2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
ventricle. Patient 1 had postnatal growth retardation (weight 2200 g at
birth), general developmental delay and recurrent bronchitis. She had
mild mental retardation with learning and social difficulties. She had
also, a peculiar face characterized by eversion of the lower lateral eyelid,
arched eyebrows, mild ptosis, strabismus, depressed nasal tip with
prominent nose and short nasal septum, malformed ears and abnormal
teeth (delayed teething at 7 years old). The patient had abnormally
short fifth digits in hands, foetal fingertip pads and deformities of the
feet fingers. She had also bilateral perception deafness. Patient 2 had
postnatal growth retardation and hypotonia, short stature and learning
difficulties. She had characteristic facial features of KS syndrome
with hair abnormalities (brittle hair) and severe skeletal malformation
particularly butterfly vertebrae with scoliosis.
Chromosomal studies showed a normal female 46,XX pattern with no
evidence of del22q11 by FISH.
There was history of consanguinity for our 2 patients with background
of mental disability associated to congenital blindness or to seizures,
multiple new born deaths, celiac disease, scoliosis and male infertility.
P02.058
Knobloch syndrome : a cause of encephalocele and vitreoretinal
degeneration.
V.Drouin-Garraud 1 , G. Brasseur 2 , B.Leducq 2 , JL Bouin 3 , P.Saugier-Veber 1 ,
T.Frébourg 1 ;
1 Department of Medical Genetics, Rouen, France, 2 Department of Ophtalmology,
Rouen, France, 3 Department of Medical Genetics, Genève, Switzerland.
Knobloch syndrome is a rare autosomal recessive disorder, described
in 1971 by Knobloch and Layer, characterized by vitreo-retinal degeneration,
high myopia, recurrent retinal detachment, and occipital encephalocele.
In 1996, the gene was mapped to 21q22.3, in a large
consanguineous Brazilian family (Sertie et al, 1996) and a mutation in
the COL8A1 gene was identified in this family, and in additional families
(Sertie et al, 2000).
We report here on two sibs with Knobloch syndrome.
Yacine is the second child of consanguineous Algerian parents. At 4
months of age, myopia was detected. At eleven, he had bilateral retinal
detachment with vitreal degeneration and chorio-retinal atrophy. Clinical
examination and psychomotor development were normal.
Salim, the fourth child, was born after an uneventful pregnancy with
normal birth weight. A midline occipital meningocele was noted and
confirmed by cranial resonance magnetic imaging excluding other cranial
malformation. At 4 months, ophtalmological examination revealed
high myopia and at 3 years he had amblyopia of the right eye and
vitreo-retinal degeneration. He had delayed language skills but normal
neuropsychological evaluation.
The two sibs were homozygous for COL18A1 gene region microsatellite
analysis. Screening of the exons 3, 21, 23, 35, 38 and 42 of the
COL18A1 gene has shown an homozygous duplication in the exon 23
: c.2118dupC.
These cases are illustrating the clinical variability of the phenotype in
Knobloch syndrome.
P02.059
Report of Knobloch-Layer (1971)-detached retina; encephalocele
(autosomal recessive) from iranian families
N. Almadani 1,2 , A. Kariminejad 2 , S. Amirsalari 3 , M. H. Dehghan 4 , M. H. Kariminejad
2 ;
1 Genetic Department, Reproductive Medicine Research Center, Royan Institute,
ACECR, Tehran, Islamic Republic of Iran, 2 Kariminejad-Najmabadi
Pathology & Genetics Center, 14665/154, Tehran, Islamic Republic of Iran,
3 Department of Pediatrics, Faculty of Medicine, Baqyiatallah University of Medical
Sciences, Tehran, Islamic Republic of Iran, 4 Ophtalmologic Department,
Labafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran,
Islamic Republic of Iran.
Knobloch syndrome (KS) in an autosomal recessive disorder defined
by the occurrence of high myopia, viteroretinal degeneration with retinal
detachment, macular abnormalities and occipital encephalocele.
Knobloch syndrome caused by mutations in the COL18A1. Clinical
variability is present in the manifestation of this syndrome, but ocular
abnormalitied are sever, progressive and irreversible, leading to
bilateral blindness. Scalp defect or occipital encephalocele is also a
major clinical feature. Other minor clinical abmormalities are: lens subluxation,
cardiovascular anomalies, joint hyperlaxity, genitourinary and
gasterointestinal abnormalities. We report a brother and sister with
this condition. They are resulted from consanguineous marriage (first
cousin once-removed), and too suffered from bilateral cataract, retinal
detachment, high myopia, hypertelorism, bilateral epicanthic folds and
bilateral sever chorioretinal pigmentary degeneration. They have also
epilepsy, and retardation of speech and developmental milestone. Occipital
true encephalocele was detected in two cases.
P02.060
Laryngomalacia (Omim 150280) and congenital stridor in infants
A. Petrunitchev;
Saint-Petersburg medical academy of postgraduate studies, Saint-Petersburg,
Russian Federation.
At present hundreds children with noisy breathing per year are investigated
in one large hospital. The otolaryngologists proved that laryngomalacia
provides about 70 % of these cases. About 10 % of cases are
severe and required surgical intervention. The diagnostics is based on
revealing of peculiar endoscopic sign: inspiratory collapse of laryngeal
vestibule.
It would be naive to regard all these cases as one monogenic syndrome.
This investigation includes genetic counseling in cases of endoscopically
proved laryngomalacia (100 families). The precise history
of stridor and all other peculiarities of patients were assessed. The
genealogical method was used. The proband’s parents underwent indirect
laryngoscopy.
The residual deformation of larynx looked like result of laryngomalacia
was found in 12 proband’s mothers, 7 proband’s fathers and both
parents were peculiar in 3 cases (22 % at all). The anamnestic data
(transitory noisy breathing) proved these findings in just 4 cases and
were never present in adults with normal larynx.
Anamnestic and objective peculiarities of patients allowed forming two
groups with prevalence of neurological problems (27 %) or signs of
connective tissue dysplasia (73 %). Twenty (91 %) of “family” cases
were revealed in second one. The worsening of stridor occurred in
sleep usually in “neurological” group and under exertion in another.
Conclusion: the laryngomalacia is heterogenous disorder. The genetic
counseling in cases of congenital stridor is indicated and perspective.
P02.061
mitochondrial c11777A mutation in the fourth subunit of NADH
dehydrogenase encoding gene associated with Leigh-syndrome
A. Maasz 1 , P. Kisfali 1 , E. Kalman 2 , K. Hadzsiev 1 , K. Komlosi 1 , B. Melegh 1 ;
1 Department of Medical Genetics and Child Development, University of Pecs,
Pecs, Hungary, 2 Department of Pathology, University of Pecs, Pecs, Hungary.
Leigh-syndrome as a subacute necrotizing encephalopathy has extensive
genetic heterogeneity including mitochondrial DNA alterations that
have been described previously in the background of the disease.
A 17-month-old male proband reported here was born with appropriate
parameters at term. At the age of 5 days myoclonus were observed.
West syndrome was diagnosed and treated with antiepileptic drug at
the age of 11 months. Soon after, T 2 -weighted MRI of the patients depicted
increased signal intensity within the mesenchephalon and the
medulla oblongata; moderate frontal atrophy and ventricular dilatations
were also discovered. Besides, elevated lactate levels were detected
in the cerebrospinal fluid. Suddenly, he died from cardiorespiratory arrest
at the age of 17 months.
Postmortem analyses of the respiratory chain enzyme in the skeletal
muscle revealed a defect in the complex I activity, associated with C→
A transversion in heteroplasmic form at the 11777 position of the mitochondrial
DNA causing Arg→Ser amino acid change that affects the
fourth subunit of the NADH dehydrogenase enzyme encoding gene
(MTND4).
This case represents the first report of a mitochondrial mutation associated
with Leigh-syndrome in Hungarians, to our knowledge, this
mutation was described in two Japanese and in one Italian patients
with phenotypic variations in correlation with complex I deficiency and
Leigh-disease. In our case, earlier onset of the symptoms and the aggressive
outcome of the disease are highly indicative of the pathogenicity
and the clinical importance of C11777A mitochondrial mutation in
the development of Leigh-syndrome.