By middle age, most HHT patients will demonstrate marked telangiectasia on their lips, fingertips and buccal mucosa. In addition, the majority of HHT patients will be

affected by AVMs in at least one site, particularly in the pulmonary (up to 50%), Doxorubicin solubility dmso hepatic (20–30%) and cerebral (10%) circulations. The HHT disease spectrum has recently expanded further to encompass pulmonary hypertension (two forms predominate in HHT), juvenile polyposis, a prothrombotic state and potential immune dysfunction, each affecting a relatively small proportion of HHT-affected individuals. HHT presentation patterns are highly variable even within families. Major complications of HHT include: severe anaemia from chronic nasal and GI haemorrhage; stroke (ischaemic and brain abscess from pulmonary AVMs; haemorrhagic from cerebral AVMs); deep venous thromboses; in rarer cases, symptomatic liver disease requiring liver transplantation; severe pulmonary hypertension; pregnancy-related death; and spinovascular accidents. Overall, however, life expectancy is near normal, particularly for older individuals. Most HHT-affected individuals remain unaware that their symptoms or unusual medical conditions might be connected by a multisystem vascular disorder that is often poorly recognized by doctors. Three HHT disease-causing genes have been identified to date: HHT type 1 results

from mutations in ENG encoding endoglin; HHT type 2 results from mutations in ACVRL1 encoding ALK1 and HHT in association with juvenile polyposis (JPHT) results from mutations in MADH4. There are at least two further unidentified genes that can cause classical this website HHT. ENG and ACVRL1 genes are the most frequently mutated, and genetic testing is available. There PJ34 HCl are some important genotype–phenotype correlations. Pulmonary and cerebral AVMs are more common in HHT1. Hepatic AVMs and two forms of pulmonary hypertension are more common in HHT2. However, the frequency and severity of nose and GI bleeds have

not been shown to differ between genotypes. Several helpful review articles have been published in recent years, guiding management practice. In 2009, the International HHT Guidelines were published [33]. These resulted from systematic assessments of the HHT evidence base up to October 2006 and provided 33 recommendations. While these are a very helpful starting point for the field, it is important to recognize that 30 of the 33 recommendations were based on the lowest evidence level (level 3); three had low levels of agreement, and several have already been superseded by other publications, such as the American Heart Association’s statement on antibiotic prophylaxis [34]. A 2009 reference [35] incorporated an analysis of 2007–2009 publications, with further important subsequently published data including a randomized controlled clinical trial demonstrating efficacy of tamoxifen, and highly publicized reports on anti-angiogenesis agents such as bevazicimub.