2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
ed with the recessive form of this condition: they have clubbed fingers,
painful periostitis, excessive sweating on hands and feet, thickening
of the limbs particularily knees with arthralgia of large and small joints,
and paroxysomally occurring bone pains. All these symptoms started
after the first few years of life. Radiologically, cortical thickening and
sclerosis of the tubular bones with expansion of the diaphyses, and
Wormian bones of the skull were shown. The bone symptoms grossly
faded away - however pain attacks and hyperhidrosis still persist. Molecular
analysis demonstrated the presence of frameshift mutations
of both HPGD alleles: c.120delA (paternal) and c.175_176 del- CT
(maternal). The heterozygous parents are healthy. Investigation of the
presumably increased PGE2-excretion is under way.
Conclusion. Given the causality between the painful clinical symptoms
and disturbance of the prostaglandine metabolism, antagonist drugs
like indomethacin may alleviate clinical symptoms, using PGE2-excretion
as a useful monitoring of this therapy.
P02.158
Blomstrand dysplasia - evidence of founder effect in a small
northeast Brazilian region
M. T. Sakata 1 , G. Bertrand 2 , C. Silve 2 , C. A. Moreno 1 , D. P. Cavalcanti 1 ;
1 Programa de Genética Perinatal, Dept Genética Médica, UNICAMP, Campinas,
Brazil, 2 Hôpital St Vincent de Paul INSERM U561, Paris, France.
Blomstrand Dysplasia (BD), a lethal osteochondrodysplasia (OCD),
is characterized by osteosclerosis, carpo-tarsal advanced maturation,
narrow thorax with clavicles and ribs thickening, and short limbs displaying
a dumb-bell appearance of the tubular bones. Other features
are hydrops, macroglossia, and atelia. Recessive inheritance was recently
confirmed by the description of homozygous mutations in the
PTHR1 gene. In this report we present a study of two new families
coming from three near small cities of the Brazilian northeast region.
Consanguinity was not referred by the parents of the first studied family
and the proband’s clinical-radiological natal examination revealed
a typical phenotype of BD. In the other studied family, the parents are
consanguineous and the proband’s radiological-clinical evaluation
confirmed the BD diagnosis. In both probands an identical single homozygous
point mutation at position -2 of the 5’ consensus acceptor
site at the exon 9 (c.639 -2 A>G) was identified after PCR amplification
of all coding exons and intron-exon junctions of the PTHR1 gene. The
point mutation was present at the heterozygous state in the proband
1’s parents. This mutation is expected to result in a loss of function
of the PTHR1. On the fifteen BD cases previously reported, one was
exactly from the same region referred for the families here reported. In
conclusion, considering that three families have segregated this rare
condition come from the same region and the fact that in two of the
probands were found the same mutation, we suggest a founder effect
in BD at the Brazilian northeast region.
P02.159
molecular diagnosis in Pycnodysostosis
P. Rendeiro, R. Cerqueira, L. Lameiras, H. Gabriel, L. Dias, A. Palmeiro, M.
Tavares;
CGC Genetics (www.cgcgenetics.com), Porto, Portugal.
Introduction: Pycnodysostosis is a rare autosomal recessive trait,
characterized by osteosclerosis, short stature, acro-osteolysis of the
distal phalanges, bone fragility, clavicular dysplasia, and skull deformities
with delayed suture closure. The responsible gene, cathepsin K
(CTSK), is a lysosomal cysteine proteinase critical for bone remodeling
and reabsorption. CTSK spans approximately 12 kb in 1q21 and
contains 8 exons. Its 987bp open reading frame encodes a polypeptide
of 329 amino acids. CGC Genetics is a reference laboratory for
diagnosing this disease. We report here our experience for the identification
of new Pycnodysostosis cases.
Method: During 2004-2008, we received 9 samples for CTSK gene
analysis. Our approach is the sequence analysis of the complete coding
region of this gene including adjacent intron/exon boundaries. At
this moment we designed a microarray based assay (patent pending),
to be used as a first evaluation that detects 15 mutations and includes
those referred in the present work.
Results: In 5 patients we found 1 homozygous disease causing mutation
plus 2 new mutations (1 nonsense and 1 frameshift). One patient
with 1 causative mutation and 1 new amino acid change, and 1 patient
with 1 new homozygous amino acid change. In the remaining 2
patients, no mutation was identified. The newly detected amino acid
change, in two cases, is predicted to be damaging.
Conclusion: These results, with four new mutations identified in unrelated
families, emphasize the molecular heterogeneity of the defects in
CTSK gene in Picnodysiostosis and the importance of genotyping for
diagnosis and genetic counseling.
P02.160
type 3 Rhizomelic chondrodysplasia punctata in a patient: A
case report of a very rare disorder
E. Karaca, S. Basaran Yılmaz, E. Yosunkaya, G. S. Güven, M. Seven, A. Yüksel;
Istanbul University, Cerrahpasa Medical Faculty, Department of Medical Genetics,
Istanbul, Turkey.
Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive
disorder, characterized by severe limb shortening, punctate calcification
of cartilage, flexion contractures, vertebral clefts, cataracts,
characteristic facial appearance, severe growth deficiency and mental
retardation. Three genotypes have been identified. Type 1 is associated
with a defect in the PEX7 gene, which codes for the receptor of
peroxisome targeting sequence 2. In Type 2, there is an isolated deficiency
of DHAP acyltransferase, and in Type 3, a defect of alkyl-DHAP
synthase. Plasmalogen levels are reduced in type 2 and 3 patients,
while phytanic acid levels and the processing of 3-ketothiolase are
normal. Here, we present a 3 5/12 years old patient, born to first cousin
parents. He was first referred to our clinic, when he was 5 months
old, because of growth delay, rhizomelic shortening of limbs, bilateral
cataracts, and facial dysmorphism. His physical examination revealed
that he had severe short stature, large anterior fontanel, microcephaly,
high sloping forehead, micrognathia, bilateral cataracts, low and
broad nasal bridge, anteverted nostrils, contractures, osteopenia, irregular
vertebral endplates, rhizomelic shortening of all limbs. Skeletal
radiologic studies displayed punctate calcifications on a number of
cartilages. Biochemical investigations of fibroblasts revealed deficient
alkyl-DHAP synthase. In conclusion, based on clinical picture and biochemical
enzyme assay the diagnosis of Rhizomelic chondrodysplasia
punctata type 3, which is an extremely rare disorder, has been diagnosed
in this patient.
P02.161
A new classification system for segmentation defects of the
vertebrae, and pilot validation study
P. D. Turnpenny 1 , A. Offiah 2 , P. F. Giampietro 3 , B. Alman 4 , A. S. Cornier 5 , K.
Kusumi 6 , S. Dunwoodie 7 , A. Ward 8 , O. Pourquié 9 , Intnl Consortium for Vertebral
Anomalies & Scoliosis (ICVAS);
1 Peninsula Clinical Genetic Service, Exeter, United Kingdom, 2 Great Ormond
Street Hospital, London, United Kingdom, 3 University of Wisconsin, Madison,
WI, United States, 4 University of Toronto, Toronto, ON, Canada, 5 La Concepción
Hospital, San Germán, Puerto Rico, 6 Arizona State University & UA College
of Medicine, Phoenix, AZ, United States, 7 Victor Chang Cardiac Research
Institute, Darlinghurst NSW, Australia, 8 Institute of Child Health, London, United
Kingdom, 9 Stowers Institute for Medical Research, Kansas City, MO, United
States.
The study aimed to develop and assess a new classification system
for Segmentation Defects of the Vertebrae (SDV), a frequent cause
of congenital scoliosis. Existing nomenclature for the wide range of
SDV phenotypes is inadequate and confusing, eg ‘Jarcho-Levin syndrome’.
A multidisciplinary group of ICVAS met to formulate a clinically
useful classification, based primarily on radiology, and transferable
to bioinformatic approaches. SDV are identified by number affected,
contiguity, and spinal region(s). The size, shape and symmetry of the
thoracic cage, and rib number, symmetry and fusion are included, and
familiar vertebral morphology terms retained, together with accepted
syndrome names. The terms spondylocostal and spondylothoracic
dysostosis apply only to phenotypes typified by the monogenic disorders
due to mutated DLL3, MESP2, LNFG and HES7 genes. Five IC-
VAS members (Group 1) then independently assessed 10 new cases,
inter-observer reliability assessed using kappa. Seven independent
radiologists (Group 2) then assessed the same cases before and after
introduction to the new system. Inter-observer reliability for Group 1
yielded a kappa value of 0.21 (95% confidence intervals (CI) 0.052,
0.366, p=0.0046). For Group 2, before introduction to the new system,
1/70 responses (1.4%) agreed with the Group 1 consensus,12 differ-
0