2008 Barcelona - European Society of Human Genetics

Clinical genetics
the R275C mutation demonstrate a remarkably uniform manifestation
of the pathological features and add hearing loss to the list of major
problems of Czech dysplasia .
P01.129
clinical and molecular characterization of Diastrophic Dysplasia
in the Portuguese population
M. Barbosa 1 , E. Almeida 2 , A. Oliveira 3 , N. Alegrete 4 , C. Alves 5 , A. Sousa 6 , A.
Medeira 6 , J. Saraiva 7 , J. Pinto-Basto 8 , G. Soares 1 , A. Fortuna 1 , A. Superti-
Furga 9 , L. Mittaz 10 , L. Bonafé 10 , M. Reis-Lima 1 ;
1 Centro de Genética Médica Jacinto Magalhães, Oporto, Portugal, 2 Serviço
de Ortopedia, Hospital de Crianças Maria Pia, Oporto, Portugal, 3 Serviço de
Ortopedia, Hospital Geral de Santo António, Oporto, Portugal, 4 Serviço de
Ortopedia, Hospital de São João, Oporto, Portugal, 5 Serviço de Ortopedia,
Centro Hospitalar do Funchal, Funchal, Portugal, 6 Serviço de Genética Médica,
Hospital de Santa Maria, Lisboa, Portugal, 7 Serviço de Genética Médica, Hospital
Pediátrico, Coimbra, Portugal, 8 Centro de Genética Preditiva e Preventiva,
Instituto de Biologia Molecular e Celular, Oporto, Portugal, 9 Department of
Pediatrics, Centre for Pediatrics and Adolescent Medicine, Freiburg University
Hospital,, Freiburg, Germany, 10 Division of Molecular Pediatrics, Centre Hospitalier
Universitaire Vaudois, Lausanne, Switzerland.
Diastrophic dysplasia (DTD; MIM #222600) is an autosomal recessive
chondrodysplasia, characterized by limb shortening, hitchicker
thumbs, spinal deformities and contractures. Diagnosis is confirmed
by molecular testing of the sulphate transporter SLC26A2 gene . SL-
C26A2- related dysplasias encompasses a range of disease: from
lethal achondrogenesis type 1B and atelosteogenesis type 2 (AO2)
to classical DTD and mild recessive multiple epiphyseal dysplasia
(rMED) . Genotype-phenotype correlations have been described . This
study aimed at characterizing clinically, radiologically and molecularly,
14 patients and 3 foetuses affected by SLC26A2- related dysplasias
and to evaluate genotype-phenotype correlation . The main Portuguese
Departments of Genetics and Orthopaedics were contacted in order to
recruit patients from all the country .
Phenotypically, 8 patients were classified as classical DTD, 3 patients
as rMED, and 3 patients had an intermediate phenotype (mild DTD) .
Foetuses had a homogenous presentation of severe DTD/AO2 . Molecular
analysis showed that the R279W mutation is present in all living
patients, in homozygosity in rMED and in compound heterozygosity
with the known severe allele R178X in classical DTD .
This report shows the clinical and molecular spectrum of SLC26A2- related
skeletal dysplasias in the Portuguese population . R279W mutation
in homozygosity causes rMED and the association of this mild allele
with a null mutation causes classical DTD . The “Finnish mutation”,
was not found and is probably very rare in the Portuguese population .
The data of this series indicate that screening for common SLC26A2
mutations allows to confirm the diagnosis in the majority of Portuguese
patients or at least to identify one pathogenic allele .
P01.130
compound heterozygosity for GDF5 in Du Pan type
chondrodysplasia
S. Douzgou1,2 , K. Lehmann3 , R. Mingarelli1 , S. Mundlos3 , B. Dallapiccola1,2 ;
1IRCCS-C.S.S. San Giovanni Rotondo and C.S.S. Mendel Institute, Rome,
Italy, 2Department of Experimental Medicine, Sapienza University, Rome, Italy,
3Institut für Medizinische Genetik, Universitätsmedizin Berlin Charité, Berlin,
Germany.
Du Pan type Chondrodysplasia (DPC) represents the milder end of the
Growth Differentiation Factor 5 (GDF5) morphopathies which, according
to an increasing gradient of clinical severity, include also the Hunter-Thompson
type and the Grebe type acromesomelic chondrodysplasias
. DPC is characterised by mild short stature, complex brachydactyly,
and fibular aplasia. Affected individuals are homozygotes for lossof-function
mutations in the highly conserved mature domain of GDF5
that result in an impaired GDF5 signaling through the Bone Morphogenetic
Protein Receptor 1B (BMPR1B) . We investigated a 20 month-old
child with complex brachydactyly and mild proximal fibular hypoplasia,
consistent with DPC, in the absence of short stature and other long
bones’ and joints’ anomalies . Mutational analysis disclosed compound
heterozygosity for two novel GDF5 mutations, the P436T mutation in
the mature domain, that most likely results in reduced binding to BM-
PR1B and the R378Q mutation at the end of the prodomain . The mutation
R378Q is located within the recognition motif at the processing site
of GDF5 where the precursor protein is cleaved and probably results in
at least a partial loss of protein function. Metacarpophalangeal profile
(MCPP) analysis on radiographs of the parents disclosed unremarkable
results for the P436T mutation, transmitted from the mother, while
the father’s R378Q mutation was associated with a MCPP showing
overlap with BDA1, including brachymesophalangy of all digits and
mild shortening of the entire first digit. This observation connects DPC
with the BDA1 phenotype and further expands the clinical variability of
GDF5 associated phenotypes .
P01.131
Early recognition of Ellis van creveld syndrome: report of a new
case
V. Plaiasu, G. Motei, F. Nedelea, E. Neagu, M. Iordachescu;
IOMC Prof.dr.Alfred Rusescu, Bucharest, Romania.
Ellis van Creveld is a rare chondro-ectodermal dysplasia characterized
by short ribs, polydactyly, growth retardation and ectodermal defects .
Significant findings in the general survey of our male case were narrow
thorax, postaxial polydactyly of the hands, bones deformities with
extremities markedly shortened, dysplastic fingernails, neonatal teeth,
respiratory distress due to narrow chest .
Aspects of the ribs and dystrophic nails are the major criteria in establishing
the diagnosis . It may be differentiated from other chondrodystrophies
or syndromes associated with polydactyly .
Early recognition is important in order to identify the real diagnosis, to
know evolution and prognosis and to offer proper genetic counselling .
Prognosis of our case is linked to the respiratory difficulties.
Acknowledgements: CEEX National Program 2008, Module I
P01.132
New molecular findings in Hypochondroplasia: clinical,
radiological and molecular review of a cohort of 15 Portuguese
patients
M. Gonçalves-Rocha 1 , G. Soares 1 , J. Pinto-Basto 1 , M. Martins 1 , F. Macedo 2 ,
M. Almeida 3 , B. Campos-Xavier 3,4 , H. G. Santos 3 , M. Reis-Lima 1 ;
1 Centro de Genética Médica, Porto, Portugal, 2 SMIC - Serviço Médico de Imagem
Computorizada, Porto, Portugal, 3 GenoMed, Diagnósticos de Medicina
Molecular SA, Lisboa, Portugal, 4 Division of Molecular Pediatrics, Centre Hospitalier
Universitaire Vaudois (currently affiliation), Lausanne, Switzerland.
Short stature in childhood is a frequent clinical presentation, being
1% of these cases due to bone dysplasias . Achondroplasia
(Ach;MIM#100800)/ Hypochondroplasia (Hch;MIM#146000) are the
two most common autosomal dominant skeletal dysplasias . FGFR3
gene is the only currently known gene to be implicated .
In Hch, p .N540K mutation in tyrosine-kinase domain 1 accounts for up
to 65% of cases .
These two conditions have overlapping phenotypes characterized by
disproportionate short stature with rhizomelic limb shortening, Ach being
more severe .
We reviewed 13 probands and their first relatives (16 patients) followed
at our Genetics Clinic with diagnosis of Hch . Clinical and radiological
findings were assessed independently by two clinical geneticists.
Differential diagnosis were considered and systematically excluded
whenever indicated .
Molecular study of FGFR3 gene was performed in all cases .
Seven mutations were identified in 16 patients: three N540K, one rare
mutation R200C (described once) and a new mutation p .E360K in a
pair of sibs and their mother .
When there is a high (clinical/radiological) suspicion of hypochondroplasia,
and after negative mutation scanning, full sequencing FGFR3
coding region is indicated .
This allows a higher detection rate uncovering rare/new mutations . In
our series one new mutation and another rare one were identified by
this method .
Sequencing of FGFR3 coding region was negative in 7 patients . These
patients also have clinical and radiological features within the spectrum
of Hch . In these patients hypochondroplasia is most probably not
FGFR3 related, raising attention to the role of other unknown (at the
moment) genes may play in this condition .