2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
mal with advanced bone age. Mild unilateral transmission hearing loss
was detected. Strabismus was noted and electroretinogram showed
macular retinopathy.
Patient 2, a 10 year old female, presented similar clinical features as
patient 1 leading to a diagnosis of Myhre syndrome. She had intra uterine
growth retardation and then showed normal stature with advanced
bone age. She presented mild transmission hearing loss. Unilateral
cataract was diagnosed at 6 months. Severe myopia was noted and
electroretinogram showed macular retinopathy.
Karyotype banding, subtelomeric analysis, and metabolic screening
were normal, and CGH array analysis is underway for both patients.
Description of retinopathy in our patients suggests that electroretinogram
should be systematically undertaken in Myhre patients, in order
to confirm this new feature.
At this time, the main differential diagnoses of Myhre syndrome are
mainly bone disorders (such as geleophysic and acromicric dysplasia).
However, the association of bone, muscular, auditory and retinal involvement
could suggest that a metabolic disorder, such as mitochondrial
dysfunction, could be responsible for Myhre syndrome.
P02.081
Pancreatic hypoplasia presenting with neonatal diabetes
mellitus in association with congenital heart disease and
developmental delay
M. Balasubramanian 1 , J. P. H. Shield 2,3 , C. Acerini 4,5 , S. Ellard 6 , J. Walker 7 , J.
Crolla 8 , D. J. G. Mackay 9,10 , I. K. Temple 11,12 ;
1 Sheffield Clinical Genetics Service, Sheffield Children’s NHS Foundation Trust,
Sheffield, United Kingdom, 2 Department of Child Health, Bristol Royal Hospital
for Children, Bristol, United Kingdom, 3 University of Bristol, United Kingdom,
4 Department Of Paediatrics, Addenbrooke’s Hospital, Cambridge, United Kingdom,
5 University Of Cambridge, United Kingdom, 6 Institute of Biomedical and
Clinical Science, Peninsula Medical School, Exeter, United Kingdom, 7 Department
of Paediatrics, St Mary’s Hospital, Portsmouth, United Kingdom, 8 Wessex
Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury,
United Kingdom, 9 Division of Human Genetics, University of Southampton,
Southampton, United Kingdom, 10 Wessex Regional Genetics Laboratory, Salisbury
NHS Foundation Trust, Salsibury, United Kingdom, 11 Academic Unit Of
Genetic Medicine, Division of Human Genetics, University Of Southampton,
Southampton, United Kingdom, 12 Wessex Clinical Genetics Service, Princess
Anne Hospital, Southampton, United Kingdom.
Congenital pancreatic hypoplasia is a rare cause of neonatal diabetes.
We report a case series with pancreatic agenesis and congenital heart
disease. Case (1) was born prematurely at 34+2 weeks gestation and
developed hyperglycemia within the first 12 hours of life requiring insulin.
She also has exocrine pancreatic insufficiency needing supplementation.
Cardiac imaging revealed ventricular septal defect, patent
ductus arteriosus and pulmonary artery stenosis. She is severely developmentally
delayed and has abnormalities on cranial imaging (focal
microcalcification, gliosis and cerebral atrophy).
Case (2) is a child who had antenatally detected truncus arteriosus
who developed diabetes in the neonatal period post surgery. Imaging
of the abdomen confirmed pancreatic agenesis. He has microcephaly
and is developmentally delayed
Case (3) is a female infant born at 34 weeks gestation with an antenatal
diagnosis of Tetralogy of Fallot. She manifested hyperglycemia
and pancreatic insufficiency from day 3 of life requiring replacement
therapy. Repeated imaging failed to visualise the pancreas. She had
initial motor delay, but is currently well.
Investigations included sequencing of GCK, ABCC8, IPF1, SUR1,
NEUROD1, GATA4, PTF1A and KCNJ11 genes, but no mutation was
found. Genetic investigation to exclude paternal UPD 6, methylation
aberrations and duplications of 6q24 was also negative. Array CGH in
case (1) showed a paternally inherited ~250 kb dup(12)(q24.33), not
present in the others.
Permanent neonatal diabetes mellitus due to pancreatic hypoplasia
with congenital heart disease has been reported before and may represent
a distinct condition (Gurson CT et al 1970; Yorifuji T et al 1994).
P02.082
Severe combined immunodeficiency, microcephaly and failure to
thrive. A chromosomal breakage syndrome with mutations in the
NHEJ gene
G. Gillessen-Kaesbach1 , H. Neitzel2 , V. Dutrannoy2 , K. Konrad2 , R. Varon2 ;
1 2 Institut für Humangenetik, Lübeck, Germany, Institute of Human Genetics,
Charité, Berlin, Germany.
Recently mutations in the NHEJ (nonhomologous end-joining factor)
gene have been described (Ahnesorg et al., 2006; Buck et al., 2006)
causative for a new chromosomal breakage syndrome characterized
by severe combined immunodeficiency, microcephaly, developmental
delay and subtle facial dysmorphism.
Here we present the clinical, cellular and molecular findings in a Turkish
boy, first son of consanguineous parents. At term, he showed low
birth measurements [weight 2290g (-4.2 SD), length 49 cm (-2 SD),
OFC 32 cm (-4 SD). He developed respiratory infections and a severe
autoimmune anemia. At age 13 months he had a weight of 5200g (-3.3
SD), height: 64 cm (-2.8 SD) and OFC: 38,5 cm (-5,3 SD). Motor and
mental developmental development was nearly normal. At the age of 4
months a tentative clinical diagnosis of Nijmegen breakage syndrome
was made. Chromosomal breakage analysis revealed a high rate of
chromosomal breakage and extremely high levels of damage after irradiation.
Molecular testing showed a known homozygous mutation
(R178X) in exon 5 of the NHEJ gene.
We describe the clinical, cellular and molecular findings of this new
autosomal recessive chromosome breakage syndrome with respect
to the literature.
P02.083
Broad first digits, facial and oral anomalies, and developmental
delay in a three-generation family: A Novel syndrome?
E. Lisi1 , V. Mardo1 , A. Hata2 , D. Riegert-Johnson1 , S. A. Boyadjiev2 ;
1McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University,
Baltimore, MD, United States, 2Section of Genetics, University of California
Davis, Sacramento, CA, United States.
A characteristic combination of facial, oral, and digital anomalies was
observed in a three-generation Caucasian family, with a segregation
pattern suggestive of an autosomal dominant inheritance. The facial
dysmorphism included prominent forehead, almond shaped eyes with
upslanting palpebral fissures and medial epicanthal folds, broad nasal
bridge, thin upper lip, and posteriorly rotated ears. Observed oral
anomalies included high arched palate, torus palatinus and midline
groove of the lower lip. All affected family members had broad thumbs
and great toes, speech delay, and mild mental retardation. Seizures,
macrocephaly, abnormal brain MRI, somatic overgrowth, congenital
heart defects (VSD with coarctation of the aorta), and cryptorchidism
were also observed among various members of this family. Microsatellite
analysis excluded linkage to CREBBP and EP300, the genes associated
with Rubinstein-Taybi syndrome. Additionally, Simpson-Golabi-Behmel
syndrome was considered, but X-linked inheritance was
excluded by the presence of male-to-male transmissions and two affected
females. Cytogenetic studies, including karyotype, subtelomere
screen, and FISH for 22q11 deletion syndrome, were normal. Taken
together, we believe that this condition represents a novel dysmorphic
genetic syndrome.
P02.084
Xp11.4 deletion identified by array-CGH in a mother and her
daughters causing OFcD phenotype
N. Pasz 1 , A. Dieux-Coeslier 1 , C. Morisot 2 , E. Laumonier 3 , S. Manouvrier-Hanu 1 ,
J. Andrieux 4 ;
1 Service de génétique Guy Fontaine, Lille, France, 2 Service de Réanimation
et Médecine Néonatale, Lens, France, 3 Service d’ophtalomogie, Lille, France,
4 Service de Cyto-génétique, Lille, France.
We report on a familial case of syndromic bilateral congenital cataract
with dysmorphic features in a mother and both of her daughters.
The younger daughter, referred to the genetic clinic, showed additional
malformations comprising atrial septal defect, facial dysmorphic features
(synophris, high nasal bridge, small cup shaped ears, bifid uvula,
long philtrum, microstomia), dental anomalies (delayed eruption, oligodontia),
skeletal manifestations (irregular metacarpal epiphyses ossification)
and moderate developmental delay. High resolution karyotype
was normal. The array-CGH analysis identified an Xp11.4 deletion of