2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.169
A variant in the ZRS sonic hedgehog regulatory sequence is
associated with triphalangeal thumb and deregulates expression
in the developing limb
D. Furniss 1,2 , L. A. Lettice 3 , I. B. Taylor 1 , P. S. Critchley 2 , H. Giele 2 , R. E. Hill 3 , A.
O. M. Wilkie 1 ;
1 Weatherall Institute of Molecular Medicine, Oxford, United Kingdom, 2 Department
of Plastic and Reconstructive Surgery, Oxford, United Kingdom, 3 MRC
Human Genetics Unit, Edinburgh, United Kingdom.
A locus for triphalangeal thumb, variably associated with preaxial
polydactyly, was previously identified in the Zone of Polarizing Activity
Regulatory Sequence (ZRS), a long range limb-specific enhancer
of the Sonic Hedgehog gene (SHH) at human chromosome 7q36 .3 .
Here, we demonstrate that a 295T>C variant in the ZRS, previously
thought to represent a neutral polymorphism, acts as a dominant mutation
with reduced penetrance . We found this variant in 3 independently
ascertained probands from southern England with triphalangeal
thumb, demonstrated significant linkage of the phenotype to the variant
(LOD = 4.1), and identified a shared microsatellite haplotype around
the ZRS, suggesting that the probands share a common ancestor . An
individual homozygous for the 295C allele presented with isolated bilateral
triphalangeal thumb resembling the heterozygous phenotype,
suggesting that the variant is largely dominant to the wild type allele .
As a functional test of the pathogenicity of the 295C allele, we utilised a
mutated ZRS construct to demonstrate that it can drive ectopic anterior
expression of a reporter gene in the developing mouse forelimb . We
conclude that the 295T>C variant is in fact pathogenic and appears to
be the most common cause of triphalangeal thumb in southern England
. Depending on the dispersal of the founding mutation, it may play
a wider role on the aetiology of this disorder .
P01.170
Fetal Alcohol syndrome a phenocopy of spondylocarpotarsal
synostosis syndrome?
R. Rupps 1 , D. Krakow 2 , N. Puvanachandra 3 , J. Gardiner 3 , C. F. Boerkoel 1 ;
1 Department of Medical Genetics, University of British Columbia, Vancouver,
BC, Canada, 2 Skeletal Dysplasia Registry, Cedars-Sinai Medical Center, Los
Angeles, CA, United States, 3 Department of Ophthalmology and Visual Sciences,
University of British Columbia, Vancouver, BC, Canada.
Spondylocarpotarsal synostosis syndrome is characterized by disproportionate
short stature with fusion of vertebrae, carpal and tarsal
bones, thoracic scoliosis and pes planus . Other features often
described include delayed bone age, epiphyseal ossification delay,
cleft palate, dental enamel hypoplasia and renal anomalies . Skeletal
manifestations of fetal alcohol syndrome (FAS) include poor growth,
delayed bone age, congenital fusion of cervical vertebrae, coalition of
the capitate and hamate carpal bones and transverse limb defects . We
report a 6-year-old girl born to a 32-year-old mother and a 62 year old
father after a pregnancy complicated by alcohol abuse . She presented
with short stature, hypotonia, dysmorphic facial features, generalized
joint laxity and hyperextensibility and hearing loss . She also had poor
visual acuity, extremely high bilateral myopia, pale optic nerves, thin
retinal vessels and tigroid retinae . Subsequently, she developed an
asymptomatic complete funnel retinal detachment of the right eye . Her
skeletal survey revealed normal bone age, fusion of vertebral facet
joints of C2-4 and C5-6 with narrowing of these disc spaces but widening
of the C4-5 and C6-7 disc spaces, flared ilii, longer proximal than
distal long bones, fused capiate and hamate ossification centres and
bilateral coxa valga . We postulate that prenatal alcohol exposure can
phenocopy spondylocarpotarsal synostosis syndrome . Alternately, this
patient’s features could represent an overlap of fetal alcohol spectrum
disorder with spondylocarpotarsal synostosis syndrome, an extension
of the spondylocarpotarsal synostosis syndrome or an undescribed
syndrome .
P01.171
Variable phenotype of Hennekam syndrome
P. Blanchet, L. Pinson, C. Coubes, G. Lefort, P. Sarda;
Hôpital Arnaud de Villeneuve, Service de Génétique, Montpellier, France.
Hennekam syndrome is a rare autosomal recessive anomaly characterized
by lymphedema, lymphangiectasia, facial dysmorphism and
developmental delay . Heart, renal, skeletal anomalies and growth retardation
may also be a part of the spectrum . Severity of the syndrome
is due to lymphangiectasia, preferentially intestinal, and mental retardation
.
We describe two new unrelated cases of Hennekam syndrome .
The first patient, a 3-year-old girl, is the only infant born of non-consanguineous
parents . At birth, she presented facial edema . Lymphedema
rapidly extended to legs and feet . Enteropathy appeared during the
first year. At 3 years, she presented the facial dysmorphism of Hennekam
syndrome and psychomotor development was normal .
The second case, a 36-year-old woman, is the only child of non-consanguineous
parents .
At birth, syndactyly of toes was present associated with particular
facial features . Later, she developed psychomotor delay with mental
retardation and seizures . Lymphedema appeared on the right leg at 3
years and on the left leg at 15 years . Recurrent episodes of diarrhoea
were present without enteropathy .
Abdominal cystic lymphangioma were surgically corrected at 30 years .
At 36 years, facial dysmorphism ressembled that of Hennekam syndrome
. She had short hands, hypoplastic thumbs, short feet with bilateral
syndactylies. These two observations confirm the variable expressivity
of Hennekam syndrome . Lymphedema of the limbs and facial
dysmorphy are the only constant features . All others traits, in particular
intestinal lymphangiectasia, may be absent .
P01.172
Novel VEGFR3 missense mutation in a spanish family with
milroy disease
M. Ballesta-Martínez1 , E. Guillén-Navarro1 , V. López-González1 , S. Jeffery2 ;
1 2 Hospital Universitario Virgen de la Arrixaca, Murcia, Spain, St. George’s University
of London, London, United Kingdom.
Introduction: Milroy disease, or hereditary lymphedema type 1
(MIM153100), is characterized by lower limb lymphedema usually
present at birth . Variability in expression has been reported both within
and among families . Mutations in VEGFR3 with resultant dysgenesis
of microlymphatic vessels cause this disease . It is inherited in an autosomal
dominant manner with incomplete penetrance (85-90%) .
Objective: We describe phenotype of Milroy disease in two-generation
Spanish family . Molecular analysis of VEGFR3 gene has been
performed .
Clinical description: A girl was referred at 2 years of age because of
bilateral swelling of feet since birth, more evident on the right foot,
which partially decreased during the first year of life. She had dysplastic
2-4rth toenails. She was the first child of a young and non-consanguineous
couple . Her father referred swelling of feet at birth which
disappeared progressively during childhood . He had dysplastic toenails
. Soon after a sister was born with swelling of feet and distal part
of limbs as well . She is now 4 years old and the lymphedema is stable;
dysplastic nails are not present . The son of a father’s asymptomatic
sister has also been born with bilateral swelling of feet . Analysis of
VEGFR3 gene revealed a heterozygote mutation c .3056T>C in exon
22 in the two girls and their father .
Conclusions: 1- We describe a novel VEGFR3 mutation in exon 22
causing Milroy disease . 2- Clinical variability and incomplete penetrance
is present in this family .
P01.173
VEGFR mutation frequency in milroy disease and other primary
lymphoedema
F. C. Connell, P. Ostergaard, G. Brice, C. Carver, N. Williams, S. Mansour, P.
S. Mortimer, S. Jeffery;
St George’s University of London, London, United Kingdom.
Milroy disease (Hereditary Lymphoedema type I) is a congenital onset
primary lymphoedema with autosomal dominant inheritance . Mutations
in the gene, vasculo-endothelial growth factor receptor, VEGFR3
(FLT4), are known to cause Milroy disease, but there is uncertainty
about the prevalence of VEGFR3 mutations in patients with primary
lymphoedema and more specifically in those with a phenotype that
resembles Milroy disease . This study addresses this issue and thereby
delineates the Milroy disease phenotype . Fifty-four patients with
primary lymphoedema were analysed for mutations in VEGFR3 . Patients
were divided into four groups: Typical Milroy disease with family
history (group I), typical Milroy disease with no family history (group
II), atypical Milroy disease (group III), and complex primary lymphoedema
(group IV) . Results demonstrated that with rigorous phenotyping