2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
Referred to our Genetics consultation at the age of four. Physical examination
showed knee and elbow dislocation, arthrogryposis, kyphoscoliosis
and spatulate fingers with broad thumbs and halluces. Face
was flat with prominent forehead and short nose with flat nasal bridge.
Psychomotor development was normal.
Skeletal radiography showed rhizomelia of upper and lower limbs and
multiple joint dislocations. Anterior decompression and posterior fusion
was attempted at the age of 5.
The molecular study was performed after informed consent within a
research environment. The mutation 4580T>C was found, leading to
an aminoacid substitution at position 1527 of the Filamin B protein.
Discussion: The mutation 4580T>C had not been described before.
Examination of parental samples showed that this mutation has occurred
de novo. Additional investigation is ongoing to further characterize
this new mutation, including functional studies in fibroblasts.
P02.154
“Laurin-sandrow syndrome”: a new family with rare genetic
disorder
N. Rumyantseva 1,2 , B. Zoll 3 , R. Chmel 1 ;
1 Republican Medical Center “Mother and Child”, Minsk, Belarus, 2 Belarusian
Medical Academy of Post-Graduate Education, Minsk, Belarus, 3 Institut für
Humangenetik, Göttingen, Germany.
“Laurin-Sandrow syndrome” (LSS) (OMIM 135750) is rare disorder
characterized by distinct combination of mirror polysyndactyly, symmetric
tetramelia, nasal defects.
We described a new family with autosomal dominant transmission of
LSS, presented a clinical findings of affected child and father, reviewed
a literature data according diagnostic criteria.
Proposita - second child of young couple (G1- healthy sister) was born
at term BW=2110; BL=42cm; OFC=32 cm. Female infant showed prenatal
hypoplasia, microcephaly, posterior encephalocele, dysmorphic
ears, facial appearance similar to frontonasal dysplasia (hypertelorism,
microphthalmia, partial aplasia of nasal bones, partial atresia of nasal
canals, wide flat nose, nares defects, unilateral cleft lip and palate,
micrognathia), heart defect (ASD), bilateral mesomelic anomalies of
lower limbs, pre- and postaxial polydactyly of feet (8 toes), syndactyly,
clubfoot. At follow-up growth and mental delay, neurological signs, pyeloectasia
were developed. Child died at 3 months age.
Father presented normal limbs, growth (W-63kg, L-172cm, OFC-
55cm), mental development, unusual facial features - small soft mass
(no biopsy) on the left part of forehead, hypertelorism (40 mm), ectopia
of lacrimal ducts, myopia, astigmatism, angiopathia of retina, wide
flat nasal bridge, abnormal nostrils (nasal defects were operated at
18 years old). Echocardiography: additional chorder of left ventriculus.
Karyotype: 46, XY. His parents, sister, nephew showed normal
phenotype.
Clinical features of our patients were compared with published data.
We diagnosed “Laurin-Sandrow syndrome” based on association of
characteristic signs - mirror polysyndactyly, bilateral mesomelic limbs,
nasal defects. Presented family illustrated a wide variability of phenotype’s
spectrum and confirmed autosomal dominant inheritance of
LSS.
P02.155
Array-cGH analysis in a series of 54 index patients with limb
malformation identified more than 10% anomalies
S. Manouvrier-Hanu 1,2 , A. Mezel 3 , F. Escande-Narducci 4 , P. Saugier-Veber 5 ,
S. Odent 6 , A. Verloes 7 , S. Lyonnet 8 , V. Drouin 5 , B. Leheup 9 , C. Francannet 10 ,
L. Faivre 11 , C. Vincent-Delorme 1 , A. Dieux-Coeslier 1 , O. Boute-Bénéjean 1 , B.
Herbaux 3,2 , M. Holder-Espinasse 1,2 , J. Andrieux 12,2 ;
1 Clinical Genetic Department, CHRU Lille, Lille, France, 2 Lille 2 University, Lille,
France, 3 Paediatric orthopaedics Department, CHRU Lille, Lille, France, 4 Molecular
genetic Department, CHRU Lille, Lille, France, 5 Genetic Department,
CHU Rouen, Rouen, France, 6 Genetic Department, CHU Rennes, Rennes,
France, 7 Genetic Department, CHU Robert-Debré, Paris, France, 8 Genetic
Department, CHU Necker, Paris, France, 9 Genetic Department, CHU Nancy,
Nancy, France, 10 Genetic Department, CHRU Clermont-Ferrand, Clermont
Ferrand, France, 11 Genetic Department, CHRU Dijon, Dijon, France, 12 Genetic
Department, CHRU Lille, Lille, France.
Congenital limb malformations (CLM) affect approximately 1 in 500
new-borns. They can be isolated or part of multiple congenital anomalies
(MCA) syndromes and are due to two major causes: intrauterine
disruptions (ID) and genetic abnormalities. The second group is very
heterogeneous and, although many chromosomal abnormalities and
genomic alterations have been described, most of CLM remain unexplained.
We performed array-CGH (Agilent 244K) in a series of 54 index patients
with normal karyotype and unexplained CLM either isolated (10)
or part of known or unknown MCA syndromes (44). In 19 patients, the
gene responsible for the disease had been previously unsuccessfully
tested. In the remaining 35 patients, no gene testing was available or
a precise clinical diagnosis could not be achieved.
Thirty analyses detected either no genomic variation or known CNVs
(55%). In 5 index patients, array-CGH revealed one or more unknown
CNVs which either were present in one asymptomatic parent (4) or did
not segregate with the malformation (1). We identified anomalies in the
remaining 19 index patients. Three of them were deleterious, either de
novo (1) or familial (2). One recurrent identical anomaly identified in 3
index patients sharing similar radial malformations could be deleterious,
but familial additional analyses are still pending for these and the
other 13.
Overall, at least 6 genomic anomalies have been identified in this series
of 54 patients presenting limb malformations (≥ 11%).
Conclusion: After precise clinical and genetic evaluation, unexplained
CLM are good candidates for Array-CGH analysis.
P02.156
A study of the Genetics of Limb Reduction Defects
M. S. Aglan, M. O. El-Ruby, S. A. Temtamy;
National Research Centre, Cairo, Egypt.
Limb reduction defects are an important group of congenital limb malformations
that requires thorough assessment. They can be isolated
or associated with other malformations as a part of syndrome. Causes
of limb deficiencies include single gene disorders, chromosomal abnormalities
or teratogens. However, the etiology remains unknown in
many cases. The present study aimed at the proper diagnosis and
classification of 30 cases with limb defects referred to the Limb Malformations
and Skeletal Dysplasia Clinic, NRC, Egypt in order to provide
accurate and efficient genetic counseling. Detailed history, three generation
pedigree analysis, examination of different body systems with
specific studies of different parts of the limbs documented by radiological
examination, photography and basic anthropometric measurements
were conducted for all cases. Dermatoglyphic analysis, cytogenetic
studies and other investigations were done whenever indicated.
Cases were classified according to Temtamy and McKusick (1978) into
8 groups; isolated terminal transverse defects (6/30), terminal transverse
defect as a part of syndrome (2/30), isolated radial defect (1/30),
radial defect as a part of syndrome (9/30), isolated ulnar defect (2/30),
ulnar defect as a part of syndrome (6/30), pre and postaxial defect
(1/30) and axial defect as a part of syndrome (3/30). The results of
this study have shown that limb absence or reduction defects are not
an uncommon malformation among Egyptian children. Delineation of
the exact cause, correct classification and diagnosis are essential for
proper genetic counselling. Molecular studies are recommended for
accurate diagnosis and understanding of the pathogenesis.
P02.157
Autosomal-recessive primary hypertrophic osteoarthropathy
due to mutations in the 15-OH-prostaglandin dehydrogenase
gene: 15- year follow-up in two Austrian siblings
O. Rittinger 1 , C. P. Diggle 2 , I. M. Carr 3 , D. T. Bonthron 4 ;
1 Universitätsklinik fü rKinder- und Jugendheilkunde, Salzburg, Austria, 2 Leeds
Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom,
3 Leeds Institute of Molecular Medicine, University of Leeds, U.K., Leeds, United
Kingdom, 4 Leeds Institute of Molecular Medicine, University of Leeds, Salzburg,
United Kingdom.
Background. Hypertrophic osteoarthropathy (HO) is commonly associated
with clubbed fingers as a consequence of cardiopulmonary
disease. In contrast, primary forms (PHO) are rare familial disorders
which may show dominantor recessive inheritance. Features may include
skin thickening (usually referred to as pachydermoperiostosis)
cranial vault abnormalities and patent ductus arteriosus. Recently, the
pathogenesis of these disorders was shown to be related to mutations
of the 15-OH-prostaglandin dehydrogenase (HPGD) gene.
Clinical report. We report on the clinical course of Austrian sibs affect-