2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
amplification (MPLA) probe mixes. Thereafter, positive or inclusive results
are referred to cytogenetics for confirmation through FISH. To
date, 350 patients have been reported across 17 separate phenotypes
using 9 separate MLPA probe mixes (supplied by MRC Holland). Of
these patients 15 (4%) have been reported with a pathogenic deletion
or duplication associated with DiGeorge Syndrome 22q11 (4), telomere
/ subtelomere (7), Williams Syndrome 7q11.23 (1), Rubinstein-
Taybi Syndrome 16p13.3 (1) and Prader Willi (2). The effectiveness of
this strategy when considering the concordance of results, the limitations
of the methodologies, turnaround times and overall cost-benefit
will be presented.
P02.032
Evaluation of three patients with disorders of sexual
development
V. Belengeanu, D. Stoicanescu, S. Farcas, C. Popa, M. Stoian, N. Andreescu;
University of Medicine and Pharmacy “Victor Babes”, Timişoara, Romania.
Disorders of sexual development represent a clinically heterogeneous
group of conditions that interfere with normal sex determination and
differentiation. The manifestations in affected individuals may fluctuate
from the neonatal period to adulthood. Disorders of sexual development
arise from chromosomal, genic, gonadal, or anatomic abnormalities
in the pathway of sexual differentiation, occasionally being associated
with other malformations. We report clinical, hormonal and other
parameters, together with the karyotype, FISH and molecular analysis
in three cases born with disorders of sexual development. One case
had facial dysmorphism suggesting an autosomal chromosomal abnormality.
Surprisingly, cytogenetic investigation revealed a 47, XXY
karyotype in all metaphases. Another case had ambivalent external
genitalia and chromosomal investigation showed male genetic sex.
Exploratory laparascopy and histopathological examination revealed
that gonads were exclusively testes. As all the investigations led to
the diagnosis of 46,XY disorder of sexual development, adequate
hormonal and surgical treatment was initiated. The third case was
also born with ambiguous external genitalia, chromosomal analysis
together with FISH and molecular analysis for SRY region revealing
female genetic sex. Clinical and hormonal data led to the diagnosis
of 21-hydroxylase deficiency. Ambiguous genitalia do not occur in all
disorders of sex development, but whenever ambiguity is present, it
needs immediate action, to try to establish the diagnosis and to decide
the best choice for the sex of rearing. A multidisciplinary approach,
with a patient-centered model of care, is necessary in order to reach a
prompt and correct diagnosis and treatment.
P02.033
Partial distal aphalangia, duplication of metatarsal iV,
microcephaly and borderline intelligence: a third patient
suggesting autosomal recessive inheritance
G. Utine, Y. Alanay, D. Aktaş, M. Alikaşifoğlu, K. Boduroğlu;
Hacettepe University, Ankara, Turkey.
Partial distal aphalangia, duplication of metatarsal IV, microcephaly
and borderline intelligence (OMIM %600384) has been reported twice
previously [Martinez-Frias et al.; 1995, Di Rocco et al.; 2002]. We describe
a third patient with the same condition, from a family with parental
consanguinity. The patient is a 10 year-old boy referred for oligodactyly.
He was born at term with a birth weight of 3500 gr to healthy
first cousins, as their first and only child. On physical examination, he
was tall and obese, his height being 150 cm (90-97th centiles), his
weight 52.5 kg (over 90th centile) and his head circumference 52 cm
(3rd-10th centiles). Fingers were structurally normal. However, there
were three toes on the left and four on the right with partial cutaneous
syndactyly between 2nd and 3rd. Both halluces were normal structurally,
but the distal phalanx of the left hallux assumed a valgus position.
X-rays showed duplication of both metatarsal IVs. On the right,
last toe overrided the 5th and the bifid 4th metacarpals, and had 3
proximal phalanges lying over these metacarpals. On the left, 2nd and
4th metatarsals were rudimentary, the fourth being partially duplicated.
Last toe overrided the 4th and the 5th metatarsals. X-rays of hands
were normal. His IQ was calculated as 50. The pedigree of the first
family suggested an autosomal dominant pattern of inheritance whereas
the second report suggested an autosomal recessive pattern. The
present patient may support the existence of the latter pattern.
P02.034
severe autosomal dominant dyskeratosis congenita (Dc) due to
TINF gene mutation
Y. J. Sznajer 1,2 , A. Walne 3 , T. Vulliamy 3 , A. Ferster 4 , C. Dangoisse 5 , F. Roulez 6 ,
I. Dokal 7 ;
1 Hopital Universitaire des Enfants Reine Fabiola, Brussels, Belgium, 2 Center
for Human Genetics, Hôpital Erasme, Université Libre de Bruxelles (U.L.B),
Brussels,, Belgium, 3 Centre for Pediatrics, Barts and the London SMD, Queen
Mary University of London, London, United Kingdom, 4 Haematology and Oncology,
Hopital Universitaire des Enfants Reine Fabiola, ULB, Brussels, Belgium,
5 Dermatology,Hopital Universitaire des Enfants Reine Fabiola, ULB, Brussels,
Belgium, 6 Ophthalmology, Hopital Universitaire des Enfants Reine Fabiola,
ULB, Brussels, Belgium, 7 Centre for Pediatrics, Barts and the London SMD,
Queen Mary University of London;, London, United Kingdom.
DC represents a genetically heterogeneous disease which may result
from the three conventional mendelian mode of inheritance: X-linked
recessive to mutation in dyskerin (DKC1) gene; autosomal recessive
(biallelic mutations) in NOP10, NHP2or TERT genes and autosomal
dominant (heterozygous mutations) in TERC, TERT or TINF2 genes.
TINF2 is member of genes encoding the shelterin complex of proteins
identified mutated in sporadic patients with severe DC. TINF2 gene
accounts for up to 11% of patients with DC (1). Affected patients developed
dermatologic signs (leukoplakia, nail dystrophy, abnormal skin
pigmentation) with bone marrow failure syndrome.
We report the natural history of a 14 year-old girl, second child from
healthy consanguineous parents. She developed aplastic anemia at
the age of 3 yrs and had from her sister HLA homologous bone marrow
transplant. Her intelligence and development were normal. She
had few premature grey hairs, small area of alopecia, oral leukoplakia,
right peripheral retinal ischemia, localized keratitis, nail dystrophy
with pterygia, large dyskeratosis on the perineal region and hypoplastic
dental roots. She didn’t had poïkiloderma, cerebellar hypoplasia,
brain anomaly nor any digestive problem. Graft versus host disease
was suspected but dermatologic features are not found so that dyskeratosis
congenita was diagnosed. Molecular investigation ruled out
mutation in DKC1 or TERC genes. Combined DHPLC and direct DNA
sequencing of TINF2 gene identified a c.847C>G (p.Pro283Ala) mutation
in the index patient and was absent in both parents. The molecular
diagnosis allowed precise genetic counseling to the family.
(1) Savage S.A. et al. Am J Hum Genet 2008;82:501-509
P02.035
congenital cytomegalovirus infection as one of the main causes
of early onset sensorineural hearing loss; case report
R. Teek 1,2 , T. Reimand 1,3 , R. Rein 3 , K. Õunap 1,3 ;
1 Department of Genetics, United Laboratories, Tartu University Hospital, Tartu,
Estonia, 2 Department of Oto-Rhino-Laryngology, University of Tartu, Tartu,
Estonia, 3 Department of Pediatrics, University of Tartu, Tartu, Estonia.
Cytomegalovirus (CMV) infection is one of the most common congenital
infection, the overall birth precalence is estimated to ~0,64%. Only
11% of infected infants have non-specific symptoms at birth. Congenital
CMV is an important but underestimated cause of hearing loss
(HL). Children with congenital CMV have a risk 15-22% of developing
sensorineural HL.
We report a term-born girl, birthweight 3075 g, length 53 cm. Since
first year of the life she had speech delay and bilateral profound sensorineural
HL. At the DNA investigation, which covers 201 mutations in
8 genes we didn’t find any mutations causing HL. Brain MRI showed
non-progressive leukoencephalopathy. The congenital CMV infection
was diagnosed by using PCR testing to detect CMV DNA on neonatal
screening card.
HL occurs up to 22% of children with congenital CMV and HL can be
from mild to profound. The severity of the neurologic impairment of patients
with congenital CMV is highly variable and neuroimaging studies
have revealed multiple anomalies. The white matter abnormalities occur
up to 22% of congenital CMV patients. In the differential diagnosis
of patients with white matter lesions and sensorineural hearing loss,
one should consider congenital CMV infection. Congenital CMV infection
is one of the most important causes of hearing loss in young children,
second only to genetic mutations. The CMV DNA analysis from
neonatal screening card of Estonian children with HL of unknown aetiology
is in work and results will be presented (102 cases from group of
219 patients with early onset HL).