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