SHA24/039003

M. Elhoury, E. Faqeih, A. Almoukirish, M. Galal PSHC, KFMC, Riyadh, KSA

Definition  The gene  History  Clinical presentation  Phenotype  echocardiography  Follow up  Conclusions 

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GD is an extremely rare acromelic skeletal dysplasia

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< 40 cases reported, none from Arab countries

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Resembles lysosomal storage disease

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Most have cardiac valve involvement •Scott A, Yeung S, Dickinson FD, Karbani G, Crow YJ. Natural History of Cardiac Involvement in Geleophysic Dysplasia. Am J of Med Genet 2005; 132A:320–323

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Characterized by: ◦ Characteristic facial phenotype ◦ Short stature ◦ Micromelia ◦ Joints contracture ◦ Cardiac valvular involvement

•Scott A, Yeung S, Dickinson FD, Karbani G, Crow YJ. Natural History of Cardiac Involvement in Geleophysic Dysplasia.

Am J of Med Genet 2005; 132A:320–323.

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Described in 1960 as atypical gargoylism by Vanace et al

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Spranger et al 1971 as a focal mucopolysacchriodosis

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Spranger coined the term of GD (geleos= happy. physis= nature) •Vanace PW, Friedman S, Wagner BM. Mitral stenosis in an atypical case of gargoylism: A case report with pathological and histochemical studies of the cardiac tissues. Circulation 1960; 21:80–89.

•Spranger JW, Gilbert EF, Tuffli GA, Rossiter FP, Opitz JM. Geleophysic dwarfism a ‘focal’ mucopolysaccharidosis? Lancet 1971; 2:97–98.

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Gene identified by Le Goff et al in 2008

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ADAMTSL2 gene ( A Disintegrin And Metalloproteinase with ThromboSpondin repeats–Like 2)

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Located in chromosome 9p34.2 • Le Goff C, Morice-Picard F, Dagoneau N, et al. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTSlike proteins in TGF-β bioavailabilityregulation, Nat Genet. 2008; 40(9): 1119–1123

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ADAMTSL2 belongs to a large superfamily containing 19 ADAMTS Some ADAMTS proteases participate ◦ Extracellular matrix turnover in arthritis ◦ Von Willebrand ◦ In angiogenesis

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ADAMTSL-2 (5 types) their functions are not yet known Le Goff C, Morice-Picard F, Dagoneau N, et al. ADAMTSL2 mutations in geleophysic dysplasia demonstrate a role for ADAMTS-like proteins in TGF-β bioavailabilityregulation, Nat Genet. 2008; 40(9): 1119–1123

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Two sisters referred to us 3 years back At age of 4 ½ and 3 ½ years Young cousin parents Short stature and heart murmur History of respiratory illness Have normal development and intelligence Later the third sibling seen at age of 15 month

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All are < 3rd centile for Wt and Ht

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They all have facial phenotype of: ◦ Thin upper lips ◦ Smooth and wide philtrum ◦ Anteverted nares ◦ hypertelorism and broad nasal bridge ◦ All have happy personality and normal intelligence

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Hands and feet are small and broad

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Limitations of flexion of hands

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Can not make a fist

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Bilateral contractures of both elbow and

knee joints 

Walk on tip – toes

Oldest Child

Middle Child

Youngest Child

Here

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Skeletal survey showed: ◦ Short tubular bones of the hands and feet ◦ Small irregular capital femoral epiphyses ◦ Ovoid vertebral bodies

A

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ADAMTSL2 gene mutation is confirmed showed heterozygous mutations ◦ 1- The c.338 G>T has been reported in GD ◦ 2- IVS5-89G>A transition is novel mutation has not been published

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The eldest sister: ◦ Small atrial septal defect (ASDII) ◦ Thickened AV valves ◦ Peak mitral inflow 9mmHg mean of 2 mmHg ◦ Mild TR, moderate MR ◦ Mild PS gradient 21mmHg ◦ Mild AS gradient 39 mmHg

Gradient 32

Gradient 43 Gradient 39

dient 21

Gradient 30

Gradient 21

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The second sister: ◦ Thickened AV valves ◦ Peak mitral inflow 10 mmHg mean of 4 mmHg ◦ Mild TR, mild MR ◦ No PS, no AS

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The youngest sister: ◦ Thickened AV valves ◦ Peak mitral inflow 9 mmHg mean of 4 mmHg ◦ Mild TR, moderate MR ◦ Mild PS gradient 36 mmHg ◦ Mild post stenotic dilatation of MPA ◦ Severe AS peak systolic gradient 95 mmHg mean of 47 mmHg ◦ Post stenotic dilatation of the As Ao ◦ Small PDA

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The two elder sisters followed for two years

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All valve involvement remained static

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They remained asymptomatic

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We managed the third one conservatively despite severe AS After one year the AS gradient unchanged

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All three sisters have same dysmorphic features.

Short stature

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The youngest has severe valve involvement

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The middle sister has the least involvement

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Could mean, that gene expression might determine the severity, rather than progression over time

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This is the first report of GD from Arab countries

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Only few cases reported worldwide

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The expression of the gene could determine the severity of valve involvement, rather than the progression with age

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In rare conditions the management decision might be very difficult as the natural history of the disease is not known