European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Clinical genetics
this form of CDG type II the gene defect has not been discovered yet.
Based on the recently defined clinical syndromes with N- and O-linked
glycosylation defects one should consider the diagnosis of Congenital
Disorders of Glycosylation in patients with a broad spectrum of different
features, including pachygyria, hypotonia with adducted thumbs,
cutis laxa, cardiac and cranio-skeletal anomalies.
P0046. Neurological manifestations of the Cardio-faciocutaneous
Syndrome (CFC)
G. Yoon1 , J. Rosenberg1 , S. Blaser1 , K. Rauen2 ;
1 2 University of Toronto, Toronto, ON, Canada, University of California San Francisco,
San Francisco, CA, United States.
The cardio-facio-cutaneous syndrome (CFC) is a multiple congenital
anomaly disorder characterized by craniofacial dysmorphia, ectodermal
abnormalities, congenital heart defects, developmental delay and
growth retardation. Neurological complications associated with CFC
remain to be clearly defined. Recent discovery of causative mutations
in the MAPK pathway now permit accurate molecular diagnosis of
CFC. Objective: To characterize the neurological features of patients
with molecularly-confirmed CFC. Methods: Medical records, laboratory
and imaging data were reviewed for 37 mutation-positive CFC
patients. Patients with a clinical diagnosis of CFC but a negative result
on mutation screening of the BRAF, KRAS, MEK1 and MEK2 genes
were excluded from the study. Results: Hypotonia, motor delay, speech
delay and learning disability were universally present in this cohort.
Macrocephaly was present in 59%, ptosis in 50%, strabismus in 64%
and nystagmus in 50% of patients. Corticospinal tract findings were
present in 32% of the group. Ventriculomegaly or hydrocephalus was
present in 66% of patients. Other findings on MRI included prominent
Virchow-Robin spaces (19%) and abnormal myelination (13%). Seizures
were present in 46% of patients. No specific genotype-phenotype
correlations were observed. Interpretation: Alteration of function
through the Ras/MAPK cascade has traditionally been associated with
oncogenesis. Germline mutations in this pathway have an adverse impact
on neurodevelopment, and appear to play an important role in
ocular function, structural brain anatomy and electrical activity.
P0047. BRAF gene mutation in a patient with cardio-faciocutaneous
(CFC) syndrome presenting with lipoma of corpus
callosum, hepatic and renal cysts
E. Papadopoulou1 , S. Sifakis1 , K. Gripp2 , S. Kirwin2 , K. Sol-Church2 , D. Stabley2
, P. Vorgia1 , M. Kalmanti1 ;
1 2 University Hospital of Heraklion, Heraklion, Greece, Department of Biomedical
Research, Nemours’ Children Clinic, Willmington, DE, United States.
Introduction: Cardio-facio-cutaneous syndrome (CFC) is characterized
by craniofacial features, cardiac defects, ectodermal abnormalities,
and psychomotor delay. It has phenotypic similarities with Noonan and
Costello syndromes.
Case presentation: a 20-month-old boy, the first child of phenotypically
normal parents, who during infancy presented poor suck, and failure to
thrive. At 20th month of life he presents dysmorphic features, postnatal
onset growth deficiency, hypertrophic cardiomyopathy, hypotonia, and
mental retardation. Dysmorphic features include relatively large head,
downslanting palpebral fissures, broad nasal base, protruding nostrils,
high arched palate, papilloma-lile lesion on midline of the fontal region,
deep palmar and plantar creases, sparse curly hair, and hyperextensible
fingers. Brain MRI reveals a lipoma of corpus callosum. Abdomen
ultrasound shows hepatic and renal cysts. DNA analysis initially performed
excluded Noonan and Costello syndromes. Further examination
revealed a 770A-G transition in exon 6 of the BRAF gene, predicting
a gln257-to-arg (Q257R) amino acid change.
Conclusion: CFC syndrome can be caused by gain of function mutations
in 1 of 4 different genes: KRAS, BRAF, MEK1, and MEK2. The
protein products of these genes interact in a common RAS/ERK pathway
that regulates cell differentiation, proliferation, and apoptosis. The
mutation found in our patient has been earlier described in 3 unrelated
CFC patients (BRAF, gln257arg), by Niihori et al. (Nat Genet, 2006).
Hepatomegaly and absence or hypoplasia of corpus callosum has
been described in CFC syndrome. To our knowledge, our patient is the
first who presents lipoma of corpus callosum, as well as hepatic and
renal cystic formations.
P0048. Brain imaging in patients with KRAS, BRAF and MEK
mutations
C. Nava 1 , C. Michot 1 , N. Hanna 2 , S. Pereira 1 , B. Parfait 2 , J. Elion 1 , A. Verloes 1 ,
H. Cavé 1 ;
1 department of genetics APHP hopital Robert Debré, Paris, France, 2 Inserm
U745, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris
V, Paris, France.
Cardio-facio-cutaneous syndrome (CFC) is a severe developmental
disorder clinically related to Noonan syndrome and Costello syndrome
(CS), which has been recently linked to mutations in 4 genes of the
RAS/MEK/ERK signaling pathway. Developmental delay is frequent in
those diseases but abnormalities of brain imaging aren’t often reported
in these patients. In this study, we performed mutation analysis of
KRAS, BRAF, MEK1, and MEK2 in 40 patients with a CFC, 20 patients
with a CS without HRAS mutations, and 82 patients with NS without
PTPN11 mutations. We found 22 BRAF mutations, 7 KRAS mutations,
11 MEK1 mutations, and 5 MEK2 mutations. 21/45 patients with a mutation
had a brain imagery. It was abnormal in 11/21 of cases (table 1).
5/14 CS with a mutation in KRAS, BRAF or MEK had abnormal MRI (4
patients: normal, 5 patients : unrealized). Cerebral malformations were
less frequent in CFC patients (abnormalities in 3/23, 5 normal, 15 unrealized).
3 patients with NS present a ventricular dilatation associated
with a cerebral atrophy.
Brain abnormalities are frequent in all gene mutated and clinical diagnosis
and a brain imaging seems to be justified in medical care of
these patients.
KRAS
(/7)
BRAF
(/22)
MEK1
(/11)
MEK2
(/5)
Brain RMI abnormalities in patients with KRAS, BRAF, MEK mutations
CFC CS NS
0 (/3)
1 (/2)
ventricular dilatation
2 (/3)
-cerebral atrophy
-tuberous sclerosis
(Bourneville disease
associated)
1(/1)
ventricular dilatation and
cerebral atrophy
4 (/5)
-
ventricular dilatation
- periventricular grey matter
heterotopia and thin corpus
callosum
- ventricular dilatation and
gyral abnormalities
0 (/3)
2 (/3)
ventricular dilatation
and cerebral
atrophy
1 (/1)
ventricular dilatation
and cerebral
atrophy
P0049. Contiguous gene deletions involving EFNB1, OPHN1 and
PRAJA1 in patients with craniofrontonasal syndrome (CFNS)
and mild developmental delay
I. Wieland1 , C. Weidner1 , R. Ciccone2 , E. Lapi3 , D. McDonald-McGinn4 , W.
Kress5 , S. Jakubiczka1 , H. Collmann6 , O. Zuffardi2,7 , E. Zackai4 , P. F. Wieacker1 ;
1Institut für Humangenetik, Otto-von-Guericke-Universität, Magdeburg, Germany,
2Institute of General Biology and Medical Genetics, University of Pavia, Italy,
3 4 Medical Genetics Unit, Children’s Hospital AOU Meyer, Florence, Italy, Clinical
Genetics Center, Children’s Hospital of Philadelphia, PA, United States, 5Med izinische Genetik im Institut für Humangenetik, Universität Würzburg, Germany,
6 7 Kinderklinik und Poliklinik, Universität Würzburg, Germany, IRCCS San Matteo
Hospital, Pavia, Italy.
Craniofrontonasal syndrome (CFNS [MIM 3404110]) is an X-linked
malformation syndrome characterized by craniofrontonasal dysplasia,
body asymmetry, midline defects and abnormalities of the fingers,
toes and hair. Unlike classical X-linked diseases, CFNS manifests in
females, whereas male carriers are usually mildly affected. CFNS is
caused by mutations in the EFNB1 gene (MIM 300035) encoding the
transmembrane ligand ephrinB1 of cognate ephrin (Eph) receptor tyrosine
kinases. However, psychomotor delay has been observed only
in a few patients. We identified three females with classical CFNS and
mild developmental delay harbouring de novo deletions of the EFNB1
gene. Applying haplotype analysis, Southern blot hybridisation and
array-comparative genomic hybridisation (array-CGH), deletion of