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

Clinical genetics
eight patients associates early psychomotor development delay with
predominant cognitive defects, autistic features and epilepsy. Their
values of hyperprolinemia ranged from 400 to 2200 µmol/L. Patients
with biallelic PRODH alterations resulting in severely impaired POX
activity had an early onset and severe neurological features. Thus,
children with this phenotype and those with a microdeletion in chromosome
22q11, especially those with mental retardation and autistic features,
should be tested for hyperprolinemia. Hyperprolinemic patients
should be screened for PRODH mutations
P0142. A novel mutation L324V in the fibroblast growth factor
receptor 3 in familial hypochondroplasia
C. Collet 1 , A. Verloes 2 , M. Lenne 1 , J. L. Laplanche 1 ;
1 Service de biochimie et biologie moléculaire, Hôpital Lariboisière, Paris, France,
2 Unité fonctionnelle de génétique clinique, Fédération de génétique, Hôpital
Robert Debré, Paris, France.
Hypochondroplasia is an autosomal dominant skeletal dysplasia characterized
by short-limb dwarfism with rhizomelic shortening. This phenotype
is similar to achondroplasia, but the features tend to be milder,
as macrocephaly with relatively normal facies. Diagnosis is made by
careful physical examination and x-rays. The diagnosis is also often
made later in childhood (2-4 years of age). Before three years of age,
the diagnosis is difficult, as skeletal disproportion tends to be mild and
many of the radiographic features are subtle during infancy. Its incidence
is 1:30000 live births. Actually, about 80 percent of hypochondroplasia
cases are caused by heterozygous mutations in the FGFR3
gene, unique gene known to be associated with hypochondroplasia.
Two recurrent mutations in exon 13, c.1620C>G or c.1620C>A, resulting
in an p.N540K substitution in the proximal tyrosine kinase domain
represent ~ 60% of all cases of hypochondroplasia. Sequence analysis
of others FGFR3 exons detects rare mutations. We report a new
heterozygous mutation in exon 9 of FGFR3, p.L324V, c. 970C>G, in
a familial hypochondroplasia. The father and his son presented mild
phenotype with a more severe expression in the father than in his son.
This mutation, not reported as SNP, is located in the third immunoglobulin
(Ig)-like domain, in a highly conserved tripeptide sequence residue
within the FGFR family. This result strongly suggests that p.L324V mutation
is responsible for hypochondroplasia.
P0143. Dental symptoms - clue to the diagnosis of
hypophosphatasia of childhood type
B. Tumiene 1 , A. Utkus 1 , R. Cerkauskiene 2 , K. Becker 3 , W. Reardon 4 , R. Janavicius
1 , J. Songailiene 1 , L. J. M. Spaapen 5 , V. Kucinskas 1 ;
1 Department of Human and Medical Genetics, Vilnius, Lithuania, 2 Vilnius
University Children’s hospital, Vilnius, Lithuania, 3 North Wales Clinical Genetics
Service, Glan Clwyd Hospital, North Wales, United Kingdom, 4 Our Lady’s
Hospital for Sick Children, Crumlin, Ireland, 5 Dept. of Biochemical Genetics,
Academic Hospital Maastricht, Maastricht, The Netherlands.
Hypophosphatasia is an inherited disorder characterized by defective
bone and teeth mineralization. The disease is due to mutations in the
ALPL gene. Variable clinical expression of the disease ranging from
stillbirth to pathologic skeletal fractures in adult years reflects allelic
heterogeneity in this disease.
Our presented patient is a 4 year old female with uneventful pre- and
postnatal history until the age of 3 months. A head deformity was noticed
at that time (turricephaly) and progressed thereafter with premature
closure of cranial sutures and fontanelles. Increased intracranial
pressure developed and became symptomatic (bulging fontanelle,
bilateral edema of optical nerve, exophthalmos, prominent subcutaneous
veins, nausea and vomiting). Skeletal symptoms appeared at
about 6 months of age with the signs of rickets and waddling gait.
Dental symptoms included delayed eruption of deciduous teeth (the
first at 9 months of age), premature loss of both incisors and later additional
6 teeth and severe caries. These dental symptoms specifically
pointed to a possible diagnosis of hypophosphatasia. Additional signs
were small stature and muscular hypotony. Biochemical assays revealed
low-normal serum alkaline phosphatase (37.3 UI/l, n.35-281 UI/
l), significant hyperphosphaturia (fractional excretion 19.1→24.8 %),
and low serum intact parathormone (1-6 pg/ml, n.10-69 pg/ml). Clearly
increased phosphoetanolamine in urine was detected (152 μmol/mmol
creat., n.0-21 μmol/mmol creat), plasma pyridoxal 5’-phosphate was
also highly elevated (1233 nmol/l, ref.