2008 Barcelona - European Society of Human Genetics

Clinical genetics
We report a case in order to illustrate the clinical features of this
progeroid disease . The proband is a 13 years old male that presents:
short stature (-2 .3 SD) and microcephaly (-3 .7 SD; without bulging
sutures) . Clinical examination also reveals: poorly muscled build with
lipoatrophy, thin skin with pigmented naevi, small prematurely aged
face with pointed chin and retrognathia, small mouth and total anodontia
(confirmed by radiologic examination). The patient has mild mental
retardation, speech defect and hoarse voice . Family history is positive
for anodontia (the mother has no teeth) .
We made differential diagnosis with Leopard syndrome and other
progeroid syndromes .
In conclusion, we present a male with Mulvihill-Smith syndrome in order
to illustrate a rare disorder and to discuss the importance of clinical
features like dwarfism, anodontia and pigmented naevi for diagnosis.
P01.330
Nail patella-syndrome: Phenotype and genotype correlation
B. Çolak 1 , N. H. Elçioglu 1 , B. Erol 2 , S. Yalçin 2 ;
1 Department of Pediatric Genetics, Marmara University Hospital, Istanbul,
Turkey, 2 Department of Orthopaedics, Marmara University Hospital, Istanbul,
Turkey.
Nail patella-syndrome (OMIM: 161200) is a rare autosomal dominant
connective tissue disorder with a prevalence 1 in 50 000 . The phenotype
is associated with multiple deformities affecting the nails, skeletal
system, kidneys, and eyes . Skeletal features include absent or
hypoplastic patellae, patella dislocations, scoliosis, elbow abnormalities,
talipes and iliac horns . Inter- and intrafamilial clinical variability are
common in this disorder particularly for skeletal abnormalities, presence
and severity of nephropathy and ocular anomalies like glaucoma .
Mutations in the gene encoding the Lim Homeo Box Transcription Factor-1
(LMX1B), mapped on chromosome 9 (9q34), are responsible for
the clinical phenotype of NPS . No clear genotype-phenotype association
have been found to date by the published cases .
We present here the phenotype and genotype of two different NPS
Families . First family presented an isolated case and the second one
a dominatly inherited three generations NPS family with multiple affected
family members . The main clinical symptoms were lower limbs
disabilities and nail dyplasia with remarkable inter- and intrafamilial
variablity . Neither nephropathy nor ocular problems were found in our
all examined cases . Molecular analysis of the LMXB1 showed a denovo
wide deletion in intron 2 by the first family and an inherited heterozygous
deletion in exon 3 (430delG) in the second Family .
Genetic counseling and follow-up regarding the different manifestations
are important for all family members who have inherited the disease
but could have a milder phenotype and remain underdiagnosed .
P01.331
clinical characterisation of NBiA patients with and without
mutation in PANK2 gene (PKAN)
M. Hempel 1 , T. Kmiec 2 , M. Hartig 1 , H. Prokisch 3 , T. Meitinger 3 ;
1 Institute of Human Genetics, Munich, Germany, 2 Memorial Children’s Health
Institute, Warsaw, Poland, 3 Helmholtz Zentrum München, Munich, Germany.
Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogeneous
group of disorders sharing the underlying and by MR imaging
detectable feature of iron accumulation in the basal ganglia . A substantial
part of these patients have mutations in PANK2 (Patothenate Kinase-Assocciated
Neurodegeneration, PKAN) . NBIA patients with and
without PANK2 gene mutations share common clinical symptoms like
dystonia, parkinsonism, pyramidal signs, cognitive deficits and dysartria.
Analysis of clinical symptoms of NBIA patients is often difficult because
of the small patient numbers and several different investigators
involved . We took advantage of a large collection of 43 NBIA patients
characterized by a single investigator (T . K .) . Screening PLA2G6 not
mutations were found, in 24 patients two mutations have been identified
in PANK2. The eye of the tiger sign were found in the majority of
patients (21 out of 24) with PANK2 mutation . The group of patients
with PANK2 mutations can be distinguished from the group without
mutation by age of onset, loss of gait, the occurrence of generalized
dystonia, parkinsonism, cognitive deficits, oromandibular dystonia and
dysartria .
P01.332
cytogenetic and molecular analysis of patients with Nijmegen
breakage syndrome in serbia
S. S. Cirkovic1 , M. Guc-Scekic1,2 , S. Pasic1 , D. Radivojevic1 , A. Jovanovic1 ;
1Mother and Child Health Care Institute of Serbia “Dr Vukan Cupic”, Belgrade,
Serbia, 2Faculty of Biology, University of Belgrade, Belgrade, Serbia.
Nijmegen breakage syndrome (NBS) is a rare autosomal recessive
chromosome instability disorder, characterized by microcephaly,
growth retardation and elevated risk of cancer . Cells cultured from
NBS patients exhibit an increased cellular hypersensitivity to specific
mutagenic agents such as bleomycin (BLE) . It was shown that patients
with NBS have mutations in the NBN gene, which is involved in the
sensing and repair of DNA double strand breaks . Most of the known
NBS patients so far are of Slavic origin and share the founder NBN
mutation, 657del5 .
Here we report on five Serbian children with NBS,diagnosed and
treated at the Mother and Child Health Care Institute of Serbia from
July 2005 to September 2007 . Cytogenetic analyses were performed
on control and BLE (1μg/ml) - treated, peripheral blood cultures using
standard procedure .Metaphases were examined for chromosome
breaks and aberrations .Three cultures were successfully established
revealing increased chromosome breaks (0 .27-0 .81 vs . 0 .02-0 .05
breaks/cell) and various aberrations including chromosomes 7 and 14,
with significant difference as compared to their control counterparts.
Molecular analysis for the presence of the 657del5 mutation was
carried out in five patients on DNA samples extracted from peripheral
blood,using modified PCR method and heteroduplex analysis on
PAGE gel .Homozygosity for the 657del5 mutation was detected in all
analyzed NBS children .
Patients described here are the first Serbian NBS patients reported so
far . Considering that NBS patients are extremely sensitive to ionizing
radiation an early and precise cytogenetic and molecular diagnosis is
very important for the management of the disease in case of malignancy
.
P01.333
Recurrent severe pulmonary manifestations in 6 patients with
nodular periventricular heterotopia associated and FLNA
mutation
A. Masurel-Paulet 1 , C. Goizet 2 , E. M. Thompson 3 , A. Tai 3 , D. Kennedy 3 , E.
Haan 3 , E. Landre 4 , N. Mejean 5 , A. Houzel 6 , N. Bahi-Buisson 7 , C. Thauvin-Robinet
1 , F. Huet 6 , S. Roberston 8 , L. Faivre 1 ;
1 Centre de Génétique, Hôpital d’Enfants, Dijon, France, 2 Département de
Génétique, Hôpital Pellegrin, Bordeaux, France, 3 Clinical Genetics Service,
Women’s and Children’s Hospital, Adelaide, Australia, 4 Service de Neurochirurgie,
Hôpital St Anne, Paris, France, 5 Radiologie pédiatrique, Hôpital d’Enfants,
Dijon, France, 6 Pédiatrie, Hôpital d’Enfants, Dijon, France, 7 Neurologie pédiatrique,
Hôpital Necker-Enfants Malades, Paris, France, 8 Paediatric Genetics,
University of Otago, Dunedin, New Zealand.
Nodular periventricular heterotopia is an X linked dominant neuronal
migration disorder caused by mutations in the filamin A (FLNA) gene.
FLNA is an actin-binding protein and has a role in the modulation of cell
shape and migration . A high phenotypic diversity has been described
in association with FLNA mutations, from nodular periventricular heterotopia
to otopalatodigital syndrome and frontometaphysal dysplasia .
Extra neurological features have sometimes been described in patients
with nodular periventricular heterotopia, including patent ductus
arteriosus, coagulopathy, or Ehlers Danlos phenotype . In this study,
we reported on 6 females aged 2 to 48 years, presenting with nodular
periventricular heterotopia, FLNA gene mutation and notable lung
manifestations . The median age of onset of lung manifestations was
4 .5 months (1 .5-240) . Manifestations included recurrent early-onset
pneumopathies in 5/6 patients, recurrent bronchiolitis in 4/6 patients
and asthma in 4/6 patients . 5/6 patients had to be hospitalized at
least once for lung involvement, including one-year cumulative length
of hospitalisation in one child and hospitalisation in intensive care in
another . Long-term oxygenodependance was described in 2 patients .
The symptomatology appears to improve with age . We believe that
such lung phenotype can be a recurrent manifestation in patients with
nodular periventricular heterotopia, consequence of the mutation in the
FLNA gene . This hypothesis is supported by the recent demonstration
of interaction between FLNA and CFTR, the ubiquitous distribution of
FLNA and its role in the cytoskeleton .