ESHG Posters 3

Single central incisor, pyriform aperture stenosis, midfacial hypoplasia and limb abnormalities: a new syndrome?

L. Basel-Vanagaite¹, A. Kornecki², M. Ludman¹, Y. Ben-Ari³, P. Merlob⁴;
¹Department of Medical Genetics, Rabin Medical Center, Petah Tiqva, ISRAEL, ²Pediatric Intensive Care Unit, Dana Children's Hospital, Tel Aviv Medical Center,, Tel Aviv, ISRAEL, ³Division of Pediatric Intensive Care Unit, Schneider Children's Medical Center,, Petah Tiqva, ISRAEL, ⁴Department of Neonatology, Rabin Medical Center, Petah Tiqva, ISRAEL.

Solitary median maxillary central incisor (SMMCI) has been reported as an isolated abnormality or in association with other systemic abnormalities including pituitary insufficiency, nasal pyriform aperture stenosis and holoprosencephaly. SMMCI can also be a feature of recognized syndromes or chromosomal abnormalities. SHH and SIX3 mutations have been reported in patients with SMMCI.
We report on an infant with a previously undescribed pattern of malformations including brachycephaly, proptosis, midfacial hypoplasia, SMMCI, abnormal ears, arachnodactyly, partial cutaneous syndactyly and joint contractures. CT scan revealed pyriform aperture stenosis. At the age of eleven months, the patient has developmental delay and suffers from seizures.
Laboratory investigations were within normal limits. Roentgenologic skeletal survey was normal apart from the finding of 11 pairs of ribs. CT scan of the brain was normal. BAER examination revealed hearing loss on the left side. Chromosomal studies including high-resolution chromosomal analysis showed a normal female karyotype. Sequencing of the exons IIIa and IIIc of FGFR2 did not reveal mutations.
We suggest that this combination of anomalies constitutes a unique syndrome. Searching for mutations in the genes responsible for the development of the midline structures should provide a greater understanding of the mechanisms underlying the development of this unique combination of abnormalities.

L. M. J. Albano¹, R. M. Moyses², M. F. Barba³, A. C. Paula¹, C. A. Kim¹;
¹Instituto da Crianca, Genetics Unit, Sao Paulo, BRAZIL, ²Instituto da Crianca, Cardiology Unit, Sao Paulo, BRAZIL, ³Instituto da Crianca, Radiology, Sao Paulo, BRAZIL.

Majewsky et al. (1993) reported on female with serpentine fibulae and reviewed one of the Dereymaeker et al. (1986) and Exner (1988) patients, believing that they represented a rare condition named as Serpentine fibula-polycystic kidney syndrome (SFPKS) characterized by growth retardation, abnormal face, hirsutism, short neck, elongated serpentine fibulae, metatarsus adductus, deafness, normal intelligence and polycystic kidneys. We reported on a sporadic case of a 8-year-old woman with SFPKS brachycephaly, thin upper lip with down turned corners of the mouth, wide nasal tip, long and flat philtrum, dysplastic and dorsally rotated ears, large and short neck, flat chest, widened and prominent distal regions of her arms, deafness, language disturbances and normal intelligence. X-Ray skeletal survey showed: bathrocephaly, sclerosis of mastoids, absent frontal sinuses, diastasis of skull sutures, prominent parieto-occipital synchondrosis, wormian bones, scoliosis, increased anterior height of the lumbar vertebral bodies with abnormal pedicles and reduced intervertebral distances, elongated and serpentine fibulae. She also had multiple polycystic kidneys and an interventricular communication. Similarities between Melnick-Needles (MNS), Hajdu-Cheney (HCS) and SFPKS syndromes were reported, however MNS is rather a skeletal dysplasia rarely presenting ureteral abnormalities. Peculiar facies, marked growth retardation, webbed neck, polycystic kidneys, serpentine fibulae, and metatarsus adductus is typical of SFPKS. Both MNS and SFPKS do not present acro-osteolysis as HCS does. Only six cases were reported and further patients should be identified in order to reinforce the phenotypic spectrum of SFPKS and also to clarify if MNS, HCS and SFPKS are distinct entities or allelic disorders.

Evidences of autosomal recessive inheritance in unifocal subtype of fibromuscular dysplasia of the renal arteries.

C. A. Kim¹, L. M. J. Albano¹, R. B. Palhares², S. Mesquita², A. C. Pereira³, J. E. Krieger⁴;
¹Instituto da Crianca, Genetics Unit, Sao Paulo, BRAZIL, ²Cardiology Institute, INCOR, Sao Paulo, BRAZIL, ³Cardiology Inestitute, Sao Paulo, BRAZIL, ⁴Cardiology Institute, Sao Paulo, BRAZIL.

Fibromuscular dysplasia (FMD) is a group of nonatherosclerotic, noninflammatory occlusive diseases that most commonly involve the renal and carotid arteries whose etiology remains unknown. Dominant inheritance with variable penetrance was demonstrated. Dysplasic stenoses can be multifocal, unifocal and tubular. The most common manifestation of renal artery FMD is renovascular hypertension, between 30 to 50 years.Its prevalence is underestimated due to many FMD cases with normotensive or asymptomatic hypertensive patient remain undiagnosed. We report on three sibs with unifocal FMD renal arteries, two of them with bilateral affected arteries associated to congenital cardiac abnormalities. Interestingly, all presented an early onset of renovascular hypertension (2y-3y)with normal renal function. Only one with unilateral renal stenosis is still alive at 5 years old, after surgical correction. The others witj bilateral affected renal arteries died at about 3 years old. The parents were normotensive and although there was no consanguinity, we thought that a recessive pattern of inheritance should be considered in unifocal FMD of the renal arteries.

G. M. H. Abdel-Salam, M. S. Zaki, N. A. Meguid;
Department of Human Genetics, National Research Centre, Cairo, EGYPT.

Calcification of the basal ganglia was observed in more than 30 medical conditions including infections, trauma and hemorrhage and many genetic syndromes. Diverse neurobehavioral and psychiatric, manifestations have been linked to this disorder. However, its etiology remains obscure. Eleven cases were investigated who showed calcification of the basal ganglia on computed tomography (CT). Main presenting neurological symptoms were loss of acquired milestones (3 cases), epilepsy (5 cases) and developmental delay (8 cases). Age of onset and course of the disease were variable. Calcification in the basal ganglia was bilateral in most of the cases (8 cases). Globus pallidus was by far the most common site of calcification in the basal ganglia. Further calcification in different parts of the brain rather than basal ganglia was present in (4 cases) cortical, subcortical, white matter or dentate nucleus. Measurements of the size of calcification of basal ganglia and the neurological scoring were constructed. Correlation of the neurological impairment and the size of calcification were non-significant. However, the neurological impairment was significantly inversely correlated with the head circumference (p<0.002). In addition, the site of calcification inside the basal ganglia was not pathognomonic. Parenatal consanguinity was documented in 9 cases and positive history of affected family members in 7 cases emphasizing the major role of the autosomal recessive gene in the inheritance in these cases. We represent different phenotypes of this mysterious sign and highlights the importance of computed tomography in verification of calcification to overcome the difficulties in genetic counseling of such cases.

I. R. Assumpcao¹, A. Z. Pfeiffer¹, Y. K. L. Koda¹, K. A. Furuta¹, C. J. Abe¹, K. Yhira², L. M. J. Albano³, C. A. Kim³;
¹Instituto da Crianca, Sao Paulo, BRAZIL, ²Dept Pathology of FMUSP, Sao Paulo, BRAZIL, ³Instituto da Crianca, Genetics Unit, Sao Paulo, BRAZIL.

Intestinal lymphangiectasia is characterized by obstruction of lymph drainage from the small intestine and dilated lacteal vessels that distort the villus architeture. Primary intestinal lymphangiectasia probably represents a congenital disorder of lymphatics and is often associated with lymphatic anomalies outside the gastrointestinal tract. Patients with this condition have a picture comparable to experimental thoracic duct drainage with lymphedema, hypogammaglobulinemia, lymphocytopenia, skin anergy and impaired allograft rejection. We reported on a sporadic case from a nonconsanguineous and healthy parents, a 9 months girl with
lower leg progressive lymphedema (since 15 days of life), right palpebral ptosis, severe chylousascite and chylothorax, hypogammaglobulinemia, hypoalbuminemia, and lymphopenia. Endoscopy revealed a severe edema and a white-tipped villi appearance with well-circumscribed white plaques of varying sizes throughout the proximal duodenum. Small-intestinal biopsy showed numerous dilated lymphatic vessels within the lamina propria and submucosa. There was no evidence of lymphomatous transformation at the proximal small bowel. Lymphoscintigraphy did not revealed any lower leg lymphatic vessels. Medium-chain triglycerids on dietary and albumin associated with diuretic therapy decreased the enteric protein loss, improving not so much the lymphedema, that became softier. Serum albumin and immunoglobulins levels were increased. No signs of colestasis neither Yellow-nail, Lymphedema-distichiasis, Turner, Noonan or Hennekam syndromes were observed. Primary intestinal lymphangiectasia has been described in association with lymphoma in few cases. Thus, we consider important to establish the definitive diagnosis of this condition and to perform an endoscopic evaluation of the proximal small bowel, in order to detect a lymphomatous transformation.

M. Yaghoobi, L. Gholamrezai, F. Imanzadeh, M. Sohrabi, A. A. Sayyari, S. Benfield;
Research Unit, Dep.of Gastroenterology, Mofid Medical Center, Shahid Beheshti University, Tehran, IRAN (ISLAMIC REPUBLIC OF).

Introduction: Mutation in AAAS gene has been proposed as the underlying mechanism of triple A syndrome. We have studied these mutations in a family in order to determine whether the healthy family member is involved.
Method: A family with involved triple A and double A syndrome as well as alacrimia itself comprised study population. Control group was from the noninvolved members of the family. 10 cc of peripheral blood sample were obtained from each member. DNA was extracted from Buffy coat layer and stored in 4 oC. Sequencing analysis was performed for the exon 10 of each member.
Results: Proband was a 17 years old boy with triple A. He had two sisters; A 19 years old otherwise healthy and a 12 years old with double A syndrome. They have been born of a consanguineous marriage. Aunt of their grandfather was involved by alacrimia according to the family history. Sequencing analysis revealed a single-basepair insertion in exon 10 of the AAAS gene (1-BP INS, 1071T) in proband and the younger sister. Interestingly, we found the mutation in his father which was otherwise healthy. Unfortunately, the grandparents were not alive at the time of the study. Other members of the family showed no mutation in the AAAS.
Conclusion: It seems that 1-BP INS, 1071T which was reported previously in turkey is the responsible gene for the disease in Iran. We propose that the mutation in AAAS alone can not induce triple A in involved cases.

Spondylothoracic dysplasia (Jarcho-Levin syndrome) and Spondylocostal dysostosis, the confusing vertebral malsegmentation syndromes. Report of six cases

A. Semiç¹, N. Elçioglu², S. Yalçin³, T. Biren⁴;
¹Department of Pediatrics, Istanbul, TURKEY, ²Dep. of Pediatric Genetics, Marmara Univ. Hospital, Istanbul, TURKEY, ³Dep. of Orthopedics, Marmara University Hospital, Istanbul, TURKEY, ⁴Dep. of Radiology, Marmara Univ. Hospital, Istanbul, TURKEY.

Jarcho- Levin Syndrome (JLS, Spondylothoracic dysplasia) is the severest form of vertebral malsegmentation syndromes with reduced stature resulting from axial skeleton. The main features are short, immobile neck and small thorax with the patognomonic “crab-like” rib cage associated with multiple vertebral defects, what frequently leads to respiratory problems and death in infancy. Carefully prenatal ultrasound examination during the second trimester should done for subsequent pregnancies. A clinically similar disorders is Spondylocostal dysostosis (SCD). The main features are abnormalities of vertebral segmentation and of the ribs, including multiple hemivertebrae, vertebral clefting and fused, hypoplastic vertebrae, rib fusions and deletions with a non-progressive kyphoscoliosis. Survival is much better and neural tube defects only rarely occur. Cases are sporadic or familial, both recessive and dominant autosomal inheritance has been reported. The identification of genes affecting somitogenesis will be assist better classification. Recently mutations in the recessive form were demonstrated in the Notch pathway gene, DLL3, mapped at 19q13. We describe here six cases of multiple vertebral segmentation defects. Two newborns with the classical features of JLS, both had respiratory problems with "fan-like" chest deformities and one associated with thoracic meningomyelocele and club foot deformity. The remaining four infant presented features of SCD. These had short neck and trunk, different degree kyphoscoliosis and occasional spina bifida. All six patients were sporadic, and parental consanguinity were present by half of them. We believe that appropriate classification of these similar phenotypes will improve molecular research and genetic counselling concerning recurrence risk, management, prognosis and prenatal diagnosis.

Prenatal Diagnosis Of Dysmorphic Syndromes By Routine Fetal Ultrasonographic Examination Across Europe

C. Stoll¹, M. Clementi²;
¹Hôpital de Hautepierre, Strasbourg, FRANCE, ²University of Padova, Padova, ITALY.

Objectives
Ultrasound scan in the midtrimester of pregnancy is now a routine part of antenatal care in most European countries. The objectives of this study was to evaluate the prenatal diagnosis of non chromosomal dysmorphic syndromes by fetal ultrasonographic examination.
Methods
Data from 20 registries of congenital malformations in 12 European countries were included in the study.
Results
There were 2454 cases with congenital heart diseases, including 104 syndromes, 49% of them were detected prenatally.
1130 cases with renal anomalies including 64 syndromes, 83% of them were detected prenatally, 250 cases with limb reduction deficiencies including 38,12 were syndromes diagnosed prenatally.
Prenatal diagnosis was performed in 7 out of 7 cases with gastroschisis, in 12 out of 14 of cases with omphalocele and in 37,5% of cases with intestinal anomalies (24 out of 64).
There were 553 cleft lip and palate (CL(P)) and 198 cleft palate (CP) 73 recognised syndromes. Prenatal diagnosis was done in 51 CL(P) (53.1%) and 7 CP (13.7%).
Few anencephalic cases were syndromic. Out of 290 cases with spina bifida, 18 were recognized syndromes, 17 of them were diagnosed prenatally. All 11 syndromic encephaloceles were diagnosed antenatally.
Conclusions
In conclusion this study showed that around 50% of the recognized syndromes can be detected antenatally by the anomaly scan. However the detection rate varied with the type of syndromes and with the policy of prenatal screening between countries.

Polish group of PWS patients - clinical, cytogenetic and molecular investigations

A. Z. Szpecht-Potocka, E. Obersztyn, E. Bocian, J. Bal, T. Mazurczak;
National Research Institute of Mother and Child, Warsaw, POLAND.

Introduction: We present results of the clinical, cytogenetic and molecular studies carried out in the group of 77 patients with verified clinical diagnosis of Prader-Willi syndrome (PWS) selected from 202 patients with tentative clinical diagnosis of PWS. Methods: Clinical manifestation, family data, history of pregnancy, parental age and anthropometric traits were analysed and compared in two groups of patients with deletion and mUPD. Cytogenetic analysis was routinely performed using HRBT in all patients. FISH was done in all cases which were diagnosed in our genetic unit. Methylation analysis, gene dosage analysis for SNRPN and polymorphism analysis for loci within the PWS/AS region are included in our molecular diagnostic procedure. Results: PWS diagnosis was confirmed by methylation test in 77 (38%) patients. Among them deletion was detected in 40 (25%) patients, mUPD in 11 (14,2%) and imprinting mutation in 1 (1.3%) patient. Detection of the molecular defect was impossible in 6 (7,8%) patients because of uninformative polymorphism analysis results. For 19 patients the procedure for the purpose of molecular defect detection is in progress. Detailed comparison of phenotype and anthropometric evaluation will be presented in the group of deletion and non-deletion patients. Discussion: Our results of clinical and molecular investigations are comparable with those from published analyses. The numerous group of clinicaly missdiagnosed patients indicated on difficulties in the process of PWS diagnosis. It points to how much still needs to be done to increase practical knowledge of PWS natural history and clinical symptoms among medical doctors in Poland.

M. Babicz, K. Kaczanowska, M. Lejman, D. Przadka, A. Gaworczyk, D. Winnicka, J. R. Kowalczyk;
Childrens Univ. Hospital, Depart. of Pediatric Hematology and Onkology, Cytogenetic Laboratory, Lublin, POLAND.

We would like to report 12 cases of chromosome 18 aberrations that were evaluated recently in our laboratory. The purpose of the study was to analyze the cytogenetic, clinical and available familial data of these patients. Cytogenetic findings: the GTG banding technique demonstrated in 8 cases the presence of trisomy 18. The remaining karyotypes were the following: 46,XY, r18 and 46, XY, t(4;18). Clinical data: in all cases the family history showed no special disorders. All the infants with trisomy 18 ( 7 girls and 1 boy -ratio which confirms the female predominance observed in this syndrome) were diagnosed at birth and in all cases the physical examination revealed characteristic phenotypical features: low birth weight, low-set ears, protuberant occiput, characteristic positioning of the hands, limitation of thigh abduction and cardiac malformations. The phenotype of the patient with r18 shared the features of 18p.- and those of 18q- syndrome. Low birth weight, cryptorchidism and micrognathia were the only physical abnormalities observed in a boy with t(4; 18). Outcome: as expected 11 out of 12 infants bearing trisomy 18 died shortly after the birth. It is noteworthy that one girl survived the first year of life which is unusal for the patients with a free homogenous trisomy 18. Infants with aberrations other than trisomy 18 are both alive.

E. Geán¹, A. Martínez¹, B. Domenech², E. González-Bosquet¹, M. Sostoa³;
¹Hospital Sant Joan de Déu, Esplugues, Barcelona, SPAIN, ²Hospital Pius de Valls, Tarragona, SPAIN, ³Centre de Diagnòstic Prenatal, Barcelona, SPAIN.

Case history: Healthy non consanguineous parents, no previous miscarriages.
First pregnancy: Ultrasonogram at 22 weeks revealed severe intrauterine growth retardation and a set of malformations: corpus callosum agenesis, sloped forehead, hypertrophic crystalline lens, microretrognathia with lower maxilla hypoplasia, interventricular septal defect, bilateral pyelic ectasia, hypoplasia in 2nd phalange of both index fingers, malpositioned feet and ambiguous genitalia. Karyotype: 46,XY.
Voluntarily termination of gestation. Necropsy confirmed the ultrasonogram findings.
Second pregnancy: Ultrasonogram at 24 weeks revealed growth retardation, bilateral pyelic ectasia and moderate retrognathia. Parents decided to continue with pregnancy. 35 weeks: ultrasonogram showed growth retardation, prominent orbits and retrognathia; echocardiography revealed pericardial effusion without morphological cardiac alterations. 36 weeks: delivery was induced. Neonatal exploration: growth retardation, microcephaly, microretrognathia, dysplasic ears, festooned gums, craniosynostosis, hypospadias, cryptorchidia, pulmonary artery stenosis with persistence of the ductus, aracnodactyly in fingers and toes, bilateral glaucoma and generalized arthrogryposis. Karyotype: 46,XY. At age 3 months, the infant died with diabetes mellitus type I and hypertrophic cardiomyopathy. Necropsy report: weight 1.1 kg, cardiomegaly with myocardial hypertrophy and multiple septal infarcts, microcephaly, diffuse cortical anomalies, severe myelinization delay.
Diagnosis: The died patient was compatible with non-typical Seckel Sd. and Bowen Sd. The previous fetus was compatible only with Bowen Sd.
Conclusions: Because both Seckel and Bowen Sd. are infrequent entities, our belief is both cases correspond to Bowen Sd. Recurrence risk for these parents is 25% per pregnancy. Prenatal diagnosis is limited to ultrasonographic findings.

Phenotype and differential diagnosis of a neonatal Marfan syndrome due to a new FBN-1 exon 25 mutation

N. Revencu¹, G. Quenum¹, V. van Scherpenzeel Thim¹, L. Collard², G. Verellen², A. De Paepe³, C. Verellen-Dumoulin¹;
¹Center for Human Genetics, UCL, St Luc, Brussels, BELGIUM, ²Neonatology,UCL, St Luc, Brussels, BELGIUM, ³Departement of Medical Genetics, University Hospital, Gent, BELGIUM.

Neonatal Marfan syndrome (nMFS) is the most severe presentation of Marfan phenotypes. nMFS is characterized by flexion contractures, arachnodactyly, crumpled ears, loose redundant skin and visceral anomalies : pronounced atrioventricular valve dysfunction and sometimes ectopia lentis. Death usually occurs within the first year of life from heart failure.
nMFS results from mutations clustering in exons 24 to 32 of the fibrillin-1 gene (FBN-1). Until now, only 19 mutations have been described.
This disorder has to be differentiated from severe lethal Congenital Contractural Arachnodactyly (CCA), caused by mutations in the fibrillin-2 gene (FBN-2). Severe lethal CCA is characterized by a nMFS-like appearance, but there is no ectopia lentis and visceral anomalies are different : cardiac septal defects, interrupted aortic arch and gastrointestinal abnormalities.
We describe a newborn male, born from nonconsanguineous healthy parents. At birth, he presented with a severe respiratory distress. Characteristic features of nMFS and CCA were seen at physical examination. An echocardiogram showed marked prolapse and regurgitation of both mitral and tricuspid valves. Neither gastrointestinal, nor ocular abnormalities were present. Despite vigorous treatment, death occurred at 62 hours from cardiac failure. The visceral anomalies suggested the diagnosis of nMFS. Molecular analysis confirmed this diagnosis with the detection of a new FBN-1 missense mutation at nucleotide 3165 in exon 25 (C1055W).
In conclusion, nMFS and severe lethal CCA can be clinically distinguished by visceral anomalies. The FBN-1 exon 25 mutation in our patient confirmed the diagnosis of nMFS and is in agreement with the previously described genotype-phenotype correlation.

Jacobsen syndrome is a rare cytogenetic abnormality, the literature reports about 30 children with this aberration. Main features of affected patients are: psychomotor development retardation, trigonocephaly, microcephaly, dysmorphy ( low set ears, hypertelorism).
Here we present a boy with the diagnosis of Jacobsen syndrome. Reason for refferal was dysmorphy. During physical examination we found; low birth weight, microcephaly, psychomotor retardation, trigonocephaly, hypertelorism, wide nose with aplastic bridge, low set and dephormed ears, clinical features of laryngomalatia. Our cytogenetic examination revealed: 46, XY del 11q2- ter ( G- banding).We decided to present the boy because of therapeutic problems, i.e; laryngomalatia, reccurent infections of lower respiratory tract, especialy pulmonary infections, renal malformations, reccurent infections of genitourunary tract. Severe mental retardation required neurological care and neurologic disturbances and delayed physical development were observed as well.
We want to underline the fact, that child with dysmorphic features requires cytogenetic examination and the care over child is a multidisciplinary problem.

E. Tabolacci¹, V. Leuzzi², J. M. Opitz³, G. Neri¹;
¹Istituto di Genetica Medica, Università Cattolica del S. Cuore, Roma, ITALY, ²Dipartimento di Scienze Neurologiche e Psichiatriche dell’Età Evolutiva, Università "La Sapienza", Roma, ITALY, ³Department of Pediatrics, Division of Human Genetics, University of Utah, Salt Lake City, UT.

The Clark-Baraitser syndrome of multiple congenital anomalies, tall stature, macrocephaly and mental retardation, has been in a limbo for many years. In the original report (Am J Med Genet 26:13-15,1987), Clark and Baraitser suggested that their patients, two brothers and a carrier mother, may have the Atkin-Flaitz syndrome. In the subsequent description of affected cousins (Am J Med Genet 57:380-384,1995), Baraitser et al. favored the view that all of their patients had a condition distinct from the Atkin-Flaitz syndrome. We support the same view, by describing two brothers, who do not have the Atkin-Flaitz syndrome and strongly resemble Baraitser’s patients. These boys are obese, macrocephalic, one of them excessively tall and both have a characteristic face with square forehead, prominent supraorbital ridges, bulbous tip of nose, short philtrum, gap between upper central incisors, large ears. Genitalia are normal. They also have big hands and feet and advanced bone age. They are moderately-to-severely retarded, with a quiet but stubborn personality. On brain MRI they have lateral ventricular dilatation, cortical and cerebellar vermis hypoplasia. The fragile X syndrome was ruled out by DNA testing and the Simpson-Golabi-Behmel syndrome can also be ruled out for lack of specific signs. The FG syndrome may be worth testing, once the gene has been identified. However, our prevailing view is that these cases confirm the existence of the Clark-Baraitser syndrome as a nosologically distinct entity that should be added to the list of X- linked mental retardation syndromes.

Kabuki syndrome: clinical data in 21 patients, literature review and guidelines for preventive management

C. T. R. M. Schrander-Stumpel;
Department of clinical genetics, Maastricht, NETHERLANDS.

Kabuki syndrome (KS) was first described in 1981 independently by Niikawa et al. and Kuroki et al. Since than, over 250 reliable cases have been reported from many countries. Etiology of KS is still unknown.
In close collaboration with the Dutch network of Kabuki syndrome, 21 patients were studied. There were 7 males and 14 females, ranging from 2 years to 34 years. In addition, we reviewed the data of 260 KS patients (127M and 133F) in literature and compared them with those in our group. In this presentation we focus on the medical data and tables reviewing the data will be presented. Psychological - and language/speech data are reported separately.
In general, facial features are characteristic with long palpebral fissures, a thin upper lip and full lower lip with ‘lip pits’ without classical pits. Many patients have hypodontia with at least 2 upper incisors missing. Hands are small. The fingers show fetal fingertip pads. Mental retardation generally is moderate and the KS individuals have a positive personality.
We propose guidelines for preventive management. In early childhood the hypotonia, feeding problems and joint laxity pose major problems. The cleft palate needs surgery; recurrent ear infections and possible hearing loss are important issues. Growth and development should be closely monitored. Overweight can occur in early puberty.

E. Morava¹, M. Czakó², K. Hadzsiev³, G. Kosztolányi¹, K. Méhes⁴;
¹Department of Medical Genetics and Child Development,University of Pécs, Pécs, HUNGARY, ²MTA-PTE Clinical Genetic Research Group,University of Pécs, Pécs, HUNGARY, ³Department of Medical Genetics and Child Development, University of Pécs, Pécs, HUNGARY, ⁴Department of Medical Genetics and Child Development, MTA-PTE Clinical Genetic Research Group,University of Pécs, Pécs, HUNGARY.

Postaxial oligodactyly with or without limb defects is most commonly an isolated anomaly. There are a few syndromes presenting with ulnar ray defects and postaxial finger malformation/reduction, however, these occure mostly sporadically. The highly penetrant ulnar-mammary syndrome includes postaxial ray defects, abnormalities of growth, delayed sexual development and mamillar and apocrin gland hypoplasia. We describe a three-generation family with variable expression of ulnar/fibular hypoplasia, ulnar ray defects and short stature. The proband had ulnar hypoplasia with missing IV-Vth fingers, fibular hypoplasia on the right, bilateral club feet, growth retardation, hypoplastic midface, ASD and hemangiomas. She had normal mamillary tissue and normal sweating. The mother had short stature, midfacial hypoplasia, hypoplastic ulna and hypoplasia of the carpal bones in the ulnar ray (brachydactyly type IV) on the right without other associated malformations. A maternal grandfather had mild unilateral fibular hypoplasia, and a maternal grandaunt had shortening of the IVth metacarpus of the left hand. Segregation studies did not confirm linkage to the locus (D12S79) of the Pallister UMS syndrome (MIM 181450). The patients may have a previously undescribed syndrome.

Cranioectodermal dysplasia: two new Egyptian cases with expansion of the phenotype.

H. H. Afifi, S. A. Temtamy, M. I. Mostafa, M. S. Zaki;
Human Genetics Department, National Research Centre, Cairo, EGYPT.

Cranioectodermal dysplasia is a rare syndrome characterized by craniofacial, ectodermal and skeletal dysplasia. We report two new cases, an eleven-year-old boy and a 2-year-old girl. The variability of clinical manifestations included dolicocephaly with or without sagittal suture synotosis, sparse hair, thin nails, brachydactyly, and advanced bone age. Varied dental anomalies consisted of microdontia with discrepancy of eruption and shedding, together with labial and jaws abnormalities. These cases are the first Egyptian cases of cranioectodermal dysplasia. Neuroimaging showed various changes in the form of periventricular hypodense areas and frontal atrophic changes. Fundus examination, electro-retinography, visual evoked potential, electro-cardiography, audiometry, IQ evaluation, abdominal sonar, kidney function tests, serum calcium, phosphorus and alkaline phosphatase were all normal. Advanced bone age in our two cases, which was not previously reported, expands the phenotype and indicates that cranioectodermal dysplasia is both a morphogenetic and maturation disorder.

K. Hadzsiev¹, S. Funke², E. Morava¹, J. Karteszi¹, O. Bartsch³, K. Mehes¹;
¹Dep. Med. Genet. and Child Development, Pécs, HUNGARY, ²Dep. Obst. and Gyn., Pécs, HUNGARY, ³Institut für Kliniksche Genetik Technische Univ., Dresden, GERMANY.

In 1987 Cotsirilos et al. described a family with 2 sibs and their mother presenting a Rubinstein-Taybi-like phenotype (MIM 180850). Autosomal or X-linked dominant inheritence was suggested.
We report on newborn male twins of healty unrelated parents with broad terminal phalanges of hallux, short stature, microcephaly, down slanting palpebral fissures, epicanthic folds, ptosis of eyelids, beaked profile of nose, low-set ears, high palate and a single palmar crease. A prominent metopic ridge was present, more prevailingly in one of the sibs,who also had pectus excavatum and hypospadias.
Early neurodevelopment was normal.
There were no cardiac or eye anomalies. The cranial ultrasound examination showed no brain malformation. X-ray examination of the skull revealed partial cranio-synostosis at the metopic suture and hypertrophy of bone and solid tissues of halluces.
Both children had a normal karyotype at 550-band resolution. FISH with DNA probes RT100 RT191, RT 166 (16q13.3:CREBBP) were normal.
Rubinstein-Taybi syndrome presents with broad hallux and typical facial features. The lack of typical cardiac and ophthalmolgic features and the presence of metopic ridge in our patients did not support this diagnosis. In craniosynostosis syndromes with broad hallux (Crouson, Apert) polydactyly/syndactyly is caracteristic, however it was excluded by the x-ray examination in our cases. br />The observed phenotype fits most probably into Cotsirilos syndrome and supports the primary observers' suggestion that it might be a distinct entity.

Byelorussian Down Syndrome Registry - rare cytogenetical abnormalities and clinical data characterization.

N. Rumyantseva, A. Polityko, I. Naumchik, T. Asadchuk;
Institute for Hereditary Diseases, Minsk, BELARUS.

We reviewed Down syndrome (DS) cases, registered in National Registry of Chromosomal Abnormalities during 1983-2000 years. Patients with mental retardation, congenital malformations and DS phenotype were studied by conventional cytogenetic method (GTG-banding, lymphocytes). Among 909 detected Down syndrome cases 834 patients with full trisomy 21 (included 18 cases with mosaicism) and 75 patients with DS due to de novo and inherited Robertsonian translocations (1 mosaic karyotype) were found. The following rare chromosomal abnormalities were observed: numerical aberrations - 48, XXY, +21 (2 cases); structural unbalance - 46,XX, inv dup (21) (two patients, in one case breakpoints were additionally investigated using FISH); complex rearrangements included 2 cases full trisomy 21 with balanced reciprocal translocations - 47,XX,t(11;21)(q21;q22)mat,+21; 47,XY, t(12;22)(p11.2;q13)pat,+21 and 6 cases pericentric inversions - 47,XY, inv(7)(p12q21.1)mat,+21 (1 case); 47,XX, inv(9),+21 (5 cases). Mosaic forms presented as numerical abnormalities - 47,XY,+21/48,XY,+21,+21 and 47,XY,+21/46,XX as structural 46,XX,t(21;21)/46,XX aberrations and complex rearrangements 48,XY,+21,+mar/46,XY. All individuals with DS including cases with rare cytogenetic variants and complex abnormalities demonstrated typical DS manifestations. In 2 mosaic cases the patients with low rate of the trisomic cells (8% trisomic metaphases) showed mild mental delay and less typical dysmorphic features. The cytogenetical and clinical data of DS will be discussed.

I. Naumchik, N. Rumyantseva, N. Nehai;
Institute of Hereditary Diseases, Minsk, BELARUS.

Pseudoachondroplasia (PSACH) is a spondyloepiphyseal dysplasia characterized by dysproportionate short stature with relatively long trunk, short bowed arms and legs and normal skull and face. On the basis of severity of radiographic findings Hall and Dorst (1969) classified PSACH into 4 types, 2 dominant (I, 177150 and III, 177170 MIM) and 2 recessive (II, 264150 and IV, 264160 MIM). In some cases gonadal mosaicism was proposed.
FP was the only child of young healthy nonconsanguineous parents of average height. He was born after 37 wk pregnancy with BW 3000 g (75th percentile) and BL 48 cm (75th percentile). His motor development was normal. Bowing of the legs and abnormal gait were present from 18 months. At 4 years of age he was 88 cm tall (3rd percentile) with good intelligence and showed normal skull, relatively long trunk, exaggerated lumbar lordosis, and asymmetric bowed legs. Radiographs showed widened metaphyses, small epiphyses of the long bones with delayed ossification, mild platyspondyly. Laboratory testing for metabolic diseases was normal. PSACH was diagnosed although the sub-type of the disorder was not verified.
Detection of PSACH subtypes in early childhood is difficult due to overlap the main clinical and radiological signs and limited pathological changes for young children. We will compare our data with those in the literature and discuss the differential criteria of the sub-types of PSACH.

Mutation analysis of the inhibin alpha gene in an Italian survey of women affected by ovarian failure

A. Marozzi¹, C. Porta¹, W. Vegetti², P. Crosignani², M. Tibiletti³, E. Ginelli¹, L. Dalprà⁴;
¹Dept. of Biology and Genetics -University of Milan, Milan, ITALY, ²I Dept of Obstetrics and Gynecology - University of Milan, Milan, ITALY, ³Department of Clinical and Biological Sciences - Ospedale di Circolo, Varese, ITALY, ⁴Department of Experimental and Environmental Medicine and Medical Biotechnology - University of Milan-Bicocca, Monza, ITALY.

Patients affected by premature ovarian failure (POF) (n=157), early menopause (EM) (n=36) and primary amenorrhoea (n=12) were analysed for the missense mutation (769G->A transition) in the exon 2 of the inhibin alpha gene (INHa). The incidence of the mutation was statistically significant within both the POF (sporadic and familial) (7/157, 4.5%) (Fisher’s exact test, P= 0.030) and primary amenohrroea (3/12, 25%) (Fisher’s exact test, P=9.6X10-4) patients, in regard to the control group (0/100), comprising women who experienced physiological menopause. No mutation was found in the group of EM patients. Furthermore, the likelihood of finding the mutation was statistically different for familial (5/65; 7.7%) (Fisher’s exact test, P=8.6X10-3) and sporadic (2/95; 2%) (Fisher’s exact test, P=0.23) POF conditions. Moreover, the analysis of pedigrees showing the running of both the 769G->A mutation and POF strengthens the concept of the disease heterogeneity, since the POF phenotype was not always associated with the mutation. During this work, we also evidenced the prevalence in the POF patients (80.3%) in regard to the control group (66.7%) of the C allele of a SNP, located in the 5’UTR of the INHa gene. Although these data tend to indicate that the INHa gene can be considered a candidate gene for premature menopause, the assessment of its true diagnostic value requires further investigations.

Meier-Gorlin syndrome: New clinical findings and exclusion of BMP5 as a causative gene

E. M. H. F. Bongers¹, A. Toutain², H. Viëtor¹, A. Verrips³, B. Otten⁴, J. M. Opitz⁵, A. Fryer⁶, P. Sarda⁷, R. C. M. Hennekam⁸, H. van Bokhoven¹, B. C. J. Hamel¹, N. V. A. M. Knoers¹;
¹Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, NETHERLANDS, ²Department of Medical Genetics, Hôpital Bretonneau, Tours, FRANCE, ³Department of Pediatric Neurology, University Medical Center Nijmegen, Nijmegen, NETHERLANDS, ⁴Department of Pediatric Endocrinology, University Medical Center Nijmegen, Nijmegen, NETHERLANDS, ⁵Division of Medical Genetics, Department of Pediatrics, Human Genetics, and Obstetrics and Gynecology, Primary Children’s Medical Center, University of Utah, Salt Lake City, UT, ⁶Mersey Regional Clinical Genetics Service, Royal Liverpool Children's Hospital, Liverpool, UNITED KINGDOM, ⁷Department of Medical Genetics, University Hospital Arnaud de Villeneuve, Montpellier, FRANCE, ⁸Department of Pediatrics and department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, NETHERLANDS.

Meier-Gorlin syndrome (MGS) or ear, patella, short stature syndrome (MIM 224690) is a rare autosomal recessive disorder, characterized by microtia, patellar a-/hypoplasia, and growth retardation. The most serious aspects are feeding problems and recurrent respiratory infections in early infancy. Here, we present the results of growth-, neuromuscular-, and immunological investigation in the largest cohort of MGS patients (8) described in literature. Endocrinological investigations showed normal IGF and growth hormone test results in most patients. Growth hormone therapy resulted in minimal/no effect in all four cases that received treatment. In two sporadic patients available for neuromuscular examination, proximal weakness and a-/hypotrophic ventral muscle groups of the upper and lower extremities was found. Light microscopy of quadriceps muscle biopsies revealed muscle fibre hypoplasia in one, but normal appearance in the other patient. Immunological studies showed decreased numbers of cytotoxic memory T-cells (CD8+ /CD45RO+) in the three examined infants.
Based on the striking similarities between MGS and the murine short ear phenotype caused by homozygous mutations in the BMP5 gene, Lacombe et al. [Ann Genet, 1994;37:184-191] proposed BMP5 as candidate gene for MGS. Recently, the BMP5 gene was sequenced in one MGS patient, and no mutations were detected [Cohen et al., Am J Med Genet, 2002;107:48-51]. Simultaneously, we excluded the BMP5 locus as candidate region by linkage analysis in two consanguineous families, including one family with three affected sibs. Homozygosity mapping in consanguineous MGS families is presently being performed as a first step towards the molecular identification of the gene responsible for MGS.

Alstrom syndrome - the overlooked syndrome? Case report and review. T.Datkhaeva, E. Elias and E. Sujansky. Division of Genetics and Metabolism, University of Colorado School of Medicine, the Children Hospital, Denver, UCHSC.

T. Datkhaeva¹, E. Elias², E. Sujansky¹;
¹University of Colorado School of Medicine, Denver, CO, ²The Children Hospital, Denver, CO.

Severe early-onset inherited cone dysfunction, secondary rod degeneration and obesity are the hallmarks of Alstrom syndrome, a very rare autosomal recessive disorder.
We present a 2 ½ year old male first seen in ophthalmology at age 8 months with nystagmus, retinal degeneration and bilateral high myopia. Other than repeated otitis media, he has been healthy. He has shown normal cognitive development. The patient’s father and two paternal second cousins have retinal abnormalities.
Physical exam at age 10 months disclosed a weight of 50th% for age 2-years. Mildly dysmorphic features included telecanthus, narrow and high palate and equinovarus. Alstrom syndrome was suspected. Brain MRI, hearing tests and renal ultrasound were normal. His karyotype was normal (46,XY). When reviewed at 27 and 30 months he wad found to have progressive visual loss, hypertriglyceridemia and progressive obesity, despite caloric restriction. DNA-testing for Alstrom syndrome mutations on chromosome 2 is pending.
The differential diagnosis of cone-rod dystrophy presenting in early infancy is broad, but when associated with early obesity should suggest the diagnosis of Alstrom Syndrome. Sensorineural deafness, cardiomyopathy, hyperlipidemia, and diabetes may not present until later in childhood. In contrast to patients with Bardet-Biedl syndrome, patients with Alstrom syndrome display normal cognitive development, and normal digits. It is important that clinicians and ophthalmologists consider Alstrom syndrome in the differential diagnosis of retinal dysfunction. DNA testing is now available to confirm the diagnosis, and allow optimal subspecialty care for these complex patients.

Microsatellite mapping and screening of a candidate gene, TRPC5 (Transient Receptor Potential Channel) in a second family with Arts syndrome

L. S. Raffaele¹^,2, J. Christodoulou¹^,2, B. Bennetts¹^,2, R. Ouvrier¹;
¹Royal Alexandra Hospital for Children, Westmead, AUSTRALIA, ²University of Sydney, Sydney, AUSTRALIA.

Arts syndrome was first described in a Dutch family with X-linked ataxia, muscle weakness in response to infections, deafness, loss of vision in early childhood and a fatal course. We describe a family with two affected brothers and a maternal uncle who died at 2 years of age of a “muscular dystrophy” without having developed any speech. The two brothers have profound sensorineural deafness, peripheral neuropathy with generalised muscle weakness and, in the older boy, symptomatic optic atrophy. They are predisposed to severe muscle weakness during recurrent infections which has led to mechanical ventilation on a number of occasions.
To localise the region for this syndrome, an exclusion mapping approach was taken, using 33 microsatellite markers covering the X chromosome. DNA was available from the affected brothers, their normal sister, parents, maternal grandparents and an unaffected maternal uncle. Two candidate regions were identified: Xq23 between DXS 1106 and DXS 8064 (~13cM), and Xq27 between DXS 1227 and DXS 8091 (~21.4cM). The candidate region Xq21.33-q24 was identified in the original family, so the Xq23 region was deemed most likely. Databases were searched for likely candidate genes. TRPC5 was selected as the most likely because of its involvement in Ca2 flux, and its expression in mammalian brain and Drosophila eye. Screening of this gene is in progress. To date one A>G change has been identified at 919-42 (intron 1) in the affected boys, their normal father and maternal grandfather. It is therefore likely to be a common polymorphism.

Absent sacrum in terminal deletion of the long arm of chromosome 7:a further case

E. Steichen-Gersdorf¹, O. Rittinger², I. Gaßner¹;
¹Universitätsklinik f. Kinder-und Jugendheilkunde, Innsbruck, AUSTRIA, ²Klinische Genetik, Landeskinderklinik, Salzburg, AUSTRIA.

Small deletions of chromosome 7qter are rarely reported. The literature contains 7 cases with deletions distal to 7q35. In conventional cytogenetics these deletions may be overlooked, so that clinical characteristics have to be elaborated to further delineate a specific syndrome.
Case report: The girl was born as the second child to a 22 years old mother and a 28 years old father. She was born at 39 weeks of gestation. She had low birth weight with 2625g (5th centile), length:47cm(10th centile), head circumference:30,8cm(<10th centile). The cry was weak and she had severe problems with sucking, so that gavage feeding was necessary. The most striking features were microcephaly with a narrow forhead and large dysplastic ears with a wide exernal meatus. The palpebral fissures slanted up. The nose was short with a bulbous tip, the philtrum was simple, the maxilla hypoplastic. The muscle tone was generally reduced. The EEG was abnormal. X-ray showed thin ribs and an vertically absent sacrum, which could not be suspected clinically.Sonographic investigations revealed a tethered cord with a very low lying conus medullaris inserting in a small lipoma. Hearing was severely impared. Standard chromosomal analysis was normal, but subtelomeric analysisis using a comercial multitelomere FISH.kit(Cytocell) revealed the absent signal on 7qter. The parents chromosomes will be studied.
We stress that children with micrcephaly and absent sacrum should be looked for a cryptic deletion on 7q.

Gorlin Syndrome in a patient with deletion of the distal part of chromosome 9q and fine mapping of the break points with Fluorescence In Situ Hybridization (FISH).

S. E. Boonen¹, Z. Tümer², N. Tommerup², D. Stahl³, T. Rosenberg⁴, S. Kreiborg⁵, V. Kalscheuer⁶, K. Brøndum-Nielsen¹;
¹John F. Kennedy Institute, Glostrup, DENMARK, ²Wilhelm Johannesen Centre for Functional Genome Research, IMBG, Panum Institute, University of Copenhagen, Copenhagen, DENMARK, ³Clinic in Dermatology, Hørsholm, DENMARK, ⁴The National Eye Clinic for the Visually Impaired, Hellerup, DENMARK, ⁵School of Dentistry, University of Copenhagen, Copenhagen, DENMARK, ⁶Max-Planck Institute for Molecular Genetics, Berlin, GERMANY.

We present a 20 year-old male with many nevi of the skin and three basal-cell carcinomas who was referred by a dermatologist for further investigation. Previously a chromosome analysis was carried out showing the karyotype 46,XY,del (9)(q21.3;q31) de novo. PTCH located at 9q22.3 was shown by FISH to be deleted confirming the diagnosis of Nevoid Basal Cell Carcinoma Syndrome or Gorlin Syndrome. In addition he has developmental delay, dental and cardiac malformation and dysmorphic features, probably caused by loss of chromosomal material around PTCH. Further characterization of the deletion showed the proximal breakpoint at 9q22.2 and the distal breakpoint distal to 9q31.2. Further fine mapping will be presented.

A family with Seathre Chotzen syndrome and mutations in the TWIST and FGFR2 genes

M. Stuhrmann¹, S. Morlot², R. Stephan³, W. Kress⁴;
¹Institut fuer Humangenetik, Hannover, GERMANY, ²Genetische Praxis, Hannover, GERMANY, ³Staedtisches Krankenhaus, Hildesheim, GERMANY, ⁴Institut fuer Humangenetik, Wuerzburg, GERMANY.

Most cases with Saethre-Chotzen syndrome (SCS), a relatively frequent autosomal-dominant craniosynostosis syndrome, are due to mutations in the TWIST gene. Other SCS patients carry the missense mutation P250R in the FGFR3 gene, leading to a similar phenotype. The classical SCS phenotype includes brachycephaly or acrocephaly and partial cutaneous syndactyly of hands and feet.
The phenotypic expression of SCS is highly variable also within families. These variability is very likely due to an influence of modifying genes. Under the assumption that special alleles of the FGFR1, 2 or 3 genes may be such modifiers, we investigated several members of a German SCS family. Two members of this family, a 6 months old boy and his father, displayed the classical SCS phenotype. With the exception of partial cutaneous syndactyly, no further symptoms were present in the boys paternal uncle, grandmother and grand-grandmother.
Both the boy and his father carried two mutations: D161X in the TWIST gene and S252L in the FGFR2 gene. D161X had previously been described in a SCS patient, and S252L was associated with a mild Crouzon phenotype. No other family member carried D161X. However, S252L was present in all family members with syndactyly. We conclude that D161X arose de novo, leading to the classical SCS phenotype, while S252L was associated with cutaneous syndactyly only and spread from the paternal grandmother over the whole family. To the best of our knowledge, this is the first family in which both a TWIST and a FGFR2 mutation were present in SCS patients.

G. Balta¹, O. Onalan², A. Oto², A. Gurgey¹, C. Altay¹;
¹Hacettepe University, Pediatric Hematology Unit, Ankara, TURKEY, ²Hacettepe University, Department of Cardiology, Ankara, TURKEY.

The relation of PAI-1 gene promoter 4G/5G genotype and the risk of developing Coronary Artery Disease (CAD) is still controversial. The objective of this study is to evaluate the role of 4G/5G genotype on development of CAD. Distributions of 4G/5G genotype were studied in consecutive CAD patients with Myocardial Infarction (MI, n=158), Stable Angina Pectoris (SAP, n=124) and in 282 unrelated healthy controls. 1- The frequencies of both 4G/4G and 4G/5G genotypes were 33% and 48% respectively in CAD patients with MI and 26% and 40% respectively in controls, the differences in the frequencies of both genotypes were statistically significant (OR: 2.3 and 2.2; 95% CI 1.3-4.0 and 1.3-3.6 respectively). 2- There was statistically significant differences in 4G/5G genotype between CAD patients with SAP (57%) and control (40%) (OR: 1.9; 95% CI 1.2-3.2). 3- Comparison of the frequencies of 4G/4G genotype in patients with MI (33%) and SAP (17%) was statistically significant (OR: 2.6; 95% CI 1.3-5.4). Hyperlipidemia appeared to be an additional risk factor for development of MI in patients with 4G/4G genotype (OR: 3.0; 95%CI 1.5-6.2). Although smoking is an independent risk factor (OR: 1.7; 95% CI: 1.1-2.8), it did not effect the risk of developing MI associated with 4G/4G genotype. The results of the study suggested that 4G/4G and 4G/5G genotypes may be associated with an increased risk of developing MI while presence of only 4G/5G genotype seemed to be related to the risk of developing SAP. This study was supported by Hacettepe University research grant (9902101003).

Coffin-Siris syndrome in a girl with a 15qter deletion encompassing the IGF-1 receptor gene.

P. Failla, L. Ragusa, O. Galesi, L. Castiglia, R. M. Ragusa, A. Ragusa, C. Romano;
Oasi Institute, Troina, ITALY.

We report on a 11.5-year-old girl with features of multiple congenital anomalies/mental retardation overlapping those of Coffin-Siris syndrome (MIM 135900) and a deletion on 15 qter, not seen by standard karyotype, but only by multiFISH subtelomeric assay. Weight, length and OFC were all below the third centile at birth. Impaired sucking and swallowing were referred up to 8 months. Developmental delay was noted since the very beginning. She shows now severe mental retardation, dwarfism (height 102 cm), microcephaly, large mouth with flat philtrum, unilateral palpebral ptosis, hirsutism on the lombosacral area. Hands and feet are very small with shortening of fifth fingers and fourth and fifth toes, and nail hypoplasia of fifth fingers and of second, third, fourth and fifth toes. X-ray examination reveals very short terminal phalanx of the fifth fingers and toes, double epiphisis on second, third, fourth and fifth methacarpal bone and short middle phalanx of fifth finger. The bone age is severely retarded (6.1 years). Growth hormone, IGF-1, IGFBP-3, thyroid function are normal. As additional features the girl has multicistic kidney with mild renal failure. Previous reports by McPherson et al. (1997) and McGhee et al. (2000) assigned a locus for the Coffin-Siris syndrome to the 7q32-q34 region. Our report may raise the chance of a second locus for such syndrome in the 15qter region. We conclude highlighting the presence in the 15q25-q26 region of the IGF-1 receptor gene, which may be a clue for the etiology of the phenotype and possibly for the Coffin-Siris syndrome.

A novel approach for determining the parental origin of GNAS1 mutations in sporadic patients with Albright’s Hereditary Osteodystrophy using overlapping imprinted transcripts: Clinical application for predicting endocrine phenotype.

L. C. Wilson¹, S. J. Rickard²;
¹Institute of Child Health & Great Ormond Street Hospital, London, UNITED KINGDOM, ²Institute of Child Health, London, UNITED KINGDOM.

Albright’s Hereditary Osteodystrophy (AHO) results from heterozygous deactivating mutations in the GNAS1 gene which encodes the alpha subunit of the adenylyl cyclase stimulatory G-protein, Gs. Associated clinical features include short stature, obesity, brachymetaphalangia, ectopic ossifications and learning disability. Inheritance is autosomal dominant but modified by genomic imprinting. Maternal transmission is associated with the endocrine features of pseudohypoparathyroidism (PHPIa) whereas paternal transmission is usually not (pseudo-pseudohypoparathyroidism, PPHP).
GNAS1 comprises 13 exons and the imprinting appears to be tissue specific. However, 3 discrete upstream exons (NESP55, XLAS, exon 1A) which are spliced to exons 2-13 of GNAS are imprinted in all tissues tested. Expression is exclusively maternal for NESP55 and paternal for XLAS and 1A.
We have screened for sequence changes in all the exons and splice junctions of GNAS1 in a cohort of patients with AHO and found a variety of mutations. We have confirmed that imprinting of NESP55 and exon 1A is conserved in lymphoblastoid cell lines. In AHO patients with mutations in exons 2 - 13 of GNAS from whom lymphoblastoid cell-lines were available, we have tested directly for the mutation in the NESP55 and 1A cDNA transcripts. In 3 sporadic patients with PPHP we have confirmed the mutation is present in the 1A transcript, but not NESP55 indicating paternal origin. In 6 patients with AHO and PHP Ia we have confirmed the converse indicating maternal origin. With the discontinuation of PTH for stimulation testing, the clinical application for predicting the endocrine phenotype in AHO patients will be discussed.

A case of Zimmermann-Laband syndrome with a chromosomal translocation t(3;8)(p13;q24.1)

M. Stefanova, T. Krastev, D. Atanassov;
Higher Medical Institute, Plovdiv, BULGARIA.

Zimmermann-Laband syndrome (ZLS) is a rare autosomal dominant disease characterized by gingival hyperplasia or fibromatosis, hypoplasia of the finger- and toenails, hypoplastic changes in the terminal phalanges of fingers and toes, coarse facial features, hepatosplenomegaly, inconsistent mental retardation (Pfeiffer et al, 1992). All reported cases have normal karyotype. Molecular basis of this condition remains unknown.
Here we report on an apparently balanced chromosomal aberration, t(3;8)(p13;q24.1) in a mother and her daughter, both with typical ZLS features characterized by gingival hyperplasia, finger- and toenails hypo- and aplasia and course facial features, including large nose, thickened lips and flashy ears. None of the closely related family members were affected with ZLS, nor had a chromosomal aberration. It is suggested that the causative gene for ZLS is located at the translocation breakpoint(s).

Segregation of a t(1:3)(q42.3;p25) Translocation Resulting in Different Recombinant Chromosomes in Multiple Family Members

C. Kozma¹, A. A. Slavotinek², J. M. Meck¹;
¹Georgetown University, Washington, DC, ²National Human Genome Research Institute, National Institute of Health, Bethesda, MD.

A subtle familial balanced translocation involving the terminal regions of 1q and 3p was identified in a large family by high-resolution karyotype analysis and confirmed by (FISH) analysis.
In this family, segregation of a balanced t(1:3)(q42.3;p25) chromosome translocation in two phenotypically normal sisters led to two types of viable unbalanced complements which corresponded to two distinct phenotypes in affected individuals. The proband had inherited the derivative chromosome 3 resulting in partial trisomy of chromosome 1q and partial monosomy of chromosome 3p. A paternal uncle and cousin had the reciprocal rearrangement with a derivative of chromosome 1 resulting in partial monosomy for chromosome 1q and partial trisomy for chromosome 3p.
While profound mental and physical retardation, poor survival, congenital heart defects, and neurologic abnormities were characteristic for both rearrangements, facial dysmorphism was quite distinct for each recombinant. Individuals who had the derivative chromosome 3 had a long face, wide eyebrows, small palpebral fissures, hypertelorism, prominent glabella, a large tip of the nose, long philtrum with thin upper lip, and low set-ears with prominent helices. In contrast, family members with the derivative chromosome 1 had a tall forehead with bifrontal narrowing, full and large cheeks, and large simple ears.
In this kindred, the ratio of normal to abnormal individuals born to balanced carriers is believed to be 1:1.5. This suggests that the recurrence risk for carriers is at least as great as 50%.

M. Ikbal, A. Tastekin, R. Ors, B. Erdogmus;
Ataturk Universty, Erzurum, TURKEY.

We present a 4-hour old male infant born at term to healthy parents who related as first cousins, with spontaneous vaginal delivery after an uncomplicated pregnancy. His weight, length and head circumference were 2250 g, 43 cm and 33 cm, respectively. The boy showed immobile face, hypertelorism, blepharophimosis, antimongoloid eye slant, bulging cheeks, small nose, small mouth, symmetric clenched fingers, camptodactyly, ulnar deviation of the hands. These clinical findings suggested ‘’Whistling Face Syndrome’’. In addition, intrauterine growth retardation, microcephaly, microphthalmos, micrognathia, bilateral incomplet choanal atresia, laryngomalasia, low and malforme ears, short neck, wide spaced nipples, pelvicaliectasia, uretheral dilatation, absence of one costa, sandal gap and weak primitive reflexes were determined. Chromosomal analysis was normal (46, XY). We suggested that this patient is a variant of Whistling Face Syndrome or a new syndrome

Blepharophimosis to craniostenosis: the human and murine phenotypic spectrum related to TWIST haploinsufficiency

H. Dollfus¹, G. Kumaramanickavel², P. Biswas³, C. Stoetzel⁴, R. Quillet⁴, M. Denton⁵, M. Maw⁵, F. Perrin-Schmitt⁴;
¹IGBMC and Faculté de Médecine, Strasbourg, FRANCE, ²Sankara Nethralaya Medical Institution Research Foundation, Chennai, INDIA, ³Anadalok, Calcutta, INDIA, ⁴IGBMC, Strasbourg, FRANCE, ⁵Biochemistry Department, Dunedine, NEW ZEALAND.

Introduction
The TWIST gene, a bHLH transcription factor, is mutated in patients with Saethre-Chotzen syndrome (SCS). Twist null/+ mice have been found to reproduce the main clinical features of SCS.
The aim of this work is the analysis of the phenotypic spectrum related to haploinsufficiency in the TWIST gene through the study of a large Indian family and the observation of the murine phenotype.
Material and Methods:
The TWIST gene was a candidate gene in a large Indian family presenting with an autosomal dominant phenotype initially classified as Blepharophimosis-Epicanthus Inversus Syndrome (BPES) linked to 7p21.
The eyelid phenotype of twist null/+ mice bred on different genetic backgrounds was observed.
Results:
A new nonsense mutation, at codon 82, was detected for 16 members of the family (excluding the 7p21 locus as the second BPES locus as initially suggested).
The clinical reappraisal of these 16 individuals carrying the mutation identified a complete SCS phenotype for only 4 patients (25%). 75% of the patients did not show craniostenosis, 25% had a phenotype considered to be normal and 75% of the patients had eyelid anomalies. Isolated eyelid anomalies, without any cranial anomalies, were also observed on Twist null/+ mice bred on a mixed background.
Conclusions:
The clinical analysis of the Indian family confirms the wide variability of the phenotype related to TWIST haploinsufficiency ranging form a normal phenotype, an isolated eyelid malformation to severe craniostenosis. In parallel, the wide phenotypic variability was also observed in twist-null/+ mice bred on different genetic backgrounds.

Dup(3)(q26>qter) & del(3)(pter>p25) Due To Paternal Pericentric Inv(3) But With Phenotypic Abnormalities Not Consistent With Both Well-known Clinical Syndromes - A Case Report

R. Puttinger¹, G. Kronberger¹, J. Kraus², M. R. Speicher², O. Rittinger¹;
¹Klinische Genetik, Landeskinderklinik, Salzburg, AUSTRIA, ²Institut für Humangenetik, TU, Muenchen, GERMANY.

Cytogenetic studies remain the cornerstone in defining mental retardation syndromes associated with dysmorphic features. Chromosome 3 structural aberrations to a considerable extent result from unbalanced recombinations. We report on a 5 year old boy who by detailed cytogenetic procedures was diagnosed as having a distal deletion 3p as well as a duplication (3)(q26>qter) due to a large pericentric inv(3) inherited from his father. In addition to conventional karyotyping, final diagnosis was achieved using multiprobe telomer testing (Cytocell) and region-specific FISH probes. Theoretically our patient should express both the partial dup (3)(q26>qter) and the deletion (3)(p25>pter) syndromes. In contrast we noted a mild but apparent dysmorphic pattern with distinct features - square face, temporal indentation, broad eyebrows, full cheeks, bulbous nose, and full lips - suggestive of a mitigated partial dup 3p syndrome. No major malformation was observed. Causal parental pericentric inversion was reported in a number of cases with similar breakpoints, but the children were mostly severely affected with short survival. This report should draw attention to some interesting details: (i) Loss of the most distal region of 3p may be noticed without phenotypic effect (Knight, J Med Genet 1995).(ii) Prediction of the phenotype seems difficult even in well-described conditions like 3qter-syndrome (iii) In a given pericentric inversion, survival would be more probable in great duplication plus a small subtelomeric deletion than vice versa.

L. C. Enache¹, I. Dimofte², P. D. Balaban³, R. Airinei⁴, A. Popa², V. Broasca Madar⁵;
¹Cell and Molecular Biology Deparment, UMF "Gr.T.Popa", Iasi, ROMANIA, ²Medical Genetics Department, Faculty of Medicine, Constanta, ROMANIA, ³Biochemistry Department, Faculty of Medicine, Constanta, ROMANIA, ⁴Faculty of Medicine, Constanta, ROMANIA, ⁵Management and Public Health Department, Faculty of Medicine, Constanta, ROMANIA.

A mother and her son are described with neonatal trigonocephaly, multiple suture synostosis; shallow orbits; unusual nose; deviation of the terminal phalanges of fingers 1, 2 and 5; and broad toes which radiologically may show duplication of the terminal phalanx.
Untreated, the condition leads to a disfiguring oxycephaly with hypotelorism.
This appears to be the first documented instance of autosomal dominant trigonocephaly.
The importance of the minor anomalies in its recognition and its good prognosis are emphasized.

C. Rusu¹, I. Cernescu², M. Volosciuc¹, M. Covic¹;
¹University of Medicine, Iasi, ROMANIA, ²Children's Hospital, Iasi, ROMANIA.

We are presenting a case of chondrodysplasia punctata Conradi-Hunermann type in order to illustrate this rare entity and discuss the importance of different features for the diagnosis, differential diagnosis and genetic counselling.
Our proband is a male infant, first child of a healthy, young, unrelated couple, first examined in the Maternity Hospital (4 days old). Clinical features: mild dysproportionate short stature (short limbs with contractures); dysmorphic face (coarse face, frontal bossing, flat, broad nose, macrostoma, abnormal ears); ichthiosiform erithroderma with curled, linear distribution, keratotic papules (fingers and toes); club foot. 7 months later physical examination showed: dysproportionate short stature (short limbs, rhizomelic segment mainly affected), the same dysmorphic face, depigmented curled linear areas of skin (trunk, abdomen and limbs), follicular atrophoderma and bilateral club foot (ortopedically treated). X-ray investigation: stippled calcifications (proximal humeral epiphyse and sacral area), short humeral and femoral bone and delayed ossification of the femoral head. Karyotype: 46,XY. We have established the diagnosis of chondrodysplasia punctata Conradi-Hunermann type. Detailed positive diagnosis, differential diagnosis (of dysproportionate short stature and linear ichthiosiform erithroderma) and problems of the genetic counselling will be provided.
In conclusion, we present a case of chondrodysplasia punctata Conradi-Hunermann type (AD) to discuss different diagnostic aspects.

J. Zenteno¹, S. Carranza-Lira², S. Kofman-Alfaro³;
¹Genetics,Hospital General de Mexico, Mexico City, MEXICO, ²Hosp "Luis Castelazo Ayala" IMSS, Mexico City, MEXICO, ³Hospital General de Mexico, Mexico City, MEXICO.

Müllerian agenesis, also known as Mayer-Rokitansky-Kuster-Hauser syndrome (MRKHS) is the second most common cause of primary amenorrhea. The syndrome involves the absence of the fallopian tubes, the uterus, and the upper third of the vagina in otherwise normally developed females. To date the etiology has not been elucidated and the search for molecular variants in these patients has been focused to genes involved in the Müllerian regression system. We present the results of molecular studies in the AMH, AMH receptor, and GALT (galactose-1-phosphate uridyl transferase)genes in a group of 12 Mexican patients with MRKHS. Methods: DNA extraction from blood leukocytes, PCR amplification of all exons and all exon/intron junctions of the AMH and AMHR genes, and PCR amplification of exon 10 of GALT. Results: No mutations were found in any of the patients in the AMH or AMHR. However, we identified 5 new polymorphisms: two in intron 6 of the AMHR gene, 1 in exon 1 of the AMH gene, and two in exon 5 of the AMH gene. All three polymorphisms in the AMH gene change the encoded aminoacid. When compared with 30 control alleles AMH exon 1 polymorphism showed a preliminar association with the disease. The GALT N314D allele, previously associated with the disease, was observed only in one of our patients. These results demonstrate that mutations at the AMH or AMHR genes are not a common cause of MRKHS. Polymorphisms at the AMH or AMHR genes may contribute to develop the phenotype.

Maternal Heterodisomy for chromosome 14, and 13/14 Robertsonian Translocation, in a female with normal mental development, short stature and dysmorphic features

L. Giunti, E. Lapi, S. Guarducci, U. Ricci, A. Cecconi, E. Andreucci, M. Ottaviani, M. L. Giovannucci Uzielli;
University of Florence, Firenze, ITALY.

Maternal Uniparental Disomy for chromosome 14 was reported in the literature in about ten subjects, after the first description by Temple in 1991. A distinct maternal UPD(14) phenotype is emerging from the published data, but the clinical spectrum is only partially homogeneous.
We report on a new case of maternal heterodisomy for chromosome 14 in a thirty years old female, referred to our Centre, with her husband, for genetic counseling aimed to procreation.
Physical examination of the proposita showed a completely normal mental development, with short stature recalling hypochondroplasia, but associated with unrelated dysmorphic features.
Cytogenetic analysis showed a balanced, de novo, Robertsonian translocation 45,XX,der(13;14). Based on the cytogenetic results, we performed the molecular analysis for UPD (14), by using a battery of microsatellites markers in the lymphocites DNA of the proposita and her parents.
A maternal heterodisomy for chromosome 14 was demonstrated by several informative markers, derived from different regions of short and long arms: we confirmed these results by means of a paternity testing with normal biparental contribution. FISH analysis was also completed. From the clinical point of view, of special interest is the long and well documented natural history of this patient, that adds new elements to the clinical spectrum of this rare disorder. We also report data on the skeletal morphology and development, and clinical phenotype at different ages.

De novo partial duplication of chromosome 15, resulting from an unbalanced translocation of an extra segment 15p13-q22 on the short arm of a chromosome 8, in a child with severe and global development delay

S. Guarducci, L. Giunti, U. Ricci, E. Lapi, A. Cecconi, S. Coviello, I. Sani, I. Giotti, M. L. Giovannucci Uzielli;
University of Florence, Firenze, ITALY.

The proposita is a newborn female of Albanian origin, referred at age 23 days, for severe prenatal and postnatal growth, “anaemia” and dysmorphic features.
Cytogenetic analysis showed, in all metaphases of the proposita, an abnormal short arm of chromosome 8, with the presence of extra material of unknown origin, translocated on the 8p23 band. The chromosomes of the parents were normal.
Molecular cytogenetic analysis was performed to characterise this chromosomal rearrangement. FISH, using a chromosome 8 and chromosome 15 painting probes, demonstrated an apparently pure, partial Trisomy of chromosome 15. Molecular analysis, using microsatellite DNA markers mapping to the short and long arms of chromosome 15, showed that the duplication was of maternal origin.
Proximal Trisomy 15q is a rare disorder and the clinical spectrum is not well characterised. Microcephaly and cardiac malformation, described a few times, are also present in this new patient.
Mental retardation is to be expected: it is not yet well assessable in the proposita.
A bone marrow dysplasia is documented, and could represent a major aspect of the karyotype/phenotype correlation, and of the prognostic problems for this child.

Identification of a TP63 gene R298Q mutation in a family with EEC/ADULT syndrome phenotype.

E. Spadoni¹, H. van Bokhoven², H. Scheffer², C. De Giacomo³, C. Danesino¹;
¹Università degli Studi di Pavia - Dip. Patologia Umana ed Ereditaria - Sez. Biologia Generale e Genetica Medica, Pavia, ITALY, ²Department of Human Genetics - University Medical Centre Nijmegen, Nijmegen, NETHERLANDS, ³Clinica Pediatrica - IRCCS San Matteo, Pavia, ITALY.

G.N., a boy, presented at birth with: absence of right hand middle finger, skin syndactyly of feet, polydactyly of right foot and bilateral obstruction of tear ducts. At physical examination, at 4 years of age, we noted an albinism-like appearance with very lightly pigmented hair and skin, dryness of skin and high photosensitivity, brittle and dysplastic nails with pitting, hypoplasic teeth and hypoplastic nipples. He suffers from chronic conjunctivitis. His mother, C.R. (who had never been investigated before), presented: dry and lightly pigmented skin with high photosensitivity and "dermatitis-like" lesions of face and hands, brittle and dysplastic nails with pitting and dysplastic teeth with absence of a permanent canine tooth. She now has dark blonde hair but she had lighter hair in childhood. She also suffers from chronic conjunctivitis. The clinical phenotype we observed in G.N. suggested differential diagnosis between EEC (ectrodactily, ectodermal dysplasia, cleft lip/palate) and ADULT (acro-dermato-ungual-lacrimal-tooth) syndromes. According to autosomal dominant inheritance and variable expressivity, recognized for both syndromes, we thought C.R. could be mildly affected be the same disorder of his son. TP63 gene (3q27) mutations have recently been identified in patients with either EEC or ADULT syndrome. Mutation analysis in this gene revealed a heterozygous R298Q mutation in both the patient and his mother. The same mutation had been previously identified in a large ADULT syndrome family. The proband and his mother, and other family members who are likely to be equally affected, will be further investigated to better define clinical diagnosis and genotype-phenotype correlation.

M. Kheirollahi, B. Azadeh;
Medical Genetics Counselling Center, Welfare Organization, Isfahan, IRAN (ISLAMIC REPUBLIC OF).

This fact that there is not fibula in the human body is one of the clinical signs of several rare syndromes which is often autosomal recessive. The case of study is a four-year-old girl in whom this fact that there is not the bi-directional fibula has been observed. No mental retardation is observed in this child.
In radiographic studies no fibula as well as phalanges and metacarpus are visible in the child's right hand. The tibia bones are very short. The family pedigree of this child shows that her parents had family marriage with the relative of aunt's son-aunt's daughter (F=1/16). But, no other similar case wase observed in the family.
This case was compared with fibula aplasia and complex brachydactyly (MIM: 228900). As a result, though there were many similarities, some differences were observed in this case.

E. Gross¹, K. Seck¹, S. Neubauer¹, H. Hellebrand², A. Meindl², S. Riemer³, J. Mayr³, V. Lutz³, M. Kiechle¹;
¹Dept. of Gynecology, Technical University, Munich, GERMANY, ²Medizinische Genetik, Ludwig-Maximilian-University, Munich, GERMANY, ³Roche Diagnostics, Penzberg, GERMANY.

A decreased dihydropyrimidine dehydrogenase (DPD) activity has been described in cancer patients with intolerance to the fluoropyrimidine anticancer drug 5-fluoro-uracil (5FU). So far, 17 inherited mutations probably related to this impaired enzyme function were found in the DPYD gene. We performed a research-based population study to unravel new mutations and to get sufficient data to determine genotype-phenotype relations in the DPD deficiency syndrome. The entire coding region and the exon/intron boundaries of the DPYD gene were screened by denaturing HPLC (DHPLC). DPD protein levels were quantitatively analyzed by ELISA and DPD mRNA levels were determined by using a DPD mRNA Quantification Kit. Several polymorphisms and intron variants were frequently detected in 160 German individuals. The 85T>C mutation as well as the 1601G>A substitution, both controversially discussed as mutations with relation to 5FU-toxicity in the literature, could be detected in various individuals with normal DPD protein level and additionally in a patient showing toxic reactions under CMF chemotherapy. Finally, the splice mutation IVS14+1G>A and the frameshift mutation 296delTCAT which result in truncated proteins devoid of activity were found in the heterozygous state in our population study. The data are correlated with DPD protein- and DPD mRNA expression level. The rapid and sensitive screening of cancer patients for mutations associated with 5FU-intolerance might be useful prior to the onset of chemotherapy because the risk for 5FU-related toxicity is not entirely rare. We show that the DHPLC technology could be a reliable tool for mutation detection in pharmacogenetics.

A third case of progressive macrocephaly with dilated Virchow-Robin spaces on MRI

G. Viot;
Unité de Génétique Clinique, Maternité Port-Royal, Paris, FRANCE.

We report the case of a boy referred for a quickly progressive macrocephaly. He was the first child of young non-consanguineous and healthy parents. The family history was unremarkable.
Clinical evaluation revealed at 6 months of age a head circumference (HC) at +5 SD whereas the HC was +2 SD at birth. Neurologic exam was normal except a minor axial hypotonia. Neither associated dysmorphic features nor delayed motor development were noted at this time. No signs of intracranial pressure were present. Magnetic resonance images showed prominent Virchow-Robin spaces in occipital regions without increased size of the ventricles or involvement of the cerebral white matter. This pattern is usually a sign of storage disease but after investigations, there was no argument in favor of lysosomal disorder or muco/oligosaccharidosis. We also excluded a mitochondrial disorder.
The present case appears similar to those reported by Artigas et al. in 1999, which exhibited a progressive macrocephaly with an onset in the first year of life, dilated Virchow-Robin (DVR) spaces within the white matter of the cerebral convexities and normal neurodevelopmental status. Our reported case agrees with the hypothesis that macrocephaly with DVR can be considered as a new entity. Follow-up of our very young patient in the future will be necessary to confirm the good neurological prognosis of this entity.

E. Petek¹, C. Windpassinger¹, S. W. Scherer², K. Wagner¹, P. M. Kroisel¹;
¹University of Graz, Graz, AUSTRIA, ²Hospital for Sick Children, Toronto, ON, CANADA.

We have identified six children with a de novo deletion involving the chromosomal band 7p13 associated with Greig cephalopolysyndactyly syndrome (GCPS) and various other clinical features. Here we want to focus on the delineation of the phenotype in all patients in particular on those symptoms, that are not typically related to GCPS like a moderate psychomotor retardation, seizures, muscle fibre anomalies, cardiac anomalies, hyperglycaemia or hirsutism. We studied genotype-phenotype correlation in our patients, by using the combination of classic cytogenetics, FISH, and the analysis of polymorphic DNA markers. All deletion breakpoints were precisely mapped and based on these results in combination with genomic sequence data available by now, we were able to identify several candidate genes mapped to the deleted chromosomal segments.
This research was supported by grant #9522 from the Oesterreichischen Nationalbank to E.P

Ohdo blepharophimosis syndrome: report of two new unrelated cases and review of literature

K. Õunap, 1964¹, R. Zordania², P. Laidre³, R. Nõmmela⁴;
¹Tartu University Clinics, Tartu, ESTONIA, ²Tallinn Children's Hospital, Tallinn, ESTONIA, ³Infants'Home of Tartu, Tartu, ESTONIA, ⁴Clinics of Stomatology, University of Tartu, Tartu, ESTONIA.

Ohdo blepharophimosis syndrome (OBS) is a rare condition first reported by Ohdo et al. (1986). The exact aetiology of this syndrome has not been established yet. Here we report two new unrelated cases of OBS and review the literature.
Both our patients had moderate developmental delay, peculiar facies with blepharophimosis, ptosis, broad nasal bridge, flat nasal tip, flat philtrum, small mouth, and low-set dysplastic ears, and muscular hypotonia in neonatal period.
Case 1 was born prematurely on 35th week of pregnancy with proportionate failure to thrive (-3.0 SD). Soon after the birth the heart defect was diagnosed (supravalvular aortic and pulmonary stenosis). Clinical evaluation at age 4.5 years showed proportionate failure to thrive (-3.0 SD). Her teeth were peg-like, irregular and with dysplastic enamel. Clinodactyly of 5th fingers was also observed.
Case 2 was born at term with low birth weight (-3.0 SD). She had probably some alcohol exposure during the pregnancy. Our examination at age 7 years revealed failure to thrive (-2.5 SD), microcephaly (-4.0 SD), high palate, dental hypoplasia, hypertrophic gingivitis, bilateral cross-bite, anterior open bite, ear canal stenosis, and café au lait spot.
Overall 16 cases have been described until now. Our patients show similar features to the previously reported patients with OBS. All previously described had blepharophimosis and developmental delay. The second most common finding was dental abnormalities. Features, occurred in two-third of the cases, were ptosis, broad and/or flat nasal bridge, distinctive nasal tip, dysmorphic and/or small ears, failure to thrive and muscular hypotonia.

R. Jordania¹, O. Bartsch², T. Zõrjanova¹, L. Kallas¹, E. Rattasep¹, K. Uibo¹;
¹Tallinn Children`s Hospital, Tallinn, ESTONIA, ²Institut für Klinische Genetik, Technische Universität, Dresden, GERMANY.

The CATCH phenotype (Cardiac abnormalities, Abnormal face, Thymic hypoplasia, Cleft palate, Hypocalcemia) comprises developmental defects of the 3rd and 4th pharyngeal pouches and other areas. Frequency is 1 in 4000 live births. Clinical signs are highly variable. About 90% of affecteds demonstrate the typical 22q11 deletion, which in 10-20% of cases may be inherited. - We report on 6 unrelated infants, age newborn to one year, who showed clinical signs of the CATCH phenotype and were seen at Tallinn Childrens Hospital. Complications during pregnancy (drug,alcohol abuse, threatened abortion) occurred in 4 families. All subjects demonstrated dysmorphic signs. Five had a congenital heart defect (truncus arteriosus communis [3 cases]; tetralogy of Fallot; combined ASD and VSD). In one child, thymus aplasia was observed during cardiac surgery. Two out of three investigated probands showed reduced numbers of T and B lymphocytes. Hypocalcemia was observed in 5 children. - FISH studies were performed in 4 children using a set of 4 DNA probes, (i) BAC 201c11 that detects the common large and the proximal 22q11 deletion (area, HIRA/D22S553/D22S609), (ii) BAC 219g6 detecting the common large but not the proximal 22q11 deletion (area, HCF2), (iii) BAC 384d8 (ARSA, 22q13, reference probe) and (iv) PAC 323N1 that detects the DGS2 area on chromosome 10p14. Three children demonstrated the typical common large 22q11 deletion.For diagnostic purposes and genetic counselling, we now aim to maintain a stringent policy of studying all our patients with probably CATCH phenotype for the presence of the 22q11 deletion.

Juvenile Hyalin Fibromatosis in three sibs from a consanguineous family: Clinical, histopathological and imminohistochemical findings

S. Balci¹, S. Kulacoglu², O. Senoz³, I. Vargel⁴, Y. Erk⁴, S. Onder⁵, A. Gokoz⁵, A. N. Akarsu⁶;
¹Hacettepe University, Department of Clinical Genetics, Ankara, TURKEY, ²Numune State Hospital, Department of Pathology, Ankara, TURKEY, ³Numune State Hospital, Department of Plastic and Reconstructive Surgery, Ankara, TURKEY, ⁴Hacettepe University, Department of Plastic and Reconstructive Surgery, Ankara, TURKEY, ⁵Hacettepe University, Department of Pathology, Ankara, TURKEY, ⁶Hacettepe University, Gene Mapping Laboratory, Ankara, TURKEY.

Juvenile hyalin fibromatosis (JHF; Murray-Puretic-Drescher Syndome; OMIM #228600) is a rare autosomal recessive disorder characterized by progressive tumors in the skin and scalp, flexion contractures of joints. We have observed a consanguineous family from Urfa, Turkey with three affected (8 and 3 years old boys and 1 year old girl) and two normal sibs. All affected sibs were normal at birth. Flexion contractures and multiple subcutaneous fibrous tumors initiated in a range in between two months to 4 years of life. The hyalin tumors were distributed in the scalp, face, ear cup, chin, back and legs. These lessions progressively enlarged and later ulcerated. All sibs had severe growth and motor retardation. Histopathological evaluation of these masses revealed homogenous eosinophilic matrix with single cells or cords of spindle shaped cells. Histochemically, the extracellular matrix was periodic acid schiff (PAS) positive and diastase resistant.Alcian blue, toluidin blue and congo red were negative. In reticulin preperation, the cellular areas were rich with reticulin fibers. Immunohistochemically, vimentin was strongly expressed in both spindle shaped and single round cells. In some areas, these cells also showed actin positivity suggesting myofibroblastic nature. Altogether these findings support JHF diagnosis. Interestingly, myeloid cells show an apparent intracytoplasmic vacualization in these patients. Neither a locus or a gene have been reported for JHF as yet. Investigating homozygosity in inbred families is a very efficient tool to identify new genetic localizations. Thus, this family with 10 informative meiosis will be a good source to identify JHF locus using homozygosity mapping.

M. Kuklik¹^,2, J. Spatenka³, I. Marik⁴;
¹1st and 2nd Faculty of Medicine, Prague 5, CZECH REPUBLIC, ²Charles University, Prague, CZECH REPUBLIC, ³Faculty Hospital Motol, Cardiological Centre, Prague 5, CZECH REPUBLIC, ⁴Out - Patient´s Dept. of Orthopaedics, Prague 3, CZECH REPUBLIC.

The syndrom Parkes - Weber - Klippel - Trenaunay is a heterogenic clinical unit of hemihypetrophia of the limb and the adequate part of body, angiodysplastic changes with varices and other facultative characteristics.
Hemangiomatosis and affections of the skin, soft tissues and adjacent bones and a partial hypertrophy (mainly of the lower limbs) are the substance of the disease.
The Parkes - Weber - Klippel - Trenaunay syndrome is an associated mesodermal and ectodermal dysplasia of congenital and polygenic character.
The authors investigated the group of 23 patients with this diagnosis for a long period of time. There were provided the complex pediatric and genetic examinations, including genealogy and anthropometry.
Phenotypic characteristics of this biomechanically important disease were photographically documented.
The genealogic examination found the microsymptoms in the families, such as varices cruris.
The genetic examination has a specific position in the complex of the clinical examinations. It estimates the risk of the affection in offsprings and brothers and sisters, i.e. the relatives of the 1st. degree.
The majority of the cases were isolated with good genetic prognosis. Rarely we found the transmission in two generations with remarkable deviations.
The patients are often treated for other /symptomatic/ diagnosis. Biomechanical and therapeutical aspects of the disease are discussed.

Secular Trend: Better Growth Of Indian Thalassemia Major Patients Compared To Old Indian Growth Standards

A. Saxena¹, S. R. Phadke²;
¹Sanjay Gandhi Post Graduate Institue of Medical Sciences, Lucknow, Uttar Pradesh, INDIA, ²Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, INDIA.

Beta Thalssemia major is one of the commonest single gene disorder in India with a mean prevalence of 3.5 %. Short stature and delayed puberty, which affect individual’s personal image, are common complications associated with thalassemia major (TM) patients. Such problems have psychological implications which deter an individual from participating in peer group activities. In developing countries, thalassemic patients are at a high risk of developing endocrine deficiencies and hence growth failure. We evaluated growth pattern of TM patients to see if they are experiencing secular trend in height and weight as has been observed in the world populations.
Material: Height, weight, serum ferritin and pretransfusion hemoglobin of 90 patients (2-17 years) were evaluated over a period of 3 years. Growth pattern of these patients was compared with New and Old Indian growth Standards and thalassemic patients from New Delhi.
Results: Growth pattern of patients shows that they were significantly shorter than New Indian Growth Standards . There was no significant difference between height and weight of our patients and thalassemic patients from New Delhi. Although our patients above the age of 11 years were short, the prepubertal patients were taller and heavier than 35 years old Indian growth Standards. This suggests that our patients are experiencing secular trend in height and weight.
Conclusion: We attribute gain in height and weight to better treatment regime. Better treatment and management can improve growth of TM patients. However, this is possible provided financial support from national and international agencies is available.

M. Valduga¹, C. Philippe¹, V. Bourdon¹, C. Marchal², C. Ragage³, P. Jonveaux¹;
¹Laboratory of Human Genetics, Vandoeuvre les Nancy, FRANCE, ²Department of Pediatrics, Thionville, FRANCE, ³Department of Radiology, Metz, FRANCE.

CHAR syndrome, first described in 1978, is an autosomal dominant disorder comprising facial dysmorphy, digital abnormalities and patent ductus arteriosus (PDA). Facial dysmorphy seems to be the major criterion to establish clinical diagnosis: wide-set eyes, ptosis, strabismus, flat nasal bridge, short philtrum, large triangular mouth with duck-bill lips, low-set ears). An incomplete penetrance of the patent ductus arteriosus is observed in several families, intelligence is usually normal. Missense mutations with dominant negative effect in the TFAP-2b gene localized in 6p12 were recently described. TFAP-2b encodes a transcription factor expressed in neural crest cells, it was shown that this gene is also involved in ductal, facial and limb development in the mouse. We report the case of a young woman born in 1978 who presents with a typical CHAR syndrome facial dysmorphy without any cardiac anomalies. The karyotype shows a pericentric inv(6)(p12q16), the breakpoint on 6p is located within the region 6p12 harboring the TFAP-2b gene. Using FISH, we have demonstrated that the TFAP-2b locus is disrupted by the 6p12 breakpoint, however we did not detect any junction fragment by Southern blot analysis with the TFAP-2b cDNA. We assume that the breakpoint is close but outside the TFAP-2b coding region, the use of pulse field gel electrophoresis should clarify this point. This young woman recently underwent amniocentesis for prenatal chromosome analysis for her first pregnancy. The fœtus inherited the maternal inv(6)(p12q16) and ultrasonic scan showed the same phenotype as observed in the mother (facial dysmorphy without cardiac anomalies).

U. Radhakrishna¹, U. Ratnamala¹, U. Chalapathi Rao¹, K. Sudhakara Rao¹, M. Ravindrababu¹, U. Radhakrishna¹, J. V. Solanki²;
¹Green Cross Blood Bank & Genetic Centre, Ahmedabad, INDIA, ²Department of Animal Genetics & Breeding, Veterinary college, Gujarat Agriculture University, Anand, INDIA.

Hereditary syndactyly was classified into five different types. Syndactyly type-I (SDTY1) (OMIM 185900) involves complete or partial bilateral syndactyly between third and fifth fingers which is occasionally associated with fusion of the distal phalanges. Feet are rarely affected. It may be an isolated condition. The genes responsible for SDTY1 and SDTY2 have been mapped to chromosome 2q34-q36 (Am J Hum Genet 67:492-97, 2000; Am J Med Genet 104:147-151, 2001 and 2q31 (Hum Molec Genet 4:1453-1458,1995), respectively.We have studied six large Indian pedigrees with an autosomal dominant SDTY1. Pedigrees consist of 157 individuals, including 65 affected (31-males/34 females). Severity of the phenotype was quite variable among the families and no skipping of generation was observed. In five families, 39 members were bilaterally affected with typical features of syndactyly type-1 affecting the 3rd and 4th fingers and 18 members had only unilateral findings. Few of these also had unilateral partial syndactyly of 2nd and 3rd toes. In the sixth family, complete unilateral or bilateral syndactyly affecting 3rd, 4th and 5th fingers was observed. Few of the affecteds in this family had unilateral elongation of 2nd and 3rd toes with syndacytly. Phalangeal bones were not affected in any of these families, eventhough the nails are involved in 15 affecteds. Linkage studies with markers closely linked to SDTY1 and SDTY2 will either confirm allelism to these loci or provide evidence for genetic heterogeneity.

J. De Backer, B. Loeys, F. Malfait, M. De Pauw, D. Mathys, A. De Paepe;
Ghent University Hospital, Ghent, BELGIUM.

EDS (Ehlers Danlos Syndrome) is commonly mentioned in the context of heritable connective tissue diseases with cardiac involvement. Among these abnormalities aortic root dilatation is frequently reported. Unlike in Marfan patients, where aortic root dilatation is one of the major criteria, literature data in EDS patients are controversial.
We report on aortic root diameter measurement with echocardiography in a prospective cohort of 40 patients with established EDS. According to the clinical criteria from the Villefranche Nosology (1) 6 were classified with classical EDS, 23 with hypermobile EDS and 11 with vascular EDS.
The mean age of the patients was 24.7 (4-41) yrs and 30% were male. Mean BSA was 1.54m²
Mean aortic diameter at the sinuses of Valsalva was 26.9mm (SD 4.6mm). Mean aortic diameter at the supra-aortic ridge was 23.8mm (SD 3.69mm).
For each patient we compared the aortic root diameter with the population based norms (Roman et al (2)). None of the patients showed aortic dilatation at the sinuses of Valsalva. One 17y old female patient with hypermobile EDS had an aortic diameter at the supra-aortic ridge that was slightly higher than 2SD
In conclusion, we could not demonstrate aortic root dilatation in our series of 40 patients with EDS. This is important with respect to the management and genetic counselling in EDS. Longitudinal follow up studies are necessary to evaluate the evolution of aortic root diameters in this patient group.
1. Beighton et al, Am J Med Genet;77(1):31-7.
2. Roman et al, American journal of cardiology;64(8):507-12.

Clinical phenotype of a familial translocation t(3 ;5)(p23 ;p14) with partial trisomy 3p2 and partial monosomy 5p.

Y. Alembik¹, E. Ginglinger², C. Lagier-Tourenne³, E. Flori³, F. Girard-Lemaire³, E. Jeandidier²;
¹Hôpital de Hautepierre, Strasbourg, FRANCE, ²Centre Hospitalier, Mulhouse, FRANCE, ³Hôpital de Hautepierre, Laboratoire de Cytogénétique, Strasbourg, FRANCE.

Trisomy3p and monosomy 5p are characterized by facial dysmorphism, mental retardation and malformations.
We report two siblings with partial trisomy 3p2 and partial monosomy 5p.
The first baby was a stillborn female with pulmonary hypoplasia, intrauterine growth retardation. She presented with facial dysmorphism, flat face, hypertelorism, large anterior fontanel, almond-shaped eyes, simian palmar crease, abnormal cerebral maturation, hepatomegaly and bilateral renal cysts. Familial history was negative.
The second child was a male born with hypotrophy, auricular septal defect, genital hypoplasia, cryptorchidism and hypospadias, microcephaly, partial corpus callosum agenesis and brachydactyly. Facial dysmorphism was obvious with a flat face, hypertelorism, large forehead, small nose, short filtrum, thick everted inferior lip, microretrognathia, short neck, and dysplastic ears. At the age of 6 years, he had a severe mental retardation, no language but a normal growth.
Both cases in the same family were suggestive of a cryptic chromosomal anomaly as the standard caryotype was normal. Extensive metabolic screening was normal but high resolution caryotype with incorporated BrDU revealed a cryptic translocation confirmed by 3 and 5 chromosomal painting and specific FISH, due to a non-balanced translocation transmitted by the maternal grandfather : 46, XY, der(5)t(3 ;5)(p23 ;p14)mat)
We compared the clinical phenotype to other trisomy 3p and monosomy 5p cases and observed marked trisomy 3p2 clinical features as described in other cases where this region is also involved with other chromosomal partners. This observation will help establish the correlation of this critical chromosomal region and the clinical features.

L. Pasquier¹, K. Fourcade¹, C. Henry², F. Le Mee², S. Odent¹;
¹Service de Génétique Médicale Hôpital Pontchaillou, Rennes, FRANCE, ²Laboratoire de Cytogénétique CHU Pontchaillou, Rennes, FRANCE.

Among terminal 2q37 deletion, very few cases (Reddy et al 1999) have already been described in adulthood. We report on one young female, 19 years old, with mild mental delay, obesity, joint hyperlaxity. The diagnosis was suspected because of dysmorphic features leading to Albright Hereditary Osteodystrophy (AHO) - like phenotype. The phosphocalcic level and routine resolution karyotype were normal in blood, but this de novo 2q37 deletion was confirmed by a specific subtelomeric 2q probe (FISH).
This patient might help us to give more specific informations, as medical follow-up, to parents of an affected young child, even if the range of clinical findings is wide. In fact, we compare our patient with cases already reported in litterature.

Glomuvenous Malformation (“glomangioma”) Is A Distinct Clinicopathologic And Genetic Entity

L. Boon¹^,2, J. Mulliken³, O. Enjolras⁴, M. Vikkula²;
¹Division of Plastic Surgery, Center for Vascular Anomalies, Cliniques universitaires St-Luc, Université catholique de Louvain, Brussels, BELGIUM, ²Laboratory of Human Molecular Genetics, Christian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Brussels, BELGIUM, ³Division of Plastic Surgery, Center for Vascular Anomalies, Children's Hospital, Boston, MA, ⁴Consultation des Angiomes, Hôpital Lariboisière, Paris, FRANCE.

Glomuvenous malformation (“glomangioma”) (GVM) is a cutaneous vascular lesion histologically characterized by ectatic vein-like channels with mural “glomus cells”. Discovery of the molecular basis for GVM permitted delineation of the clinical phenotype and comparisons between GVM and other venous anomalies.
Clinical data based on physical examination, and review of medical records and clinical slides was compiled for 1716 patients with inherited or sporadic venous anomalies. Diagnosis was histologically and/or genetically confirmed for all inherited venous lesions and most sporadic lesions. The data were statistically analyzed using the Fisher’s exact test (two-tailed) with SYSTAT software (version 10, http:// www.spssscience.com/systat).
We identified 30 patients with sporadic GVM, 105 with inherited GVM, 1548 with sporadic venous malformation (VM), and 33 with inherited mucocutaneous venous malformation (CMVM). GVMs, accounting for 5% of venous anomalies, were frequently inherited (78%), whereas venous malformations were rarely familial (2%). GVMs always involved skin and subcutis, in contrast to CMVMs and VMs (p<0,001). GVMs had a distinct raised cobblestone appearance. Trauma was reported as an inciting factor for appearance of new lesion by patients with inherited GVM (p=0,007), in contrast to patients with CMVM. None of the patients with extensive GVM presented with coagulopathy, in contrast to patients with large VM.
This is the largest series of patients with cutaneous venous anomalies. It establishes clinical criteria for differential diagnosis between GVM and other subtypes of venous anomalies. This differential diagnosis is essential as the treatment and outcome are different. (vikkula@bchm.ucl.ac.be)

Inherited Capillary Malformation Is Associated With A High Flow Vascular Malformation

L. Boon¹, J. Mulliken², A. Bataille¹, B. Lengele³, G. Vittu⁴, R. Vanwijck⁵, M. Vikkula⁶;
¹Center for Vascular Anomalies, Cliniques universitaires St-Luc, Université catholique de Louvain, Brussels, BELGIUM, ²Division of Plastic Surgery, Children's Hospital, Boston, MA, ³Center for Vascular Anomalies, Cliniques universitaires St-Luc, Brussels, BELGIUM, ⁴Division of Neonatology, Hôpital Pédiatrique Saint-Antoine, Universite catholique de Lille, Lille, FRANCE, ⁵Center for Vascular Anomlies, Cliniques universitaires St-Luc, Brussels, BELGIUM, ⁶Laboratory of Human Molecular Genetics, Chrsitian de Duve Institute of Cellular Pathology, Université catholique de Louvain, Brussels, BELGIUM.

Capillary malformation (CM) is a common cutaneous vascular anomaly occurring in 0,3% of neonates. Except for rare reports of familial nuchal CM (“stork bite”), CM is considered sporadic. Clinical diagnosis is usually straightforward, however, CM can masquerade a high-flow vascular lesion, i.e., stage one AVM or AVF. We identified several families with inherited CM. We clinically examined each family member, noted all vascular anomalies and collected informed consents and blood samples.
Inter- and intrafamilial variation was observed, from nuchal CM persisting throughout life and extending below the hairline, to solitary or multiple CM disseminated all over the body. Seven of our families with inherited CM had a member affected with a high-flow vascular malformation: three with either AVM (n=2) or AVF (n=1). Four families had two members with AVM (n=8) including Parkes Weber syndrome (n=3), AVM with multiple CM (n= 3), and intraosseus AVM with cutaneous blush (n=1) or with extensive CM (n=1).
These data confirmed autosomal inheritance of CM. The high incidence of high-flow vascular malformations within families with inherited CM suggests genetic predisposition for AVM and/or AVF in these families. (vikkula@bchm.ucl.ac.be)

M. Havlovicova¹, M. Malikova¹, V. Krutilkova¹, D. Novotna¹, M. Simandlova¹, A. Janda², K. Michalova³, V. Brysova⁴, A. Baxova⁵, P. Goetz¹;
¹UBLG,Prague Motol, Prague, CZECH REPUBLIC, ²1st Children Clinic, Prague Motol, Prague, CZECH REPUBLIC, ³3rd Medical Dpt., General Faculty Hospital and 1st Medical Faculty of Charles University, Prague, CZECH REPUBLIC, ⁴Childrens Hospital Brno, Brno, CZECH REPUBLIC, ⁵General Teaching Hospital of First Faculty of Medicine, Charles University, Prague, CZECH REPUBLIC.

We describe a case of a girl with craniosynostosis syndrome and finding of chromosomal aberration.
Fenotype: Severe failure to thrive, psychomotoric delay, hypotonia, skull malformation ( craniosynostosis of sagittal and coronal sutures). Facial features consists of severe coloboma of the right palpebrae, high prominent forehead and frontal bossing, flattened face with beaked nose, long philtrum, narrow lips, dysplastic ears, preauricular pit. Other features were clinodactyly of the fifth fingers, umbilical hernia, ventricular septal defect and optic nerve atrophy.
In our index case a 46,XX, del (10) (q25-qter) was proven by cytogenetic analysis.
In this region gene FGFR2 is located , mutation of this gene results in various disorder: Crouzon sy, Pfeiffer sy, Jackson -Weiss, Apert sy, Seather Chotzen sy.
We assume that the phenotype in our patient is in causal relationship with the chromosomal 10 q deletion. However, cases previously reported in the literature had less dysmorphic features, than our propositus. Possible explanation of this observation will be discussed. Molecular cytogenetic methods and DNA analysis of the critical region is further proceeding.

M. I. Kavamura¹^,2, R. Lecce¹, M. Zollino¹, D. Brunoni², J. M. Opitz³, G. Neri¹;
¹Istituto di Genetica Medica, Università Cattolica del Sacro Cuore, Rome, ITALY, ²Centro de Genética Médica, Universidade Federal de Sao Paulo - Escola Paulista de Medicina, Sao Paolo, BRAZIL, ³University of Utah, Salt Lake City, UT.

Cardiofaciocutaneous (CFC) syndrome is a rare disorder described by Reynolds et al.[1986] in eight unrelated patients with very similar facial appearance, mental retardation, failure to thrive, congenital heart defect, short stature and ectodermal abnormalities. All patients diagnosed with CFC syndrome are sporadic, born to non consanguineous parents and had normal chromosomes on conventional cytogenetics.
Rauen et al. [2000] reported on a patient with CFC phenotype and an interstitial deletion of the 12q21.2q22 chromosome region. The authors concluded that a gene responsible for the CFC syndrome is likely to reside in this chromosome region. We looked for microdeletions within this region in 17 CFC patients (12 males and 5 females), aged 2 to 25 years, by FISH, using 12 BAC probes covering the 12q21.2q22 region at average intervals of about 1 Mb. The patients presented with mental retardation (17/17), typical facial appearance, with high forehead, bitemporal constriction, bulbous nose, low set and posteriorly angulated ears, palpebral ptosis and downslanting eyes (17/17), ectodermal abnormalities, consisting of thin, sparse and curly hair, absent or sparse eyelashes and eyebrows, keratosis pilaris, or hyperkeratotic skin patches (17/17), speech delay (17/17), short stature (16/17), heart defect (14/17) and relative macrocephaly (12/17). No microdeletion was detected in any of the patients. Based on these results, we conclude that CFC syndrome is unlikely to be caused by a microdeletion in the 12q21.2q22 region. We suggest that Rauen et al.'s case could represent a different chromosomal syndrome, with some phenotypic resemblance to the CFC syndrome.

D. Wieczorek¹, H. S. Loos², C. von der Malsburg², B. Horsthemke¹;
¹Institut für Humangenetik, Universitaetsklinikum Essen, GERMANY, ²Institut für Neuroinformatik, Ruhr-Universitaet Bochum, GERMANY.

Syndromes are often defined by a specific facial appearance. Experienced geneticists usually make a diagnosis through immediate pattern recognition. We have investigated how well a computer can do this. In view of the fact that patients with a syndrome look more similar than unrelated individuals do, we have chosen a pattern recognition program that was developed to identify a person by matching his face to faces stored in a database. It is not based on anthropometric measurements, but uses digital photographs of 256x256 pixels which are subjected to a Gabor Wavelet Transformation to create a vector with 40 complex coefficients (jet) for every pixel. For the purpose of this study, each face was automatically labeled with 48 nodes. The jets attached to each node of a face were then compared to the jets of all nodes at the same fiducial points of every face in the data base (bunch graph). Classification was based on a majority decision of all analysed nodes of a face (jet voting). Analysis of 32 innerfacial nodes from 55 frontal view photographs of patients with mucopolysaccharidosis type III (n=6), Cornelia de Lange (n=12), fragile X (n=12), Prader-Willi (n=12), and Williams-Beuren syndrome (n=13) revealed correct syndrome recognition in 42/55 (76%) of the patients. In another four patients (7%), a correct and an incorrect diagnosis scored equally well. Our results indicate that it may be feasible to develop a program which may aid the clinical diagnosis of genetic syndromes and the study of genetic variation of facial patterns.

B. Grskovic, G. Ferencak, A. Stavljenic-Rukavina;
Clinical Institute of Laboratory Diagnosis, Zagreb University School of Medicine and Clinical Hospital Center Zagreb, Zagreb, CROATIA.

Charcot-Marie-Tooth (CMT) disease is the most common genetic disorder of the peripheral nervous system. The major CMT1 form is associated with 1.5 Mb tandem duplication in band 17p11.2-p12 containing the gene for the peripheral myelin protein 22 (PMP22). Point mutations have been found in PMP22, myelin protein zero (MPZ) (CMT1B phenotype), connexin 32 (Cx32) (CMTX phenotype) and early-growth response 2 (EGR2) genes which have important role in the CMT pathogenesis.
Aim of this study was to investigate mutations in MPZ and PMP22 genes in Croatian patients with different neuromuscular and neurodegenerative diseases.
We employed single-strand conformational polymorphism analysis (SSCP) for mutational screening. PCR products with altered mobility patterns were sequenced to analyze the type of mutation.
A novel Ser8Ser mutation was found in exon 1 of the MPZ gene in two heterozygous subjects, in a father with mild CMT2 phenotype and his daughter with normal clinical data. Thr118Met polymorphism was found in exon 5 of the PMP22 gene. For the first time we found heterozygosity for 118Met allele with nemalin myopathy. The second heterozygous patient for 118Met allele had CMT1 disease.
We conclude that the occurrence of the 118Met allele does not usually cause CMT1 and is not a clinically relevant disease marker.

F. Ozkinay, T. Cankaya, O. Cogulu, C. Ozkinay;
Ege University,Faculty of Medicine,Dept.of Pediatrics,Subdivision of Genetics and Teratology, Izmir, TURKEY.

Three Turkish patients, a female and two males; 15, 8, 2 years of age with Kabuki Make-up syndrome were reported. All three individuals had the cardinal features of the syndrome such as motor and mental retardation, peculiar facies including long palpebral fissures, large malformed ears, depressed nasal tips. Two cases showed postnatal growth retardation; one case had a history of recurrent otitis media, all they had normal chromosomal composition. In one of them pedigree analysis indicated that the condition showed autosomal dominant inheritance with variable expression. .
Additionally cranial MRI of one of them revealed hypoplasic corpus collosum and periventricular leukomalasia which has not been described before in this syndrome.

O. Cogulu¹, F. F. Ozkinay¹, C. Gunduz¹, T. Çankaya¹, S. Aydogdu², F. Ozgenc², N. Kutukculer², C. Ozkinay¹;
¹Ege University, Faculty of Medicine,Dept.of Pediatrics,Subdivision of Genetics and Teratology, Izmir, TURKEY, ²Ege University, Faculty of Medicine,Dept.of Pediatrics, Izmir, TURKEY.

Celiac disease, also known as gluten-sensitive enteropathy is a chronic inflammation disease of the small intestinal mucosa. Detection of antigliadin and antiendomysial antibodies in serum is important in diagnosis and screening of celiac disease. Ig A antiendomysial antibodies have greater sensitivity compared to antigliadin antibodies. It has been reported that the prevalence of celiac disease is higher in Down syndrome children as the other autoimmune conditions. In this study, 32 Down syndrome children (22 male / 10 female) have been evaluated for antigliadin antibodies and antiendomysial antibodies. Total blood count and immunglobuline values were in normal levels. There was no known disease or no abnormality in biochemical levels at entry into the study. [The youngest was 2 year-old and the oldest one was 17 year-old (average: 6.55±3.88)]. None of the 32 children had known celiac disease at entry. Six out of 32 patients (18.75%) were found to be serological positive, 5 (15.63%) were found to have antigliadin antibodies’ levels above normal; and 5 (15.63%) to be antiendomysial antibodies positive. In four patients (12.5%) both AGA Ig A levels were above normal and AEA Ig A were positive. One patient (%3.3) was only AGA Ig A positive, and one (%3.3) was only AEA Ig A positive. Duodenal biopsies of two cases out of 6 serological positive cases showed villous atrophy (males with both AEA and AGA positive), and two cases revealed normal mucosa (male with both AEA and AGA positive, male with only AEA positive).

O. Kirillova, M. Gornaya, T. Semenova, T. Kuznetzova;
Ott's Institute of Obstetrics and Gynecology RAMS, St-Petersburg, RUSSIAN FEDERATION.

A male foetus with multiple malformation was found by ultrasound examination at 25-26 weeks` of gestation. Cytogenetic investigations revealed a 46,XY,del(21)(q22) karyotype in of the umbilical cord blood lymphocytes. Molecular analyses showed that the deletion occurred on the maternal chromosome between markers IFNAR and D21S1255, including “critical region” of Down`s syndrome (21q22.3). In view of the poor fetal prognosis, the woman elected pregnancy termination. The autopsy revealed: intra-uterine growth retardation, hydrocephaly, facial dysmorphy characterized by microcephaly, hypertelorism, low-set deformed ears, micrognaty, microphthalmy, dextrocardia, polycystic lungs, skeletal abnormalities including deformity of the chest, 13 ribs on right, flexion contractures of the right foot, deformities of the fingers, hypoplastic fallus bound by chordee, hipoplastic scrotum.
The histological pictures of the different fetal tissues showed pathological immaturity of the liver, kidney, suprarenal glands, lien, hypoplasia of eye chambers. The lung was contained of the multiple cyst cavities of different forms. The placenta showed the indication of pathological differentiation of villous maturation with frequent persistence of embryonic forms of villi, which are non specific lesions and can be observed in a variety of other conditions.

D. Greco¹, C. Cuoco², M. Di Rocco², C. Romano¹;
¹Oasi Institute, Troina, ITALY, ²G. Gaslini Institute, Genova, ITALY.

We report on a boy showing features suggesting Donohue syndrome (MIM 246200) and a deletion on 13q12.3-q21.2 region, seen by standard karyotype. After an uneventful pregnancy from unrelated parents with a negative family history, he was born small for gestational age. Developmental delay has been referred from the very beginning. Failure to thrive not caused by celiac disease and poor growth continued up to 3 years when a diagnosis of growth hormone impairment was made. Before this diagnosis he had two sudden episodes of fasting hypoglicemia, which continued during treatment with recombinant growth hormone, up to the last one reported 4 months ago. We have observed him for the first time at the age of 7.9 years. He has moderate mental retardation, short stature, long elfin-like face with large everted ears, thick lips and gum hypertrophy, joint hyperlaxity and wrinkled loose skin. Donohue syndrome has been already associated to mutations in the insulin receptor gene, on 19p13.2. The 13q12.3 region is the breakpoint of our deletion on the centromeric side, but also the region where the insulin-regulating transcription factor CDX3 (MIM 600297) maps. CDX3 works as homeodomain protein binding an A/T-rich sequence in the promoter of the insulin gene (MIM 176730). We hypothesize that the deletion of CDX3 may be involved in the clinical features of our patient and provide a new candidate for the genotype of Donohue syndrome.

J. van den Ende¹, A. Laridon², J. Wauters¹, M. Nöthen¹;
¹University of Antwerp, Antwerp, BELGIUM, ²University Hospital of Antwerp, Antwerp, BELGIUM.

The 3p- syndrome results from deletion of a terminal segment of the short arm of one chromosome 3, and is characterized by mental retardation, growth failure, hypotonia, and multiple congenital anomalies, such as microcephaly, blepharoptosis, hypertelorism, ear anomalies, heart defects and deafness. The constellation of symptoms depends on the extent of the deletion.
Most deletion breakpoints are at 3p25-26, and among the genes mapped in region 3p25-3pter are ATP2B2 (involved in cardiac development), the VHL gene (involved in Von Hippel Lindau disease) and the CALL gene (possible role in brain development).
In most cases of 3p-syndrome the deletion arose de novo.
We describe a female patient who was presented to us soon after birth showing the following features: intrauterine growth retardation, single umbilical artery, hypotonia, microcephaly, blepharoptosis, hypertelorism, micrognathia, low set ears, ear pits, a long philtrum and a thin upper lip. At follow up at the age of 6 months an 1 year she showed severe reflux, developmental delay, and a thickened artrial valve at ultrasound of the heart.
Chromosomal analysis showed an apparantly balanced translocation (3;5)(p25;q31.1) inherited from the healthy father. Further subtelomeric studies of the patient showed a terminal deletion of the short arm of chromosome 3. Possible mechanisms are discussed and the importance of subtelomere studies is stressed in apparantly balanced translocations with very small segments involved.

Craniosynostosis, branchial cyst and inguinal calcifications, an unusual presentation of AHO (Albright hereditary osteodystrophy)

Y. van Bever¹, J. van den Ende¹, A. Jespers², F. Eyskens³, M. Aldred⁴, M. Nöthen¹;
¹University of Antwerp, Antwerp, BELGIUM, ²General Hospital Middelheim, Antwerp, BELGIUM, ³University Hospital of Antwerp, Antwerp, BELGIUM, ⁴Leicestershire Genetics Centre, Leicester, UNITED KINGDOM.

Albright hereditary osteodystrophy (AHO) is characterized by phenotypic signs that typically include brachydactyly and subcutaneous calcifications occurring with or without hormone resistance toward PTH or other hormones such as thyroid hormone or gonadotropins. We were presented a male dysmature baby born after 36 weeks of pregnancy. On exam, he showed a trigonocephalic, asymmetric skull, abnormally formed orbits, a branchial cyst and subcutaneous calcifications around the ankles and in the inguinal region. Laboratory investigations showed a transient hypoglycemia and a hypothyroidism. The patient was treated with L-thyroxine and had an operation of a metopic suture synostosis. The diagnosis of AHO was confirmed by identifying a mutation (701G->A)in the GNAS1 gene. While the majority of symptoms of our patient are typical for AHO, to our knowledge, a branchial cyst has not yet been reported in AHO. Coincidence or genetic relationship will be discussed and a follow-up of the patient will be presented.

Ectrodactyly is encountered in mendelian traits as well as in rare chromosomal anomalies and as sporadic. The anomaly occurs during organogenesis and recently its pathogenesis is better understood (Wolpert, 1999). Retrospective analysis of the 48 probands with confirmed or suspected ectrodactyly evaluated at the USF genetics/dysmorphology and prenatal clinics between 1/2/82 and 12/31/00 is presented. The probands were part of the 38,706 probands/families evaluated during the period. They were retrieved using patient database. Ectrodactyly/split hand was one of the 3 primary diagnoses. Four of the 48 were no shows in the clinic and were excluded. There were 27 males and 17 females. Twenty-two of 44 were Caucasian, 9 Hispanic, and 9 African-American matching the racial ratio of the population of West Central Florida. Typical lobster claw anomaly type I was present in 19 and atypical in 25. Two had chromosome anomaly, t(13q14q) with maternal class A 1 diabetes mellitus in one and another with complex chromosome rearrangement with 6 breaks on chromosomes 2,3,5,11, and 13 resulting in interstitial deletion 13q. Two probands had mothers with diabetes mellitus but no other anomalies to diagnose diabetic embryopathy. Eleven of the 44 had positive family history indicative of autosomal dominant trait with reduced penetrance. Fourteen of the 44 had associated anomalies implying syndromes. Among them were 3 probands with ectrodactyly-ectodermal dysplasia-cleft palate. This study showed that ectrodactyly has 1. varied phenotypes difficult to classify and 2. is genetically heterogeneous. As to a candidate gene only the probands with chromosomal abnormalities implied chromosome 13.

E. G. Simeonov¹, V. Kleijer², D. M. Avdjieva¹, S. A. Shopova¹, B. I. Dimitrov¹;
¹Section of Clinical Genetics, University Pediatric Hospital, Medical Faculty, Sofia, BULGARIA, ²Erasmus University, Rotterdam, NETHERLANDS.

Cockayne syndrome/CS/ is an autosomal recessive dysmorphic syndrome,caused by defects of transcription-coupled DNA repair due to truncating mutations, point mutations, or deletions of CSA(chr.5) and CSB(10q11-q21) genes.CS manifests a wide clinical spectrum including CS type I, the "classical" form; CS type II(connatal form), a more severe form with symptoms present at birth,CS type III, a milder form; and xeroderma pigmentosa-Cockayne syndrome (XP-CS).Patients with "connatal" CS have evidence of growth failure at birth, with little or no postnatal neurological development. Congenital cataracts or other structural anomalies of the eye as well, as arthrogryposis or early postnatal contractures of the spine (kyphosis, scoliosis) and joints may be present.This group overlaps clinically with two genetic conditions bearing different names, the cerebro-oculo-facial syndrome (COFS) and Pena-Shokeir type II syndrome.
The authors present clinical observations of a 3 year old girl/DOB-24.04.98/,second child of healthy,unrelated parents/father-30,mother-32/.The girl was born 18 days before term/W-1900 gr.,L-44 cm./ and manifested developmental delay and repeated respiratory infections during the first year of life.Photosensibility has been noted at 11 months.At 2 2/12 yrs. she is underweighed/wSDS - -2.71/,microcephalic/hcSDS -3.5/,with short neck,dysmorphic face,mild thoracic kyphosis,unsteady gait and moderate mental retardation/IQ - 44/.Abnormal retinal pigment distribution has been detected.Routine laboratory investigations,chromosome analysis and CT scan showed normal results.Cockayne,Bloom,Rothmund-Thompson and COFS syndromes have been discussed.DNA repair studies on skin fibroblasts disclosed strongly inhibited DNA synthesis after UV-irradiation,thus confirming the diagnosis of CS.Mutation analysis is in progress.
Imrovment of motor development and cognitive functions has been achieved during 1 year follow-up and symptomatic treatment.

Clinical and molecular genetic investigation of the classic type of Ehlers-Danlos syndrome in Russia

M. Kournikova¹, O. Blinnikova², A. Semyachkina³, G. Mutovin², S. Tverskaya¹, A. Polyakov¹;
¹Research Centre for Medical Genetics, Moscow, RUSSIAN FEDERATION, ²Russian State Medical University, Moscow, RUSSIAN FEDERATION, ³Institution for pediatric and children surgery, Moscow, RUSSIAN FEDERATION.

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of connective tissue disorders characterized by skin hyperextensibility, impaired wound healing, joint laxity, tissue fragility, skeletal deformities and other changes. “Classic” EDS type (Villefranche Nosology, Beighton et al., 1997) which includes EDS types I (MIM 130000) and II (MIM 130010) is the commonest variant of the EDS with genetic heterogeneity. Mutations in type V collagen, COL5A1 and COL5A2 genes, have been shown to underlie this type of EDS in some cases. Thirty four patients from 21 families with diagnosis of EDS I or II types and their 21 relativies were clinically investigated. To evaluate the role of COL5A2 gene mutations in this group of patients skin biopsy samples were taken from 6 patients with EDS I and 5 patients with EDS II. We isolated mRNA from cultured fibrobasts and made RT-PCR to get cDNA . Eleven pairs of primers for about 4,5 kb mRNA COL5A2 were designed and carried out the PCR-SSCP analysis. We have found the absence of first fragment including the first ATG codon in EDS II patient. The clinical signs included thin skin with moderate hyperextensibity, easy bruising, joint laxity, scoliosis, pectus excavatum, flat feet, myopia, retinal bleeding and varicose rectal veins. Other manifestations were striae and recurrent hyperbilirubinemia, which are not typical for EDS. The study is in a progress now.

F. Malfait¹, B. Loeys¹, P. De Coster², A. De Paepe¹;
¹Centre for Medical Genetics, Ghent University Hospital, B-9000 Ghent, BELGIUM, ²Centre for Paediatric Dentistry, Ghent University Hospital, B-9000 Ghent, BELGIUM.

Ehlers-Danlos Syndrome (EDS) type VIIC (human dermatosparaxis) is a recessively inherited connective-tissue disorder, characterized by extreme skin fragility, premature rupture of the membranes, umbilical hernia, blue sclerae, characteristic facies and joint laxity. Like the animal model it is caused by defects of procollagen-I-N-proteinase-activity, resulting in an inability to cleave the N-terminal propeptides of procollagen-I-N-chains. Electron microscopy typically consists of a characteristic “hieroglyphic” pattern of collagen fibrils. To date only 7 human cases have been recorded, most of them being aged under 2 years. We report the clinical follow-up history of one of the first reported patients (20 months;Nusgens et al, 1992). Now, at the age of twelve, marked skin fragility and easy bruisability continue to predominate the clinical picture. During the past years, she encountered several problems due to extreme tissue fragility, such as spontaneous bladder rupture, persisting bladder diverticulae with recurrent urinary infections, and rupture of the diaphragm with para-esophageal hiatus hernia after vomiting. On physical examination, she presents with an old appearance, with sagging skin and excessive wrinkles in her face and on hands and feet. Her stature is below P3. Joint hyperextensibility is very mild. She presents several unusual oral and dental anomalies. Being of normal intelligence, she was confined to home education untill the age of ten because of her extreme vulnerability. Now she attends a school for physically handicapped children.
EDS VIIC appears to be a severe debilitating disease due to lifelong skin and tissue fragility.
Nusgens et al, Nat Genet 1:214-17, 1992

A. R. Janecke¹, T. Müller², A. S. Knisely³, Ø. Aagenaes⁴, L. Bull⁵, M. Frühwirth², H. Ellemunter², G. Utermann¹;
¹Institute of Medical Biology and Human Genetics, University of Innsbruck, Innsbruck, AUSTRIA, ²Department of Pediatrics; University Hospital Innsbruck, Innsbruck, AUSTRIA, ³Institute of Liver Studies, King´s College School of Medicine and Dentistry, London, UNITED KINGDOM, ⁴Ulleval University Hospital of Oslo, Oslo, NORWAY, ⁵Liver Center Laboratory, San Francisco General Hospital, University of California, San Francisco, CA.

Lymphoedema – cholestasis syndrome (LCS, Aagenaes syndrome, MIM 214900) is the only form of hereditary lymphoedema associated with cholestasis. Most patients are of Norwegian origin. A locus for LCS, LCS1, has recently been mapped to chromosome 15q in the original extended kindred reported by Aagenaes and coworkers. We have studied a family of Serbian gypsies in which a child born to consanguine parents had LCS, and performed linkage and haplotype analysis at marker loci (D15S979, D15S202, D15S996, D15S127, FES, IP15M9, D15S158, D15S963, D15S652) spanning the LCS1 region on 15q. This excluded the disease locus from this region, implying locus heterogeneity for LCS.

Bilateral Congenital Ptosis and Variable Toe Anomalies: A New Autosomal Recessive Syndrome?

N. A. Al-Sanna'a¹, A. S. Teebi²;
¹Division of Pediatrics, Dhahran Health Center, Dhahran, SAUDI ARABIA, ²Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, CANADA.

Congenital ptosis with digital anomalies among other manifestations has been reported in a variety of syndromes. Here, we describe two Saudi Arabian brothers with congenital ptosis and variable toe anomalies including hypoplasia, clinodactyly, bifid great toe, partial syndactyly between the second and third toe, overriding toes, and absent toe nails. Both children have displayed normal growth and development with no evidence of other system involvement. Their karyotypes were normal. The parents are first cousins and phenotypically normal. An older brother has an isolated ptosis with no digital anomalies.
We think this constellation of anomalies in this family represents a new autosomal recessive entity with variable statement.

Clinical and genetic heterogeneity and ethnic differences in Bulgarian FSHD patients

B. Tzankov¹, I. Tournev¹, M. Janpierre²;
¹Department of Neurology, Medical University, Sofia, BULGARIA, ²Laboratory of Biochemistry and Molecular Pathology, Hopital Cochin, Paris, France, Paris, FRANCE.

FSHD is an AD inherited desease, associated with a deletion within the telomeric portion of chromosome 4. The gene responsible for development of the disease is still unknown. FSHD presents with a high degree of clinical variability, with respect to age of onset, severity and pattern of muscle involvement. Twenty patients from 7 families and eight sporadic cases were studied. The families were of different ethnic origin- bulgarian, turkish and gipsy. The disease started before the twentieth year of age in 90 % of cases. We determined significant inter- and intrafamilial clinical variations in the course of the FSHD. Some of our families showed phenomenon of anticipation. In most of the cases additional features, like cardiac disturbances, deafness and retinal vasculopathy were found. Mental retardation and schisophrenic psychosis were specified in the members of the two most severely affected turkish families. Some of the patients presented with a phenotype of limb-girdle muscular dystrophy or another unusual phenotype.
Some of the cases were genetically determined as being connected with the FSHD1 locus in 4q35. Sizes of the fragments were inversely connected with the clinical severity of the disease. Several patients were not connected with the locus, which instituted genetic heterogeneity of FSHD for Bulgarian patients.

I. L. Tournev¹, P. Thomas², D. Angrlicheva³, T. Rogers³, R. King⁴, B. Ishpekova⁵, B. Youl⁶, D. Chandler³, V. Guergeltcheva¹, A. Savov⁵, A. Shmarov⁵, L. Kalaydjieva⁷;
¹Medical University - Sofia, Ethnic Minorities Health Problems Foundation, Sofia, BULGARIA, ²Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, U.K., London, UNITED KINGDOM, ³Edith Cowan University, Perth, AUSTRALIA, ⁴Royal Free and University college Medical School, London, U. K., London, UNITED KINGDOM, ⁵Medical University - Sofia, Sofia, BULGARIA, ⁶National Hospital for Neurology and Neurosurgery, London, U.K., Royal Free and University College Medical School, London, U.K., London, UNITED KINGDOM, ⁷Edith Cowan University, Western Australian Institute for Medical Research, Perth, Australia, Perth, AUSTRALIA.

For variety of social and cultural practices various Gypsy groups in our country represent genetic isolates with a very high rate of some autosomal recessive neuromuscular disorders. During the last 7 years we identified several single gene disorders limited to specific traditionally endogamous Gypsy groups in Bulgaria:
1. Hereditary motor and sensory neuropathy type Lom (HMSNL) is a severe demyelinating peripheral neuropathy associated with sensorineural deafness, mapped to chromosome 8q24 (Kalaydjieva et al., 1996, 1998) and caused by a truncating mutation in the N-myc downstream-regulated gene-1 (Kalaydjieva et al, 2000). The disorder affects different endogamous Gypsy metagroups belong to the Wallachian Gypsy group: Kalderas, Kopanari and Lom Gypsies.
2. Congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome is a novel multisystem genetic disorder which combines both developmental abnormalities and a progressive neurological deficit (Tournev et al., 1999). The most important features of the syndrome include congenital cataracts and microcorneae, dysmorphic facial features and small stature, mental retardation, a predominantly motor peripheral neuropathy and hypogonadotropic hypogonadism. The CCFDN syndrome was mapped on 18q23 (D. Angelicheva et al., 1999).
3. Hereditary motor and sensory neuropathy type Russe (HMSNR) is a severe, progressive, sensorimotor neuropathy with prominent sensory loss in association with an intermediate reducton in nerve conduction velocity (P.K. Thomas et al., 2001). Linkage analysis localized the HMSN-R gene to chromosome 10q23, in close proximity to the EGR2 gene (T. Rogers, 2000).

A Jagged 1 gene mutation for abdominal coarctation of the Aorta in Alagille syndrome

A. Raas-Rothschild¹, E. Shteyer², I. Lerer³, A. J. J. T. Rein⁴;
¹Department of Human Genetics,Hadassah Hebrew University Hospital, Jerusalem, ISRAEL, ²Department of Pediatrics, Hadassah Hebrew University Hospital, Jerusalem, ISRAEL, ³Department of Human Genetics, Hadassah Hebrew University Hospital, Jerusalem, ISRAEL, ⁴Department of Pediatric Cardiology,Hadassah Hebrew University Hospital, Jerusalem, ISRAEL.

Structural cardiac defects such as peripheral pulmonary stenosis are well described in Alagille syndrome (AGS), which is transmitted in an autosomal dominant inheritance. Haploinsufficiency of the Jagged 1 gene (JAG1) has been shown to cause Alagille syndrome. Abdominal coarctation is an uncommon vascular congenital anomaly and has been described only twice in AGS. We report on two more patients with coarctation of the abdominal aorta in AGS.
Recently, Loomes et al (Hum-Mol-Genet. 1999; 8(13): 2443-9) have shown that Jagged1 gene is expressed in the developing heart and in multiple associated vascular structure including the descending aorta. Jones et al (J Med Genet 2000;37:658-662) studied the tissue expression of JAG1 in human embryo and noticed that JAG1 was also expressed in the developing aorta. We performed molecular analysis of the Jagged1 gene in one of our patients with AGS and abdominal coarctation and found a mutation deletion (1485 Del CT). This corroborates with Loomes and Jones studies and confirms that coarctation of aorta might be a part of the Alagille syndrome. This additional report brings the number of children with Alagille syndrome and coarctation of abdominal aorta to four and emphasizes the need to follow children with Alagille for the development of coarctation of the abdominal aorta.

Two cases of coincidence of monogenic autosomal linked neurodegenerative disorders and the chromosomal abnormality of gonosomes.

V. Matoska¹, T. Marikova², H. Petra², Z. Musova², D. Novotna², M. Havlovicova², P. Seeman³, E. Seemanova², P. Bauer², J. Kraus³, A. Zumrova³, R. Mazanec⁴, P. Goetz²;
¹Institute of Biology and Medical Gentics, Prague, CZECH REPUBLIC, ²Institute of Biology and Medical Genetics, Prague, CZECH REPUBLIC, ³Child Neurology Clinic, University Hospital Motol, Prague, CZECH REPUBLIC, ⁴Neurology Clinic, University Hospital Motol, Prague, CZECH REPUBLIC.

We present here two cases of autosomal monogenic disorder in combination with numeric failure of gonosomes. Though the coincidence of abnormality of gonosomes and X-linked neurodegenerative disorder is not unexpected finding, the combination with autosomal gene disorder is quite rare.
The first case is the four-month old girl with the symptomatology of spinal muscular atrophy. Chromosomal abnormality 47,XXX was found, and SMN1 gene dysfunction was diagnosed by DNA analysis. The proband died at the age of 8 month.
The second case is a patient followed up from the age of 2 years because of the symptomatology of HSMN and progressive growth retardation. Her maternal grandfather died at the age of 46 having neurodegenerative disorder (HMSN -FRDA??). DNA analysis encrypted the specific duplication of the 17p11.2-p12- the CMT1A. The chromosomal investigation revealed de novo 45,X/46XY (1:2) karyotype.
Supported by grant IGA MZ 6506-3 and VZ 111300003.

Interdisciplinary strategies design: evaluation of sensorineural hearing loss (SNHL) pedigrees from patients classified as indeterminate. The importance of professional formation

M. B. Bravo-Luna¹, A. Spadoni², M. T. Trincavelli³, A. Jannelli⁴, G. Dotto⁵, M. C. Fumagalli², M. Dalmasso⁶, M. Chinellato³;
¹CIUNR-Universidad Nacional de Rosario, Rosario, ARGENTINA, ²Esc. de Fonoaudiologia-Fac. Cs. Medicas -UNR, Rosario, ARGENTINA, ³Esc. de Fonoaudiologia-Fac. Cs Medicas-UNR, Rosario, ARGENTINA, ⁴Esc. Fonoaudiologia, Fac. Cs. Medicas-UNR, Rosario, ARGENTINA, ⁵Esc. de Fonoaudiologia-Fac. Cs. Medicas-UNR, Rosario, ARGENTINA, ⁶Esc. de Fonoaudiologia-Fac. Cs Medicas UNR, Rosario, ARGENTINA.

Prevalence of genetic SNHL is low in Argentina (12%). We attempted to revise the diagnosis of SNHL, according the worldwide accepted classification: genetic, environmental, indeterminate to estimate the actual prevalence of the genetic component, exerting prevention, and guiding of groups at risk, institutions and professionals closed involved. A qualified population of SNHL patients (n=260), aged 0-15yr attending public/private services, and educational institutions of Rosario, is divided as follows: genetic (10%), environmental (51%), indeterminate (39%) groups. Further familial information to draw the corresponding pedigrees was obtained (n=101probands), detecting syndromic and non-syndromic SNHL cases. This investigation provided us with two perspectives: 1) adequate training of the staff to prepare the pedigrees; 2) counselling of subjects at risk. It is to be noted the importance of improving the professional practice to construct a “new professional”. Regarding counselling of subjects at risk it is admitted that: A) transfer of results (diagnosis, prognosis) must warrant privacy, based on psychological, sociocultural, ethical and philosophical principles. B) there is a well known impact produced by “knowing oneself and the own expectations”, thus it is convenient to provide psychological support and/or preserve the subject emotionally, as well as to suggest a consultation with specialists. C) The task must be centred on the patient. We do not adhere to directiveness, conversely, emphasising the patient and/or family -and other subjects at risk- decision. Hence, it is obligatory to organize workshops for professionals focused mainly on prevention and promote the re-enactment of the individual and collective construction of the professional profile.

O. Brumariu, C. Rusu, I. Cernescu, G. Stan;
Childrens Hospital, Iasi, ROMANIA.

We present a case of Menkes syndrome in order to discuss the importance of different clinical features and the management of the patient and his family. Our proband is a 5 Mo old male infant, second child of an young, apparently normal, unrelated couple. Physical examination revealed mild growth deficiency, microcephaly, sparse, hypopigmented, kinky hair, pale skin, expressionless face with full cheeks and hypotonic muscles. Radiologic investigation showed wormian bones in the lambdoid sutures and widened metaphyses of the long bones. Hair microscopic examination showed pili torti. Serum levels of copper and ceruloplasmin were low. Based on the clinical features and specific investigations we have establishes the diagnosis of Menkes syndrome. Detailed differential diagnosis with other XLMR entities and other syndromes with pili torti will be provided. The management of the family will be discussed. In conclusion, we present this case of Menkes syndrome to illustrate a rare entity and to discuss the importance of the features for the diagnosis and the management of the family.

Chondrodysplasia punctata 1, X-linked recessive (CDPX1) and Ichthyosis associated with 46,Y,der(X)t(X;Y)(p22.31;q11.21) karyotype in the son of a mother carrier of the derivative X chromosome

E. Andreucci, S. Guarducci, L. Giunti, E. Lapi, A. Cecconi, U. Ricci, I. Sani, S. Coviello, E. Anichini, M. Ottaviani, A. Lasagni, M. L. Giovannucci Uzielli;
University of Florence, Firenze, ITALY.

We report a new case of CDPX1 and ichthyosis in a newborn with the characteristic phenotype, both clinical and X-ray, of this X-linked recessive disorder. Cytogenetic analysis showed his karyotype to be 46,y,der(X)(p22.31;q11.21). The psychometric testing is not well applicable because of the age of the child, but the psychomotor development was apparently delayed at age 8 months. The STS activity is obviously deficient. The mother is a carrier of the derivative X chromosome and has carrier levels of STS activity: she is somewhat short of stature and has mildly short arms.
FISH studies were performed on metaphase chromosomes using Xyqtel, Xyptel, STS and KALI Xp22.3 region probe with DXZ1 chromosome X control probe (ONCOR). A battery of DNA polymorphic markers was used to localize the Xp breakpoint (DXYS233, DXS996, DXS6837, DXS1139, DXS6834, DXS1130, DXS237, DXS278, DXS987). In the mother we also performed the study of DNA markers from Y chromosome, to well determine the location of the Yq breakpoint in the derivative X chromosome.
The mapping studies indicate the precise location of the well characterised genes, SHOX, CDPX1 (arylsulphatase E), steroid sulphatase (STS), and Kallmann (KALI) genes. Further analyses are in progress to better establish a phenotype-karyotype-genotype correlation.

A. Babamohammadi¹, G. Babamohammadi¹^,2, Y. Shafeghati³, M. Karimi-Nejad¹;
¹Karimi-Nejad Pathology and Genetic Center, Tehran, IRAN (ISLAMIC REPUBLIC OF), ²National Research Center for Genetic Engineering and Biotechnology, Tehran, IRAN (ISLAMIC REPUBLIC OF), ³University of Welfare and Rehabilitation, Tehran, IRAN (ISLAMIC REPUBLIC OF).

Costello Syndrome is an extremely rare disorder characterized by growth delay after birth (postnatal), leading to short stature; excessive, redundant loose skin on the neck, palms of the hands, fingers, and soles of the feet; development of benign (non-cancerous) growths (papillomata) around the mouth (perioral) and nostrils (nares); mental retardation; and/or characteristic facial appearance. Other physical features may include the development of dry hardened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis), abnormally deep creases on the palms and soles, and/or abnormally flexible joints of the fingers (hyperextensible). There is an increased incidence of congenital abnormalities of the heart and thickening of the heart muscle called a cardiomyopathy. Characteristic craniofacial features may include an abnormally large head (macrocephaly); low-set ears with large, thick lobes; unusually thick lips; and/or abnormally wide nostrils (nares). Most cases are sporadic and a significant increase of mean paternal age has been reported, suggesting de novo dominant mutations. The exact cause of Costello Syndrome is unknown. We report three new patients with typical clinical findings and emphasize the importance of clinical experience for diagnosis of this disorder.

Duplication of intrachromosomal insertion segments 4q32-q35 confirmed by comparative genome hybridization and FISH

S. Park¹, Y. Kim¹, M. Lee¹, H. Ryu²;
¹SamsungCheil Hosp. Lab. of Medical Genetics, Seoul, REPUBLIC OF KOREA, ²SamsungCheil Hosp. Dep. of Obstetrics & Gynecology, Seoul, REPUBLIC OF KOREA.

A 35-year-old man with oligozoospermia was referred for chromosomal analysis. In routine cytogenetic analysis, the patient was seen to have an additional material of unknown origin on the terminal region of the short arm of chromosome 4. To figure out the origin of the unknown material, we carried out high-resolution banding, fluorescent in situ hybridization (FISH) and comparative genomic hybridization (CGH). CGH showed a gain of signal on the region of 4q32-35. By using whole chromosome painting and subtelomeric region probes for chromosome 4, we confirmed the aberrant chromosome as intrachromosomal insertion duplication of 4q32-35. We didn’t carry out parent’s chromosome analysis, but we predicted one of parents might have a ins(4)(p16q32q35) because the abnormal chromosome was a type of possible recombinants from crossing over in carriers with the between-arm intrachromosomal insertion of chromosome 4. Duplication often leads to some phenotypic abnormalities, however, our patient showed almost normal phenotype except for sperm counts.

E. Kurvinen¹, R. Jordania²;
¹Tallinn Children`s Outpatient Clinic, Tallinn, ESTONIA, ²Tallinn Children`s Outpatient Clinic, Tallinn, ESTONIA.

Mesomelic dysplasia - a heterogeneous group of bone dysplasias with disproportionate shortening of middle segment of limbs. Clinic is variable. AD, AR, X-linked heredity forms have been described. We report family where two offsprings 27 year old son and 24 year old daughter with short height (-2SD). Both patients showed radiologically hypoplastic and shortened tibia and fibula, shortened radius and curved ulna.Madelung deformation, radio-ulnar and tarsal synostosis were diagnosed. Mental development is normal. Both parents were phenotypically healthy with normal height. AR mesomelic dysplasia was suspected and low risk for sick offsprings future children was prognosed.During sons` wife pregnancy fetal tibia shortening was diagnosed sonographically on 18 th week of pregnancy. Parents´s detailed radiological investigation revealed in mother deviation of ulna. Therefore AD mesomelic dysplasia (Nievergelt) type was diagnosed. Newborn baby clinical and radiological investigation confirmed diagnose.Family members careful investigation usually is helpful for correct diagnosis and prognosis during genetic counselling.

A new polyepiphyseal dysplasia with extreme delay in ossification and normal stature in sibs

A. Verloes¹^,2, C. Garel³, M. Hassan³, C. Baumann¹;
¹Clinical Genetics Unit, Hôpital Robert Debré, Paris, FRANCE, ²INSERM E9935, Hôpital Robert Debré, Paris, FRANCE, ³Radiology Dept, Hôpital Robert Debré, Paris, FRANCE.

We report on a pair of dizygotic twins born to consanguineous parents, showing both an extreme delay in skeletal maturation (roughly corresponding to a newborn at age 4 10/12), mild metaphyseal irregularities, and a phenotype associating normal to large stature (+1 to + 2 SD) with normal growth pattern, long fingers, generalized small joint hyperlaxity with flat feet, genua valga, and low normal intellectual development. This combination appears to represent a new AR - or possibly XLR - skeletal dysplasia belonging to the polyepipyseal dysplasia spectrum of disorders.

Identification of differentially expressed genes during development of cardiac hypertrophy in rat

T. Hahn, D. Schlote, I. Hansmann, M. Schlicker;
Institut für Humangenetik und Medizinische Biologie, Martin-Luther-Universität, Halle-Wittenberg, GERMANY.

Cardiac hypertrophy is an adaptive response to chronic increased workload and is associated with changes of gene expression. To identify candidate genes contributing to the initiation or progression of cardiac hypertrophy we have screened differential gene expression in the heart of spontaneously hypertensive rats (SHR) at different stages of their development. Up to 4 weeks after birth the animals are normotensive. Males first develop hypertension around 12 weeks pp and hypertrophy of the left heart ventricle around 26 weeks pp. We established a subtractive hybridization system based on cDNA selection and suppression PCR using mRNA from these stages. Subtractive hybridization using age groups 4- versus 12- as well as 12- versus 26-weeks identified 145 different cDNA clones. Screening of these clones revealed 56 cDNAs as candidates for differentially expressed genes during development to cardiac hypertrophy. Northern blot analysis of 42 cDNAs identified 16 genes to be upregulated in cardiac tissue of SHR in comparison to the wild type Wistar-Kyoto rat. In silico analysis of cDNA sequences identified several known genes which are being discussed already in the context with cardiomyopathy (g-sarcoglycan) or cardiac hypertrophy (acyl-coA dehydrogenase). In addition to these genes our analysis revealed so far 8 novel and unknown genes which are differentially expressed in the heart of SHR. Mapping of these novel genes with respect to rat chromosome segments harboring known QTLs for cardiac hypertrophy and analysis of their expression pattern might be relevant to understand processes leading to cardiac hypertrophy in rat and man.

High prevalence of a screening detected, HFE-unrelated, mild idiopathic iron overload (possible hereditary hemochromatosis) in Northern Italy.

M. Grasso¹, G. Barosi², S. Ansaldi¹, L. Pillitteri¹, L. Salvaneschi³, M. Martinetti³, M. Marchetti², U. Bodini⁴, A. Reggiani⁵, F. D'Agostino⁶, G. Nalli⁷, E. Arbustini¹;
¹Cardiovascular Pathol. and Molec. Diagn. - Res.Transplantation Lab. , IRCCS Policlinico S.Matteo, Pavia, ITALY, ²Laboratory of Medical Informatics, IRCCS Policlinico S.Matteo, Pavia, ITALY, ³Immunoematology and Transfusion Service, IRCCS Policlinico S.Matteo, Pavia, ITALY, ⁴Transfusion Service, Istituti Ospedalieri, Cremona, ITALY, ⁵Division of Medicine, Istituti Ospedalieri, Cremona, ITALY, ⁶Transfusion Service, Ospedale Civile, Lodi, ITALY, ⁷Division of Medicine, Ospedale Civile, Lodi, ITALY.

In Italian population, typical HFE mutations account for 64% of overt hereditary hemochromatosis (HH)(versus 100% in other countries of Celtic descent).A common HFE-unrelated disease was hypothesized.
One thousand and fifty candidate blood donors were screened by iron tests,C282Y and H63D HFE mutations in a region in North Italy. Subjects with repeated fasting transferrin saturation of 45% or more and no secondary iron overload were defined as probands with idiopathic iron overload. To assess the inheritance of iron overload, relatives of probands were screened.
The overall frequency of idiopathic iron overload probands was 3.43% (95% confidence interval, 2.32 to 4.52). 8.4% of them had genotypes associated with HH (compound heterozygous for H63D/C282Y or homozygous for H63D HFE mutations). 91.6% had atypical genotypes: 47.2% were heterozygous for C282Y or H63D HFE mutations, and 44.4% had wild type homozygote genotype.Iron overload was familial in 33.3% of probands with atypical genotypes (1.04% of the overall population). Pedigree analysis excluded linkage of heterozygous HFE mutations with iron overload (cumulative lod score -2.41) and documented a recessive non HLA-linked locus accounting for iron overload in wild type homozygote genotypes. None of the probands had clinical signs of iron accumulation; in males, serum ferritin positively correlated with age (r=0.63, P<0.01), and the regression model predicted a serum ferritin of 700 ng per millilitre at the age of 58.
Conclusions. In Northern Italy an HFE-unrelated, mild idiopathic iron overload is highly prevalent. A recessive locus accounts for iron overload in at least 1.04% of the overall population.

A. Bloch-Zupan¹^,2, P. Ashley¹, N. Attari¹;
¹Department of Paediatric Dentistry, Eastman Dental Institute for Oral Health Care Sciences, University College, London, UNITED KINGDOM, ²Institute of Child Health, London, UNITED KINGDOM.

More than 5878 gene loci for inherited human diseases and disorders are listed in OMIM of NCBI database with over 1250 related to oral-dental-craniofacial diseases and disorders. Dental defects are seen in numerous of these syndromes. Each dental abnormality or phenotype: number, shape, size, structure, colour, eruption, corresponds to specific genetic and developmental issues. Today more than 200 genes regulating tooth development have been identified (http://bite-it.helsinki.fi). Unfortunately these dental phenotypes are vague and poorly described in the genetic literature. The involvement of a specialised dentist in a genetic diagnostic and counselling clinic provides a dental examination and therefore dental phenotypic data to the genetic team. Systematised data collection and recording of this information are necessary as these observations may relate to rare undiagnosed conditions that might in the near future be revisited and accurately diagnosed. Explaining the oral components of the disease to the patients and their families as well as coordinating appropriate dental referrals according to treatment needs is also important. This service will contribute to the general wellbeing and dental health care of the patient.

J. Handzel, M. Kuklik;
1st Faculty of Medicine, Charles University Prague, Prague, CZECH REPUBLIC.

We are presenting six families with apparently new genetic disorder characterized by:
1)special unwillingness of the permanent teeth to eruption: eruption is often delayed or incomplete, or the affected teeth remain impacted
2) permanent molars are always affected, other type of teeth less often
3) teeth in infra-occlusion develop ankylosis
4)the disorder is resistant to orthodontic treatment
Less frequently occuring signs are:
5) submersion of deciduous molars
6) delayed eruption of deciduous dentition
7) submersion of some permanent teeth
8) rarely hyperodontia in permanent molar region or
9) transposition of cuspids and bicuspids
Our families could by divided in two groups according to the type of affected teeth and other features, genealogical analysis shows in both groups very probably autosomal dominant type of inheritance. But, the occurence of the disorder in three generations, higher female sex ratio and genealogic data showing no male to male transmission suggest in one group even X-linked dominant inheritance.

Constitutional mosaicism for a partial trisomy 8 in a patient with a Chromosome Breakage Syndrome

S. Sodia¹, W. Emberger¹, L. Rauter², E. Petek¹, H. Zierler¹, K. Wagner¹, P. M. Kroisel¹;
¹Medical Biology & Human Genetics, University of Graz, Graz, AUSTRIA, ²Department of Pediatrics,LKH-Leoben, Leoben, AUSTRIA.

We report on a male infant with mosaicism for partial trisomy 8 and a generally increased chromosome instability. He was born at term, birth weight 2940 g, head circumference 30 cm (< 3rd percentile).
Due to microcephaly, failure to thrive and additional dysmorphic facial features as sloping forehead, retrognathia, low set ears and clinical suspicion of fragile X syndrome the patient was subjected for cytogenetic and DNA analysis at an age of 3 month. There were no genetic disorders or anomalies in family history, except one patient with Down Syndrome. By molecular genetic analysis of FMR1 gene a FRAXA syndrome could be excluded. However cytogenetic results showed a mosaic for a marker chromosome in about 25% of all mitoses and a high number of chromosomal rearrangements, in particular balanced and unbalanced translocations preferentially involving chromosomes 7,8 and 14 with decreasing relative incidence. Multicolour FISH and whole chromosome paint analysis demonstrated that the marker chromosome is derived from chromosome 8 leading to the following karyotype: mos 47,XY,+mar.ish der(8)(wcp8+) [7] / 46,XY [23]. Improved banding analysis performed subsequently allowed to specify a terminal deletion with a breakpoint at 8q21.1 in the aberrant chromosome 8. So far there is no indication for a hematological anomaly or malignancy, but a cytogenetic analysis of fibroblasts was also not performed yet to confirm a constitutional mosaicism. It is interesting that the breakpoint in 8q21 is identical at the cytogenetic level with the Nijmegen Breakage Syndrome (NBS1) gene locus. Therefore further molecular studies will be performed.

E. Spanou Aristidou¹, P. C. Patsalis¹, N. Rose¹, C. Sismani¹, V. Christophidou Anastasiadou¹^,2;
¹The Cyprus Institute of Neurology and Genetics, Nicosia, CYPRUS, ²Archbishop Makarios III Hospital, Nicosia, CYPRUS.

We present a 2.5 year old girl with global developmental delay, dysmorphic features and a complex translocation as follows: 46, XX t(6;7;8;12). This child was born at 35 weeks gestation following a complicated twin pregnancy. Her birth weight was on the 10th percentile. She was first seen at the age of eight months presenting with developmental delay, compared to her twin brother, and soft dysmorphic features. Her developmental milestones remained delayed and she also had behaviour disturbances. A.S. has a round face with a prominent metopic ridge, short upslanting palpebral fissures, a mildly depressed nasal bridge and a long philtum. Her twin brother has none of the afore mentioned features. She was thoroughly investigated and cytogenetic analysis revealed a 46,XX t(6;7;8;12) karyotype. This was confirmed by FISH analysis.
Her family was tested and this chromosomal aberration was not found in either her twin or her parents. We therefore present this case of de novo 46,XX t(6;7;8;12) translocation.

The Macrocephaly-Cutis Marmorata Telangiectatica Congenita Syndrome. Report of six patients and definition of the diagnosis criteria.

F. Giuliano¹^,2, A. David³, S. Sigaudy², V. Cormier-Daire⁴, P. Edery², J. J. C. Lambert¹, N. Philip²;
¹Hôpital Archet II, Nice, FRANCE, ²Hôpital La Timone Enfants, Marseille, FRANCE, ³Hôpital Mère-Enfants, Nantes, FRANCE, ⁴Hôpital Necker Enfants Malades, Paris, FRANCE.

The macrocephaly-cutis marmorata telangiectatica congenita syndrome (M-CMTC) was recently defined as a new overgrowth syndrome characterized, in particular, by specific neurologic and cutaneous conditions. Previously, this disorder was just described as « cutis marmorata telangiectatica congenita syndrome with additional clinical features ». Since then, 39 patients were reported with a high degree of phenotypic variability.
We report 6 additional cases, in particular, we describe the first patient with an arterial dysplasia (Nishimoto desease) and cardiac malformations (atrial septal defect and atrial septal aneurism). Moreover, the analysis of our cases and a review of the literature allowed us to delineate the diagnosis criteria of the M-CMTC. These data suggest that major diagnostic criteria clearly comprise a neonatal hypotonia, a macrocephaly >>2 S.D., a cutis marmorata, a midline facial naevus flammeus, a hypertelorism, and abnormalities at the cerebral imaging. Minor criteria are represented by a 2,3 syndactyly of the toes, a facial or body hemihypertrophy, some distinctive facial features, a naevus flammeus of the upper lip and /or the philtrum and a hydrocephaly. We propose that the presence of, at least, five of the six major criteria or four major criteria with three minor criteria are necessary for the diagnostic of M-CMTC.

A balanced 9;18-translocation associated with growth retardation, speech impairment, deep-set eyes and prominent nose.

I. Bache¹, Z. Tümer¹, S. Markus², S. Ebner², C. Lundsteen³, V. Kalscheuer⁴, H. H. Ropers⁴, N. Tommerup¹;
¹Wilhelm Johannsen Centre for Functional Genome Research, University of Copenhagen, DENMARK, ²Gemeinschaftspraxis für Medizinische Genetik, Regensburg, GERMANY, ³Dept of Clinical Genetics, Rigshospitalet, Copenhagen, DENMARK, ⁴Max-Planck-Institute for Molecular Genetics, Berlin, GERMANY.

We describe a four-year-old boy with growth retardation below the third percentile, hyperactivity, no speech development, deep set eyes, long brushy eyebrows and a broad, prominent nose. The karyotype showed a balanced translocation 46,XY,t(9;18)(q31.2;q21.3). The phenotypically normal father carried the same balanced translocation. High resolution comparative genomic hybridization did not reveal any imbalance in the proband. By fluorescence in situ hybridisation with BAC probes the breakpoint regions have been narrowed to 500 kb on 18q21 and distal to CAPE on 9q31.3. Initially, the diagnosis of Floating-Harbor syndrome was considered, which is a rare disorder of unknown etiology characterised by prenatal onset of short stature with delayed bone age, language delay and a triangular face with a prominent nose and deep-set eyes. However, some features including the metacarpo-phalangeal profile and the postnatal onset of the short stature were not characteristic for this syndrome. Although the association between the translocation and the clinical features may be a chance finding, this translocation presents the first potential lead to the identification of chromosomal regions and candidate genes associated with Floating-Harbor like features. This possibility will be tested in a panel of patients with classical Floating-Harbor syndrome.

V. Christophidou Anastasiadou¹^,2, E. Spanou Aristidou¹, G. Stylianidou², N. Rose¹, C. Sismani³, P. C. Patsalis³;
¹The Cyprus Institute of Neurology and Genetics, Nicosia, CYPRUS, ²Archbishop Makarios III Hospital, Nicosia, CYPRUS, ³The Cyprus Institute of Neurology and Gene, Nicosia, CYPRUS.

We present a 15 year old boy with dysmorphic features, a seizure disorder, learning difficulties, and a chromosomal constitution of 46,XY,t(2;3;15).
P.D. was born at 37 weeks gestation with a birth weight just below the 50th percentile. He was diagnosed as having an arrested hydrocephalus (a CT scan revealed dilatation of the ventricles) at the age of 6 months. He had frequent urinary tract infections, which were attributed to vesicoureteral reflux (this resolved itself). He had constipation attributed to dolichosigmoid. On examination he was found to be a short young man, with a head circumference above the 95th percentile. He had synophrys, a high nasal bridge, long columella and hypoplastic nostrils. His philtrum was upturning and his chin prominent. P.D. also had rhizomelic shortening of his upper limbs. He was on treatment for seizures. He was thoroughly investigated and found to have a 46,XY,t(2;3;15) karyotype, by giemsa banding and FISH.
His family was also tested, except for his father who is deceased, and were all found to have normal karyotypes.
We believe that this is a de novo translocation in either the father or the son.

M. P. Audrezet, P. Marcorelles, J. J. Chabaud, M. J. Le Bris, A. Collet, M. De Braekeeler, P. Parent, C. Ferec;
CHU, Brest, FRANCE.

Complete hydatiforme mole coexistant with a normal fœtus is a rare obstetric pathology, the incidence reported varying from 1/10000 to 1/100000. It results from fertilization of an empty egg by a hapoid sperm which duplicates without cytokinesis and restores diploidy, or by two sperms.
Outcome depends on maternal criteria of gravity : the risk of persistent trophoblastic disease (PTD) is higher than is single complete mole and seems to be correlated to zygocity mechanism identified by molecular analysis.
We report 4 well-documented cases of complete hydatidiform mole (CHM) coexistent with a twin-live fetus (CHMLF). All of them were spontaneous pregnancies, 2 ended by delivery of a live-born baby, the 2 others were terminated because of maternal pre-eclampsia associated with intra-uterine fetal death.
If cytogenetic studies are sufficient for determining the ploidy, molecular analysis are necessary to confirm the mecanism.
Genomic DNA was extracted from the placenta, molar tissue and peripheral blood leucocytes of parents. Using 10 microsatellites marquers, we showed the paternal origin the molar tissue, and homozygosity of the mole was confirmed in the four cases.
As very rare, more cases are needed to predict the outcome. Expectant management can be only discussed in absence of maternal complications, associated with a normal fetal karyotype. However, treatment criteria are still to be improved and diligent maternal follow-up is always warranted in post-partum.

M. Piemontese¹, P. Gasparini², L. Zelante¹;
¹IRCCS CSS, S. Giovanni Rotondo, ITALY, ²TIGEM, Napoli, ITALY.

Blepharophimosis-ptosis-epycanthus inversus syndrome (BPES ) is an autosomal dominant disorder recently ascribed to mutations in the FOXL2 gene, a forkhead transcription factor. In type I BPES a complex eyelid malformation is associated with premature ovarian failure (POF), whereas in type II BPES the eyelid defect occurs as an isolated entity. Here, we report a family with one child affected by BPES.Both parents were clinically unaffected , and there was no family history of an eyelid defect.
Screening for mutations in the FOXL2 gene in the patient using direct sequencing revealed a frameshift deletion in the coding region, giving rise to a truncating protein.The same mutation was found in both peripheral blood and fibroblasts of the father in mosaicism with a percentage of about 25%. A reexamination of clinical findings in the father revealed, indeed, a minimal reduction of the horizontal diameter of the palpebral fissures.
This study reports the first documented case of costitutional mosaicism in BPES and serves as a reminder that mosaicism should be considered in every case when a mutation is found. This observation has a significant impact on genetic counseling of sporadic cases of BPES. In case of the paternal mosaicism an accurate evaluation of the mosaicism distribution in the germinal cells could provide an important tool to assign an accurate risk of recurrence in the family.

Haplotype Analysis of Related ATM Markers Facilitate Prenatal Diagnosis in Iranian Ataxia Telangiectasia Patients

B. Bayat¹, M. H. Sanati¹, A. Aleyasin¹, A. Farhoudi², M. Moin², A. Isaian²;
¹National Research Center for Engineering and Biotechnology (NRCGEB), Tehran, IRAN (ISLAMIC REPUBLIC OF), ²Children's Medical Center, Tehran, IRAN (ISLAMIC REPUBLIC OF).

Ataxia Telangiectasia is an autosomal recessive disorder in 1/40000 to 1/100000 in reported populations. There is 25% possibility for having an affected child when parents are carrier for ATM gene mutation. There is no cure available for this disease and prenatal testing is strongly recommended in preventation of this disease.
Although preference method is the direct mutation analysis of ATM gene, but large size of the ATM gene with 63 exons and the large number of possible mutation in patients considerably limit the facibility of mutations analysis as a choice in diagnosis. Indirect method is a better tool when parent are not carrier of founder mutation and pass different mutations to their children. Indirect molecular diagnosis using ATM related molecular markers facilitate prenatal diagnosis of AT children. In this study four molecular markers: D11S2179,D11S1787,D11S535,D11S1343 are genotype in 18 unrelated families from different region of IRAN. Those markers are amplified using extracted sequence primers from Gene Bank with their described PCR conditions. The amplified products were separated using denaturing PAGE gels, and the data were analyzed to detect their pattern of inheritance in each family. In all families segregation of alleles were recording to mandelian inheritance and affected chromosomes were distinguishable form unaffected ones. All carriers and affected patients were diagnosed accurately. Thus this method is effectively usable in prenatal diagnosis of ataxia telangiectasia.

D. Hèron¹, D. Geneviève¹, B. Bader-Meunier², N. Seta³;
¹Département de Génétique, Hôpital de la Pitié-Salpétrière, Paris, FRANCE, ²Service de Pédiatrie Générale, Hôpital Bicêtre, Paris, FRANCE, ³Biochimie A, Hôpital Bichat, Paris, FRANCE.

Congenital disorders of glycosylation (CDG syndromes) are a new group of inherited metabolic disorders. They are characterised by a defect in the synthesis of the glycan chain of the glycoproteins. To date, 8 enzymatic defects are identified. Here we report on a girl with a new type of congenital disorders of glycosylation.
She was the third child from healthy consanguineous Tunisian parents, born at 35 weeks gestation after an uneventful pregnancy by caesarean section. Birth weight was 2440 g (-1 SD), length 49 cm (+1 SD), and head circumference 33 cm (+1 SD). Poor sucking, generalised hypotonia, facial dysmorphism and hypocalcemia marked neonatal period. Cardiac and transfontanellar ultrasounds and blood chromosome with 22q11 in situ hybridisation were normal. At 6 months she had failure to thrive, feeding difficulties requiring tube feeding and gastrostomy, severe psychomotor involvement, major hypotonia, progressive microcephaly and frequent ORL and respiratory infections. At 18 months, she was not able to sit and speech. Cerebral MRI was normal. Coagulation factors, serum cholesterol level and hepatic function were normal. Metabolic investigations were normal. Immunologic investigations showed a low IgG level with normal IgA, IgM . Iso electric focusing and western blot analysis showed a mild hypoglycosylation of proteins but phosphomannomutase and phophomannose isomerase activities were normal, excluding CDG Ia and Ib. The patient's fibroblasts showed a incompletely assembled dolichol linked oligosaccharides with 7 mannose residues secondary to an inefficient addition of the last mannose containing branch that is required for protein N-glycosylation. Molecular biology investigations are in progress.

Spectral karyotyping study of three patients with constitutional supernumerary chromosomal markers.

E. S. Ramos¹, L. Martelli¹, J. Karaskova², J. Huber¹, L. D. R. Giuliani¹, B. R. Versiani¹, M. L. Machado¹, L. A. F. Laureano¹, J. Squire²;
¹School of Medicine of Ribeirao Preto - University of São Paulo, Ribeirao Preto, BRAZIL, ²University of Toronto, Toronto, ON, CANADA.

Currently, the GTG-banding technique is the most commonly used diagnostic method in clinical cytogenetics. This analysis of markers can be inadequate because of poor chromosome morphology, size of markers and/or an insufficient yield of analyzable metaphases. The usefulness of the FISH remains limited by the number of spectrally distinguishable fluorochromes or fluorochrome combinations. Spectral karyotyping (SKY) has been developed to unambiguously display and identify all chromosomes at one time using a spectral signature that generates 24 unique colors. Three cases of constitutional supernumerary chromosomal markers and different clinical manifestations are described in this report. Case 1: a male (9 months of age) with microcephaly, up-slanting palpebral fissures, malformed ears, cryptorchidism, and "schawl" scrotum. Case 2: a 6-year-old female with facial asymmetry, strabismus, prominent nasal bridge, micrognathia, and cubitus valgus. Case 3: a 14-year-old male with seizures, triangular face, strabismus, prominent ears, thoracic asymmetry, scoliosis, cubitus valgus, macro-orchidism, and wide gap between first and second toes. SKY reveals the origin of the three markers (Cases 1, 2, 3) as der(2), der(9), and der(15), respectively. The identification of the chromosomal origin of the markers by SKY provides better information for the physician, and genetic counselor, for more appropriate management of patients with specific aneusomies.
Supported by: FAEPA, CAPES, FAPESP, CNPq, CCS, NCIC

CDG syndome type 1 : Ovarian histopathologic anomalies in a woman with hypergonadotrophic hypogonadism

P. Sarda¹, F. Dalla Vale², B. Hashemi¹, J. Puechberty¹, C. Coubes¹, P. Blanchet¹;
¹Genetics Department - Arnaud de Villeneuve Hospital, Montpellier, FRANCE, ²Pediatric Endocrinology Department - Arnaud de Villeneuve Hospital, Montpellier, FRANCE.

Carbohydrate Deficient Glycoprotein (CDG) syndrome type 1 is a genetic disorder with multisystemic manifestations. Few affected adults have been reported and most females show absent or delayed pubertal development due to ovarian failure but no histopathological examination in adult patients has been reported to date.
We present the case of a 22-year-old woman, with CDG syndrome type 1. At age of 17 she had no sign of pubertal development. No ovaries were present on ultrasound examination and endocrine testing revealed hypergonadotrophic hypogonadism.
Pelvic laparoscopy showed bilateral streak-like ovaries with dysmorphic fallopian tubes and a normal uterus. Biopsy specimen of ovaries revealed ovarian like stroma with no follicle.
Less than 10 adult women with CDG syndrome have been reported. Only one woman had normal puberty. All the others present with hypergonadotrophic hypogonadism. In half of the cases no ovary is detectable by ultrasound examination, in the other half of cases ultrasound revealed presence of ovaries but without signs of follicular activity.
Abnormal protein glycosylation has complex and heterogeneous effects which result in ovarian failure. Details of pathogenesis remain to be determined.

An autosomal recessive cerebello-oculo-renal syndrome unlinked to both the JBTS1 and NPH1 loci

B. Utermann¹, A. R. Janecke¹, T. Müller², H. Duba¹, R. Scheithauer³, G. Utermann¹;
¹Institute of Medical Biology and Human Genetics, University of Innsbruck, Innsbruck, AUSTRIA, ²Department of Paediatrics; University Hospital Innsbruck, Innsbruck, AUSTRIA, ³Institute of Legal Medicine, University of Innsbruck, Innsbruck, AUSTRIA.

A delineation of several syndroms featuring cerebellar vermis hypoplasia, and ocular, renal, or hepatic involvement has proven difficult. Cerebellar vermis hypoplasia occurs as an isolated trait, or together with hypotonia, developmental delay, and abnormal breathing or abnormal eye movements in Joubert syndrome, and is further observed associated with other ocular, renal, or hepatic involvement. These combinations including Arima, Senior-Löken and COACH syndromes, have been considered by some authors as variants of Joubert syndrome and as distinct disease entities by others. In addition, cerebellar vermis hypoplasia occurs together with juvenile nephronophthisis. We report a large consanguineous Austrian family with three children, two sibs and their cousin, being variably affected by cerebellar, ocular, and renal malformations. We present a comparison of the clinical findings with known cerebello-oculo-renal syndromes, and the exclusion of both the Joubert syndrome and juvenile nephronophthisis loci, JBTS1 and NPH1, respectively, as the site of the mutant gene.

Computer assisted diagnosis of chromosomal aberrations using a Bayesian and a counting approach with the help of the database SYNDROC

U. Tautenhahn¹, J. Kunze², J. Pelz¹;
¹Reformstudiengang Medizin, Charité Campus Mitte, Berlin, GERMANY, ²Institut für Humangenetik, Charité Campus Virchow, Berlin, GERMANY.

The possibility to diagnose chromosomal aberrations using a computerized database was tested using 101 patients with an established chromosomal aberration using the database SYNDROC. This system provides the user with two different algorithms for the calculation of a diagnosis:
- a descriptive algorithm which proposes a diagnosis counting a set of phenotypic markers all having the same weight.
- a Bayesian-algorithm which, evaluating calculates probabilities for competing diagnoses by analyzing phenotypic anomalies.
Three levels of precision were used assessing the diagnoses: suggestion of the correct (1) chromosome number, (2) chromosome arm, (3) aberration type and rough location.
The combination of both algorithms yielded 51 consensus diagnoses for the level of the correct chromosome, 24 for the chromosome arm, and 15 for the aberration type. Additional diagnoses solely with the descriptive algorithm were yielded for 43, 52 and 47 cases and using the Bayesian-algorithm for 1, 4 and 1 diagnoses respectively. Since with the Bayesian-algorithm, when evaluating an uncertain diagnosis using a combination of symptoms, one does so by calculating the probability of the claim in the light of given information. This seems to be a much more promising for a correct diagnosis than the pure counting of numbers of matches. The Bayesian coefficients were in the range between 0.57 and 0.05; the 0.5 margin as a trustworthy one announced by the authors of SYNDROC was reached by only one of the correctly recognized cases. The prior probabilities for the calculations of the Bayesian-formula do not seem to use serviceable weights.

Another observation with VATER and a deficiency of complex IV respiratory chain disorder.

C. Thauvin-Robinet¹, L. Faivre², P. Journeau³, F. Huet⁴, P. Rustin⁵, A. Rötig⁵, A. Munnich⁵, V. Cormier-Daire⁵;
¹Centre de Génétique, Dijon, FRANCE, ²centre de génétique, Dijon, FRANCE, ³Service de Traumatologie et Orthopédie, Hôpital Nécker-Enfants, Paris, FRANCE, ⁴Service de Pédiatrie 1, Hôpital d’Enfants, Dijon, FRANCE, ⁵Département de Génétique, Hôpital Nécker-Enfants, Paris, FRANCE.

The VATER association of vertebral anomalies (V), anal atresia (A), esophageal atresia and/or tracheo-esophageal fistula (TE), radial and renal anomalies (R) is a common congenital disorder of unknown origin with probably heterogeneous causes. Here, we report on a girl presenting with pre- and postnatal growth retardation, esophageal atresia, vertebral and costal anomalies and a unilateral radial defect, consistent with the diagnosis of VATER association. In the first months of life, she presented with failure to thrive, severe episodes of hypoglycemia, and liver cytolysis which prompted us to perform a metabolic screening. Hyperlactatemia was observed and a complex IV respiratory chain deficiency was found on a liver biopsy. The respiratory chain deficiency was not observed in skin fibroblasts. No mtDNA point mutation or deletion was identified. The girl is now 6 years old and has a normal mental development but persistent feeding difficulties and moderate hyperlactatemia (2.6mM). To our knowledge, this is the second report of VATER association with a mitochondrial disorder. In a previous report (Damian et al., 1996), a VACTERL association was observed in a girl who presented, in addition, the mitochondrial NP3243 point mutation. The observation of VATER association in combination with a mitochondrial disorder may be coincidental but could suggest also that the presence of multiple malformations and antenatal manifestations does not rule out the diagnosis of respiratory chain deficiency.

L. Benjemaa, F. Maazoul, R. Mrad, M. Chaabouni, M. Ksontini, H. Chaabouni;
Service des Maladies Congénitales et Héréditaires, EPS Charles Nicolle, Tunis, TUNISIA.

Nager acrofacial dysostosis was recognized as a specific entity by Nager and de Reynier syndrome(1948). It’s a rare desorder, approximately 40 documented cases. The inheritance is autosomal dominant, most cases have been sporadic. Zori(1993) suggested that the gene may reside on chromosome 9.
We reported a young boy offspring of young and non consanguineous parents, he presented a mandibulofacial dysostosis and a skeletal anomalies, evoking Nager’s syndrome.The investigates genetics is negative. We begin in this work a comparative study with the data of the literature and we discuss the differential diagnosis.

S. Sabine, A. Moncla, N. Philip;
Département de Génétique Médicale, Marseille, FRANCE.

In 1988, Toriello and Carey described a rare congenital disorder characterized by telecanthus, short palpebral fissures, a small nose, abnormal ears, Robin sequence cardiac defect, corpus callosum agenesis, hypotonia, postnatal growth retardation and developmental delay. Originally an autosomal recessive mode of inheritance was suspected. Since that times a total of fourteen patients have been reported. The predominance of affected male and the milder phenotype in female patients suggested an X linked or sex influenced gene. We report the follow up of an additional male patient with a Toriello-Carey syndrome born from unconsanguineous parents from birth to the age of 7 years.

C. Orssaud, D. P. Germain;
Hopital Europeen Georges Pompidou, Paris, FRANCE.

Background: Fabry disease (FD) is an X-linked inborn error of glycosphingolipid metabolism due to deficient activity of lysosomal a-galactosidase A. Progressive glycosphingolipid storage is responsible for renal failure and ischemic complications, involving brain and heart. Much interest is currently paid to emerging a-galactosidase A replacement therapy.
Methods: We carried out a complete baseline ophthalmologic examination of 25 hemizygotes affected with FD, prior to enzyme replacement therapy.
Results: The mean age at time of examination was 36 ± 13 years. No patient had any functional complain. The measured refractive values were unremarkable. However, the incidence of myopia was high (46.00 %). Thirty-nine eyes (78.00 %) reached a far best corrected visual acuity (BCVA) of 20/20. Seven eyes had a BCVA of 20/25 and none of them had an acuity lower than 20/33. All the eyes had normal BCVA in near vision. The mean value of the Schirmer 2 test was normal in 18 patients. Seven patients (28.00 %) presented a reduction of the lacrimal secretion. Vascular abnormalities of the bulbar conjunctiva were found in 34 eyes (68.00 %). Cornea verticillata was observed in 23 eyes (46.00%). A corneal haze was the most frequent corneal abnormality, observed in 45 eyes (90.00 %). Lens anterior capsule deposits were observed in 4 patients and the Fabry posterior cataract in 9 patients. Retinal vascular tortuosities were observed in 12 patients (48 %). The optic discs were unremarkable. An enlargement of the blind spot was noted in 35.00 % of the eyes at visual field examination.

P. M. Kroisel, C. Windpassinger, H. Zierler, K. Wagner, E. Petek;
Institute of Medical Biology & Human Genetics, University of Graz, Graz, AUSTRIA.

A de novo deletion of the long arm of chromosome 22 distal to the DiGeorge/Catch22 critical region as verified by FISH analysis in a 7 1/2 year old girl is described. This type of cytogenetically visible microdeletion was not reported so far. The patient was born as the second child to healthy unrelated parents following an uneventful pregnancy. Her phenotypic anomalies are relatively mild including a moderate growth and mental retardation and discrete dysmorphic facial features can be seen as well. Initial cytogenetic results obtained by standard G-banding were confirmed by high resolution RBG/GBG banding and characterized in more detail by analysis of the patient and her parents using more than 8 informative microsatellite markers including D22S536, D22S1167, D22S273, D22S278 and D22S1156. The patient does not show cafe-au-lait spots or neurofibromas at her skin however since the gene for neurofibromatosis 2 coding for the merlin/Schwannomin tumor suppressor protein maps to 22q12.2, which is by cytogenetic resolution within the deleted segment, further molecular studies are required to provide the patient with the optimal disease prevention and medical management.

Mutations in EDA, EDAR, XEDAR and NEMO genes reveal a new signal transduction pathway participating in differentiation of skin appendages.

S. A. Wisniewski, B. Marszalek, K. Kobielak, A. Kobielak, W. H. Trzeciak;
USOMS Poznan, Poznan, POLAND.

Anhidrotic ectodermal dysplasia (EDA) is caused by the defect in the differentiation of skin appendages during embryonic development, resulting from improper interactions between ectoderm and mesenchyme at a molecular level. Initiation of the differentiation process requires protein products of EDA, XEDAR and NEMO genes localised on the X chromosome and EDAR gene localised on chromosome 2. These genes encode a ligand (ectodysplasin A), receptors (EDAR and XEDAR) belonging to TNF/TNFR families, as well as a protein (NEMO), participating in signal transducting pathway involving NFk B. Patients harbouring mutations of these genes exhibit an identical phenotype: oligodontia or anodontia, sparse hair and hypertermia, caused by the lack of sweat glands.
The structure of EDAR and XEDAR genes was investigated in 20 patients with clinical symptoms of anhidrotic ectodermal dysplasia and their 80 relatives. In these patients no mutations in EDA, and NEMO genes were found. Appropriate fragments of genomic DNA were amplified by PCR and were subjected to multiple temperature, single stranded conformation polymorphism analysis (MTSSCP) followed by direct sequencing using automated sequencer. In one patient, sequence analysis revealed a novel T1109C transition resulting in (Val370Ala) substitution in the death domain of EDAR. In the other patient, sequence analysis demonstrated deletion of G (del252G) in exon 2 of XEDAR gene resulting in premature termination of translation and truncated form of the receptor devoid of transmembrane and intracellular domains. The correlation between the phenotype and the localisation of the molecular defect was investigated.

G. Graetschel, J. Pelz;
Reformstudiengang Medizin, Charité Campus Mitte, Berlin, GERMANY.

Computer programs which can be used as an aid to diagnose multiple congenital malformation syndromes have been used for many years. These programs are based either on algorithms, which define a diagnosis by a set of phenotypic components all having the same weight or on algorithms based on a concept of Bayesian statistics. A new approach for this field are artificial neuronal networks (ANNs). A commercially available shell was applied, suitable for building up feedforeward ANNs trained by using backpropagation of errors. The data of 234 patients representing individual examples of 21 different malformation syndromes were used. The numbers of symptoms/combinations for the description of cases were limited to 28, 55 and 78 in different series of tests. After the export of the patients data to the shell the data of about 2/3 of the patients were used for the training of the ANN. The remaining 1/3 of patients data-sets were used to test the diagnostic capacities of the different ANNs. The most efficient yielded a diagnosis in more than 95 % of all tests. Correct diagnoses without any concurrent differential diagnoses were generated in 26 %; adding all tests producing the correct diagnosis among other diagnoses amounted to 74 %. The application of ANNs in the diagnostic process of malformation syndromes is efficient - one shortcoming is, that different sets of training data produce models with different generalization accuracies. The significance of an ANN is to a great extent influenced by chance and the experience of the developer.

Can OMIM be used as a decision support system in the diagnotic process of malformation syndromes?

F. von Luebken¹, J. Kunze², J. Pelz¹;
¹Reformstudiengang Medizin, Charité Campus Mitte, Berlin, GERMANY, ²Institut für Humangenetik, Charité Campus Virchow, Berlin, GERMANY.

The increasing number of malformation syndromes causes difficulties for the diagnostic process of the clinician. OMIM (Online Mendelian Inheritance in Man) was tested as a decision support system for the differential diagnostic process of patients with malformations. The data of 119 patients with different clinically confirmed syndromes were used to search differential diagnoses in OMIM feeding the signs of the respective patient in all possible combinations. Four different search strategies were tested (1) utilization of all signs of the patient, (2) usage of those signs, that a clinical expert considered to be important in diagnosis, (3) input of head-neck-signs (4) feeding all but (3). The combinations of signs for the searches in OMIM were created using the 'AND' and the 'OR'-junction.
With the AND-junction the number of differential diagnoses decreased with the number of signs used in combination, while the OR-junction resulted in more than 200 differential diagnoses for every syndrome and search strategy on the average. All four search strategies yielded more than 50% positive results, interestingly even strategy (4) was very effective. The number of differential diagnoses decreased with the number of signs read in in combinations applying the AND-junction.
The application of OMIM is sometimes tedious, but it is an acceptable and useful tool in all four strategies although it has not been developed as a decision support system in the realm of malformation syndromes.

Stuve -Wiedemann syndrome in long-term survivors: a neuro-myo-skeletal disorder with prominent neurovegetative features

M. Di Rocco¹, G. Stella², C. Bruno³, L. Doria Lamba⁴, M. Bado³, A. Superti-Furga⁵;
¹Second Unit of Pediatrics, Istituto G Gaslini, Genoa, ITALY, ²Second Unit of Orthopaedics, Istituto G Gaslini, Genoa, ITALY, ³Unit of Neuromuscular Disorders, Istituto G Gaslini, Genoa, ITALY, ⁴Unit of Pediatric Neurology, Istituto G Gaslini, Genoa, ITALY, ⁵Department of Pediatrics, University of Zurich, Zurich, SWITZERLAND.

In 1971 Stuve and Wiedemann described a syndrome characterized by bowing of long bones, camptodactyly, respiratory distress, hypertermic episodes and death in the first year of life (Z Kinderheilkd 11:184-92,1971). Clinical features of long-survivor patients with SWS are not studied in great detail, owing to the rarity of individuals.
We follow two patients with SWS aged 12 and 3 years. The first had congenital bowing of the long bones, respiratory distress, swallowing difficulties and unexplained fevers in the first year of life. After, he developed intolerance to low temperature, paradoxical sweeting, hypolacrimation and lack of corneal reflex leading to keratitis and corneal leukomas, recurrent ulcerations of the tongue, chronic gingivitis and dental decay. Cognitive level is normal. He has no clinical signs of myopathy, but muscle examination showed an increased number of lipid droplets and reduced respiratory chain activities. No mtDNA mutations were detected. After the first years of life he also showed severe progressive scoliosis. The second patient had respiratory distress, hypertermia, bowing of legs and camptodactyly at the birth. In the second year of age he developed intolerance to low temperature, paradoxical sweeting, tongue ulcerations with loss of tongue fragments, poor dentition, chronic gingivitis, corneal anesthesia leading to keratitis and corneal leukomas. Cognitive level, electromyography and motor nerve conduction are normal.
Clinical history of our patients expands the clinical phenotype of this intriguing disorder and may help in pinpointing candidate genes.