No live individual homozygous for a novel endoglin mutation was found in a consanguineous Arab family with hereditary haemorrhagic telangiectasia.

H ereditary haemorrhagic telangiectasia (HHT or RenduOsler-Weber syndrome; MIM 187300) is characterised by vascular dysplasia and is inherited in an autosomal dominant manner. HHT occurs among many ethnic groups over a wide geographical area. Recent epidemiological studies have revealed an incidence for this disease of 1 in 5000– 8000. 2 In most cases, the manifestations of HHT are not present at birth, but develop with age; epistaxis is usually the earliest sign, often occurring in childhood, while mucocutaneous and gastrointestinal telangiectases develop progressively with age. Arteriovenous malformations (AVMs) in the pulmonary, cerebral, or hepatic circulations account for some of the most devastating clinical complications of HHT and are due to direct connections between arteries and veins. The shunting of blood through these lesions can lead to serious complications such as hypoxemia, stroke, brain abscess, heart failure, and fatal haemorrhage. 5 Pulmonary and cerebral AVMs can occur in children, while hepatic complications increase with age. HHT1 is associated with a higher prevalence of pulmonary and cerebral AVMs than HHT2. HHT1 is due to mutations in the Endoglin gene (ENG; MIM 131195), which codes for a homodimeric integral membrane glycoprotein expressed predominantly on the vascular endothelium. A total of 112 distinct ENG mutations distributed throughout the gene have been reported. Mutations in the ALK-1 gene (ACVRL1; MIM 601284), coding for an activin-like kinase receptor type I of the TGF-b superfamily predominantly expressed in endothelial cells, 12–14 are responsible for HHT2. A total of 80 mutations of different types have been identified to date. 11 The underlying mechanism of HHT1 (and probably HHT2) is haploinsufficiency, which implies that a reduction in the amount of protein to half normal levels predisposes to disease and that mutation type or position does not affect the clinical outcome. Mice engineered to express a single copy of Endoglin (Eng) can develop signs of disease including nose and ear bleeds, telangiectases, and cerebral AVMs, as well as serious complications such as internal haemorrhage and stroke. However, Endoglin null (Eng) mice die at embryonic day E10.5, with severe impairment in the development of blood vessels and heart. Mice heterozygous for Alk-1 can also develop signs of HHT, while Alk-1 null mice die at mid-gestation of vascular defects. These results demonstrate that both genes responsible for HHT when expressed as single alleles are embryonically lethal in the homozygous state. There is currently no report of a genetically confirmed case of homozygosity in human HHT. Snyder and Doan reported a newborn with generalised telangiectasia who died at 11 weeks of age due to internal organ haemorrhage as was demonstrated in post mortem examination. Both parents were found to have multiple telangiectasia but no evidence of bleeding or visceral involvement. Muller et al later described a large Arab family with 87 affected individuals in six generations and known consanguinity. One individual who had 13 affected children was predicted by statistical analysis to be homozygous for the disease. These two reports were published long before the discovery of causative genes and therefore were not confirmed by mutation analysis. As the clinical diagnosis of HHT is often confounding, one can speculate that it was not definite in all clinically diagnosed individuals. For example, someone with nosebleeds or skin telangiectasia might have been given a positive diagnosis because of the well known family history. We now report the analysis of a second large Arab family with a history of HHT and known consanguinity. We identified a novel ENG missense mutation that segregates with the HHT phenotype. No live child homozygous for the mutant allele was found in a marriage between first cousins, supporting the embryonic lethality observed for this phenotype in the mouse model.