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


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


GD is an extremely rare acromelic skeletal dysplasia

< 40 cases reported, none from Arab countries

Resembles lysosomal storage disease

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.


Described in 1960 as atypical gargoylism by Vanace et al

Spranger et al 1971 as a focal mucopolysacchriodosis

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.


Gene identified by Le Goff et al in 2008

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

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


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

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


      

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


All are < 3rd centile for Wt and Ht

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


Hands and feet are small and broad

Limitations of flexion of hands

Can not make a fist

Bilateral contractures of both elbow and

knee joints 

Walk on tip – toes


Oldest Child


Middle Child


Youngest Child


Here


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


A


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


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


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


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


The two elder sisters followed for two years

All valve involvement remained static

They remained asymptomatic

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


All three sisters have same dysmorphic features. Short stature

The youngest has severe valve involvement

The middle sister has the least involvement

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


This is the first report of GD from Arab countries

Only few cases reported worldwide

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

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


SHA24/039003  

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