A newborn with hereditary haemorrhagic telangiectasia and an unusually severe phenotype.

UNLABELLED: Hereditary haemorrhagic telangiectasia (HHT), associated with arteriovenous malformations, is a genetic disease of the vascular system with a frequency of approx. 1:10,000. Genetic diagnosis serves to identify individuals at risk of developing the disease and is a useful tool for genetic counselling purposes. QUESTIONS UNDER STUDY: Here we report on a child presenting severe arteriovenous malformations leading to heart failure. Her mother and grandmother present fewer symptoms of hereditary haemorrhagic telangiectasia. In this study we identify the cause of HHT in the family. METHODS: Clinical examination, PCR, DNA sequencing, quantitative PCR, Southern blot, xray, ultrasound, cardiac catheterisation and angiocardiography. RESULTS: Initially the sequence variant in c.392C>T in the endoglin gene was detected in the grandmother, but not in other affected family members. Further analyses revealed a deletion of exon 1 of endoglin, segregating with the phenotype. CONCLUSIONS: This report points out the need for careful evaluation of molecular genetic findings, particularly in diseases with highly variable phenotype.

Novel mutations in the ENG and ACVRL1 genes causing hereditary hemorrhagic teleangiectasia.

Hereditary haemorrhagic teleangiectasia (HHT) is an autosomal dominantly inherited disorder characterised by cutaneous and mucosal telangiectasias, epistaxis and arteriovenous malformations in lung, liver, central nervous system and gastrointestinal tract. Mutations in the genes for endoglin (ENG) and for activin A receptor type II-like kinase 1 (ACVRL1) have been identified to cause HHT. We performed molecular diagnosis in clinically affected probands of 52 HHT families and detected mutations in 34 cases. We report on a total of 19 novel disease-causing mutations, 7 in ENG and 12 in ACVRL1. Three of the novel mutations affected acceptor splice-sites in the ENG gene. RNA analyses in these three patients and in two further patients described before resulted in reduction of the transcript or in a shortened transcript. Furthermore, we identified a family with the mutation c.199C>T in the ACVRL1 gene with liver AVMs. This is the fifth family with this mutation and liver AVMs, clearly indicating a genotype-phenotype correlation for this mutation.