2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
P02.005
complex chromosomal rearrangement in chromosome 4q
causes acrofacial dysostosis and cardiovascular malformation
K. M. Roetzer 1 , A. C. Obenauf 1 , K. Schoner 2 , M. R. Speicher 1 , H. Rehder 3 ;
1 Institute of Human Genetics, Medical University of Graz, Graz, Austria, 2 Institute
of Pathology, University Hospital Giessen and Marburg, Marburg, Germany,
3 Department of Medical Genetics, Medical University of Vienna, Vienna,
Austria.
Acrofacial dysostoses (AFD) are characterized by the association of
mandibulofacial dysostosis in combination with limb defects. It is a heterogenous
group of syndromes which contains many different entities,
such as the Nager Syndrome, the postaxial (POAD) and the Rodriguez
type of AFD. We describe a female fetus exhibiting many features of
acrofacial dysostosis, including severe retro- and micrognathia, clinobrachysyndactyly,
arrhinencephaly and a complex heart defect. According
to these findings, AFD Rodriguez type was suspected. This is
a very rare disorder of unknown etiology first described by Rodriguez
in 1990. Chromosome analysis had been previously performed in an
outside lab and was reported to be normal (46,XX). Because of the
complex heart defect, classified as an early absent pulmonary valve
syndrome, fluorescence in-situ hybridization (FISH) for the 22q12 microdeletion
region was performed. However, no abnormalities were
found. Using high resolution array comparative genome hybridization
(aCGH) a complex rearrangement on the long arm of chromosome 4
consisting of two large duplications separated by two microdeletions
was detected. The involved region contains a large number of genes.
Interestingly, one of the deleted genes encodes a transcription factor
regulating the development of cardiovascular structures, especially of
the right ventricle. Furthermore, it was previously shown in a mouse
model that the gene product negatively regulates intramembranous
ossification of the mandible. This is the first case of an AFD syndrome
with right ventricular cardiac malformation in which an underlying genetic
cause was identified.
P02.006
Aglossia-adactyly syndrome with mental retardation
B. R. Ökcesiz, S. Basaran Yılmaz, E. Yosunkaya, E. Karaca, G. S. Güven, M.
Seven, A. Yüksel;
Istanbul University, Cerrahpasa Medical Faculty, Department of Medical Genetics,
Istanbul, Turkey.
Aglossia adactyly syndrome is characterized by the presence of aglossia,
adactyly and various malformations of the cranium, face and limbs.
Craniofacial anomalies include microstomia, micrognathia, hypoglossia,
variable tongue deformations, mandibular hypodontia, cleft palate,
cranial nerve palsy , broad nose, telecanthus, lower eyelid defects,
and facial asymmetry. The limb defects are represented by hypoplasia/
absence of the distal phalanx, total adactyly, partial limb amputation,
and syndactyly. Limb defects usually involve all four limbs. Motor development
are almost always normal, mental retardation is a very rare
occurrence in this syndrome. A 1 month-old-male patient referred to
our unit, because of congenital aglossia. His perinatal history was unremarkable.
On initial physical examination, his head circumference,
weight and height were all in normal range with 40 cm, 3.5 kg and
54 cm, respectively. He had prominent nose, frontal bossing, downslanting
palpebral fissures, large ears with hypoplastic antihelix, microretrognathia,
aplastic tongue, and bifid uvula. Metacarpal bones were
hypoplastic on his right hand. In his left hand, there was clinodactyly
and tips of finger were beaked. The distal phalanx of second, third and
fourth fingers, nail of second finger and toes on both feet were aplastic.
On follow-up period of this patient, speech therapy was started and
reconstructive plastic surgery for aglossia was planned for preschool
years. His mental status appeared to be retarded, and IQ was found
53, when he was 6 years old. Here, we report a rare event of mental
retardation for aglossia-adactyly syndrome.
P02.007
When is genetic testing helpful in Alport’s syndrome?
H. Hanson 1 , H. Story 2 , J. Pagan 2 , F. A. Flinter 1 ;
1 Clinical Genetics Department, Guy’s & St Thomas NHS Foundation Trust,
London, United Kingdom, 2 DNA laboratory, Guy’s & St Thomas NHS Foundation
Trust, London, United Kingdom.
Alport syndrome (AS) is a predominantly X-linked hereditary nephritis
associated with high-tone, sensorineural deafness and characteris-
tic eye signs. The gene frequency is1 in 5000 and it causes 0.6% of
chronic renal failure in Europe.
Most cases (85%) of AS result from mutations in the X linked collagen
gene COL4A5; mutations in the autosomal genes COL4A3/A4 on
chromosome 2 account for others. Mutation analysis of COL4A5 has
been available in a service setting for several years; mutation detection
rates using a combination of direct sequencing and MLPA now
exceed 95% in patients with classical clinical signs and an X-Linked
pedigree.
Questionnaires about the number of clinical diagnostic criteria that
families fulfilled were sent to clinicians of 250 patients whose DNA was
received for diagnostic testing; predictive tests, duplicate family members
and samples that were only partially screened were excluded.
One hundred and fifty two (61 %) were returned. Seventy four patients
(49%) had a pathogenic COL4A5 mutation.
The mutation detection rate in families fulfilling 0, 1, 2, 3 or 4 diagnostic
criteria was 0%, 8.6%, 57%, 78% and 67% respectively. Twenty five
(64 %) of patients with COL4A5 mutations apparently meeting only 2
diagnostic criteria had incomplete clinical assessments.
In patients meeting 4 diagnostic criteria without an identified COL4A5
mutation, autosomal inheritance was confirmed or suspected in three.
We recommend COL4A5 analysis in any patient meeting at least 2
diagnostic criteria. COL4A3 and COL4A4 analysis can be considered
subsequently if a COL4A5 mutation is not detected.
P02.008
Delineation of a lethal autosomal recessive disorder
characterized by alveolar capillary dysplasia and limb anomalies
A. Innes;
University of Calgary, Calgary, AB, Canada.
Alveolar capillary dysplasia (ACD) is amongst the common causes of
lethal primary pulmonary hypertension (PPHN) in the newborn. It is
ultimately unresponsive to inhaled nitric oxide and ECMO. Definitive
diagnosis requires lung biopsy, and is characterized by a reduction in
number of capillaries, with a decreased blood-air interface. The deficit
likely involves the pseudoglandular and canalicular stages of lung development.
Over 100 cases have been reported.
The etiology of most cases is unknown, but many familial cases have
been reported. Associated malformations are seen in 50% of patients,
recurrent anomalies involve the cardiovascular, genitourinary and
gastrointestinal systems. Mutations in STRA6 have been identified
in patients with anophthalmia and malformations including ACD. The
molecular basis for the majority of children with ACD is unknown. One
study excluded mutations in two candidates: BMPR2 and EMAPII (Sen
et al, 2004).
We have encountered 4 children born to consanguineous parents (2
different ethnic groups) that presented with limb reduction anomalies
and died of PPHN as newborns. In those who had autopsy, ACD
was confirmed. Review of the literature identified 4 other reports of
6 children with limb reduction anomalies and ACD (Cullinane et al,
1992; Simonton et al, 1993; Steinhorn et al, 1997; Witters et al, 2001).
Therefore, we are aware of 10 patients with ACD and limb reduction
anomalies. Given consanguinity in 4 families, this is likely an autosomal
recessive condition. This paper will include a clinical delineation of
this syndrome, as well as current data on molecular studies on these
families.
P02.009
clinical characterization of a microdeletion syndrome in Xq22.3
in a czech family
V. Horinova 1 , V. Vranova 2 , P. Kuglik 2 ;
1 Genetic ambulance and counseling, Jihlava, Czech Republic, 2 Department of
Genetics and Molecular Biology, Faculty of Science, Masaryk University, Brno,
Czech Republic.
An X-linked recessive syndrome (AMME), characterized by the Alport
syndrome, mental retardation, midface hypoplasia and elliptocytosis
associated with a microdeletion in Xq22.3 and explained by mutations
in the COL4A5 gene was reported by Jonsson et al (J. Med. Genet.1988,35:273).
We have identified a family with two affected male
(maternal uncle/nephew) members showing clinical features similar to
AMME, which was associated with an Xq22.3 microdeletion observed
also in the female members of the family. The aims of this work were
to compare the phenotypes of our patients with these cases and to