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

Clinical genetics
tion, cardiac malformations, cranio-facial dysmorphisms and pigmentary
skin anomalies following the lines of Blaschko. The chromosomal
analysis of peripheral blood cells was normal, but 69,XXY/46,XY mosaicism
was detected in skin fibroblast culture.A thorough examination
of the patient at the age of 16 revealed the usual features typical
for this type of chromosomal mosaicism (asymmetric face, prominent
and wide nasal bridge, clinodactyly, mental retardation, hypotonia,
patchy pigmentation and depigmentation of skin, cardiac malformations,
and truncular obesity), but also the absence of one of the inferior
incisors and alternating vertical bands of opaque white and translucent
enamel most evident on the central and lateral incisors. These
dental abnormalities represent the anatomic equivalent of cutaneous
Blaschko lines. Extracutaneous analogies of Blaschko lines have been
described in various organs, such as the brain, bone, lens and teeth.
These lines do not follow any known nervous, vascular or lymphatic
structures but do follow and represent the developmental growth pattern
of the skin. The embryological basis of these lines has not up to
now been elucidated.
P0037. Blepharophimosis, Ptosis, and Epicantus inversus
Syndrome (BPES). Clinical study about three cases
L. I. Butnariu 1 , C. Rusu 1 , M. Covic 1 , V. Gorduza 1 , L. Trandafir 2 ;
1 University of Medicine and Pharmacy “Gr. T. Popa”, Department of Human
Genetics, Iassy, Romania, 2 University of Medicine and Pharmacy “Gr. T. Popa”,
“Saint Mary” Children Hospital, Iassy, Romania.
BPES is a rare autosomal dominant disease (less than 1:5,000). It is
a complex eyelid malformation invariably characterized by four major
features: blepharophimosis, ptosis, epicantus inversus and telecanthus.
There are two types of BPES: type I associate the typical features
with female infertility caused by premature ovarian failure and
type II includes only palpebral anomalies.
We present two familial and one sporadic case of BPES. The diagnosis
was based by clinical signs.
Case 1, sporadic, G.L, male, 1 years old. There are no other relatives
affected. We note, normal pregnancy, newborn haemolytic disease,
febrile seizures and spastic tetraparesis. Clinical and paraclinic evaluation
revealed: typical BPES features, low-set ears, narrow external
auditory meatus, bifid uvula, internal hydrocephaly, atrial septal defect
and developmental delay.
Case 2, I.B, male, 6 years old, present clinical features of BPES type
I, like his own father; his mother had sensorineural hypoacusy. Other
features are tall stature, sparse hair, normal intelect. There are no
other relatives affected.
Case 3, A.D, female,1 years old, present on clinical evaluation typical
ocular features, low nasal bridge, low-set ears and normal intelect. The
father and other 7 relatives on paternal side (males and females) have
the same features of BPES type I: only males are transmitting, affected
females are infertile. The karyotype was normal in all three patients.
In conclusion, we emphasize the importance of the clinical features for
diagnosis, leading further to an apropiate management.
P0038. Changes in Phenotype of Bloom´s Syndrome with New
Manifestations in Adult Individuals
E. Passarge, H. Löser;
Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany.
Bloom´s syndrome results from autosomal recessive mutations in the
BLM gene located on human chromosome 15 at 15q26.1, encoding
a DNA helicase with homology to RecQ in E. coli (MIM 210900). Its
phenotype includes (i) pre- and postnatal growth retardation, (ii) facial
features with dolichocephaly and a narrow face, (iii) light-sensitive
facial telangiectasia in most patients, (iv) manifestations of genomic
instability as revealed by a 10-fold increase of spontaneous sister
chromatid exchanges, breaks and homologous exchanges between
chromosomes, and an increased rate of somatic mutations. Affected
individuals develop similar types of cancer as in the population, but
at a much younger age (about 1 in 4). We have observed the natural
history in 15 individuals with Bloom´s syndrome during the past 38
years in Germany. We found that the phenotype in adult individuals
becomes less distinctive with age than it is in children. In spite of persistent
feeding difficulties, such as lack of appetite or regurgitation,
adult individuals tend to gain weight. A new finding is development of
diabetes mellitus type 1 or type 2. This has been observed in 27 of 117
patients (23%) of individuals in the Bloom´s Syndrome Registry (J.
German, M. Sanz, E. Passarge, unpublished data). The skin manifestations
tend to improve with age. We conclude that the phenotype of
Bloom´s syndrome is wider than recorded previously. It remains to be
seen whether the molecular type of mutation present in an individual
influences the phenotype.
We thank J. German, N.A. Ellis, and M. Sanz, New York, for cooperation
and mutational analysis.
P0039. Implementation of a new high throughput sequencing
service for BRCA1 and BRCA2 gene screening to comply with
UK Government Genetics White Paper 40 day turnaround time
Y. Wallis, N. Motton, N. Morrell, C. Morgan, E. Ormshaw, J. Bell, F. Macdonald;
West Midlands Regional Genetics Service, Birmingham, United Kingdom.
In response to UK Government targets for BRCA gene screening (Genetics
White Paper) the West Midlands Regional Diagnostic Genetics
Laboratory (Birmingham, UK) devised a novel sequencing-based
strategy to screen the large BRCA1 and BRCA2 genes. The strategy is
plate-based therefore facilitating the use of highly automated processes.
63 new primer sets were designed to amplify the coding regions of
both BRCA1 and BRCA2 genes simultaneously using a 2-plate system
for each patient panel. Between September 2005 and January 2007
a total of 731 diagnostic BRCA reports were issued as a result of the
high throughput sequencing strategy. More than 98% of these reports
were issued within 40 working days (from the date of sample receipt
to date of report authorisation) with an average turnaround time for all
731 samples of 24.9 days. 79% of samples were reported in less than
30 days. 128 clearly pathogenic mutations have been identified in addition
to 121 missense mutations and other unclassified variants. The
Birmingham lab has also performed a number of follow-up studies to
investigate the pathogenicity of missense and unclassified variants as
well as undertaking RNA studies to determine the effect on splicing of
deep intronic variants. The high throughput service has been used by
a number of diagnostic genetics service laboratories and to date 100
reports have been issued to them with an average reporting time of
23 days. This high throughput BRCA sequencing service is available
upon request from the West Midlands Regional Genetics Service.
P0040. Familial Breast Cancer With Positive History In Father
And Mother : A Case Report .
R. Habibi;
Royan Institute, Tehran, Islamic Republic of Iran.
Background: A family history of breast cancer in a first-degree relative
is reported in 13% of women with the disease. In turn, over 87% of
women with a family history will not develop breast cancer. However,
only 1% of women have multiple affected relatives, a history suggestive
of a highly penetrant germ-line mutation.
The probability of breast cancer associated with a mutation in BRCA1
and BRCA2 genes increases if there are affected before menopause
and /or have multiple cancers, if there is a case of male, breast cancer,
or if family members also develop ovarian cancer. BRCA2 is associated
more frequently with male breast cancer.
Case report: We report a female case of invasive carcinoma who had
37-year-old, and positive family history with paternal and maternal involvement.
She had fibrosis, inflammation, and fact necrosis in right
breast that negative for malignancy and also she had invasive carcinoma
in left breast. For left breast, lumpectomy was performed .
Conclusions: First, in such a cases probability of the BRCA1 mutation
increases and BRCA2 mutation is possible. Then screening for
these genes should be performed for them and the other members
of relatives and genetic counseling is required, and as soon as clinical
approach for other related cancers may be performed. Second,
also other nongenetic causes in such a family may predispose cancer
susceptibility .