BRCA l/BRCA2 and XRCC, all tumoursuppressor genes, as well as the hypomethylation . oncogene, SNC G . 18, 19 Other of the pro-metastatic

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exampl es of environme ntal agents that induce cha nges to the ep igenome res ulting in increased inc idence of cancer include aniline dyes and bladder cancer, so lar UV radiation and skin cancer, and a lfatox ins found in the soi l and on plants and li ver ca ncer. :!0-22 We are a ll aware of thi s direct link between an env ironmenta l factor and the deve lopment of cancer. But what of the offspring of a person exposed to these environmental agents, are they ultimately at risk as well? Exposure to environmenta l toxins has been shown to increase the transgenerational risk of di seases, in cluding cancer. One of the most widely studied toxins is vinc lozo lin, which is an anti- androgenic compound used as a fungicide in the fruit industry.23 Transient exposure of gestating rats to vinclozolin leads to a variety of diseases in offspring up to four generations later, including tumour deve lopment, pros tate disease, kidney di sease, immune abnormalities and defects 24 in sperm formation ? 3• Bi spheno l A is perhaps the most well known endocrine di srupte r believed to change the epigenome. Bisphe nol A is an organic compound that, until recently, could be found in many baby bottles, baby and children's toys, and in the epoxy resins that coat a lmost 1? 14 every c.tOO d an d beverage can .-?Q ·--·Neonata l exposure to bisphenol A has bee n show n to a lter the methylation status of a variety of genes and result in cellular tran sformations th at promote the development of pro tate cancer. 25 Prenatal exposure to bispheno l A has been linked w ith a n ri k of breast cancer via increased 26 hypomethylation. Whil e the temporal effects of bisphenol A have been shown in the first generation, furth e r studi es are required to determine if changes are transmitted to sub equent generations. Other links have emerged betwee n environmental tox ins and cancer including the transgenerational effects of alcoho l leadin g to colon cancer and benzene leading to . Ieu k em1.a.27,28 A s th e researc h mto ep1.genetics grows, we will undoubted ly continue to see an ex pansion of the environmental agent that can alter the epigenome. The relation ship between nutrition, epigenetics and the di sease processes warrants

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further considerati on. One of first multigenerati ona l epi geneti c studies was done in Sweden, where pari sh registri es and harvest records were u ed to link di sease in generations after feasts or fa mines. 29 ,3 ° These studies found that if a paterna l grandfather experienced a surplus of foo d before th e onset of puberty, the grandc hild had a fo ur-fo ld increased chance of dying from compli cati ons of di abetes. 29 •30 Interesti ngly, the chil dren of moth ers who experienced ab unda nce of foo d before the onset of puberty had ch il dren who were pro tected from d i ea e re lated to d iabetes.29 · 0 In terms of cancer research, ev idence is emerging that links nutrition, epigenome status and cancer deve lopment. xcessive materna l weight ga in d uring pregnancy leads to increased ri sks of 31 breast cancer in th e chil d. In additi on, the nutritiona l con tent of th e di et has been shown to be important in deve loping and maintaining the epi genome. pec ifi ca ll y, the ava il abili ty of meth yl donors, including fo late, cho lin e and methi onin e seem to be important in preventin g di ea e.32 •33 In rat mode ls, decreased ava ilability of meth yl do nor has been shown to induce the deve lopment of li ver cance r, even in th e absence of any known carcin ogens.33 In th e ago uti mouse model , di etary suppl ementa ti on in utero with fo li c ac id, vitam in B 12, cho line, beta ine and zinc was assoc iated with a lowe r ri sk of cancer, diabetes and obes ity and an increased life ex pectancy. H 35 Low prote in di ets in utero a l o seem to affect DNA meth y lati on and di sease m offspring, leadi ng to increased susceptibili ty to d1.a betes, hyperten .ton and ca ncer. 3 1·36

epi genetics is the histone deacetylase (HDAC) inhibitors. These drugs have been fou~d ~o induce cell-cycle arrest and apopt~s1s ~n vitro."·37,4l,.n Suberoylanilide hydroxam1c ac1d (Vorinostat) is th e first HDAC inhibitor approved for the treatment of cancer, specifically cutaneous T-cell lymphoma. 4 1•42 While these drugs have been approved, they lack specificity for _cell ~pe which may lead to unintended effects, mcludmg th e express ion of previously silenced oncogenes. As w ith any cancer therapeutic, the eventual goal w ill be to deve lop agents that target only cancerous ce lls, sparing normal ti ssue and cells. If the las t century be longed to DNA and the genome, thi s century w ill surely belong to epigenetics and the epi genome. We are slowly di scovering that the epi genome is an important pl ayer in th e deve lopm ent of di sease. What has co me as a urpri e is the degree to which the epi genome i influenced by the environment, by everything from drugs, tox ins to vitamins and calori c intake. Even more astonishing is the emerg ing data indi cating that what we experience in our li ves w ill ultimately influence the lives of our children and perhap even their children. In effect, we are th e guardi ans of our genes and need to wa tch over th em o th at we may pass them on in the be t conditi on we ca n.

References I.

S in ce epi ge neti c changes to the DNA are reversibl e, it prov ides the perfec t target for ca ncer th erapi es. A lready, we are see ing th e emergence of therapi es th at are based on a ltering DN A meth y lati on and hi stone acetylati on.37 ln parti cul ar, in vitro ev idence using DNA demeth ylating dmgs and the ability to re-ex press tumour suppressor genes has lead to the deve lopment of clini cal thera pi es. T wo DNA demeth ylatin g drugs, 5-azacytidine (Y idaza) and 5-aza-2'-deoxycytidine (Dec itabine), have been approved for th e treatment of mye lodys pl as ti c 38 syndrome and leukemi a. -4° The other maj or class of drugs deve loped on th e principl es of Page I 68

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Ye huda R, Bie rer LM. T ran generational tran mi sion of co rti o l and PTSD ri sk. Prog Bra in Re . 2008; 167 : 12 1-35. Ye hud a R, Be ll A, Bi erer LM, Schrne idl er J. M atem a l, not patem a l, PTSD i re lated to increa ed ri sk fo r PTSD in o ffspring ofHoloca u t urv ivo r . J.P yc hi atr.Res. 2008. Ji ang YH, Bress ler J, Beaud et AL. Epi genetics and hum an di sease . Annu Rev G enomics Hum Genet. 2004;5 :4 79-5 10. Este ll er M. Epi ge neti cs in ca ncer. N En gl J Med . 2008;358: I 148-59. Este ll er M . C pG is land hy permethy lation and tu~1o r t~ppres o r genes: a booming present, a bn ghter tuture. O ncogene. 2002;2 1:5427-40. Bac hm an K.E, Park BH, Rh ee I, Raj agopalan H , Herman JG, Bay lin S B e / a /. Hi ston e modifi cati o n and silenc ing pri o r to DNA

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methylation of a tumor suppressor gene. Cancer Cell. 2003;3:89-95. Kouzarides T. Chromatin modifications and their function . Cell. 2007; 128:693-705. Feinberg AP, Vogelstein B. Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 1983 ;3 01:8992. Herranz M , Esteller M. DNA methylation and histone modifications m patients with cancer: potential prognostic and therapeutic targets. Methods Mol Biol. 2007;361:25-62. Eden A, Gaudet F, Waghmare A, Jaenisch R. Chromosomal instability and tumors promoted by DNA hypomethylation. Science 2003;300:455. Feinberg AP, Tycko B. The hi story of cancer epigenetics. Nat Rev Cancer. 2004;4: 143-53. Cui R Cruz-CotTea M, Giardiello FM, Hutcheon OF, Kafonek DR, Brandenburg S et al. Loss of IGF2 imprinting: a potential marker of colorectal cancer risk. Science. 2003 ;299: 1753-5. Kaneda A, Feinberg AP. Loss of imprinting of IGF2: a common epigenetic modifier of intestinal tumor risk. Cancer Res. 2005;65: 11236-40. Cruz-Correa M, Cui H, Giardiello FM, Powe NR, Hylind L, Robinson A et al. Loss of imprinting of insulin growth factor II gene: a potential heritable biomarker for colon neoplasia predisposition. Gastroenterology. 2004; 126:964-70. Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E et al. Promoter hypermethylation and BRCA1 inactivation m sporadic breast and ovarian tumors. J.Natl.Cancer Inst. 2000;92:564-9. Sakai T, Toguchida J, Ohtani N, Yandell DW, Rapapmt JM, Dryja TP . Allele-specific hypermethylation of the retinoblastoma tumorsuppressor gene . Am.J.Hum.Genet. 1991 ;48:8808. Greger V, Passarge E, Hopping W, Messmer E, Horsthernke B. Epigenetic changes may contribute to the fotmation and spontaneous regresswn of retinoblastoma. Hum.Genet. 1989;83 : 155-8 . Lee MN, Tseng RC, Hsu HS , Chen JY, Tzao C, Ho WL et a!. Epigenetic inactivation of the chromosomal stability control genes BRCA l, BRCA2, and XRCC5 111 non-small cell lung cancer. Clin.Cancer Res. 2007; 13:832-8. Liu H, Zhou Y, Boggs SE, Belinsky SA, Liu J. Cigarette smoke induces demethylation of prometastatic oncogene synuclein-gamma in lung cancer cells by downregulation of DNMT3B. Oncogene. 2007;26:5900-10.

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20. Heindel JJ. The fetal basis of adult disease: Role of environmental expos ures-- introduction. Birth Defects Res A Clin Mol Teratol. 2005;73:131-2. 21. Herceg Z. Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors. Mutagenesis. 2007 ;22:9 1-103. 22. Weidman JR, Dolinoy DC, Murphy SK, Jirtle RL. Cancer susceptibility: epigenetic manifestation of environmenta l exposures. Cancer J. 2007; 13 :9-16. 23. Anway MD, Leathers C, Skinner MK. Endocrine di sruptor vinclozo lin induced epigenetic transgenerational ad ult-onset disease. Endocrinology. 2006; 14 7:5515-23. 24. Anway MD, Skinner MK. Ep igenetic transgenerational actions of endocri ne disruptors. Endocrinology 2006; l47 :S43 -S49 . 25. Ho SM, Tang WY, Belmonte dF, Prins GS. Developmental exposure to estradiol and bi sphenol A increases susceptibility to prostate carcinogenesis and epigenetica lly regulates phosphodiesterase type 4 variant 4 . Cancer Res. 2006;66:5624-32 . 26. Dolinoy DC, Huang D, Jirtle RL . Maternal nutrient supplementation counteracts bisphenol A-induced DNA hypomethy lation m early development. Proc Natl Acad Sci U.S.A. 2007; l 04: 13056-61. 27. Bollati V, Baccarelli A, Hou L, Bonzini M , Fustinoni S, Cavallo D et al. C hanges in DNA methylation patterns in subjects exposed to lowdose benzene. Cancer Res. 2007 ;67:876-80. 28. Ross SA. Diet and DNA methylation interactions 111 cancer prevention. Ann N .Y. Acad Sci . 2003 ;983: 197-207. 29. Kaati G, Bygren LO , Edvinsson S. Cardiovascular and diabetes mmtality dete1mined by nutrition durin g parents' and grandparents' slow growth period . Eur J Hum Genet. 2002; 10:682-8 . 30. Kaati G, Bygren LO , Pembrey M , Sjostrom M. Transgenerational response to nutrition, early life circumstances and longev ity. Eur J Hum Genet. 2007;15:784-90. 31. Bertram C, Trowern AR, Cop in N , Jackson AA, Whorwood CB. The maternal diet durino-o pregnancy program s altered expression of the glucocorticoid receptor and type 2 11 betahydroxysteroid dehydrogenase: potential molecular mechanisms underlying the of hypertension 111 utero. programming Endocrinology. 2001; 142:284 1-53 . 32. Cooney CA, Dave AA, Wolff GL. Maternal methyl supplements m m1ce affect epigenetic

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38. Oki Y, Aoki E, Issa JP . Decitabine--bedside to bench. Crit Rev.Oncol.Hematol. 2007;61: 140-52. 39. Oki Y, Jelinek J, Shen L, Kantarjian HM, lssa JP. Induction of hypomethy1ation and molecular response after decitabine therapy in p~tients with chronic myelomonocytic leukerrua. Blood 2008 ; 111:23 82-4. 40. Kantarjian H, Oki Y, Garcia-Manero G, Huang X, O'brien S, Cortes J et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007 ;109:52-7 . 41 . Marks PA, Breslow R. Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug. Nat.Biotechnol. 2007 ;25:84-90. 42. Rosato RR, Grant S. Histone deacetylase inhibitors in cancer therapy. Cancer Biol.Ther. 2003;2:30-7.

FEATURE Amish, Mennonite and Hutterite Genetic Disorder Database Michael Payne (Meds 201 OJ Faculty Reviewers: Dr. C. Anthony Rupar and Dr. Victoria Mok Siu Clinical Example A newborn baby girl presented with bowel obstruction. The possibility of cystic fibrosis was raised, particularly since there was a positive family history of cystic fibrosis in a deceased relative. CFTR mutation ana lysis was ordered using a panel that included .6.F508 and 28 other common mutations which account for 85% of al l CF mutations. The results were negative for all mutations in the screening panel. Since the parents were members of the Old Order Am ish community, the Amish, Mennonite and Hutterite Genetic Disorder Database was accessed via the Internet and it was determined that a specific mutation (3905 ins T) had been described in the Old Order Amish. Further DNA testing confirmed that the baby was homozygous for the 3905 ins T mutation. Although the sweat ch loride test is the go ld standard for cystic fibrosis testing, it can be difficult to obtain suffic ient sweat vo lume 1 collection in the newborn period. Correct diagnosis of newborns with CF through mutation ana lysis is important as this will help direct therapies and improve overall outcomes. 2 This case illustrates the usefulness of the Amish, Mennonite and Hutterite Genetic Disorder Database as it a ll ows medical professionals to identify genetic disorders and specific mutations which otherwise may be rare in the North American general population.

Introduction The Amish, Mennonite, and Hutterite Genetic Disorder Database was created in

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response to a paucity of resources for Canadian medical practitioners who treat ''Plain People." The database focuses on genetic diseases which are found with higher prevalence in these groups due to their unique cultural history. The database can be viewed at: http ://www.biochemgenetics.ca/plainpeople/

Common Backgro und The Amish, Mennonite and Hutterite populations share some similarities. They all arose in Europe during the Protestant Reformation 1 in the 16 h century. 3 In contrast to other Protestants and Catholics, they are Anabaptists, believing that chi ldren shou ld not be baptized at birth, but instead at an age when they can make a consciou decision to join the church. They also believe in the separation of church and state. These views were seen as heretical and led to their persecution in Europe by the Protestant and Catholic majority. The Anabaptists are a lso pacifists who do not engage in war and believe in segregating themselves from the general 3 population . "P lain People" is a term which refers to their plain dress and restricted use of 4 technology .

History and Migrations In order to understand present day genetic issues surrounding the Plain People it is important to understand where they originated and how they came to Canada and the USA. They can broadly be divided into 4 groups: the Hutterites, Old Colony Mennonites, Old Order Mennonites and Amish.

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The Hutterites were follo wers of Jakob Hutter in Austria, and their co lony was founded in 5 1528. They were persecuted for most of their history and were fo rced to migrate between settlements in Morav ia, Romani a, Hungary and, U kraine. From 1874 to 1879, 443 indi viduals immi grated to the United States. 5 They settled o n the prairi es and prospered until WW 1 when they refu sed to accept conscripti on. Canada offered them land and exempti on from military serv ice. Many Hu tterites imm igrated to Canada during thi peri od and settl ed in Alberta, Saskatchewan and Mani toba. T here are a lso a few co loni es in Briti sh Co lumbia. Their curre nt population in the 5 US and Canada numbers over 40,000. The Hutteri tes beli eve in communal ow nership, w ith minima l personal posses ion . They li ve in communa l co loni es, use modem fa rming and manu fac tu rin g techni q ue , and utili ze modem hea lth care.6 Mennonites are named fo r the ir foundin g leader, Menno Simons. The Menno nites can be di vided into two groups: Dutch-North German and Swiss-South German. The Dutch-North G erman (O ld Co lony) Menno nites o ri ginated in the low countri es of Europe in th e 16th centu ry .3 A a res ult of persecuti on th ey were forced to move to Pruss ia and li ved there in re lati ve peace until the 18th centu ry. With continued growth , land shortages fo rced emi grati o n from Pruss ia to Russ ia. In 1870, 7000 Menn o nites immi grated to Manitoba, w hil e another I 0,000 immi grated to th e 3 Ameri can Midwest. Anothe r wave of Russian M enno nite came to Canada in 1920 fo llow ing th e Ru sian revo luti on.3 In the 1920s, 7000 of th e Canadi an O ld o lony Mennonites emi grated to Mex ico, Beli ze and South Ameri ca. Recentl y, many O ld Co lony Menn onites have return ed to Canada fro m M ex ico and South Ameri ca, ettling mostly in 3 So uth western Ontari o, Alberta and M anitoba. Today, O ld Co lo ny Menn onites in Canada number ove r 27,000. T hey speak Low German at ho me, and Hi g h German for more fo n11a l 3 occas io ns, uch as church. T he Sw iss-South German Mennonites were fo unded in the 16th centu ry in Sw itzerl and .

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In 1693 follow ers of Jakob Amman split from the Swiss-S,outh M ennonites to form the Ami sh sect, 7 a more conservati ve group . Both the Swiss-South German M ennonites and the Ami sh suffered persecution in Europe . Between 1683 and 18_80, approximately 8000 Sw iss-German M ennomtes 7 immigrated to the United States. With the onset of the revo lutionary wa r in the USA, members of the M ennonite and A mi h communities trave lled to Canada, settling in the Kitchener- Waterloo and Ay lmer- St. Tho mas area . In 1824, A mi sh families began immi grating directl y to the W aterloo and Perth 8 County areas of Ontari o fro m Europe. In the late 19 111 century, Old Order M ennonites (OOM) split from the oth er Sw iss-Mennonite groups in the USA and Canada due di ffe ring opinions over 7 Sunday schoo l and hig her education. OOM and the Ami sh are both quite con ervati ve and can be een dri ving buggies and wearing conservati ve 7 c lothes.

Suitability for Genetic Study T he unique hi tory of Pla in People g roups make them espec ia ll y uitabl e fo r genetic re earch. They are oc ia ll y isolated w ith little geneti c inflow . They k ep exten ive genea logica l records, mainta ined by loca l mini sters. The ir initi a l founder popul ati on are we ll know n. Th ey have ex peri enced many geneti c bottlenec k events cau ed by succe s ive mi grations over their hi story. Large fa mili es are commo n, w ith low rate of non-paterni ty . T hey have a re lati ve ly hi g h ta ndard of medi cal ca r .9 T he fo under effect i quite prono unced in Pla in Peopl e popul ati on . For exampl e, most of the over 40,000 Hutterite in North Ameri ca can trace th eir ance try bac k to a group of 89 5 founding members. T he Ami sh and M ermonite popul ation s of North Ameri ca are similar with . ma ll fo ~ndin g po pul ~ ti o n s a n~ iso lation re ulting m genetic homogene ity. T his can hi g hl y skew the preva lence of certain di eases in the i ol ated popul ati ons, particul arl y auto o ma l reces ive ~o nditi ons. For exa mpl e, nephropa thi c cy tino is 1 . a rare a uto~o m a l rece s ive lysosomal storage d1 o rder affectmg abo ut l in 100,000 children in

the general population with a carrier frequency of about 1 in 150. 10 In the Old Order Amish population of Ontario, the cystinosis carrier frequency is 1 in 4.5 , predicting an extraordinarily high incidence of 1 in 78. 11 The increased incidence of these otherwise rare conditions allow for linkage analysis and identification of causative 12 genes. These genetic studies are not only useful for Plain People, but also for the general population. Since 10-20% of each generation of Old Order Amish and Mennonite children have chosen to leave their communities, many alleles have entered the general population. 13 Also, many of the mutations causing disease in the Plain People can be found in Europe, where the 13 founding populations originated. Genetic linkage studies in the Mennonites has led to the discovery of the genes for many conditions, such as hypophosphatasia and X-linked congenital stationary night blindness. 3 The Clinic For Special Children in Pennsylvania specializes in care for Plain People and have been successful in isolating over 50 different mutations causing disease in the Mennonite and Amish communities over the past 5 years. 14

The Database The Amish, Mennonite, and Hutterite Genetic Disorder Database is intended to be used as a resource to assist in research and diagnosis of genetic conditions for patients of Plain People ancestry. It has been compiled by researching published genetic conditions for Plain People. Literature searches were performed on PubMed. Some disorders and mutations were entered based on personal communication with other genetic researchers. For each disorder, the group affected is recorded along with the geographic location (e.g. Amish, Ontario). This is important because disease prevalence can vary between locations, even within a specific group (e.g. Hutterite), as a result of differences in the founding 12 populations. The specific gene and mutation(s) are also listed, if known. The journal articles detailing the illness with specific mutation(s)

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found in Plain People are listed along with the OMIM reference number. Finally, the clinical symptoms of each condition are listed, assisting healthcare providers in recognition and diagnosi s. In order to navigate the database, users search by disorder, mutation or clinical signs and symptoms. When searching by disorder, the user is able to input either the OMIM number or the name and is directed to the corresponding page. Alternatively, the user can input a specific gene and identify any disorders which are caused by mutations in that gene. Finally, the user can search the database by clinical manifestations of the genetic conditions. This is done using a dropdown menu divided by different body systems. The clinical search may be limited to one specific Plain People group and a geographic location. Finally, users are provided a link in order to communicate with the site administrator if they have questions or new information to add to the database.

Conclusion Plain People have unique healthcare needs as a result of small founding populations and cultural isolation. It is our hope that The Amish, Mennonite, and Hutterite Genetic Disorder Database will improve the healthcare delivery to Plain People in Canada. We view it as an ongoing project, with continuing updates to the database with future discoveries.

References

Fane!, P., Rosenstein, B. , White, T., Accurso, F. , et a!. Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report. The Journal ofPediatrics. 2008 ; 153 :2. Sharp, J. and Rock, M. Newborn Screening for Cystic Fibrosis. Clinic Rev Allerg lmmunol. 2008; 35:107-115 . Orton , N, Innes, M, Chudley, A. and Torben Bech-Hansen, B. Unique Disease Heritage of the Dutch-Gennan Mennonite Population . Am J Med Genet Part A. 2008; 146A: 1072-1087. Scott, Stephen E. (1989) . "Plain People." Global Anabaptist Mennonite Encyclopedia Online. Retrieved 20 March 2009. Available from :

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8 9

http: //www.gameo.org/encyc loped ia/contents/P59 ME.html Boycott K, Parboosingh J, Chodirker B, Lowry B, et a/. Clinica l Ge netics and Hutterite Population : A Review of Mendelian Disorders . American Journal of Medical Genet ics Part A. 2008; l46A : 1088-1098 . Derek Suderman . 1998. Menno nite Hi storical Soc iety of Canada. Retrieved March 20, 2009 . Availab le from: http ://www.mhsc.ca/index.a p?content=http ://ww w.rnbsc.ca/ mennos/tami h.html Puffenberger EG. Genetic Heritage of the O ld Order Mennonite of Southeastern Pennsy lva ni a. American Journal of Med ica l Geneti cs Part C (Sem in . Med . Genet.). 2003; 12 1C : 18-3 1. No lt SM. A Hi story of the Ami b (2003). Good Books, Intercour e, PA. p 125 . Francomano C, McKu ick VA , Bi esecker L. Medica l Geneti c Studi es in the Amish : Hi stori cal Per pective. American Journal of Medical Geneti cs Pati C (Semin . Med. Genet.). 2003; 12 1C : l -4 .

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Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl W A. CTNS mutations in an Americanbased population of cystinosis patients. Am J Hum Genet. 1998;63(5): 1352-62 . Siu Y, Kuepfer S, Dewar R, Rupar CA. High carrier rate for cystinosis in the Ontario Old Order Amish. Poster presentation at the American Society of Human Genetics, Toronto, Ontario, October 26-30, 2004. A 1804. Arcos-Burgos M , Muenke M . Genetics of Population Isolates . Clin Genet. 2002: 61:233247. Morton H, Morton C, Strauss K, Robinson D, et al. Pediatri c Medicine and the Genetic Disorders of the Amish and Mennonite People of Penn sylvania. American Journal of Medical Genetics Part C (Semin. Med. Genet.). 2003 ; 12 1C: 5-17 . C lini c For Special Children. Retri eved March 20, 2009 . Available from: http ://www.clini cforspec ialchildren.org/CSC/Bro chure_ file /brochure.pdf.

FEATURE Hemochromatosis - Screening for a Common Condition Nick Sunderland (Meds 2010) Faculty Reviewer: Dr. Kami/ia Rizkalla Hemochromatosis is a common genetic disorder in the Caucasian population. It can go unrecogni zed in many patients for years before manifesting itself as multisystem end-organ damage. There is debate as to whether this condition should be screened for on a routine basis; as such this article serves to explore the basics of the disease and to review current guide lines for screening at the primary care level.

Case A 26 year old female fashion student getting lab work for allergy testing was incidentally found to have significantly increased serum transferrin and ferritin levels. Subsequent genetic testing revealed homozygous mutation for gene encoding the HFE protein . the Retrospectively , the mother reports a history of improvement in chronic fatigue and joint pains following elective phlebotomies at the local blood bank. Her testing revealed a compound (double) heterozygous mutation in the HFE gene, but no abnormality in her liver function tests or iron levels . The father and 24 year old brother have normal ferritin and liver enzymes; the 28 year o ld brother, however, has markedly increased iron stores.

Introduction Hereditary hemachromatosis (HH) is an autosomal recessive inl1erited disorder in which mutations in specific genes related to iron transport proteins lead to increa ed iron absorption from the diet. This eventua ll y leads to deposition of iron in the parenchyma of the liver, heart, pancreas and pituitary g lands if left untreated, and can cause significant long tenn 1 morbidity. This disorder was originally described as "bronze diabetes" by Armand Trouseau in 1865, when he observed an association of skin

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pigmentation with diabetic patients. 2 The first report of deposition of iron in tissue leading to dysfunction was by Yon Reckinghausen in 1890. The sequencing of the human genome has all owed identification of the specific mutations associated with the HFE protein, the commonly affected protein in HH. Mutations in this protein are the focus of this article. Note that there are other, less common hereditable defects in iron metabolism.

Genetics The most common genetic defect is in the HFE protein, which interacts with the transferrin receptor and other iron regulating proteins to regulate absorption of iron from the GI tract. There are two common mutations in HFE, C282Y and H63D. The mutation is most prevalent in Caucasians of European decent, with a homozygote prevalence (C282Y) of about l in 200. The prevalence is about l in 250 in the general population. In this same population, 12% are carriers of the C282Y and 25 % the H63D mutation. Most HH patients are homozygous for the C282Y mutation. The penetrance of the H63D mutation is considerably lower, thus compound heterozygotes (C282Y/H63D) and H63D homozygotes 35 constitute l 0% of HH patients . -

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Pathogenesis The HFE prote in as mentioned is important in regu lating the up take of iron from the diet in the G I tract. Iron can only be lost through sweat, skin and the GI tract, menses in fema les, and during times of growth such as pregnancy and ado lescence. Ma les lose approximate ly l mg/day and fe ma les proportiona ll y more ( l .5-2 mg/day). In HH, th e abi lity of the body to sense overa ll iron stores is lost, leadi ng to an extra absorpti on of l -4mg of iro n dail y, w hich ave rages over a year approx imate ly I gram . T he s low acc umul ati on of iro n i genera ll y asy mptomati c until the tota l body iron stores are greater tha n 20 grams.

the ensuing fibrotic reaction from chronic damage. Cirrhosis, pancreatic . insufficien~y secondary to islet cell destructw.n and skm pi gmentation are all fairly late findmgs , b.ut a~e considered the class ic " triad" . Hypogonadism IS related to alteration of the hypothalamic-pituitary . I ax is. The differenti a l for HH includes other causes for elevated iron stores. Most alternative di agnoses are secondary causes of iron overload, most commonl y chroni c transfu sions, either alone or in associati on w ith ineffective erythropoiesis. T he latter conditi on results from RBC being destroyed before they can leave the bone marrow. 6

Screening Excess ive iron is tox ic to ti ss ues by free radi ca l reacti ons, timul ati on of co ll age n fo rmati on, and interacti on w ith DNA. Most of th ese changes are revers ible if the iron is removed. Depos iti on of hemos iderin , an intrace llul ar iron storage compl ex, in the ce lls of th e li ver, pancreas, myoca rdium , pituitary , adrena l, th yro id and parath yro id g lands, j o ints and skin lead to di sco lourati on, fibro sis, and dysfunction. Interacti on w ith DNA has lead to increased ri sk fo r hepatoce llul ar carcinoma (HCC) in advanced cases. 1' 7 HCC and cirrhos is are the leadin g causes of morta li ty due to HH.

Presentation and Differential Most cases of HH are di scovered through screening, as either an inc idental findin g when bl oodwo rk is done for another reason or becau e of a re lati ve w ith a di agnos is. T he manifestati on of HH usua ll y occur after age 40 in ma les (50 in fe ma les), after iron stores are grea ter th an 20 grams. The most frequent symptoms in c lude hepatomega ly, abdomina l pain , skin pi gmentati on (especia ll y on sun ex posed areas), altered g lucose metabo li sm or di abetes, cardi ac arrythmias, and an atypi cal arthriti s. Hypogonadi sm resulting m amenorrh ea in fema les and a drop in libido m ma les is also a common initi a l presentati on. Eac h of the symptoms is due to hemos iderin depos iti on in orga n parenchyma and

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The understanding of the underl y ing pathophysiology of thi s di sorder has come a long way. At a popul ati on leve l, it has been debated w hether ro utine screening (via a fa sting serum transferrin saturati on ) should be implemented, due to the hi gh preva lan ce of the mutation, ability for early di agn os i and treatment, and ease of geneti c testing. However, a t thi s time widespread screening has not been recommended, due to lack of predictabili ty about the express ion of the mutati ons and lack of information on ri kstrati fy in g pati ents. 3 路 6- Labe lling of indi vidual s who test pos iti ve through geneti c testing but are a ympto matic is a l o anoth er concern and could lead to diffi culti es w ith obta ining in urance, for exa mpl e.7 T he va ri abl e ex press iOn m thi s condition has been a focus of some re latively large cree ning studi es, inc luding a study by Beutl er el a/. (2002) whi ch invo lved 4 1,000 US indi v iduals tested for the C282 Y and H63 D mutations. They found no difference in th e age di stribution or frequency of signs and symptoms of HH between the cases and contro ls. However, a more recent study of 3 1,000 Austra li an pati ents of northern ~ u ropean decent (fo ll owed for 12 year ), bowed Iron-overl oad re lated di sease in 28% of mal e and 1.2% of fema le homozygotes. 5 Other observational studi es have identifi ed a substantial percentage of first degree re la ti ve of

homozygotes with subclinical conditions related to HH. 10 Following from this, a reasonabl e strategy for screening would include targeting hi gh ri sk individua ls, such as adult men > 25 years o ld of northern European decent and first degree relatives of pati ents w ith known hered itary hemochromatosis. The screening test of choice would be a fasting serum transferrin saturation (men > 52% and women > 50%) or a fasting serum unsaturated iron binding capacity. Follow-up to 4 thi would be genetic testing. 3â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘ 10

Diagnosis The di agnos is of HH rests on a combination of the clinical features mentioned above, and an e levated serum ferritin and fasting transferrin saturation. In the past, a li ver biopsy was used in confirmation of the di sease; however, genetic testing has largely replaced thi s invas ive test except in the case of documented li ver impairment and need to determine extent of cirrhosis. The serum ferritin value needs to be analyzed with caution as it is an ac ute phase reactant. Excluding the secondary causes of iron overload is important (Table 1).

Treatment The definiti ve treatment of HH and the associated iron-overload is phlebotomy, 500ccs weekly. Thi s is continued until iron-deficien cy erythropoiesis is induced as ev idenced by a reduced MCV and decreased Hb value, and/or

se rum ferritin leve ls and transferrin saturation markers are within the target range , w hi ch are below 50% and 50ng/ mL , respectively . Patients w ill usually require a phlebotomy every 2-3 m o nths as maintenance therapy, which in many cases can be accomp lished by regular donations to the loca l bl ood bank. Patients testing pos iti ve for HF E mutati on but witho ut labo rato ry ev idence of iron ove rload can be followed annua lly for evidence of disease, but do no t require active treatment. There is no need for patients to avo id red m eats and other di etary sources rich in iron ; a well ba lanced di et is acce ptabl e. Pati ents can be at hi gher ri sk for certa in infections such as Vibrio vulnificus, and as such eating raw seafood is discouraged .

Case Discussion The case represents a common scenario, in thi s case a Caucas ian fam il y with a compo und heterozygote mother (C282Y/H63D) and the da ughter homozygous for the C282Y mutat io n. This ca e illustrates the need for aware ness on the part of family doctors of at-ri sk popul ation to determine the need for geneti c testing. Had the fashion tudent (homozygote) not bad her blood tested she may have gone years w ithout any knowl edge of her conditi o n, until pre entation w ith signs of end organ da mage. While a number of incidental cases of iron-overload are in ev itabl e until better ev idence is ava ilabl e for specifi ca ll y ide ntifying those at ri sk, targeting the at-ri sk subg roups should minimize thi occurrence.

Table 1: Cause of iron overload 6 (*focus of arti cle) Hereditary hemochromatosis

Related to HFE gene* African (Bantu) hemochromatos is Ju venile hemochromatos is Neonatal hemochromatosi

Exogenous iron overload

Chroni c iron supplementation (in ab ence of blood loss) Transfusion Iron dextran inj ection

Chronic anemias

Chronic liver diseases

Thalassemia major Sideroblastic anemia Congenital dyserythropoietic anemia Conoenital atransferrinemia b

Viral hepat iti s Alcoholic li ver di sease Nonalcoholic steatohepatitis P01phyria cutanea tarda

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References l. 2.

Kumar, Cotran and Robbins. Basic Pathology . Philadelphia : Saunders; 2003. p 6 15 . Trous eau A. "Glycosurie, diabete sucre". C linique medica te de l' Hotel-Dieu de Paris. 1865. 2: 663-98 . Phatak PO, Bonkovsky HL, and Kowdley KV. Hereditary hemochromatosis: time for targeted creenin g. Ann Intem Med . 2008; 149: 270-272 . Bacon BR, Britton RS . Editorial : clinical penetrance of heredi tary hemochrom ato is. New Engl J Med. 2008 ; 35 : 29 1. Allen KJ, G urrin L , Con tantine C, eta/. Ironoverload- related di ea e in HF E hereditary hemochromato i . ew Engl J Med . 200 ; 358 :22 1-30. Brandhagen OJ, Fa irbank VF, Baldu W. American Family Ph y ic ian : Recognition and Management of Heredit ary Hemochromato i

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[intemet]. March l , 2002. Available at: http ://www.aafp.org/afp/2002030 l /853.~t~l th 7. Rake] R. Textbook of Family Med1cme, 7 edition. Philadelphia : Saunders; 2007. Chp 56, iron overload and hemachromatosis . Online at MD Consult. 8. Qaseem A, Aranson M, Fitterman N, Snow V, Weiss K., Owens D, et al. Clinical efficacy as es ment ubcommittee of the ACP. Screening for hereditary hemochromatosis: a clinical practice guideline from the ACP . Ann lntem M ed. 2005 ; 143 :5 17-21. 9. Beutler E, Fe litti V, Koziol JA, Ho NJ, Gelbart T. Pentrance of 845G-> A (C282Y) HFE hereditary hemochromatosis mutation in the USA. Lancet. 2002; 359: 2 11-8. 10. Bulaj ZJ , Ajioka RS , Phillip ID, LaSalle BA, Jorde LB , Griffen LM, Edwards CQ, Kushner JP. Di ea e-re lated condition in relatives of patients with hemochromatosis. N Engl J Med. 2000; 343(2 1): 1529-35 .

FEATURE Amniocentesis: Safety, Reliability and Alternatives Caleb Zelenietz (Meds 2011), Kimberley Colangelo (Meds 2011), and lshvinder Chattha (Meds 2011) Faculty Reviewer: Dr. Robert Gratton Amniocentesis is the most commonly used technique for prenatal genetic diagnosi s. It is an effective procedure with a high diagnostic success rate, but carries the risk of severe complications including miscarriage. Despite the risks , amniocentesis performed in the second trimester remains the safest means of prenatal genetic diagnosis. With the introduction of biochemical and first trimester ultrasound screening for fetal aneuploidy, amniocentesis usage rates have declined.

Background of Prenatal Genetic Screening Pregnancy can be a time of worry, when concerns over fetal health and well-being are at the forefront of many women's minds. Modem clinicians have a wide array of tools at their disposal to allay parents ' fears. Prenatal screening for genetic anomalies has become a cornerstone of care for expectant mothers. In Ontario, Integrated Prenatal Screening (IPS) , Serum Integrated Prenatal Screening (SIPS), and First Trimeter Screen (FTS) are offered to all women presenting before 14 weeks gestation . 1 The testing uses serum markers and nuchal translucency (in the case of IPS and FTS) to assess the risk of trisomies 18 and 21 along with open neural tube defects. Testing is undertaken in both the first and second trimester, with results becoming available after the second set of testing. Many screening options are possible but IPS and SIPS (if nuchal translucency 23 is not available) prove most accurate and safe. ' These tests give the mother the risk of her fetus having one of these conditions, but are not diagnostic. The costs to the health care system of screening have been estimated to be around 4 $15 ,000 US per quality adjusted life year gained. The screening tests are non-invasive and do not pose a risk to the fetus in and of themselves , but are associated with an increased risk of pregnancy

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loss due to follow-up diagnostic tests. After a woman has screened positive as having increased risk of one of the fetal anomalies , she must be offered further testing; screening should therefore only be performed when follow-up diagnostic testing is available. When used in the absence of screening, based on matemal age , amniocentesis and chorionic villus sampling cost about $100,000 US per abnormal birth averted, giving substantial weight to the use of screening programs as a first step in assessing the risk of genetic abnormalities in a fetus. 5 From a safety perspective, however, the use of amniocentesis with the sole risk factor of advanced maternal age is justified as the risk of aneuploidy is comparable to the risk of miscarriage .6

Positive Screen: What Comes Next? Several options are available after a woman has screened positive: she can choose to continue the pregnancy without further testing, she can have chorionic villus sampling (CVS) in the case of FTS , or she can have amniocentesis. Both CYS and amniocentesis are invasive procedures that pose ri sks to the fetus, but are also highly effective diagnostic tools with close to l 00% 78 . . d mgnosttc success rates . ' Amniocentesis involves the withdrawal of amniotic fluid from the uterine cavity. Typically, a 20 or 22 gauge needle is inserted into the amniotic sac transabdominally under ultrasound

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guidance. It can be done both fo r obtaining cells to culture for geneti c testing, fe tal blood typing, and diagnosi ng fe ta l infec ti on. 9 When used for geneti c diagnosis, amni ocentes is is typi call y perfo rmed in the second trimester. It is most effecti ve at obtaining a usefu l sampl e after 15 weeks gestation and before 24 weeks. 1 Cell cultures typica lly take 7 days to grow before they can be tested. For more ra pid results, interphase flu orescence in situ hybridi zati on (FISH) can de tect aneupl oidy of chro mosomes 13, 18, 2 1, X, Y in one to two days . An a lternate procedure fo r obtai ni ng genetic mate ria l fro m the fe tus is chori on ic v illus sampling (CVS). CYS invo lves samp ling the place nta either transabdomina ll y or transcervically. It is usua ll y performed in the firs t trimester, after 10 weeks gestati on. T he rate of both amniocentes is and CVS use has decreased w ith the introducti on of IP S, FTS , and SIPS. 11 • 12

Safety of Early Versus Late Amniocentesis and

cvs The safety of earl y versus late (first rather than second trimes ter) amni ocentes is and CVS has been studi ed ex tensive ly in the literature. Earli er tes ting prov ides a definiti ve di agnos is mu ch qui cker after a pos iti ve test, but is not w ithout added ri sk of complicati on. A Coc hrane rev iew of 16 randomi zed contro ll ed tri a ls fo und second trimester amniocentes is to be the safest method of pre natal geneti c di agnos is.8 A mni ocentes is performed before th e second trimes ter is assoc iated w ith a hi gher rate of pregnancy loss (7.6% versus 5.9% relati ve risk of 1.29 95 % cr 1.09 to 1.8 1) than second trimes ter testing , thu s it is not as safe an a ltern ati ve as later amni oce ntes is. CVS is th e safest method of first trimester sampl ing, but has a hi gher loss rate th an second trimester a mni ocentesis w ith a hi gher tota l pregnancy loss (re lative ri sk of 1.40; 95 % Cl 1.09 to 1.8 1) and spontaneous mi scarri age (9.4%; RR 1. 50; 95 % CT 1.07 to 2.11 ).8 Risks of Amniocentesis T he materna l ri sks of amni ocentes is are low; of much greater conce rn are potenti a l feta l compli cati ons. Th e onl y randomi zed controlled tri a l comparing second trimester amni ocentes is to

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pl acebo, a study of 4606 low risk women aged 25-34 years, found the rate of spontaneous abortion to be 1.7% in the second trimester amniocentes is group versus 0.7% in the control 13 ultrasound group (relative ri sk of 2.3). Current consensus from various trials estimates the loss rate from second trimester amniocentesis to be 14 between 0.6% to 1.0%. Fluid leakage is more common after amniocentes is than in controls, but is not associated with negati ve pregnancy 13 outcomes. With ultrasound guidance, direct fetal injury is extremely rare 13 , although it has been reported. 15 • 16 Indirect feta l 111Jury is more common, w ith respiratory di stress syndrome and pneumoni a be ing more common in newborns ,., · . . 13' 11 A large a .tter secon d tnmester amniOcentesis. cohort study of women 35-49 years old (with 7 1,586 parti cipants) found an increased incidence of muscul oskeletal deformiti es and respiratory di stress in newborns w hose mothers underwent 2n d trimester amni ocentes is. There was no increase in limb reducti on defects, infant and fetal morta lity, prematu rity, low birth we ight, or fetal 18 di stress w ith amni ocentes is. There is no long tern1 increased ri sk fo r di sabiliti es in children 19 after amni ocentesis. Verti ca l transmi ss ion of infections such as cy tomega lov irus, hepatiti s C Virus, and human immuno defi c iency v irus has been linked to amni ocentesis perfonned in infected women. 20•21 L ike a ll invas ive procedures in chroni ca lly infec ted wo men, amni ocentes is should be used onl y w hen abso lute ly necessary. Advantages of Early Versus Late Diagnosis A lthough second trimester amniocentes is has been conc lu sive ly shown to be the safest meth od of prenata l geneti c di agnos is, it is not w ith out d isadvantages . Because it is performed in the second trimester, there is a long lag time between a screen pos iti ve test from IPS or SIPS and definiti ve di agnos is. C VS is ava il able in the first trimester, thus c utting the lag time considerabl y. Several studi es of women's subj ecti ve we ll being have shown shorter time to materna l feta l bonding, earli er anx iety reduction ,

and improved health related quality of life in women having a positive screening test followed by a negative CVS as compared to a negative 24 amniocentesis? 2The second trimester magnitude of the reduction of anxiety post test is the same for the CVS and amniocentesis groups, but occurs sooner because the CVS is done earlier. 23 This benefit in anxiety reduction exists despite the increased risk for miscarriage with CVS. 23 The same is true for the maternal-fetal bonding improvements, the bonding improves markedly after a negative test result, equally for CVS and amniocentesis, but the CVS is performed earlier. 22 Whether these subjective improvements outweigh the very real increased risk of miscarriage should be discussed with each patient.

amniocentesis remains the late availability of results , which gives parents little time to make deci ions based on the results of the testing. As detection rates of genetic disorders by anmiocentesis have increased, termination rates have decreased. Amniocentesis remains a valuable tool for prenatal genetic diagnosis. References I.

Aftermath of a Positive Test After a positive diagnosis of a chromosomal abnormality, the patient faces the difficult decision of whether or not to terminate the pregnancy. The attitudes and knowledge of the health care provider providing the diagnosis 26 affects the patient's choice. 25 • The patient's level of education and socio-economic status also plays a role in her decision making.25 Detection rates do not correlate with termination rates ; older women . are more l 1.k e Iy to contmue the pregnancy.-n ·28 Pregnancies with sex chromosome abnormalities (SCA) causing infertility and abnormal sexual development were more likely to be terminated than SCA's that did not affect fertility and sexual development. 28-3 1 The lowest termination rates for SCA are for the 4 7 XYY and 4 7 XXX karyotypes.28•30•31 Abnormalities visible on ultrasound make the pregnancy less likely to be continued? 8•30 -32 Overall detection rates are increasing for SCA while termination rates have 34 steadily declined.29 ' 33'

Conclusions 8.

Second trimester amniocentesis is an effective tool for prenatal genetic diagnosis. Although it is not without risks of serious complications such as miscarriage, it remains the safest technique for prenatal genetic diagnosis. The greatest limitation of second trimester

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Carroll J. Reference Guide for Health Care Provider Prenatal Screening Tests for the Detection of:Down yndrome, Trisomy 18 and Open Neural Tube Defects . London Health Sciences Center; 2007 [cited 2009 Feb 20]. Availible from: http ://www.lhsc .on .ca/programs/rmgc/ms /provider. pdf Wald NJ, Rodeck C, Hackshaw AK, Walters J, C hitty L, Mackinson. First and seco nd trimester antenata l creening for Down's syndrome : the results of the Serum, Urine and Ultrasound Screening Study (SURUSS) . Am J Med Screen 2003 ; 10:56-104. Wald, NJ, Rodeck, C, Hackshaw, AK et a!. First and second trimester antenatal screening for Down's syndrome: the results of the Serum, Urine and Ultrasound Screening Study (SURUSS). Health Techno! Assess 2003; 7: I. Harris RA, Washington AE, Nea e RF Jr, Kuppermann M. Cost utility of prenatal diagnosis and the 1isk-based threshold. Lancet. 2004 Jan 24 ;3 63 (9405) :2 76-82 . Heckerling PS, Yerp MS . A cost-effectiveness analysis of amniocentesis and chorionic vi llus sampling for prenatal genetic te ting. Med Care. 1994 Aug;32(8):863-80 . Bomstein E, Lenchner E , Donnenfeld A, Bamhard Y, Seube11 D, Divon MY . Advanced matemal age as a so le indication for genetic amn iocentesis; ri skbenefit anal ysis based on a large databa e reflecti ng the current common practice . J Perinat Med. 2009 ;37(2):99-1 02. Borrell A, Fortuny A, Lazaro L, Co ta D, Seres A, Pappa S, Soler A. First-trimester transcervical c horioni c villus sampling by biop y forceps versus mid-trimester amniocentesis : a randomized controlled trial project. Prenat Diagn. 1999 Dec ; 19( 12): 113 8-42 . Alfirevic Z, Mujezinovic F, Sundberg K. Arnniocente is and chorionic vi llu sampling for Cochrane Database of prenatal diagnosis. Systematic Reviews 2003, Issue 3. Art. No.: CD003252. DO! : l0.100 2/ 1465 1858.CD003252. Ghidini A. Amniocentesis : Technique and co mpli cations. Uptodate; l October 2008. [updated

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23 . Robin son GE, Gamer DM, Olmsted MP, Shime J, Hutton EM C rawfo rd BM. Anxiety reduction after chorionic ' vi llus sampling and genetic amniocentes is. Am J Obstet Gynecol. 1988 Oct; 159( 4 ):953 -6. 24. Feeny D, Townsend M, Furlong W , Tomkins DJ, Robinson GE, Torrance GW, Mohide PT, Wang Q . Health-related quality-of-life assessment of prenatal chorioni c villi sampling and di agnos is: amn iocentes is. Genet Test. 2002 Spring;6(1) :39-46. 25. Yilmaz Z, Sabin Fl, Bulakbasi T , Yliregir 00, Tarim E, Yanik F. Ethi cal considerations regarding parenta l dec ision for termination following prenata l diagnosis of sex chromosome abnorma lities. Genet Couns. 2008; 19(3):345 -52 . 26. Rob inson A, Bender BG, Linden MG. Decisions following the intrauterine diagnosis of sex chwmosome aneuplo idy. A m J Med Genet. 1989 Dec;34(4) :552-4. 27 . Forrester MB , Merz RD. Pregnancy outcome and prenatal diagnosi s of sex chromo orne abnorma lities in Hawaii , 1986-1 999. Am J Med Ge net A. 2003 Jun 15;11 9A(3) :305-10. 28 . Holmes-Siedle M , Ryynanen M , Lindenbaum RH . Parental decisions regarding termination of pregnancy following prenatal detection of sex chromosome abnom1ality . Prenat Diagn. 1987 May;7(4) :239-44 . 29 . Brun JL , Gangbo F, Wen ZQ, Galant K , T aine L, Maugey-Laulom B, Ro ux D, Mangione R, Horovitz J, aura R. Prenatal di agnos is and management of sex chromosome aneupl oidy: a report on 98 cases. Prenat Diagn . 2004 Mar;24(3) :213-8. 30. Mezei G, Papp , T6th-Pal E, Beke A , Papp Z. Factor influencing parental decision making 111 prenatal diagno is of ex chromo o rne aneuploidy. Obstet Gy neco l. 2004 Jul; I 04( I ):94-1 0 I . 3 1. C hri sti an SM, Koehn D , Pillay R, MacDougall A, Wilson RD . Parenta l deci ions following prenatal diagnosis of sex chromosome aneuploidy : a trend over time . Prenat Diagn . 2000 Jan ;20( I ) :37-40. 32. Hamamy HA , Dahoun S. Parental dec ision following the prenatal diagnosis of sex chromosome abnom1a lities. Eur J Obstet Gy neco l Reprod Bioi. 2004 Sep I 0; I 16(1 ):58-62 . 33 . Shaw SW, C hu h HY, C hang SD, C heng PJ, H sieh TT, Soo ng YK. Parenta l deci ions regarding prenata ll y detected fetal sex chromosomal abno nnality and th e impact of genetic counsell ing : an analysis of 57 ca es in Taiwan. Aust N J Obstet Gy naeco l. 2008 Apr;48(2): 155-9 . 34. Vestergaard H, Lidegaard 0 , Tabor A. In vas ive prenata l di agno tic practice in Denmark 1996 to 2006. Acta Obstet Gyneco l Scand . 2009 Jan 26 : 1-4. [Ep ub ahead of print]

CASE REPORT

Ductal Carcinoma in situ in a 25-Year-Oid Male with Unilateral Gynecomastia Christoph er}. Coron eos (Meds 2010) Fa culty Reviewer: Dr. Carolin e Hamm DC IS in a yo ung ma le is rarely reported. O ur pati ent is a 25 year o ld male w ho presented w ith symptomatic unilateral gynecomas tia. He presented w ith a trong fa mil y hi story of cancer on both matem al and paternal sides of hi s fa mily including breast, lung (maternal) and melanoma, co lon and pancreatic (paterna l). Hi s mother te ted negati ve fo r BRCA 1 and BRCA2. Th ere is no info rmation on the patem al geneti c testing . He was treated w ith left subcutaneous mas tectomy. Upon hi stologic rev iew of th e sampl e, concurrent gyecomas ti a and ducta l carcinoma in situ was di scovered. To date, only fo ur ca es of gynecomasti a and DC IS have been described in yo un ger ma le pa ti ents. Since onl y 30 - 50% of pati ents w ith DCIS eventua lly deve lop invas ive cancer in the subsequent 10 - 20 years, thi s fi gure in the general popul ati on may be hi gher. Thi s case underscores the importance of fa mil y history in any pati ent presen ting with a breas t mass. Patients must be made aware of the risk, however sma ll it may be, and phys icians must rema in ca utious of malignancy in yo ung ma les w ith gynecomasti a.

Introduction By definiti on, gynecomas ti a is a beni gn conditi on affecting ma les characteri zed on 1 histology by g landular ti ss ue proliferati on. It must be di stingui shed first from pseudogynecomas tia, the depos iti on of fat w ith absence of g landular ti ssue pro liferati on seen in obese ma les and second, from breast carcinoma. The increas ing size of th e breast is due to parenchyma a nd/or fatty ti ssue. Gyneco mas ti a is common and most preva lent in th e neonata l, pubertal and e lderl y peri ods. 2 However, it is a lso 2 present in 33-4 1% of adult ma les aged 25 -45 . Long-standing cases that are res istant to medi ca l management or aesthe ti ca lly displ eas ing are treated w ith surg ica l exc ision w ith or w itho ut 3 liposucti on . In contrast, cases of ma le breast cancer are uncommon, occurring in (MB C) 4 approximate ly 1 in 100 000 men and leading to 5 under 0.5% of ma le cancer deaths annua ll y. Th e 69 age of incidence is typically 65 -67 years. - Ri sk factors inc lude testicular abnorma lity, imba lance, Klin efe lter estrogeni c/androgenic

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syndrome, BRCA mutati on, pos iti ve fa mily hi story, obes ity , radi ati on exposure and li ver 8 Whil e gyneco masti a ha been di sease. hypothes ized to be associated w ith MBC , research indi cates its in cidence is not hi gher among MBC pati ents w hen compared to the . 4 Âˇ 10' II Th e rare coex i. tence o f genera I popu Iat10n. the two conditi ons has been identifi ed in the 12 13 literature. â&#x20AC;˘ Still more rare are cases of ductal carcinoma in situ (DC IS) w ith gynecomasti a, espec ia lly in the yo un g ad ult popul ati on. To date, onl y fo ur cases of DC IS in the settin g of gyneco masti a have been described in pati ents that 14 17 are 25 yea r o ld or less - and only one of th ese describes unilateral gynecomastia as our pati ent 16 does.

Case Report A 25 year o ld ma le presented in 2007 for cosmeti c mas tectomy. H e reported a hi story of new onset locali zed d iscom fo rt in the peri areo lar region of the left breast and a growth in the left breast for one year, increas ing in size. On presentati on, both the size of the mass and th e associated pain had decreased in magnitude .

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Phys ica l exam noted slight swelling deep to the left nipple areo lar compl ex w ith no ax illary lymph adenopath y. T he right breast had no di scernable changes. Family hi story was significant fo r ma li gnancy including the materna l grandmother (metas tati c lung cancer to bone and b ilatera l breast cancer at ages 4 5 and 46 respecti vely, death at 49), maternal great-aunt (breast cancer, death at 65), second materna l aunt (breast carc inoma at age 60, relapse and bone metas tases, currentl y undergo ing treatment), materna l grandfa ther (pancreatic cancer), paternal grandfa ther (co lon cancer), paternal great-unc le and two paterna l uncles (me lanoma) . He reported no other hea lth concerns, and hi story was notabl e only for surgica l herni a repa ir at age three. The rema inder of the phys ica l exam was unremarkab le. U ltrasound reported a sma ll amount ( 1.5cm ) of mi xed ec hogeni c tissue in the retroa reolar region, consistent with beni gn changes and gynecomas ti a. Left subcutaneous mastectomy was performed. Th e suspected gynecomasti a was compl etely exc ised, measuring approx imately 6.5x6 .0x2 .5cm, we ighing 48 grams. O n mi croscopi c examin ation, patho logy reported gynecoma tia hav ing abundant fib ro us stro ma separating ducts hav ing co lumnar ce lls w ith inbudding. ln additi on, a cribiform pattern of cellul ar change was prese nt. Pathology was consistent with nuc lea r grade I/ lii DCIS, largest focus 7mm . T he patho logy report menti oned the re lative rarity of intraducta l ca rc inoma in the demographi c group of our patient. -F urth er investigati on included MR ma mm ogram at three month s post-operati ve, reporting increased signal intensity in the left retroareolar reg ion cons istent with post-surgica l changes and no abnorm a l enh ancement. CA 19-9 was norma l at 13 kU/L. Ultrasound of the abdomen and bone scan de monstrated no abnorma li ties. Ultraso und of the right (un affected) breast was unremarkable. The pati ent's mother has te ted BRCA I /2 negati ve. The patient underwent fo llow- up w ith medi ca l and radi ati on onco logi sts and received genetic coun selling. G iven th e nega ti ve surg ical marg ins described on path ology, low grade mali gnancy,

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absence of ax illary findings and potential tox iciti es of adjuvant treatment in this young age group, no furth er intervention was recommended.

Discussion Breast cancer in males is far less common than in females . On average, the typical age of 6 onset is up to ten years older th an in females. Simil ar to fe male cases, incidence of MB C has increased fro m 0.86 per 100 000 in 1973 to 1.08 in 1998 . 18 HER2 overexpression, a negati ve prognosti c fac tor in women, is found less often in ma les. 19 Ma le cases are more frequently ER and PR pos itive ,8 perhaps indi cating increased 20 pro li fe rative acti vity . 21

DCIS acco unts fo r approx imately 7% of M BC and is fa r less common than invasive ductal (90% of case ), though lobular malignancy is still 18 more rare w ith only 1.5% of cases. M edian age 2 of inc idence is 65 years >~ On hi stology, the papillary form is most common though all sub types present in fe ma les can potenti a ll y occur 22 in males. Pure DC IS occurs only in 5% of cases as the path ology i often present in assoc iation w ith infi ltra ting ma li gnancy e lsewhere.22 DCIS is more common in fe ma les , representing 20% of JI case - . O nl y 30 - 50% of a ll ma le and fema le patient wi th DCIS eventua ll y deve lop invasive ca ncer in the ubseq uent 10 - 20 years, so actual preva lence in the genera l populati on may be 23 25 hi gher. - Co mpared to males, fewe r intraducta l papill ary ca e w ith hi gher grade and yo unger age 22 26 are een in fe ma les . Âˇ The eti o logy of DC IS is unknow n fo r ma le s ince they lac k the termina l duct lobul ar unit (TD LU) where th e ma li gnancy has freq uently been fo und to ori ginate in 13 fe ma le . However, not all cases are assoc iated with the T DLU and it is hypothes ized cases in ma les ori ginate from epithe lium of ducts. 22 Only a limited number of large studi es perta ining to ma le DC lS are avail abl e.22 â&#x20AC;˘ 27 â&#x20AC;˘ 28 Breast ca ncer of any fo rm in young men is excepti ona lly rare. At the time of our pati ent's presentati on, onl y six cases had been described in 14, I 5, 29-32 rna Ies un der age 25 , and only four cases of males of any age w ith breast cancer revea led on path o log ica l exa minati on fo ll ow ing urg ica l

. t

14 15 29 33

m erventJOn for gynecomastia. ' ' ' To our knowledge, among males 25 years of age or younger, a case of unilateral gynecomastia and DCIS has only been described once in the literature with Chang's account of a 16 year old 16 male. Our patient originally presented with unilateral gynecomastia, though bilateral cases are 34 more common. There is no evidence that either unilateral or bilateral gynecomastia increase risk 35 for MBC. Obesity is an independent risk factor, and may confound the associatiOn with 15 gynecomastia. Gynecomastia in adults is most often due to persistence from puberty, drugs, cirrhosis, hypogonadism , testicular tumor, 36 hyperthyroidism and idiopathic. Beyond his breast, our patient had an otherwise normal physical exam and investigations. Of note however, is the comment in the surgical pathology report of putative anabolic steroid use. Use of anabolic steroids is not mentioned anywhere else in the patient ' s medical record. Some state that cases of gynecomastia should be biopsied if presentation includes query Klinefelter' s syndrome, bloody discharge, firm, irregular or unilateral mass.37 ' 38 Others endorse mammography to recognize mass since it 39 0 distinguishes between glandular tissue and fat, A though it is not universally supported since male breasts are small and dense. 41 '..n Mammography for MBC has been reported as successful as 92% 43 sensitive, 91% specific. Our patient received an ultrasound which demonstrated findings consistent with gynecomastia but made no mention of possible malignancy. (t did not report 17 The microcalcifications typical of DCIS . patient was seen again in follow-up with no improvement and surgical intervention of gynecomastia for comesis was planned. The possible increased risk of squamous cell 44 carcinoma and testicular cancer later in life is considered prior to surgery in a younger patient and annual screening is suggested for cases of . 16 gynecomastia. DCIS will most often present with bloody 21 nipple discharge and a mass , though mild symptoms, concurrent gynecomastia and the scarcity of its incidence result in frequent misUWOMJ, Vol 78, Issue 3

diagnoses. 14 Our pati ent had ma li gnancy diagnosed on routine post-operati ve path ologica l investi gation . Thus he did not benefit from preoperati ve diagnosti c evaluati on and tagin g. Fine needle aspirati on cytology is acc urate in men when suffici ent ti ssue is obtained, th ough up to a quarter of cases have insufficient samples.45 ER, PR and HER2 profiles are obtain ed. The remainder of diagnostic routine mirrors cancer in women and investigation includes lab work, bone scan, CT pelvi s/abdomen and plain films as clinically relevant. 46 Research pertaining to the prognosi s of DCIS is conflicting. Studies in the past concluded a poorer prognosis in MBC when compared to females , though the older age and delay in diagnosis are thought to have been factors . 1 (t is currently believed that prognosis MBC is equal to that in females, 6 though specific outcomes for DCIS unavailable. Breast cancer specific survival for treated DCIS is as high as 99% in females and 85% in cases of invasive recurrence. 47 Cutuli el a/. observed four recurrences among their 27 DCIS patients in follow-up following lumpectomy who were then treated with radical savage surgery.I ~7

Treatment for DCIS in males does not have an established benchmark and no definitive trial has been published. Current treatment has been guided by experiences reported in the literature. 14 For any MBC, surgeons have the option of mastectomy, local exciSion or lumpectomy and adding adjuvant therapy as well as axillary dissection. Total mastectomy is 21 suggested and a recurrence following this 42 49 procedure has yet to be described. ' Research pertaining to lumpectomy and adjuvant radiation 21 therapy are sparse and it is not endorsed. Though it bears the potential to improve cosmesis,50 the potential long-tem1 toxicites of radiation treatment in our patient's young age group outweighs benefit. Nipple excision is often necessitated42 since the male breast most often 14 leads malignancy to a subarelor presentation. There is no evidence for axillary lymph node dissection, tamoxifen and adjuvant radiation or 21 chemotherapy. Since our patient received treatment for what was thought to be

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gynecomastia, subcutaneous mastectomy was performed. The patient was well and no recurrence was detected on follow-up at three months . There is no indication in the literature that samples from gynecomastia procedures should be routinely sent for pathological examination. Given the unilateral nature in our patient, samples were sent for examination to rule out the rare occurrence of malignancy . Liao et a/. recognize the routine hi stologica l examination of samples in 15 female cases of reduction mammaplasty. It is further suggested that the same procedure be following for gynecomastia samples when poss ible, noting suction lipectomy may make it difficult because of large volume and destruction 15 of cells. Perhaps surgical mastectomy should be applied to more cases, allowing for better review of not only the sample itself, but also the surgical margms . Our patient had a ignificant family history of breast cancer, though his mother had tested negati ve for BRCA 1 and 2. Fifteen to twenty percent of all MBC patients have a family hi story of breast cancer. Just as our patient was, all MBC cases are routinely offered genetic counselling. Beyond BRCA, MBC has been associated with PTEN mutation in Cowden's 51 syndrome as well as MLH l , a mi smatch repair gene re lated to hereditary nonpolyposis colorectal 52 cancer syndrome. Our patient did not undergo genetic testing s ince hi s moth er had tested negative .

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Surgery, gynecology & obstetrics 1993; 177:42540 . 50 . Deutsch M , Altomare FJ Jr, Mastri an AS, C hervenak JP. Carcinoma of the mal e breast thy mi c irradiation. Radiology fo llowing 19 7 5; 11 6:41 3-4. 5 1. Fac kentha l J, Marsh DJ, Richardson AL, C ummings SA, E ng C, Robinson BG, Olopade 0 1. Ma le breast cancer in Cowden syndrome pati ents w ith germline PTEN mutations. Journa l of medi cal geneti cs 200 I ;38: 159-64. 52. Boyd J, Rh ei E, Federi c i MG , Borgen PI, Watson P, Franklin B, Karr B, Lynch J, Lemon SJ, Lynch HT. M a le breast cancer in th e hereditary nonpolyposis co lorecta l cancer syndrome. Breast cancer research and treatment 1999; 53:87-9 1.

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