2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
who was admitted in the IIIrd Pediatric Clinic Timisoara. The patient,
born at 38 week of gestation, with 3000g, was the second child of
young, healthy and unrelated parents. The older brother has no anomalies.
There was no history of maternal irradiation or drug ingestion
during pregnancy, and no family history of any congenital birth anomalies.
Clinical examination revealed underdevelopment of the left pectoralis
major muscle, absence of the left areola, absence of the distal phalange
of the left index, dextrocardia (confirmed by chest radiography,
electrocardiograpy and echocardiography). He has also gastroesophageal
reflux, confirmed by Barium Swallow X-ray. Abdominal sonography
was normal. Neurologic examination revealed generalized hypotonia,
convergent strabismus, unexpressive face, right facial palsy and
swallowing difficulties. Chromosomal analysis was normal.
The patient was admitted several times in our clinic, presenting respiratory
infections with respiratory insufficiency. In time, he developed
signs of severe malnutrition, so that malabsorbtion tests were performed.
We found positive IgA/IgG anti-tissue transglutaminase antibodies
(IgA/IgG tTG), as well as Immunoglobulin A anti-endomysium
antibodies (EMA) serum levels.
We performed enteroscopy with jejunal biopsy, which revealed Marsch
IIIC villous atrophy. Haplotype analysis showed DQ2 in cis conformation
(DQA1*0501 and DQB1*0201 alleles).
Conclusion. We present a rare association between Poland-Möbius
syndrome and celiac disease. It is unclear if their etiology is common,
or there are just two coincidental factors.
P02.097
Parkinsonism, axonal neuropathy and cerebellar signs in two
siblings with recessive POLG mutations
J. Rankin 1 , N. Gutowski 2 , V. Pearce 3 , C. Smith 4 , J. Poulton 5 ;
1 Peninsula Clinical Genetics Service, Exeter, United Kingdom, 2 Department of
Neurology RD&E, Exeter, United Kingdom, 3 Department of Medicine RD&E,
Exeter, United Kingdom, 4 Oxford Medical Genetics Laboratories, Oxford, United
Kingdom, 5 Mitochondrial Genetics Service, Oxford, United Kingdom.
Mutations in POLG, which encodes the catalytic subunit of mitochondrial
DNA polymerase gamma, have been identified in patients with
diverse phenotypes. For example, recessive mutations are found in
Alpers syndrome, autosomal recessive progressive external ophthalmoplegia
(arPEO) and ataxia neuropathy spectrum (ANS) whereas
dominant mutations are found in families with autosomal dominant
PEO (adPEO) in which there may also be parkinsonism and premature
ovarian failure. In 2006, two sisters with early onset parkinsonism and
neuropathy, but without PEO, were found by Davidzon and colleagues
to be compound heterozygotes for the recessive POLG mutations
G737R and R853W.
We report a brother and sister with the same two mutations. The sister
presented with parkinsonism aged 28 years and subsequently developed
dysarthria. The brother was ataxic from age 18 years and later developed
dysarthria and nystagmus. Ophthalmoplegia and ptosis were
absent, however both had a severe, axonal, predominantly sensory
neuropathy. MRI revealed no intracranial abnormality but prominence
of the temporalis muscle was noted in both. Muscle biopsies were not
done. The heterozygous parents were clinically normal. These siblings
are remarkable firstly because parkinsonism is only rarely associated
with recessive POLG mutations and secondly because patients with
ANS due to POLG mutations usually have typical MRI abnormalities.
P02.098
mutations in Human Beta-2b tubulin Result in Asymmetrical
Polymicrogyria
K. Poirier 1 , X. Jaglin 1 , Y. Saillour 1 , E. Buhler 2 , G. Tian 3 , N. Bahi-Buisson 1,4 ,
C. Fallet-Bianco 5 , F. Phan-Dinh-Tuy 1 , P. Bomont 6 , L. Castelnau-Ptakhine 1 , S.
Odent 7 , P. Loget 8 , M. Kossorotoff 9 , G. Plessis 10 , P. Parent 11 , C. Beldjord 12 , C.
Cardoso 6 , A. Represa 6 , D. Keays 13 , N. Cowan 3 , J. Chelly 1 ;
1 Institut Cochin; Université Paris Descartes; CNRS (UMR 8104); Paris, France.
Inserm, U567, Paris, Fr, Paris, France, 2 Plate-forme Post Génomique de l’IN-
MED, INSERM U901, Marseille, France, 3 IDepartment of Biochemistry, New
York University Medical Center, New York, NY, New York, NY, United States,
4 Service de Neurologie Pédiatrique; Département de Pédiatrie; Hôpital Necker,
PAris, France, 5 Service d’Anatomie Pathologique, Hôpital Sainte Anne, 75014
Paris, France, Paris, France, 6 Institut de Neurobiologie de la Méditerranée,
INSERM U901, Marseille, France, 7 Service de génétique médicale, CHU de
Rennes, Rennes, France, 8 Département d’anatomie et cytopathologie, CHU
Pontchaillou, Rennes, France, 9 Service de Neurologie Pédiatrique; Département
de Pédiatrie; Hôpital Necker, Paris, France, 10 Service de génétique, CHU
Hôpital Clémenceau, Caen, Caen, France, 11 Département de pédiatrie et génétique
médicale, CHU Hôpital Morvan,, Brest, France, 12 Laboratoire de biochimie
et génétique moléculaire, CHU Hôpital Cochin, Paris, Paris, France, 13 Institute
of Molecular Pathology, 7 Dr Bohr-Gasse, Vienna, Vienna, Austria.
Polymicrogyria is a relatively common but poorly understood defect
of cortical development characterized by numerous small gyri and a
thick disorganized cortical plate lacking normal lamination. We show
an association between bilateral asymmetrical polymicrogyria and de
novo mutations in a beta-tubulin gene, TUBB2B, in four patients and
a 27 GW(gestational week) fetus. Neuropathological examination of
the fetus revealed an absence of cortical lamination associated with
the presence of heterotopic neuronal cells in the white matter, and
neuronal overmigration through breaches in the pial basement membrane,
reminiscent of “cobblestone-like” phenotypes observed in a
Gpr56-/- mice model. In utero RNAi-based inactivation demonstrates
that TUBB2B is a new gene that is critically involved in neuronal migration.
We also show that two disease associated mutations lead to an
impaired formation of tubulin heterodimers as a result of deficiencies
in the complex chaperone-dependent tubulin heterodimerization pathway.
These observations, together with previous data, demonstrate
that disruption of microtubule-based processes underlies a large spectrum
of neuronal migration disorders that includes not only lissencephaly/pachygyria,
but also polymicrogyria malformations.
P02.099
is the pattern of root resorption in human teeth dependent on
the gene amelogenin?
M. Bille, D. Nolting, I. Kjaer;
Department of Orthodontics, Copenhagen, Denmark.
Introduction. It has been demonstrated that abnormal resorption of
primary roots is associated with unexpected resorption of permanent
roots (Bille et al., Eur J Orthod 2008; 30(4): 346-51). This leads to
the hypothesis that root resorption is not always acquired, but can be
inherited. This preliminary study is an immunohistochemical study on
human teeth focusing on the gene amelogenin. Amelogenin has formally
been associated with root resorption in mice (Hatekeyama et al.,
J Biol Chem 2003; 278(37): 35743-8).
Material. 18 primary teeth extracted from 10 children due to dental
treatment.
Method. Paraffin sections for immunhistochemistry reaction were pretreated
with Tris-EDTA pH 9 at 60°C for 90 minutes. Sections were
washed in TBS, encircled with a Dako pen (Dako, S2002), washed
in TBS. Sections were incubated with Peroxidase-Blocking Solution
(Dako, S2023), washed in TBS, incubated in primary antibody for 60
minutes using: Anti-Amelogenin (ABIN 187765, antibodies-online.
com) diluted 1:3000 (Antibody Diluent, Dako, S2022).
Sections were washed in TBS, incubated with peroxidise labelled
polymer (Dako, K5007), washed, incubated in Substrate Buffer/DAB+
Chromagen (Dako, K5007), washed in destilled water,
counter stained in Carazzi’s haematoxylin (Dako, S3301), washed, dehydrated
and coverslipped using Pertex (Histolab, Sweden).
Results. Strong amelogenin expression was seen in the periodontal
membrane as small and well distinct islands in regions without root
resorption, while amelogenin expression was weak and mostly absent
in resorption lacunas.
Conclusion. The present study showed that amelogenin might play a
decisive role in human root resorption and therefore might influence an
inherited pattern of root resorption.
P02.100
Restrictive dermopathy in a newborn caused by null mutation in
ZmPstE24 gene
G. Yeşil 1 , I. Hatipoğlu 1 , A. De Sandre-Gionovalli 2 , B. Tüysüz 1 ;
1 İstanbul University, Cerrahpasa Medical Faculty, Pediatric Genetics, İstanbul,
Turkey, 2 Hôpital d’Enfants la Timone, Département de Génétique Médicale,
Marseille, France.
We described a 4 days boy old with tight, translucent skin, prominent
vessels, skin erosions and dysmorphic findings consisting hypertelorism,
antimongoloid axis, sparse eyelashes and eyebrows, pinched
nose, natal teeth, microretrognathia and ‘o’ shaped mouth. Multiple