2008 Barcelona - European Society of Human Genetics

Clinical genetics
and PT 19 cm. Necropsy confirmed dysmorphic features, coarse face,
and showed bilateral pulmonary hypoplasia, bilateral renal agenesia
(not previously reported in opsismodysplasia) rhizomelic micromelia
(handwriting appearance of hands fingers).
She presented: high forehead, horizontals and short palpebral fissures,
posterior rotated and low placed proeminent ears, small anteverted
nose with long philtrum, depressed bridge of nose, micrognatia, thin
upper lip), muscle hypotonia , short feet and hands, abnormalities of
fingers, dorsolumbar scoliosis. Radiographic findings were hypoplastic
vertebral bodies, marked shortness of the long bones of the hands and
feet with concave metaphyses .
Karyotype from the peripheral blood lymphocytes and G banding were
performed according to standard protocols . The karyotype was 46,XX
In our knowledge were reported only ten cases with termination of
pregnancies after the antenatal diagnoses and this is the first case of
opsismodysplasia associated with bilateral renal agenesia .
P01.125
New ocular findings among two sisters with Yunis-Varón
syndrome
J. R. Corona-Rivera 1 , C. O. Romo-Huerta 2 , S. A. Estrada-Padilla 1 , E. López-
Marure 2 , M. A. Villafuerte-Bautista 2 ;
1 Instituto de Genética Humana Dr. Enrique Corona-Rivera, Guadalajara, Mexico,
2 Hospital Civil de Guadalajara Dr. Juan I. Menchaca, Guadalajara, Mexico.
introduction. The Yunis-Varón syndrome (YVS) represents a rare autosomal
recessive syndrome characterized by cleidocranial dysplasia,
absence of thumbs and halluces, distal aphalangia, ectodermal anomalies,
and poor outcome . This report is among two sisters with YVS,
which adds ocular findings to the known features of this syndrome.
clinical reports. The first patient, a 11-month-old female infant was
the third child of a healthy consanguineous parents of Mexican descent
. She has pre- and post-natal growth retardation, wide sutures
and fontanels, sparse hair, telecanthus, short upper lip, high arched
palate, abnormal ears, micrognathia, loose skin in neck, sloping shoulders,
hypoplastic thumbs, distal aphalangia, nail hypoplasia, aplasia
of great toes, and short pointed toes . Besides, skull dystostosis, hypoplastic
clavicles, hypoplasia of proximal phalanges, agenesis of distal
phalanges, congenital cardiopathy, central nervous system anomalies,
hearing loss and visual impairment were also observed . Ophthalmologic
evaluation and fluorescein angiography showed papillo-macular
atrophic chorioretinopaty with “salt-and-pepper” appearance . Results
of TORCH titers, metabolic screening test, karyotype, and muscle biopsy
were normal or negative . The second patient was a female newborn
with physical, ophthalmologic, and radiological findings similar to
her sister. Absence of thumbs and first toes were observed on ultrasound
examination at 22 weeks .
conclusions. This appears to be the first cases of YVS associated
with chorioretinopaty that could not be attributed to environmental
causes . Other anomalies such as sclerocornea, cataracts, corneal
opacity and microphthalmos make mandatory the ophthalmologic
evaluation for patients with YVS .
P01.126
cOL2A1 mutations and related phenotypes in italian patients
with presumptive type ii collagenopathy
E. Andreucci 1 , I. Carboni 2 , E. Lapi 3 , M. F. Bedeschi 4 , F. Lalatta 4 , M. Di Rocco 5 ,
M. G. Patricelli 6 , C. Auriti 7 , G. Seganti 7 , F. Papadia 8 , L. Giunti 3 , M. Genuardi 1 , S.
Giglio 1 ;
1 Dept. of Clinical Pathophysiology, University of Florence and Medical Genetics
Unit, Meyer Children’s University Hospital, Florence, Italy, 2 Dept. of Clinical
Pathophysiology, University of Florence and Medical Genetics Unit, Meyer
Chidren’s University Hospital, Florence, Italy, 3 Medical Genetics Unit, Meyer
Children’s University Hospital, Florence, Italy, 4 Medical Genetics Unit, Policlinico
Mangiagalli Hospital, Milan, Italy, 5 Rare Disease Unit, Department of
Paediatrics, Gaslini Institute, Genoa, Italy, 6 Laboraf, “San Raffaele” Hospital,
Milan, Italy, 7 Neonatal Pathology Unit, Children’s Hospital “Bambino Gesù”,
Rome, Italy, 8 Metabolic Disease-Medical Genetics Division, Children’s Hospital
“Giovanni XXIII”, Bari, Italy.
COL2A1 mutations are associated with a wide spectrum of phenotypic
manifestations . At present little is known about the distribution of
COL2A1 defects and related phenotypes in Italian patients . We investigated
a series of 13 unrelated Italian probands with a presumptive
diagnosis of type II collagenopathy . The 54 exons of the COL2A1 gene
were screened by dHPLC, followed by sequencing of amplicons with
an abnormal profile. Overall, eight distinct mutations were detected.
Five of these had been previously described in the literature, and three
have never been reported to our knowledge . Previously described
genotype-phenotype correlations for the already reported mutations
were confirmed in this series.
Among the newly reported mutations, the IVS7+1G>A variant was
found in a female proband with typical type 1 Stickler syndrome with
a positive family history and wide intrafamilial phenotypic variability .
A nonsense mutation, K1447X, in the C-terminal region of the protein
was found in a family, mother and child, studied for a suspicion
of Kniest Dysplasia . Finally, a G891C missense variant, affecting the
triple helical domain of the protein, was associated with a clinical picture
of spondyloepimetaphyseal dysplasia, Strudwick type .
Further cases will need to be examined in order to obtain a better
definition of genotype-phenotype correlations for COL2A1 mutations
in the Italian population .
P01.127
Genetic diagnosis of the craniosynostosis in spain
D. Arroyo, D. Corella, M. Edo;
Progenie molecular, Valencia, Spain.
The craniosynostosis consist in an anomalous fusion of cranial bones
that originates problems in the normal growth of the cranium and involves
dramatic alterations in the shape of the head and the face, and
in some cases severe mental delay. The craniosynostosis is classified
under several syndromes: Apert, Crouzon, Pfeiffer, Beare-Stevenson,
Saethre-Chotzen, Muenke and Jackson-Weiss . Each one has a particular
pattern of inheritance and a few clinical specific characteristics,
but in some cases they are difficult to distinguish by the external
aspect, specially when prenatal diagnosis is done by means of the
ultrasound scans . The genetic diagnosis allows to detect the craniosynostosis
in the first stages of the pregnancy and to confirm the clinical
observations .
The most important genes associated to these disorders are FGFR1,
FGFR 2, FGFR3 and TWIST . The genetic study of the craniosynostosis
is complex, and may includes the four genes involved in the pathology
. In this communication we show the results obtained in the study
of these syndromes in Spain . We analysed 38 genes from 19 people,
including affected people and their families . We found 5 mutations that
have been reported as the genetic basis of the disease . We also done
a prenatal genetic diagnosis that confirms a Pfeiffer syndrome, previously
diagnosed by ultrasound scan . Our results suggest that most of
mutation associated to craniosynostosis are located in a few regions
of these genes, in opposition to what happens with other genetic diseases,
in which the mutations could be found along the entire gene .
P01.128
czech dysplasia: clinical and molecular delineation of a novel
cOL2A1 disorder
A. Tzschach 1 , S. Tinschert 2 , E. Kaminsky 3 , E. Lusga 3 , S. Mundlos 4 , L. M.
Graul-Neumann 4 ;
1 Max Planck Institute for Molecular Genetics, Berlin, Germany, 2 Institute of
Clinical Genetics, Technical University, Dresden, Germany, 3 Practice of Human
Genetics, Schomburgstrasse 120, Hamburg, Germany, 4 Institute of Medical
Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Czech dysplasia (OMIM 609162) is a novel type II collagen disorder
which is phenotypically distinct from other COL2A1-related diseases .
Czech dysplasia is characterized by early-onset progressive pseudorheumatoid
arthritis, short third and fourth metatarsals, mild platyspondyly,
normal height, and the absence of ophthalmological problems or
cleft palate. The disorder is caused by a specific missense mutation
(R275C, c .823C>T) in the triple helical domain of the COL2A1 gene .
We report a large German family consisting of 11 patients who not
only suffered from the typical features mentioned above, but who also
had sensorineural hearing loss, a problem that has hitherto not been
considered as a major feature of Czech dysplasia . Mutation analysis
revealed the COL2A1 c .823C>T (R275C) mutation in all patients . This
finding provides further evidence that Czech dysplasia is caused exclusively
by the R275C mutation, which is a unique situation among
the COL2A1 disorders, and indicates that this amino acid exchange
leads to specific structural changes of type II collagen. The clinical and
radiological data of this family and previously reported patients with