Long term follow up of a woman with classic form of Ehlers-Danlos syndrome associated with rare manifestations and review of the literature.

We present the case of a 46 year-old woman with the classic type of Ehlers-Danlos syndrome who developed the rare manifestations of colon diverticula and mitral valve prolapse. We emphasize on clinical features and complications associated to this type of the syndrome, which gradually developed in our patient. A review of the literature referring to the epidemiology, molecular basis and manifestations of the classic type Ehlers-Danlos syndrome is also discussed.

Complex rearrangements of chromosome 15 in two patients with mild/atypical Prader Willi syndrome.

Multiple mechanisms are responsible for the development of Prader Willi syndrome (PWS), the most common genetic cause of obesity in childhood. Molecular findings are usually deletions and uniparental disomy (UPD) of the 15q11-13 region. Rarely, structural rearrangements of the pericentromeric region of chromosome 15 are also detected. Two cases with mild PWS phenotype and complex maternal UPD identified by microsatellite analysis are described: the first patient had uniparental iso and heterodisomy and the second displayed biallelic inheritance and uniparental isodisomy.

Juvenile idiopathic arthritis-type disease associated with chromosomal aberrations.

The association of certain chromosome aberrations with arthropathy has been previously described, but there is a limited number of reports in the literature. Two children are described, one with 18q- syndrome and another with supernumary marker chromosome 15, both presenting with juvenile idiopathic arthritis-type disease, aggressive progression and moderate response to inflammatory, corticosteroid and immunosuppressive treatment.

A case of Ehlers Danlos syndrome type VI.

Ehlers Danlos type VI is a rare autosomal recessive connective tissue disease involving primarily the skin and joints. The main feature of the condition is neonatal hypotonia and rare complications are ruptures of arteries and the eye globe. A 4 year old girl with a typical clinical presentation and molecular diagnosis of EDS VI is presented. Sequencing of PLOD1 gene revealed a homozygous deletion in exon 13 (c.1362delC), leading to a frameshift and truncation of the lysyl hydroxylase, an enzyme necessary for collagen biosynthesis. Early diagnosis allowed treatment with high doses of ascorbic acid in order to prevent complications, genetic counseling of the family and prenatal diagnosis of an unaffected embryo.

Identification of autosomal supernumerary chromosome markers (SMCs) by fluorescent in situ hybridization (FISH).

Supernumerary marker chromosomes (SMCs) are rare chromosomal abnormalities resulting in partial trisomy of specific genomic regions with characteristic phenotypic effects. Twenty six cases with autosomal SMCs are reported. Four were identified prenatally and 22 postnatally in children, aged from 8 days to 15 years, who were referred for genetic evaluation because of various congenital anomalies and developmental delay. In 22 of the 26 cases, the SMCs were de novo, in two they were familial and in another two a 11;22 reciprocal translocation was revealed in the mothers. In only one patient was the SMC present in a mosaic form. Sequential fluorescent in situ hybridization studies (FISH) using Whole Chromosome Paint (WCP) probes were performed in order to determine the chromosomal origin of the SMCs. Sixteen of them originated from chromosome 15, five were shown to be an isochromosome 18p and one was derived from chromosome 22, but did not contain the DiGeorge/ VCFS critical region. In two instances, the SMCs were derivatives of chromosome 13 and in two the SMCs resulted from a 11;22 maternal translocation and contained material from both chromosomes 11 and 22. Molecular investigation of two of the patients with an SMC[15] revealed three copies of the SNRPN gene, but the diagnosis of PW/AS due to possible imprinting was excluded in both patients by a methylation-specific PCR. FISH and molecular studies have greatly facilitated the characterization of marker chromosomes. As more SMCs are classified, better genetic counseling and risk evaluation can be achieved.

Rituximab in the treatment of high responding inhibitors in severe haemophilia A.

The development of antibodies to factor VIII (FVIII) in severely affected haemophilia A patients is a serious complication associated with increased morbidity and mortality. Bypassing agents are used to treat acute bleeding episodes; however, elimination of the inhibitors can only be achieved with immune tolerance therapy (ITT) in 60-80% of cases. High responding (HR) inhibitors are more likely to respond to ITT if the titre is decreased to <5 BU over time or in selected cases after the administration of immunosuppressive drugs, plasmapheresis or immunoabsorption, techniques difficult to apply in children. Anti-CD20 (rituximab), a monoclonal antibody, was given as an alternative treatment in two haemophilic children with HR inhibitors and impaired quality of life, due to recurrent haemarthrosis. Rituximab was given at the dose of 375 mg m(-2), once weekly for four consecutive weeks. Both patients showed a partial response to rituximab reducing the inhibitor titre to <5 BU, thus facilitating ITT initiation; however, only the older patient eradicated the inhibitor within 21 days after application of ITT. The second patient, despite depletion of B cells, did not respond to ITT. No long-term side effects have been observed in both patients for a follow-up period of 20 and 18 months respectively. In conclusion, rituximab appears to be an alternative effective therapy to rapidly reduce or eliminate the inhibitor in selected cases of severely affected haemophiliacs before further proceeding to ITT. However, the dose and appropriate schedule, as well as long-term side effects need further investigation.

Detection of 22q11.2 deletion among 139 patients with Di George/Velocardiofacial syndrome features.

Cytogenetic and FISH analysis was performed in 139 patients to detect the pathognomonic of Di George/ Velocardiofacial syndrome (DGS/VFCS) deletion 22q11.2. An abnormal karyotype was revealed in 2/139 cases (47, XXY and 46, XX, 2p+). A deletion was found in 17/139 (12.2%) patients (14 males/ 3 females), inherited in 3 (2 maternal and 1 paternal). Patients with 22q11.2 deletion exhibited facial dysmorphic features (82%), congenital heart defects (70%), immunological problems (47%), multiple congenital anomalies (64%), hypocalcemia (47%), mental retardation/learning difficulties (35%), cleft palate/velopharyngeal insufficiency (23.5%), seizures/hypotonia (23%) and growth retardation (12%). Among 56/139 patients with detailed available clinical data, the 22q11.2 deletion was confirmed in all cases with hypocalcemia and in over half of the cases with multiple congenital anomalies, immunological problems and hypotonia/seizures (70%, 60% and 57%, respectively). Genetic reevaluation of 39 patients without the 22q11.2 deletion contributed to the classification of 14 (37%) under different syndromes, emphasizing the need for stricter referral criteria.