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.

Hereditary hemorrhagic telangiectasia is caused by the Q490X mutation of the ACVRL1 gene in a large Arab family: support of homozygous lethality.

In a large Saudi Arabian family with hereditary hemorrhagic telangiectasia (HHT), we identified ACVRL1 (ALK1) nonsense mutation Q490X in 40 HHT patients and three healthy children, but neither in 11 individuals with epistaxis, 41 other healthy family members, nor in 50 healthy unrelated Saudi Arabian controls. Sequence analysis of the entire coding region of the ACVRL1 and ENG genes in five of the 11 epistaxic individuals did not reveal any other disease-causing mutation. Epistaxis seems to be a relatively common phenocopy of HHT in the family under study. One couple, both affected by HHT and carriers of Q490X, had 12 pregnancies. Three of them ended in spontaneous abortion, four in early neonatal death, and only five yielded living offspring, all of which had HHT and were Q490X heterozygous. This observation corroborates previous claims that homozygosity for HHT-causing mutations is lethal.

Increased seroprevalence of human herpes virus-8 in renal transplant recipients in Saudi Arabia.

BACKGROUND: Human herpes virus-8 (HHV-8) is a herpes virus that is always associated with Kaposi's sarcoma. Previous studies suggested a high rate of Kaposi's sarcoma in renal transplant patients in Saudi Arabia. The aim of this study was to investigate the prevalence of HHV-8 in Saudi renal transplant recipients and healthy controls. METHODS: An immunofluorescence technique was used to detect antibodies to the latent nuclear antigen (LANA) of HHV-8 in renal transplant patients, members of a family affected with Kaposi sarcoma, as well as healthy controls. RESULTS: A significantly higher HHV-8 seroprevalence was detected in renal transplant recipients from Saudi Arabia (27 out of 150; 18%) and in members of a family affected with Kaposi sarcoma (seven out of 10; 70%) relative to the seroprevalence in healthy controls (10 out of 577; 1.7%). Seropositivity for HHV-8 in these transplant patients was not significantly influenced by: the existence of relatives with kidney failure, the donors' country of origin, the recipients' home region within Saudi Arabia, the haemodialysis centre, the time that elapsed since the renal transplantation operation and the immunosuppressive regimen used. CONCLUSION: The present results provide some explanation for the previously noted high incidence of Kaposi's sarcoma in Saudi transplant patients.

Hepatic manifestation is associated with ALK1 in hereditary hemorrhagic telangiectasia: identification of five novel ALK1 and one novel ENG mutations.

Hereditary hemorrhagic telangiectasia (HHT), or Osler-Rendu-Weber syndrome, is a heterogeneous inherited disorder characterized by multi-systemic vascular dysplasia and wide variation in its phenotypic expression. Hepatic manifestation is seen in about 8 to 30 % of the patients. The molecular basis for liver involvement is unknown. We screened the two known HHT disease loci, the ALK1 (ACVRL1) and ENG genes, for mutations in a clinically well-characterized group of HHT patients with or without liver involvement. Mutations in the ALK1 gene were detected in eight out of 10 HHT patients with hepatic manifestation. Among nine HHT patients without liver involvement, four had mutations in the ALK1, and three in the ENG genes, respectively. In one patient with hepatic manifestation a mutation was detected in both the ALK1 and ENG genes. No mutation could be detected in two patients with liver involvement and, likewise, in two patients without hepatic manifestation. In this study, we have identified five novel ALK1 and one ENG disease-causing mutations. We conclude that hepatic manifestation in HHT patients is associated with mutations in the ALK1 gene, but rarely with ENG mutations.

Naxos disease in an Arab family is not caused by the Pk2157del2 mutation. Evidence for exclusion of the plakoglobin gene.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The cytokine TNF-alpha. Genetics and suitability for prenatal risks assessment.

The tumor necrosis factor (TNF-alpha) is a cytokine known as a mediator of inflammation and immunity. The genes coding the tumor necrosis factors alpha and beta are considered part of class III major histocompatability complex. The 2 involved genes have been mapped to chromosome 6. Certain mutations in the TNF-alpha gene are believed to be causative for increased production of the cytokine. In this respect, the most common variant is the TNF2 allele, a single nucleotide substitution of guanine by adenine at position -308 relative to the promoter transcription site of the gene. Elevated production of TNF-alpha has been found to be associated with several infectious diseases including malaria. Elevated levels of TNF-alpha have also been observed to associate with increased risk of preterm delivery, chorioamnionitis and fetal morbidity including encephalopathy. The present article reviews the genetics of the cytokine TNF-alpha and discusses its suitability as a candidate marker for assessment of increased risk of preterm delivery and fetal morbidity.

Pre-eclampsia: maternal risk factors and perinatal outcome.

OBJECTIVE: The aim of this study was to throw light on the incidence of pre-eclampsia (PE) in women attending for care and delivery at a hospital in Saudi Arabia, and analyze the maternal risk factors and outcome of mothers and neonates in pregnancies complicated by PE. METHODS: This retrospective study involved almost all women (n = 27,787) who delivered at King Fahad Hospital of the University in a 10-year period (1992-2001). The maternal records were reviewed for age, parity, gestational age, mode of delivery, antenatal care, onset of PE, severity of proteinuria, and the frequency of antenatal and intrapartum complications. The neonatal records were reviewed for perinatal outcome including birth weight, frequency of stillbirths, and neonatal deaths. RESULTS: Among the study cohort of pregnancies, 685 women, i.e. 2.47%, were diagnosed as having PE among whom a high proportion (42.0%) were nulliparous women. Similarly, PE was encountered at a high percentage (40.0%) in women at the extreme of their reproductive age (< 20 and >40 years), and more women with PE delivered prematurely (30.2%) as compared to healthy controls (13.5%). Spontaneous vaginal deliveries were less frequent in women with PE (69.2%) as compared with healthy controls (86.2%). Instrumental deliveries, with spontaneous labor, amounted to 15.9% in women with PE, but they comprised only 2.9% in healthy women. The deliveries were more likely to be induced (22.8%) or be performed by cesarean section (14.9%) in women with PE than in healthy controls (6.8% and 9.6%). Placental abruption was the most common maternal complication (12.6%) in women with PE, followed by oligouria (7.9%), coagulopathy (6.0%), and renal failure (4.1%). The perinatal outcome of pregnancies with PE shows that stillbirths (2.34%) and early neonatal deaths (1.02%) comprised an overall mortality rate of 33.6 per 1,000. More stillbirths and neonatal deaths showed a tendency to be associated with the severe form of PE (diastolic BP > or =120), as compared with the mild form (diastolic BP 90-110). Stillbirths and neonatal deaths appear to be associated with women who had no or irregular antenatal care and whose proteinuria amounted to or exceeded 3 g per 24 h, when delivery occurred at 28th gestational week or less, and when the birth-weight of the neonates was between 500 and 1,000 g. CONCLUSION: We document a hospital-based incidence rate of PE of 2.47%, with a high proportion of PE cases occurring among nulliparous women and those at the extreme ends of the reproductive age. More maternal and neonatal complications were encountered in women with PE when the PE was severe, when the pregnancy had to be terminated early, when there was no regular antenatal care, the birth-weight was low, or the proteinuria was severe.

BRCA1 and BRCA2 mutations in breast cancer patients from Saudi Arabia.

OBJECTIVE: The aim of this pilot study was to screen the major segments of the BRCA1 and BRCA2 genes for disease-associated mutations in Arab and Asian women with breast cancer from the Kingdom of Saudi Arabia. METHODS: Deoxyribonucleic acid samples from 29 Arab women and 11 Asian women, with unilateral breast cancer were investigated for BRCA1 and BRCA2 mutations. For this purpose single strand conformation polymorphism and direct nucleotide sequencing techniques were employed. This study was carried out at King Fahad Hospital of the University, Al-Khobar, Kingdom of Saudi Arabia, during the time frame March 2000 through to August 2001. RESULTS: One novel BRCA2 truncating mutation, the frame-shift mutation 2482delGACT, was uncovered in an Arab patient of Palestinian descent. This mutation is a 4-nucleotide deletion that creates a stop signal at codon 770 of the BRCA2 transcript. The BRCA1 disease-associated mutation Arg841Trp was detected in another Arab patient from Egypt. The clinical presentation in the 2 heterozygous carriers of these 2 mutations is described here. In addition the unclassified BRCA1 variant Phe486Leu combined with Asn550His, and the unclassified BRCA2 variant Asp1420Tyr, were identified in Arab patients. Five BRCA1 polymorphisms and 6 BRCA2 polymorphisms were detected at different allele frequencies in both mutation carriers and patients with normal genotype. CONCLUSION: We conclude that BRCA1 and BRCA2 mutations are likely to contribute to the pathogenesis of familial breast cancer in female patients from the Kingdom of Saudi Arabia.

PCR-based analysis of cystic fibrosis mutations specific for Saudi patients.

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