2008 Barcelona - European Society of Human Genetics

Clinical genetics
P01.364
Familial hypodontia associated with taurodontism
E. Severin, C. Albu, D. Stanciu, D. F. Albu;
“Carol Davila” Univ Med Pharm, Bucharest, Romania.
Tooth agenesis and taurodontism are developmental dental anomalies
. Some studies support the hypothesis that isolated taurodontism
is associated with tooth agenesis, as it shows a higher prevalence in
families with missing teeth than in general population, and, therefore,
may share a common genetic cause . We report a case of a mother and
her two daughters affected of tooth agenesis . Mother and daughters
exhibited different clinical manifestation of missing teeth . Simultaneous
occurrence of taurodontism and tooth agenesis was detected only
in mother . Evaluation included clinical, radiographic and genetic examinations
. The affected members of the family did not show features
of syndrome tooth agenesis. No specific correlation between missing
teeth and taurodontism was noted .
P01.365
A de novo microdeletion of 774 kb including the entire tP53
gene - Li-Fraumeni-plus as a contiguous gene syndrome?
T. Schwarzbraun 1 , A. C. Obenauf 1 , A. Langmann 2 , U. Gruber-Sedlmayr 3 , K.
Wagner 1 , M. R. Speicher 1 , P. M. Kroisel 1 ;
1 Institute of Human Genetics/Medical University of Graz, Graz, Austria, 2 Department
of Ophthalmology/Medical University of Graz, Graz, Austria, 3 Department
of Pediatrics/Medical University of Graz, Graz, Austria.
Li-Fraumeni syndrome (LFS) is a rare genetic disorder usually characterized
by familial occurrence of various malignancies with early onset
. LFS is clinically and genetically heterogeneous . The inheritance of
LFS follows an autosomal dominant mode with high penetrance and
mutation rate in germ cells is very low . In most cases LFS is due to
a constitutional mutation of one copy of the TP53 tumor suppressor
gene in affected family members and somatic mutations in the second
copy of that gene in the process of malignant transformation . The
TP53 gene at chromosome 17p13 .1 is the most frequent target for
genetic alterations in human cancer .
Here we describe the first case of a de novo constitutional chromosomal
microdeletion including the entire TP53 gene as well as several
closely linked genes . The phenotype of the patient is striking and
includes severe psychomotor retardation, a Dandy-Walker anomaly,
Leber congenital amaurosis (LCA), seizures and dysmorphic features .
Chromosomal breakpoints (BP) were mapped by high resolution array
comparative genome hybridization (aCGH) followed by quantitative
real type PCR analysis down to base pair level . The distal BP disrupts
the ACADVL gene and the proximal BP is located about 6 .5 kb
upstream of the GUCY2D gene disrupting its upstream regulatory sequences
. SNP analysis revealed monoallelic expression of GUCY2D
which would explain the LCA of the patient . More than 40 genes have
been mapped to the 774 kb deletion interval including the FXR2 gene
which is an autosomal homolog of the FMR1 gene .
P01.366
Hypogonadism and Novel craniofacial Findings in a case of
treacher-collins syndrome with a Pathogenic mutation and a
missense Variant in the tcOF1 Gene
C. Li;
McMaster University Medical Centre, Hamilton, ON, Canada.
A severe case of Treacher-Collins syndrome with novel findings in a
newborn boy is presented here . Craniofacial features include bilateral
atrestic internal auditory canals, macrocephaly with remnant lobules of
the external ears, absence of external auditory canals, missing ossicles
with hypoplastic middle ear cavities. The nasal cavities were filled
with a soft tissue mass that may represent an encephalocele . The eye
cavities were extremely underdeveloped . The inferior wall was absent,
the zygomatic arches were absent . There was severe micrognathia
and concurrent narrowing of the pharyngeal space, resulting in markedly
narrowed upper airway . Moreover, the baby was found to have
widely space nipples, hypoplastic scrotum, bilateral cryptorchidism
and micropenis . Molecular testing revealed a pathogenic mutation
and a novel missense change . The mother carries the same missense
change and is clinically and radiographically normal . The potential significance
of these findings is discussed.
P01.367
coexistence of Unvericht-Lundborg disease and congenital
deafness in one serbian family
M. M. Kecmanovic 1 , A. Ristic 2 , D. Sokic 2 , M. Keckarevic-Markovic 1 , D. Keckarevic
1 , S. Romac 1 ;
1 Faculty of Biology, Belgrade, Serbia, 2 Institute of Neurology, Belgrade, Serbia.
Unverricht-Lundborg disease (ULD) is an autosomal recessive disorder
caused by mutations in cystatine B (CSTB) gene located on chromosome
21q22 .3 . Majority of the ULD chromosomes carry expansion of
dodecamer repeats in promoter region of the CSTB gene . The location
of TMPRSS3 gene, in which mutations cause nonsyndromic recessive
deafness, is in proximity of CSTB gene, on chromosome 21q22 .3 .
Here we present a complex syndrome in one Serbian family in which
three out of four siblings of healthy parents have inborn deafness . Action
and stimulus sensitive myoclonus appeared in two individuals (II-
1 and II-3) in 12-13 year of life (individual II-1 was not available for
this analysis) . Except congenital deafness, individual II-2 is otherwise
healthy, while the individual II-4 has none of two mentioned disorders .
Molecular diagnostics confirmed suspected ULD in sibling with progressive
myoclonic epilepsy and innate deafness, while the sibling with
isolated inborn deafness was heterozygote for expansion in the CSTB.
One could exclude coexistence of CSTB and TMPRSS3 mutations in
this pedigree due to assumed joint transmission . For that reason we
performed haplotype analysis, genotyping seven microsatellites flanking
TMPRSS3 and CSTB . Haplotype analysis showed that absence of
homozygous expansion in the individual II-2 is due to a recombination
event that occurred ahead of CSTB, what was the strong indication
that homozygous mutation in the TMPRSS3 is responsible for deafness
. Following sequencing of the TMPRSS3 revealed 207delC mutation
in fourth exon .
To our best knowledge this is the first genetically confirmed case of
coexistence of mentioned two mutations .
P01.368
central Nervous system involvement in patients with vascular
cutaneous anomalies
C. Mellado, M. Sahin;
Neurology Department , Children’s Hospital Boston, Harvard Medical School,
Boston, MA, United States.
Vascular cutaneous anomalies could be related to an underlying systemic
disease and/or involve other systems . One of these could be the
Central Neural System, leading to a various neurological complications
. The purpose of this study is to describe brain anomalies among
individuals affected with some of these syndromes, including PHACE,
Macrocephaly and Cutis Marmorata Telangectasia Congenita (M-
CMTC), Sturge Weber (SW) and Klippel Trenaunay (KT) .
We reviewed 216 clinical records of patients seen at Children’s Hospital
Boston, between 2000 and 2007, with the diagnoses mentioned
above . Brain imaging information was obtained . In 11/11 PHACE syndrome
cases, beside vascular anomalies, neuroimaging showed hypoplastic
corpus callosum (2), cerebellar involvement (3), asymmetric
ventricles (1), retro cerebellar cyst (1), moyamoya phenomenon (1) .
8/10 M-CMCT cases have images, showing hemimegalencephaly (4),
Chiari I malformation (4), asymmetric/large ventricles (4), white matter
changes (3), cortical dysplasia (2), periventricular heterotopias (1),
brain atrophy (1), periventricular leukomalacia (1) . 36/55 SW cases
have images, that showed leptomeningeal enhancement in almost all
cases, normal brain structures (5), cerebral atrophy (18), prominent
choroid plexus (17), calcifications (5), venous anomalies (5), white
matter anomaly (5), Chiari I malformation (1), asymmetric ventricles
(1), mega cisterna magna (1) . 20/140 KT cases have images that
showed normal brain images (9), white matter changes (5), Chiari I
malformation (3), calcifications (2), venous anomalies (2), asymmetric
brain hemispheres (1), cerebral atrophy (1), thick corpus callosum
(1) .
Brain imaging is important in these syndromes to define the pathologic
entity, help in the diagnosis, management and prognosis in children
at risk .