Hereditary haemorrhagic telangiectasia: a clinical and scientific review

Abstract

The autosomal-dominant trait hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5-8000 people. Genes mutated in HHT (most commonly for endoglin or activin receptor-like kinase (ALK1)) encode proteins that modulate transforming growth factor (TGF)-beta superfamily signalling in vascular endothelial cells; mutations lead to the development of fragile telangiectatic vessels and arteriovenous malformations. In this article, we review the underlying molecular, cellular and circulatory pathobiology; explore HHT clinical and genetic diagnostic strategies; present detailed considerations regarding screening for asymptomatic visceral involvement; and provide overviews of management strategies.

Figure 1

HHT images. (a) Fingertip and (b) gastrointestinal telangiectasia (largest examples arrowed). (c) × 40 magnification of oral telangiectasis in an individual with HHT compared with control (inset). Note ruptured wall denoted by arrow. (d) Pulmonary AVM (arrowed) pre (i) and post (ii) embolisation: Angiograms are presented courtesy of Dr James Jackson.

Figure 2

Circulatory explanation of HHT phenotypes. (a) Schematic of systemic and pulmonary circulations showing capillary beds in which HHT telangiectasia and AVMs occur. Note the pulmonary post capillary veins are in direct communication with the left atrium, and the portal vein which drains from the gastrointestinal tract to liver acinus. (b) Illustration of two separate pathologies resulting in severe pulmonary hypertension in two women with HHT (reported in Shovlin et al). Note case 1 has markedly elevated intrinsic pulmonary vascular resistance, whereas this is near-normal in case 2, who has hepatic AVM-associated high output cardiac failure characterised by elevated cardiac output, cardiac index (not shown), and left atrial pressure.

Figure 3

Schematic representations of HHT1-4. (a) HHT1: Summary of 311 ENG mutations reported to http://www.hhtmut.org. Note high proportion of frameshift mutations. (b) HHT2: Summary of 250 ACVRL1 mutations reported to http://www.hhtmut.org. Note higher frequency in exons 3, 7 and 8, and lower proportion of frameshift mutations. (c) HHT3: 6 Mb HHT3 interval defined by key recombinants (black bars) between D5S2011 and D5S2490. Uninformative regions are shown by shaded bars. Ensembl predicts 29 genes in this interval. (d) HHT4: 7 Mb HHT4 interval between D7S2252 and D7S510. Ensembl predicts 57 genes in this interval. Mb, mega base.

Figure 4

TGF-β superfamily signalling pathways. Endoglin can interact with type I and type II receptors. The genes mutated in HHT are highlighted in bold.

Figure 5

Schematic of management approaches. Similar principles operate throughout most HHT specialised services. (^∧,*): Further details are provided in the text.