Chuong 40

1664

CMDT 2013

40

Clinical Genetic Disorders Reed E. Pyeritz, MD, PhD

ACUTE INTERMITTENT PORPHYRIA

``

Essentials of diagnosis

Unexplained abdominal crisis, generally in young women.

Acute peripheral or central nervous system dysfunction.

Recurrent psychiatric illnesses.

Hyponatremia.

Porphobilinogen in the urine during an attack.

``

``

`` `` ``

``General Considerations Though there are several different types of porphyrias, the one with the most serious consequences and the one that usually presents in adulthood is acute intermittent porphyria (AIP), which is inherited as an autosomal dominant, though it remains clinically silent in most patients who carry a mutation in HMBS. Clinical illness usually develops in women.

Symptoms begin in the teens or 20s, but onset can begin after menopause in rare cases. The disorder is caused by partial deficiency of porphobilinogen deaminase activity, leading to increased excretion of aminolevulinic acid and porphobilinogen in the urine. The diagnosis may be elusive if not specifically considered. The characteristic abdominal pain may be due to abnormalities in autonomic innervation in the gut. In contrast to other forms of porphyria, cutaneous photosensitivity is absent in AIP. Attacks are precipitated by numerous factors, including drugs and intercurrent infections. Harmful and relatively safe drugs for use in treatment are listed in Table 40–1. Hyponatremia may be seen, due in part to inappropriate release of antidiuretic hormone, although gastrointestinal loss of sodium in some patients may be a contributing factor.

``Clinical Findings A. Symptoms and Signs Patients show intermittent abdominal pain of varying severity, and in some instances it may so simulate acute

abdomen as to lead to exploratory laparotomy. Because the origin of the abdominal pain is neurologic, there is an absence of fever and leukocytosis. Complete recovery between attacks is usual. Any part of the nervous system may be involved, with evidence for autonomic and peripheral neuropathy. Peripheral neuropathy may be symmetric or asymmetric and mild or profound; in the latter instance, it can even lead to quadriplegia with respiratory paralysis.

Other central nervous system manifestations include ­seizures, psychosis, and abnormalities of the basal ganglia.

Hyponatremia may further cause or exacerbate central nervous system manifestations.

B. Laboratory Findings Often there is profound hyponatremia. The diagnosis can be confirmed by demonstrating an increased amount of porphobilinogen in the urine during an acute attack.

Freshly voided urine is of normal color but may turn dark upon standing in light and air.

Most families have a different mutation in the porphobilinogen deaminase gene causing AIP. Mutations can be detected and used for presymptomatic and prenatal diagnosis.

``Prevention Avoidance of factors known to precipitate attacks of AIP— especially drugs—can reduce morbidity. Sulfonamides and barbiturates are the most common culprits; others are listed in Table 40–1 and on the Internet (www. drugs-porphyria.org). Starvation diets or prolonged fasting also cause attacks and so must be avoided. Hormonal changes during pregnancy can precipitate crises.

``Treatment Treatment with a high-carbohydrate diet diminishes the number of attacks in some patients and is a reasonable empiric gesture considering its benignity. Acute attacks may be life-threatening and require prompt diagnosis, withdrawal of the inciting agent (if possible), and treatment with analgesics and intravenous glucose and hematin. A minimum of 300 g of carbohydrate per day should be provided orally or intravenously. Electrolyte balance

Clinical Genetic Disorders

Table 40–1. Some of the “unsafe” and “probably safe” drugs used in the treatment of acute porphyrias.

Unsafe Alcohol Alkylating agents Barbiturates Carbamazepine Chloroquine Chlorpropamide Clonidine Dapsone Ergots Erythromycin Estrogens, synthetic Food additives Glutethimide Griseofulvin Hydralazine Ketamine Meprobamate Methyldopa Metoclopramide Nortriptyline Pentazocine Phenytoin Progestins Pyrazinamide Rifampin Spironolactone Succinimides Sulfonamides Theophylline Tolazamide Tolbutamide Valproic acid

CMDT 2013

1665

Pischik E et al. Neurological manifestations of acute intermittent porphyria. Cell Mol Biol (Noisy-le-Grand). 2009 Feb 16;55(1): 72–83. [PMID: 19268005]

Probably Safe Acetaminophen β-Adrenergic blockers Amitriptyline Aspirin Atropine Chloral hydrate Chlordiazepoxide Corticosteroids Diazepam Digoxin Diphenhydramine Guanethidine Hyoscine Ibuprofen Imipramine Insulin Lithium Naproxen Nitrofurantoin Opioid analgesics Penicillamine Penicillin and derivatives Phenothiazines Procaine Streptomycin Succinylcholine Tetracycline Thiouracil

requires close attention. Hematin therapy should be undertaken with full recognition of adverse consequences, especially phlebitis and coagulopathy. The intravenous dosage is up to 4 mg/kg once or twice daily. Liver transplantation may provide an option for patients with disease poorly controlled by medical therapy.

``When to Refer • For management of severe abdominal pain, seizures, or psychosis.

• For preventive management when a patient with porphyria contemplates pregnancy.

• For genetic counseling and molecular diagnosis.

``When to Admit The patient should be hospitalized when he or she has an acute attack accompanied by mental status changes, seizure, or hyponatremia.

Dar FS et al. Liver transplantation for acute intermittent porphyria: a viable treatment? Hepatobiliary Pancreat Dis Int. 2010 Feb;9(1):93–6. [PMID: 20133237]

ALKAPTONURIA

``

Essentials of diagnosis

Ochronosis (gray-black discoloration of connective tissue, including the sclerae, ears, and cartilage).

Characteristic radiologic changes in the spine, with radiodense intervertebral discs.

Arthropathy.

Urine darkens on standing.

``

``

`` ``

``Clinical Findings A. Symptoms and Signs Alkaptonuria is caused by a recessively inherited deficiency of the enzyme homogentisic acid oxidase. This acid derives from metabolism of both phenylalanine and tyrosine and is present in large amounts in the urine throughout the patient’s life. An oxidation product accumulates slowly in cartilage throughout the body, leading to degenerative joint disease of the spine and peripheral joints. Indeed, examination of patients in the third and fourth decades shows a slight darkish blue color below the skin in areas overlying cartilage, such as in the ears, a phenomenon called ochronosis. In some patients, a more severe hyperpigmentation can be seen in the sclera, conjunctiva, and cornea. Accumulation of metabolites in heart valves can lead to aortic or mitral stenosis. A predisposition to coronary artery disease may also be present. Although the syndrome causes considerable morbidity, life expectancy is reduced only modestly. Symptoms are more often attributable to spondylitis with back pain, leading to a clinical picture difficult to distinguish from that of ankylosing spondylitis, though on radiographic assessment the sacroiliac joints are not fused in alkaptonuria.

B. Laboratory Findings The diagnosis is established by demonstrating homo­ gentisic acid in the urine, which turns black spontaneously on exposure to the air; this reaction is particularly noteworthy if the urine is alkaline or when alkali is added to a specimen. Molecular analysis of the homogentisic acid oxidase gene (HGD) is available but not necessary for diagnosis.

``Prevention Carrier screening and prenatal diagnosis are possible by testing for genetic mutations.

1666

CMDT 2013

Chapter 40

``Treatment Treatment of the arthritis is similar to that for other arthropathies. Though, in theory, rigid dietary restriction might reduce accumulation of the pigment, this has not proved to be of practical benefit.

Al-Mahfoudh R et al. Alkaptonuria presenting with ochronotic spondyloarthropathy. Br J Neurosurg. 2008 Dec;22(6):805–7.

[PMID: 19085367] Vilboux T et al. Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria. Hum Mutat. 2009 Dec;30(12): 1611–9. [PMID: 19862842]

DOWN SYNDROME

``

Essentials of diagnosis

Typical craniofacial features (flat occiput, epicanthal folds, large tongue).

Mental retardation.

Congenital heart disease (eg, atrioventricular canal defects) in 50% of patients.

Three copies of chromosome 21 (trisomy 21) or a chromosome rearrangement that results in three copies of a region of the long arm of chromosome 21.

``

`` ``

``

will be a substantial recurrence risk of Down syndrome in future offspring of that parent and potentially that parent’s relatives.

``Prevention Nearly 0.5% of all human conceptions are trisomic for chromosome 21. Because of increased fetal mortality, birth incidence of Down syndrome is 1 per 700 but varies from 1 per 1000 in young mothers to more than three times as frequent in women of advanced maternal age. The presence of a fetus with Down syndrome can be detected in many pregnancies in the first or early second trimester through screening maternal serum for α-fetoprotein and other biomarkers (“multiple marker screening”) and by detecting increased nuchal thickness and underdevelopment of the nasal bone on fetal ultrasound. The risk of bearing a child with Down syndrome increases exponentially with the age of the mother at conception and begins a marked rise after age 35. By age 45 years, the odds of having an affected child are as high as 1 in 40. The risk of other conditions associated with trisomy also increases, because of the predisposition of older oocytes to nondisjunction during meiosis. There is little risk of trisomy associated with increased paternal age. However, older men do have an increased risk of fathering a child with a new autosomal dominant condition. Because there are so many distinct conditions, though, the chance of fathering an offspring with any given one is extremely small.

``Treatment ``Clinical Findings A. Symptoms and Signs Down syndrome is usually diagnosed at birth on the basis of the typical craniofacial features, hypotonia, and single palmar crease. Several serious problems that may be evident at birth or may develop early in childhood include duodenal atresia, congenital heart disease (especially atrioventricular canal defects), and hematologic malignancy.

The intestinal and cardiac anomalies usually respond to surgery. A transient neonatal leukemia generally responds to conservative management. The incidences of both acute lymphoblastic and myeloid leukemias are increased in childhood. Intelligence varies across a wide spectrum.

Many people with Down syndrome do well in sheltered workshops and group homes, but few achieve full independence in adulthood. Other frequent complications include atlanto-axial instability, celiac disease, and hypothyroidism. An Alzheimer-like dementia usually becomes evident in the fourth or fifth decade. Patients with Down syndrome who survive childhood and who develop dementia have a reduced life expectancy; on average, they live to about age 55 years.

B. Laboratory Findings Cytogenomic analysis should always be performed—even though most patients will have simple trisomy for chromosome 21—to detect unbalanced translocations; such patients may have a parent with a balanced translocation, and there

Duodenal atresia should be treated surgically. Congenital heart disease should be treated as in any other patient. No medical treatment has been proven to affect the intellectual capacity.

``When to Refer • For comprehensive evaluation of infants to investigate congenital heart disease, hematologic malignancy, and duodenal atresia.

• For genetic counseling of the parents.

• For signs of dementia in an adult patient.

``When to Admit An affected young patient should be hospitalized when he or she has failure to thrive, regurgitation, breathlessness, or easy bruising.

Andriolo RB et al. Aerobic exercise training programmes for improving physical and psychosocial health in adults with Down syndrome. Cochrane Database Syst Rev. 2010 May 12;5:CD005176. [PMID: 20464738] Driscoll DA et al; Professional Practice and Guidelines Committee.

First trimester diagnosis and screening for fetal aneuploidy.

Genet Med. 2008 Jan;10(1):73–4. [PMID: 18197059] Lott IT et al. Cognitive deficits and associated neurological complications in individuals with Down’s syndrome. Lancet Neurol. 2010 Jun;9(6):623–33. [PMID: 20494326] Mégarbané A et al. The 50th anniversary of the discovery of trisomy 21: the past, present, and future of research and

Clinical Genetic Disorders

t­ reatment of Down syndrome. Genet Med. 2009 Sept;11(9): 611–16. [PMID: 19636252] Wiseman FK et al. Down syndrome—recent progress and future prospects. Hum Molec Genet. 2009 Apr 15;18(R1):R75–83.

[PMID: 19297404]

FRAGILE X MENTAL RETARDATION

``

Essentials of diagnosis

Expanded trinucleotide repeat in the FMR1 gene.

Mental retardation and autism in males.

Large testes after puberty.

Learning disabilities or mental retardation in females.

Premature ovarian failure.

Late-onset tremor and ataxia in males and females with moderate trinucleotide repeat expansion (premutation carriers).

`` `` `` ``

`` ``

``Clinical Findings A. Symptoms and Signs This X-linked condition accounts for more cases of mental retardation in males than any condition except Down syndrome; about 1 in 5000 males is affected. The condition also affects intellectual function in females, although less severely and about 50% less frequently than in males.

Affected (heterozygous) young women show no physical signs other than early menopause, but they may have learning difficulties or frank retardation. Affected males show macro-orchidism (enlarged testes) after puberty, large ears and a prominent jaw, a high-pitched voice, autistic characteristics, and mental retardation. Some males show evidence of a mild connective tissue defect, with joint hypermobility and mitral valve prolapse.

Women who are premutation carriers (55–200 CGG repeats) are at increased risk for premature ovarian failure and mild cognitive abnormalities. Male and female premutation carriers are at risk for mood and anxiety disorders and the development of tremor and ataxia beyond middle age (fragile-X tremor-ataxia syndrome, FXTAS). Changes in the cerebellar white matter may be evident on MRI before symptoms appear. Because of the relatively high prevalence of premutation carriers in the general population, older people in whom any of these behavioral or neurologic problems develop should undergo testing of the FMR1 locus.

1667

this location, but as the number increases beyond 52, the chances of further expansion during spermatogenesis or oogenesis increase.

Being born with one FMR1 allele with 200 or more repeats results in mental retardation in most men, and in about 60% of women. The more repeats, the greater the likelihood that further expansion will occur during gameto-genesis; this results in anticipation, in which the disorder can worsen from one generation to the next.

``Prevention DNA diagnosis for the number of repeats has supplanted cytogenetic analysis for both clinical and prenatal diagnosis. This should be done on any male or female who has unexplained mental retardation. Newborn screening based on hypermethylation of the FMR1 gene is being considered as a means of early detection and intervention.

``Treatment No specific treatments have been developed but several based on the mouse model are in development. Valproic acid may reduce symptoms of hyperactivity and attention deficit, but standard therapies should be tried first.

``When to Refer • For otherwise unexplained mental retardation or learning difficulties in boys and girls.

• For otherwise unexplained tremor or ataxia in middleaged individuals.

• For premature ovarian failure.

• For genetic counseling.

Bourgeois JA et al. A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry. 2009 Jun;70(6):852–62. [PMID: 19422761] Coffee B et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet. 2009 Oct;85(4):503–14. [PMID: 19804849] Martin JR et al. Fragile X and reproduction. Curr Opin Obstet Gynecol. 2008 Jun;20(3):216–20. [PMID: 18460934] Sutherland GR et al. Fragile X syndrome and other causes of X-linked mental handicap. In: Rimoin DL et al (editors).

Emery and Rimoin’s Principles and Practice of Medical Genetics, 5th ed. Philadelphia: Churchill Livingstone, 2007.

Torrioli M et al. Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys. Am J Med Genet A. 2010 Jun;152A(6):1420–7. [PMID: 20503316]

GAUCHER DISEASE

``

B. Laboratory Findings The first marker for this condition was a small gap, or fragile site, evident near the tip of the long arm of the X chromosome. Subsequently, the condition was found to be due to expansion of a trinucleotide repeat (CGG) near a gene called FMR1. All individuals have some CGG repeats in

CMDT 2013

Deficiency of β-glucocerebrosidase.

Anemia and thrombocytopenia.

Hypersplenism.

Pathologic fractures.

`` `` `` ``

Essentials of diagnosis

1668

CMDT 2013

Chapter 40

``Clinical Findings A. Symptoms and Signs Gaucher disease has an autosomal recessive pattern of inheritance. A deficiency of β-glucocerebrosidase causes an accumulation of sphingolipid within phagocytic cells throughout the body. Anemia and thrombocytopenia are common and may be symptomatic; both are due primarily to hypersplenism, but marrow infiltration with Gaucher cells may be a contributing factor. Cortical erosions of bones, especially the vertebrae and femur, are due to local infarctions, but the mechanism is unclear. Episodes of bone pain (termed “crises”) are reminiscent of those in sickle cell disease. A hip fracture in a patient with a palpable spleen—especially in a Jewish person of Eastern European origin—suggests the possibility of Gaucher disease.

Two uncommon forms of Gaucher disease, called type II and type III, involve neurologic accumulation of sphingolipid and a variety of neurologic problems. Type II is of infantile onset and has a poor prognosis. Heterozygotes for Gaucher disease are at increased risk for developing Parkinson disease.

B. Laboratory Findings Bone marrow aspirates reveal typical Gaucher cells, which have an eccentric nucleus and periodic acid–Schiff (PAS)positive inclusions, along with wrinkled cytoplasm and inclusion bodies of a fibrillar type. In addition, the serum acid phosphatase is elevated. Definitive diagnosis requires the demonstration of deficient glucocerebrosidase activity in leukocytes. Hundreds of mutations have been found to cause Gaucher disease and some are highly predictive of the neuronopathic forms. Thus, mutation detection, especially in a young person, is of potential value. Only four mutations in glucocerebrosidase account for more than 90% of the disease among Ashkenazi Jews, in whom the carrier frequency is 1:15.

``Prevention Most clinical complications can be prevented by early institution of enzyme replacement therapy. Carrier screening, especially among Ashkenazi Jews, detects those couples at 25% risk of having an affected child. Prenatal diagnosis through mutation analysis is feasible.

``Treatment For many years, treatment was supportive and included splenectomy for thrombocytopenia secondary to platelet sequestration. A recombinant form of the enzyme glucocerebrosidase (imiglucerase) for intravenous administration on a regular basis now permits a reduction in total body stores of glycolipid and improvement in orthopedic and hematologic manifestations. Unfortunately, the neurologic manifestations of types II and III have not improved with enzyme replacement therapy. The major drawback is the exceptional cost of imiglucerase, which can exceed $100,000

per year for a severely affected patient. Early treatment of affected children normalizes growth and bone mineral density and improves liver and spleen size, anemia, and thrombocytopenia. Alternative or complementary therapies, including methods to reduce substrate and to provide a chaperone for a defective enzyme, are being developed.

One approved medication, miglustat, does reduce the production of glucocerebroside in some patients, but can be poorly tolerated because of adverse effects.

Andersson H et al. Eight-year clinical outcomes of long-term enzyme replacement therapy for 884 children with Gaucher disease type I. Pediatrics. 2008 Dec;122(6):1182–90. [PMID: 19047232] Cox TM et al. Management of non-neuronopathic Gaucher disease with special reference to pregnancy, splenectomy, bisphosphonate therapy, use of biomarkers and bone disease monitoring. J Inherit Metab Dis. 2008 Jun;31(3):319–36.

[PMID: 18509745] Piran S et al. Gaucher disease: a systematic review and metaanalysis of bone complications and their response to treatment. J Inherit Metab Dis. 2010 Jun;33(3):271–9. [PMID: 20336376] Sidransky E et al. Multicenter analysis of glucocerebrosidase mutation in Parkinson’s disease. N Engl J Med. 2009 Oct 22;361(17):1651–61. [PMID: 19846850] Zimran A et al. Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience. Blood. 2010 Jun 10;115(23): 4651–6. [PMID: 20299511]

Disorders of Homocysteine metabolism

``

Essentials of diagnosis

For homocystinuria, dislocated ocular lenses.

Elevated homocysteine in the urine or plasma.

`` ``

``General Considerations Considerable evidence has accumulated to support the observation that patients with clinical and angiographic evidence of coronary artery disease tend to have higher levels of plasma homocysteine than persons without coronary artery disease. The relationship has been extended to cerebrovascular and peripheral vascular diseases. Although this effect was initially thought to be due at least in part to heterozygotes for cystathionine β-synthase deficiency (see below), there is little supporting evidence. Rather, an important factor leading to hyperhomocysteinemia is folate deficiency. Pyridoxine (vitamin B6) and vitamin B12 are also important in the metabolism of methionine, and deficiency of any of these vitamins can lead to accumulation of homocysteine. A number of genes influence utilization of these vitamins and can predispose to deficiency. For example, having one—and especially two—copies of an allele that causes thermolability of methylene tetrahydrofolate

Clinical Genetic Disorders reductase predisposes people to elevated fasting homocysteine levels. Both nutritional and most genetic deficiencies of these vitamins can be corrected by dietary supplementation of folic acid and, if serum levels are low, vitamins B6 and B12. In the United States, cereal grains are fortified with folic acid. However, therapy with B vitamins and folate lowers homocysteine levels significantly but does not reduce the risk of either venous thromboembolism or complications of coronary artery disease. The role of lowering homocysteine as primary prevention for sequelae of atherosclerosis has received little direct support in clinical trials. Hyperhomocysteinemia occurs with end-stage chronic kidney disease.

``Clinical Findings A. Symptoms and Signs Homocystinuria in its classic form is caused by cystathionine β-synthase deficiency and exhibits an autosomal recessive pattern of inheritance. This results in extreme elevations of plasma and urinary homocystine levels, a basis for diagnosis of this disorder. Homocystinuria is similar in certain superficial aspects to Marfan syndrome, since patients may have a similar body habitus and ectopia lentis is almost always present. However, mental retardation is often present in homocystinuria, and the cardiovascular events are those of repeated venous and arterial thromboses whose precise cause remains obscure. Life expectancy is reduced, especially in untreated and pyridoxine-unresponsive patients; myocardial infarction, stroke, and pulmonary embolism are the most common causes of death. This condition is diagnosed by newborn screening for hypermethioninemia; however, pyridoxine-responsive infants may not be detected.

The diagnosis should be suspected in patients in the second and third decades of life who have arterial or venous thromboses without other risk factors.

CMDT 2013

methionine and supplementation of cysteine, also from infancy. The vitamin betaine is also useful in reducing plasma methionine levels by facilitating a metabolic pathway that bypasses the defective enzyme.

``Treatment Patients with classic homocystinuria who have suffered venous thrombosis receive anticoagulation therapy, but there are no studies to support prophylactic use of warfarin or antiplatelet agents.

Lee M et al. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke. 2010 Jun;41(6):1205–12. [PMID: 20413740] Miller ER 3rd et al. Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. Am J Cardiol. 2010 Aug 15;106(4):517–27. [PMID: 20691310] Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group et al.

Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010 Jun 23;303(24):2486–94. [PMID: 20571015] Varela-Moreiras G et al. Cobalamin, folic acid and homocysteine.

Nutr Rev. 2009 May;67(Suppl 1):S69–72. [PMID: 19453682]

KLINEFELTER SYNDROME

``

Essentials of diagnosis

Males with hypogonadism and small testes.

47,XXY karyotype.

`` ``

B. Laboratory Findings

``Clinical Findings

Although many mutations have been identified in the cystathionine β-synthase gene (CBC), amino acid analysis of plasma remains the most appropriate diagnostic test.

Patients should be studied after they have been off folate or pyridoxine supplementation for at least 1 week.

Relatively few laboratories currently provide highly reliable assays for homocysteine. Processing of the specimen is crucial to obtain accurate results. The plasma must be separated within 30 minutes; otherwise, blood cells release the amino acid and the measurement will then be artificially elevated.

A. Symptoms and Signs

``Prevention About 50% of patients have a form of cystathionine β-synthase deficiency that improves biochemically and clinically through pharmacologic doses of pyridoxine (50–500 mg/d) and folate (5–10 mg/d). For these patients, treatment from infancy can prevent retardation and the other clinical problems. Patients who are pyridoxine nonresponders must be treated with a dietary reduction in

1669

Boys with an extra X chromosome are normal in appearance before puberty; thereafter, they have disproportionately long legs and arms, a female escutcheon, gynecomastia, and small testes. Infertility is due to azoospermia; the seminiferous tubules are hyalinized. The diagnosis is often not made until a couple is evaluated for inability to conceive. Mental retardation is somewhat more common than in the general population. Many men with Klinefelter syndrome have learning problems. However, their intelligence usually tests within the broad range of normal. As adults, detailed psychometric testing may reveal a deficiency in executive skills. The risk of breast cancer and diabetes mellitus is much higher in men with Klinefelter syndrome than in 46,XY men.

B. Laboratory Findings Low serum testosterone is common. The karyotype is ­typically 47,XXY.

1670

CMDT 2013

Chapter 40

``Prevention Screening for cancer, especially of the breast, and for glucose intolerance are indicated.

with elongated chordae tendineae, which on occasion may rupture.

``Clinical Findings

``Treatment

A. Symptoms and Signs

Treatment with testosterone after puberty is advisable but will not restore fertility. However, men with Klinefelter syndrome have had mature sperm aspirated from their testes and injected into oocytes, resulting in fertilization.

After the blastocysts have been implanted into the uterus of a partner, conception has resulted. However, men with Klinefelter syndrome do have an increased risk for aneuploidy in sperm, and therefore genomic analysis of a blastocyst should be considered before implantation.

Affected patients are typically tall, with particularly long arms, legs, and digits (arachnodactyly). However, there can be wide variability in the clinical presentation. Commonly, scoliosis and anterior chest deformity, such as pectus excavatum, are found. Ectopia lentis is present in about half of patients; severe myopia is common and retinal detachment can occur. Mitral valve prolapse is seen in about 85% of patients. Aortic root dilation is common and leads to aortic regurgitation or dissection with rupture. To diagnose Marfan syndrome, people with an affected relative need features in at least two systems. People with no family history need features in the skeletal system, two other systems, and one of the major criteria of ectopia lentis, dilation of the aortic root, or aortic dissection. Patients with homocystinuria due to cystathionine synthase deficiency also have dislocated lenses; tall, disproportionate stature; and thoracic deformity. They tend to have below normal intelligence, stiff joints, and a predisposition to arterial and venous occlusive disease. Males with Klinefelter syndrome do not show the typical ocular or cardiovascular features of Marfan syndrome and are generally sporadic occurrences in the family.

Gravholt CH. Sex chromosome abnormalities. In: Rimoin DL et al (editors). Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th ed. Philadelphia: Churchill Livingstone, 2012.

Radicioni AF et al. Strategies and advantages of early diagnosis in Klinefelter’s syndrome. Mol Hum Reprod. 2010 Jun; 16(6):434–40. [PMID: 20392711] Ramasamy R et al. Successful fertility treatment for Kline­ felter’s syndrome. J Urol. 2009 Sept;182(3):1108–13. [PMID: 19616796] Turriff A et al. Prevalence and psychosocial correlates of depressive symptoms among adolescents and adults with Klinefelter syndrome. Genet Med. 2011 Nov;13(11):966–72. [PMID: 21799429] Vignozzi L et al. Clinical and therapeutic aspects of Kline­ felter’s syndrome: sexual function. Mol Hum Reprod. 2010 Jun;16(6):418–24. [PMID: 20348547]

MARFAN SYNDROME

``

Essentials of diagnosis

Disproportionately tall stature, thoracic deformity, and joint laxity or contractures.

Ectopia lentis and myopia.

Aortic dilation and dissection.

Mitral valve prolapse.

``

`` `` ``

``General Considerations Marfan syndrome, a systemic connective tissue disease, has an autosomal dominant pattern of inheritance. It is characterized by abnormalities of the skeletal, ocular, and cardiovascular systems; spontaneous pneumothorax; dural ectasia; and striae atrophicae. Of most concern is disease of the ascending aorta, which begins as a dilated aortic root. Histology of the aorta shows diffuse medial degeneration. Mitral valve leaflets are also abnormal and mitral prolapse and regurgitation may be present, often

B. Laboratory Findings Mutations in the fibrillin gene (FBN1) on chromosome 15 cause Marfan syndrome. Nonetheless, no simple laboratory test is available to support the diagnosis in questionable cases because related conditions may also be due to defects in fibrillin. The nature of the FBN1 mutation has little predictive value in terms of prognosis. The pathogenesis of Marfan syndrome involves aberrant regulation of transforming growth factor (TGF) β activity. Mutations in either of two receptors for TGFβ (TGFBR1 and TGFBR2) can cause conditions that resemble Marfan syndrome in terms of aortic aneurysm and dissection and autosomal dominant inheritance.

``Prevention There is prenatal and presymptomatic diagnosis for patients in whom the molecular defect in fibrillin has been found.

``Treatment Children with Marfan syndrome require regular ophthalmologic surveillance to correct visual acuity and thus prevent amblyopia, and annual orthopedic consultation for diagnosis of scoliosis at an early enough stage so that bracing might delay progression. Patients of all ages require echocardiography at least annually to monitor aortic diameter and mitral valve function. Long-term

Clinical Genetic Disorders β-adrenergic blockade, titrated to individual tolerance but enough to produce a negative inotropic effect (atenolol, 1–2 mg/kg orally daily) retards the rate of aortic dilation.

Several clinical trials comparing the effectiveness of atenolol and losartan, a drug that reduces activity of TGFβ, are underway. Restriction from vigorous physical exertion protects from aortic dissection. Prophylactic replacement of the aortic root with a composite graft when the diameter reaches 45–50 mm in an adult (normal: < 40 mm) prolongs life. A procedure to reimplant the patient’s native aortic valve and replace just the aneurysmal sinuses of Valsalva avoids the need for lifelong anti­ coagulation.

``Prognosis People with Marfan syndrome who are untreated commonly die in the fourth or fifth decade from aortic dissection or congestive heart failure secondary to aortic regurgitation. However, because of earlier diagnosis, lifestyle modifications, β-adrenergic blockade, and prophy­ lactic aortic surgery, life expectancy has increased by several decades in the past 25 years.

``When to Refer • • • • •

For detailed ophthalmologic examination.

For at least annual cardiologic evaluation.

For moderate scoliosis.

For pregnancy in a woman with Marfan syndrome.

For genetic counseling.

``When to Admit Any patient with Marfan syndrome in whom severe or unusual chest pain develops should be hospitalized to exclude pneumothorax and aortic dissection.

Brooke BS et al. Angiotensin II blockade and aortic-root dilation in Marfan’s syndrome. N Engl J Med. 2008 Jun 26;358(26): 2787–95. [PMID: 18579813] Keane M et al. Medical management of Marfan syndrome.

Circulation. 2008 May 27;117(21):2802–13. [PMID: 18506019] Loeys BL et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010 Jul;47(7):476–85. [PMID: 20591885] Pyeritz RE. Evaluation of the adolescent or adult with some features of Marfan syndrome. Genet Med. 2012 Jan;14(1): 171–7. [PMID: 22237449] Pyeritz RE. Marfan syndrome and related disorders. In: Rimoin DL et al (editors). Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th ed. Philadelphia: Churchill Livingstone, 2012.

Volguina IV et al; Aortic Valve Operative Outcomes in Marfan Patients Study Group. Valve-sparing and valve-replacing techniques for aortic root replacement in patients with Marfan syndrome: analysis of early outcome. J Thorac Cardiovasc Surg. 2009 May;137(5):1124–31. [PMID: 19379977]

CMDT 2013

1671

HEREDITARY HEMORRHAGIC TELANGiECTASIA

``

Essentials of diagnosis

Recurrent epistaxis.

Mucocutaneous telangiectases.

Visceral arteriovenous malformations (especially lung, liver, brain, bowel).

`` `` ``

``Clinical Findings A. Symptoms and Signs Hereditary hemorrhagic telangiectasia (HHT), formerly termed “Osler-Weber-Rendu syndrome,” is an autosomal dominant disorder of development of the vasculature.

Epistaxis may begin in childhood or later in adolescence.

Punctate telangiectases of the lips, tongue, fingers, and skin generally appear in later childhood and adolescence.

Arteriovenous malformations (AVMs) can occur at any age in the brain, lungs, and liver. Bleeding from the gastrointestinal tract is due to mucosal vascular malformations and usually is not a problem until mid-adult years or later.

Pulmonary AVMs can cause hypoxemia (with peripheral cyanosis, dyspnea, and clubbing) and right-to-left shunting (with embolic stroke or brain abscess). The criteria for diagnosis require presence of three of the following four features: (1) recurrent epistaxis, (2) visceral AVMs, (3) mucocutaneous telangiectases, and (4) being the near relative of a clearly affected individual. Mutation analysis can be used for presymptomatic diagnosis or exclusion of the worry of HHT.

B. Laboratory Findings MR or CT arteriography detects AVMs. Mutations in at least five genes can cause HHT. Three have been identified and molecular analysis to identify them is available; these mutations in ENG, ALK1, and SMAD4 account for about 87% of families with HHT. When the familial mutation is known, molecular testing is far more cost effective than repeated screening of relatives who are at risk.

``Prevention Embolization of pulmonary AVMs with wire coils or other occlusive devices reduces the risk of stroke and brain abscess. Treatment of brain AVMs reduces the risk of hemorrhagic stroke. All patients with HHT with evidence of a pulmonary shunt should practice routine endocarditis prophylaxis (see Table 33–6). All intravenous lines (except those for transfusion of red blood cells and radiographic contrast) should have an air-filter to prevent embolization of an air bubble. Prenatal diagnosis through mutation detection is possible.

1672

CMDT 2013

Chapter 40

``Treatment All patients in whom the diagnosis of HHT is considered should have an MRI of the brain with contrast. A contrast echocardiogram will detect most pulmonary AVMs when “bubbles” appear on the left side of the heart after 3–6 cardiac cycles. A positive contrast echocardiogram should be followed by a high-resolution CT angiogram for localization of pulmonary AVMs. Patients who have AVMs with a feeding artery of 1–2 mm diameter or greater should undergo embolization. After successful embolization of all treatable pulmonary AVMs, the CT angiogram should be repeated in 3 years. A person with a negative contrast echocardiogram should have the test repeated every 5 years.

Bernhardt BA et al. Cost savings through molecular diagnosis for hereditary hemorrhagic telangiectasia. Genet Med. 2012 Jan 26. [Epub ahead of print] [PMID: 22281938] Faughnan ME et al; HHT Guidelines Working Group.

International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011 Feb;48(2):73–87. [PMID: 19553198] Guttmacher AE et al. Hereditary hemorrhagic telangiectasia. In: Rimoin DL et al (editors). Emery and Rimoin’s Principles and Practice of Medical Genetics, 6th ed. Philadelphia: Churchill Livingstone, 2012.

McDonald J et al. Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis. Genet Med. 2011 Jul;13(7):607–16. [PMID: 21546842] Trerotola SO, Pyeritz RE. PAVM embolization: an update. AJR Am J Roentgenol. 2010 Oct;195(4):837–45. [PMID: 20858807]