2008 Barcelona - European Society of Human Genetics

Clinical genetics
lacrimal and salivary glands (ALSG) only . This variability in phenotype
has been seen within families with the same mutation .
LADD syndrome is a genetically heterogeneous disorder caused by
heterozygous mutations in the FGF10, FGFR2 and FGFR3 genes .
As the Oxford Molecular Genetics Laboratory already offers FGFR2
and FGFR3 gene testing as part of the Craniofacial service, testing for
LADD syndrome was introduced in 2007 .
Testing is done using bi-directional sequencing of the coding region
and exon/ intron boundaries of the FGF10 gene, and bi-directional sequencing
of exon 16 of the FGFR2 gene and exon 13 of the FGFR3
gene . This screening strategy is expected to pick up all known point
mutations in FGFR2, FGFR3 and FGF10, but not exonic deletions . An
exonic deletion of FGF10 has been reported .
Three cases have been analysed to date . The presented case has a
maternally inherited c .1942G>A (p .A648T) mutation in FGFR2 exon
16 . Both mother and son have classical facial features, cup-shaped
ears, variable nail dysplasia and lacrimal duct obstruction . The proband
also had unilateral renal agenesis .
P01.312
Limb Body Wall complex in a monochorial mono-amniotic twin
M. M. G. Biervliet1 , J. van den Ende2 , N. Van der Aa2 ;
1 2 Center of Medical Genetics, Atwerp, Belgium, Center of Medical Genetics,
Antwerp, Belgium.
The limb-body wall complex (LBWC) or body stalk anomaly is a variable
group of congenital defects characterized by a combination of
anterior body wall defects, limb defects and/or encephalocoele or exencephaly
. There are often additional structural defects such as urogenital
anomalies and abnormalities of the cloaca .
Three pathogenic mechanisms have been proposed for this anomaly
: a mechanical origin by early amnion rupture, a vascular disruption
during embryonal development and an embryonic origin due to an mutation
in a developmental gene .
We report of a monochorial mono-amniotic twin pregnancy with ultrasound
abnormalities seen in the 13-th week . The pregnancy was
terminated. Post mortem examination on the first foetus showed only
one kidney, a megabladder and anal atresia . The second foetus had
a severe hydrops, anal atresia, a large abdominal wall defect and absence
of the external genitalia .
In our case we presume that the body stalk anomaly in both foetuses
results from a mutation in a developmental gene .
This case supports the hypothesis of a possible embryonal origin of
limb-body wall complex .
P01.313
Novel LMNA mutation seen in a patient with leanness, severe
insulin resistance and facial dismorphisms
F. Lombardi 1 , M. R. D’Apice 1 , S. Latini 1 , M. D’Adamo 2 , P. Sbraccia 2 , S. Servidei
3 , G. Novelli 1,4 ;
1 Departments of Biopathology and Diagnostic Imaging, University of Rome Tor
Vergata, Rome, Italy, 2 Departments of Internal Medicine University of Rome Tor
Vergata, Rome, Italy, 3 Department of Neuroscience, Catholic University, Rome,
Italy, 4 University of Arkansas for Medical Sciences, Little Rock, AR, United
States.
Here we describe a novel LMNA gene mutation in a 27-year-old woman
with a complex disorder characterized by extreme leanness, severe
insulin resistance, mixed calcific valvulopathy involving both mitral and
aortic valves, slight facial dismorphism, low femoral bone mass . The
patient is the 2nd child of non consanguineous parents . Physical examination
showed: extreme leanness (BMI 15 .6 kg/m 2 ), especially at
the legs, craniofacial dismorphisms with sharp nose, small chin and
small mouth, narrow palate and tongue hypoplasia, micrognathia and
slight dental overcrowding; she has subtle and sparse hair . Surprisingly,
whole body DEXA scan showed normal total fat mass (25 .8%) and distribution,
whereas MRI showed no alteration of both subcutaneous and
visceral adipose tissue depots . Metabolic alterations includes hyperisulinemia
both basal and 2 hours after OGTT (respectively 57 .2 and
982 .4 µUI/ml), insulin resistance assessed by glucose clamp (M=2 .3
mg/kg/min) . LMNA sequencing evidenced a novel heterozygous missense
mutation in exon 4 that replaces well-conserved residue glutamic
acid at position 262 to lysine (p.E262K, c.784 G→A). Her parents
were negative for the same mutation, suggesting that this mutation has
de novo origin . Sequence analysis of 100 healthy normal controls did
not reveal this sequence alteration, indicating that this mutation is not
a common variation . Genetic screening of additional genes mutated in
laminophatic or lipodistrophyc disorders (ZMPSTE24, PPARγ BSCL2)
showed a wild type sequence . This study extend the large phenotypic
spectrum of laminophaties and may lead us better understanding molecular
basis of this group of disease .
P01.314
Serendipitous detection of ENG haploinsufficiency in a girl with
nail-patella syndrome and a 9q33.3-q34.11 microdeletion
E. Lapi 1 , E. Andreucci 1 , R. Ciccone 2 , S. Guarducci 1 , U. Ricci 1 , O. Zuffardi 3 , M.
Genuardi 4 ;
1 AOU Meyer, Florence, Italy, 2 Institute of General Biology and Medical Genetics
- University of Pavia - Italy, Pavia, Italy, 3 Institute of General Biology and Medical
Genetics - IRCCS San Matteo Hospital - University of Pavia - Italy, Pavia,
Italy, 4 AOU Meyer - University of Florence, Florence, Italy.
We describe the first case of a microdeletion syndrome with concurrent
loss of the LMX1B and ENG genes on 9q33 .3-q34 .11 . The proposita,
first-born of healthy non-consanguineous parents, was born at term
of a pregnancy complicated by hypertensive gestosis and IUGR . She
had a severe psychomotor delay and, during infancy, myoclonic epilepsy
and generalized seizures . Nail-patella syndrome was diagnosed
upon physical and radiological examination . She had occasional
nose-bleeding episodes since the age of 6 years . No ocular neither
renal function alteration have been detected until the current age of
14 years . Precocious puberty was blocked with triptorelin treatment
until the age of 12 yrs: regular menses began six months after therapy
withdrawal .
aCGH was performed to look for a common cause of the phenotypic
manifestations . A de novo 1 .7 Mb deletion in 9q33 .3-q34 .11 was detected
. Microsatellite analysis revealed that the deletion was of maternal
origin . The deleted region includes the LMX1B and ENG genes .
Deletion of LMX1B is responsible for manifestations of the nail-patella
syndrome displayed by the patient. ENG haploisufficiency causes hereditary
hemorrhagic teleangectasia (HHT) . At present, the only clinical
manifestation of HHT present in the patient is nose bleeding .
This observation underscores the predictive power of aCGH . This
technique does not only allow to clarify the origin of existing clinical
manifestations but may also lead to the identification of haploisufficiency
for genes causing adult-onset conditions with implementation
of appropriate surveillance .
P01.315
Discordant monozygotic twins suggests that macrocephalycapillary
malformation is a post-zygotic event
D. J. P. Lederer1,2 , O. Battisti3 , C. Verellen-Dumoulin1 ;
1 2 Center For Human Genetic, IPG, Charleroi (Gosselies), Belgium, UCL-Saint-
Luc, Bruxelles, Belgium, 3Clinique Saint-Vincent, Rocourt, Belgium.
Macrocephaly-Capillary Malformation (M-CM) is the new name for
Macrocephaly-cutis marmorata telangiectatica congenita .
We describe a 17 month old girl with M-CM . She has a healthy monozygotic
twin. She is the fourth of five girls from second degree consanguineous
Turkish parents .
The proband was born at 35 weeks of gestation by caesarean-section
for foetal distress . Birth weight was 2,47 kg (P50), birth length 46 cm
(P25) and occipito-frontal circumference (OFC) 35,5 cm (>P90) . During
the neonatal period profound hypoglycaemias were noted . Clinical
examination shows: frontal bossing, nasal and frontal angiomata, strabism
of right eye (inconstant), hypertelorism, right epicanthus, ogival
palate, abnormal palmar crease, gap between first and second toes,
axial and peripheral hypotonia, cutis marmorata, thick subcutaneous
tissue . She has psychomotor retardation and macrocephaly . The cerebral
MRI at 7 months showed cerebellar tonsillar herniation with hydrocephaly
and signs of cerebral hypertension . She had ventricular
shunting at 11 months of age with improvement of macrocephaly and
psychomotor retardation . Thermoregulation trouble appeared after
one year of age with usual temperature between 38-39°C .
The caryotype and X-inactivation pattern are normal . Twin zygosity
testing performed on buccal smear DNA proved monozygosity .
There are about 100 published cases of M-CM. Detailed clinical findings
and cerebral imaging of our case are similar to those reported
before . Thermoregulation trouble has never been described in M-CM .
All the cases of M-CM are sporadic . Our patient is a unique case of M-
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