Hereditary hemorrhagic telangiectasia Genetics, pathogenesis, clinical manifestation and management

Hereditary hemorrhagic telangiectasia HHT, Morbus Osler or Osler-Weber-Rendu syndrome OMIM 187300, is an autosomal dominant disorder characterized by epistaxis, telangiectasia, multi-systemic vascular dysplasia and clinical presentation of wide variation. The pathogenesis involves dilated post-capillary venules or telangiectases in the mucus membrane of various organs as well as larger arteriovenous malformations. Genetic heterogeneity of HHT is confirmed; 2 disease loci, ACVRL1 and ENG genes, have been identified and characterized. The 2 major types of the disease, HHT1 and HHT2, are attributed to mutations in the ENG and ACVRL1 genes. ENG and ACVRL1 genes code for proteins, namely endoglin and activin-receptor-like kinase 1 ALK-1, which are members of the TGF-beta receptor family, are essential for maintaining vascular integrity. Another gene has been implicated in HHT; the HHT3 locus linked to chromosome 5. In the last 2 decades, the genetics, pathogenesis, clinical manifestations and management of HHT have been extensively researched. At this stage, it is deemed appropriate to review the wealth of information accumulated on the topic. Better understanding of the functions of endoglin, ALK-1, and other proteins involved in the pathogenesis of HHT should facilitate better management of patients with this disorder

Naxos disease in an Arab family is not caused by the Pk2 157del2 mutation

Naxos disease is a rare hereditary disorder characterized by palmoplantar keratoderma, woolly hair and cardiomyopathy. This study aims to determine whether Naxos disease in a Saudi Arab family is caused by the Pk2157del2 mutation that was identified in Greek families from Naxos Island where the disease had originally been described. This study was undertaken at King Fahad Hospital of the University, Al-Khobar, and the Medical University of Hannover, in the spring of 2003. Naxos disease has been encountered in a 2-year-old girl and her 30-year-old aunt of a Saudi Arab family. Deoxyribonucleic acid samples of this family were analyzed by polymerase chain-reaction [PCR] amplification of the respective region of the plakoglobin gene, and direct nucleotide sequencing of the PCR-products. Segregation analysis was performed employing the newly detected IVS11+22G/A polymorphism. Molecular genetic analysis of the DNA sample of the child diagnosed with Naxos disease showed absence of the Pk2157del2 mutation. In addition, the segregation analysis revealed heterozygosity for IVS11+22G/A in the affected girl. Absence of the Pk2157del2 frameshift in the affected child proved that Naxos disease in this Saudi Arab family is not caused by the same mutation that was identified in the Greek families. Furthermore, heterozygosity for the IVS11+22G/A polymorphism provided evidence for exclusion of the plakoglobin gene in this consanguineous family

Hereditary hemorrhagic telangiectasia: a case report

We report on the clinical presentation of a Saudi Arab with hereditary hemorrhagic telangiectasia [Osler-Rendu-Weber syndrome]. The gastric, ileocecal and pharyngeal telangiectases, that are prominent in this patient, were occasionally sites of serious episodes of bleeding. The lung lesions are multiple, small and discrete telangiectases but are clinically considered non-significant since the patient did not suffer from hemoptysis. The liver and brain are apparently not affected. A recent blood investigation of the patient revealed normal hematological parameters. The pedigree record of the patient's family showed that 61 out of 156 individuals in 6 generations are affected with the disease. Hereditary hemorrhagic telangiectasia follows an autosomal dominant mode of inheritance with high penetrance and variable expression. Generally, the gastrointestinal, brain and pulmonary lesions associated with the disease are sources of substantial morbidity and can lead to mortality in severe, cases. The investigational history and the recommended strategy for symptomatic treatment are presented

potential benefits of genetic testing in breast and ovarian cancer

This article reviews some of the recent molecular aspects of breast/ovarian tumorigenesis, addresses the application of BRCA1 and BRCA2 mutations as predictory markers, and discusses the benefits and limitations of the approach of molecular testing of the malignancy. The efficacy and controversy around the option of prophylactic surgery for affected women is also discussed. Apparently, the most significant advantage of genetic testing is the increased awareness of women, of high-risk families and carriers of BRCA1 and/or BRCA2 mutations, with the importance of periodic medical examination. Analysis of some recent data of breast/ovarian cancers among the female population of Saudi Arabia shows low onset age, low frequency and diagnosis at late stages of malignancy. The potential of molecular testing for diagnostic and counselling purposes in breast/ovarian cancers in this community is presented