2008 Barcelona - European Society of Human Genetics

Concurrent Sessions
we can expand the phenotypic description of tetrasomy 18p . Findings
identified in more than 25% of our patient population included neonatal
jaundice, recurrent otitis media, hearing loss, seizures, refractive
errors, a history of constipation and gastroesophageal reflux, heart
defects, pes planus, and attention problems . Dysmorphic features that
were reported in more than 25% of the population included ptosis; posteriorly
rotated ears; unraveled helices; small ears; abnomal columella;
smooth philtrum; small mouth; thin upper lip; abnormal Cupid’s bow;
palatal abnormalities, and a prominent or pointed chin . Conclusion.
These findings further our knowledge of the clinical manifestations of
tetrasomy 18p and will enable physicians to better anticipate and manage
complications as they arise .
c01.5
congenital nephrotic syndrome, microcephaly, trigonocephaly,
polydactyly, brain and eye anomalies: a distinct autosomal
recessive disorder
M. Zenker 1 , O. Gross 2 , E. Mildenberger 3 , B. Albrecht 4 , V. Matejas 1 , D. Wieczorek
4 ;
1 Institute of Human Genetics, Erlangen, Germany, 2 Dept.
Nephrology&Rheumatology, University Hospital Goettingen, Goettingen,
Germany, 3 Dept. of Pediatrics, University Hospital Benjamin Franklin, Berlin,
Germany, 4 Institute of Human Genetics, University Hospital Essen, Essen,
Germany.
Congenital nephrotic syndrome (CNS) is a heterogeneous disease .
While genetic causes of isolated CNS are well established, the knowledge
on the genetic basis of various syndromic forms is still fragmentary
. One of them is characterized by the association of CNS with microcephaly
/ brain anomalies, also known as Galloway-Mowat syndrome
(GMS) . It is obvious that GMS itself is not a homogeneous entity .
We observed a strikingly similar form of syndromic CNS in four children
originating from unrelated consanguineous families . All affected
children had gross proteinuria from birth and rapid progress to end
stage renal failure . Two had evidence of additional tubular involvement .
Head circumference fell below the 3rd centile within the first months of
life in all patients . Trigonocephalic head shape was present in three of
them . All children had cerebral gyration anomalies, and Dandy-Walker
malformation was present in two. Further constant findings were
postaxial hexadactyly and eye anomalies including iris atrophy, nonreactive
miosis, coloboma, and microphthalmia . Three children had an
atrial septal defect .
One of these patients was reported previously (Mildenberger et al .: Acta
Paediatr 1998), but no other similar reports exist to our knowledge . We
propose that this is a distinct autosomal recessive disorder within the
heterogeneous group of microcephaly-nephrosis syndromes . It may
be considered a subtype of GMS or a separate entity (Mildenberger
syndrome) . There is an obvious overlap with Pierson syndrome (OMIM
609049), which is caused by LAMB2 mutations, but no mutations in
this gene were found in the disorder presented here .
c01.6
An undescribed phenotype associated with cranio-fronto-facionasal
malformations, total alopecia and genital abnormalities
N. A. Akarsu 1 , H. Kayserili 2 , I. Vargel 3 , Y. Alanay 4 , S. Candan 2 , G. Tuncbilek 5 ,
O. Uyguner 2 , S. Balci 6 ;
1 Hacettepe University, Pediatrics, Gene Mapping Laboratory, Ankara, Turkey,
2 Istanbul University Medical Genetics, Istanbul, Turkey, 3 Kirikkale University,
Plastic and Reconstructive Surgery, Kirikkale, Turkey, 4 Hacettepe University,
Pediatrics, Clinical Genetics, Ankara, Turkey, 5 Hacettepe University, Plastic
and Reconstructive Surgery, Ankara, Turkey, 6 Hacettepe University, Pediatrics,
Clinical Genetics (Emeritus Member), Ankara, Turkey.
We report an unusual malformation in the craniofrontonasal region of
four males from two distinct inbred families . Major characteristics are;
1-) total alopecia; 2-) brachycephaly due to coronal suture synostosis;
3-) frontonasal dysostosis providing hypertelorism, blepharophimosis,
severely depressed nasal bridge with bifid tips; 4-) posterior cranial
skull defects; 5-) small naevi on the posterior skull; 6-) rotatory nystagmus
and 7-) corpus callosum agenesis . These malformations are also
associated with bilateral cryptorchism and hypogonadism. The first
family contains three affected individuals with one premature death at
the age of two months, the others, 13 and 45 years old respectively,
belong to different branches of the same family . The second pedigree
contains a three months old single affected male with similar symp-
toms . Since both families originated from nearby cities in the Blacksea
region of Turkey, this suggested a possible role of a founder mutation
. As a consequence of the highly inbred nature of these families an
autosomal recessive mode of inheritance is likely . Alternatively, since
all patients are males, X-linked inheritance challenged by inbreeding
should also be considered. Some of these findings apparently overlap
with cerebrofrontofacial (OMIM 6085789) and craniofrontonasal
(OMIM 304110) syndromes . However, neither a total alopecia, nor hypogonadism
has been associated with the aforementioned conditions
previously . To the best of our knowledge, this is a new disorder with
severe cranio-fronto-nasal malformations in association with alopecia
and genital abnormalities . Clinical and molecular investigations of this
new disorder are done within the CRANIRARE consortium supported
by the European Research Area Network “E-RARE” .
c02.1
Fas-associated factor-1, a protein involved in apoptosis, causes
cleft lip and palate
M. Ghassibe 1 , L. Desmyter 2 , F. Claes 3,4 , O. Boute 5 , B. Bayet 6 , P. Pellerin 7 , L.
Backx 8 , K. Hermans 3,4 , P. Brouillard 1 , N. Revencu 1 , R. Vanwijck 6 , J. R. Vermeesch
8 , H. A. Poirel 1,9 , P. Carmeliet 3,4 , M. Vikkula 1 ;
1 Laboratory of Human Genetics, de Duve Institute, Brussels, Belgium, 2 Laboratory
of Human Genetics, de Duve Institute, université catholique de Louvain,
Brussels, Belgium, 3 Department for Transgene Technology and Gene Therapy,
VIB, Leuven, Belgium, 4 Center for Transgene Technology and Gene Therapy
(CTG), K.U.Leuven, Leuven, Belgium, 5 Centre de Génétique, CHU de Lille,
Lille, France, 6 Centre Labiopalatin, Service de Chirurgie Plastique, Cliniques
universitaires Saint-Luc, Brussels, Belgium, 7 Service de Chirurgie Plastique
et Reconstructive, CHU de Lille, Lille, France, 8 Center for Human Genetics,
Leuven University Hospital, Leuven, Belgium, 9 Center for Human Genetics,
Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels,
Belgium.
Cleft lip and palate is the most common craniofacial birth defect with
complex etiology . We show that a reciprocal translocation, which
cosegregates with cleft palate in a family, disrupts the Fas-Associated
Factor-1 (FAF1) gene . The mutation results in lowered expression, and
likely haploinsufficiency. Transmission disequilibrium analysis demonstrates
that FAF1 associates with cleft lip and palate . In situ hybridization
unravels high levels of mFaf1 along the lips and the medial edge
epithelium (MEE) of the fusing palate in mice. Moreover, in zebrafish
larvae, zFaf1 is mostly expressed in the pharyngeal cartilages, where
its knock-down results in orofacial defects . As FAF1 is a member of the
Fas death-inducing complex that initiates apoptosis, it likely causes
cleft palate by preventing MEE degeneration . The data provides strong
molecular evidence that “death”, rather than epithelial mesenchymal
transformation or anterior/posterior migration, is the major fate for
MEE . These data also predict that other factors in the FAS-induced
apoptosis pathway likely play a role in cleft pathogenesis .
c02.2
sporadic venous malformation is caused by somatic mutations
in tiE2
M. Uebelhoer 1 , V. Wouters 1 , N. Limaye 1 , L. M. Boon 1,2 , J. B. Mulliken 3 , M. Vikkula
1 ;
1 de Duve Institute, Université catholique de Louvain, Brussels, Belgium, 2 Center
for Vascular Anomalies, Cliniques Universitaires St-Luc, Université catholique
de Louvain, Brussels, Belgium, 3 Vascular Anomalies Center, Children’s Hospital,
Boston, MA, United States.
Venous malformations (VM) are the most frequent vascular malformations
referred to vascular anomaly centers . An autosomal dominant
familial form, termed cutaneomucosal venous malformation (VMCM),
representing about 1% of venous lesions, is caused by gain-of-function
mutations in the TIE2 gene . The aetiology of sporadic VM, which
represents more than 95% of venous lesions, has however remained
unknown . Here we show that sporadic VMs are caused by somatic
mutations in TIE2. We identified seven missense mutations in VM
tissue-derived DNA, which were however absent in blood DNA from
these patients, and in tissue DNA from 90 controls . All of the mutations,
predicted by bioinformatic analysis to have deleterious effects of
varying severity on protein function, were found to result in a strong in
vitro ligand-independent increase in phosphorylation of TIE2 . In some
patients, we observed two mutations acting in cis . Such combinations
on the same allele induced even higher phosphorylation levels of the