Introduction
Hereditary hemorrhagic telangiectasia (HHT), also referred to as the
Osler-Weber-Rendu syndrome, is a rare autosomal dominant hereditary
disease that results in abnormal vasculogenesis in the skin, mucous
membranes, and visceral organs such as the liver, lungs, and brain
[1]. The prevalence of HHT ranges from one in every 5,000 people to
one in every 8,000 people with an estimated 85,000 cases in Europe [2,
3] and the rate of diagnosis is lower in lower socioeconomic groups
[4].
Four important genes, including ENG (endoglin), ACVRL1 (activin
receptor-like kinase 1), SMAD4 (mothers against decapentaplegic homolog
4), and GDF2 (growth differentiation factor 2), have recently been
linked to the underlying mechanism of HHT [5]. Arterio-venous
malformations (AVMs) are caused by mutations in these genes that
interfere with the TGF-β (transforming growth factor)-beta signaling
pathways in vascular endothelial cells, which impair cell division
[5]. Heterozygous mutations are the common cause of the two primary
kinds of HHT. Endoglin (ENG) is mutated in HHT1. Patients, especially
women, with this type are more likely to develop pulmonary and cerebral
AVMs. Activin A receptor-like type 1 (ACVRL1), commonly referred to as
ALK1, is mutated in HHT2. Of the mutations known to cause HHT, ENG makes
up around 61% and ACVRL1 makes up about 37% [7, 8].
About 90% of those with the condition experience recurrent nosebleeds,
which usually begin in childhood. Other symptoms include
gastrointestinal bleeding (25–30%), which can cause melena and severe
symptomatic microcytic anemia; pulmonary AVMs (50%) that can cause
dyspnea, hemoptysis, paradoxical emboli, and cerebral abscesses;
cerebral AVMs (10%) that can cause headache, seizures, and focal
neurological deficits; and hepatic AVM (40–70%), which are typically
asymptomatic but might show signs of high output cardiac failure and
hepatic decompensation, ultimately necessitating liver transplantation
[9].
Clinical diagnosis of HHT is made using the Curacao criteria, which
include first-degree family history of HHT, visceral involvement,
recurrent spontaneous nosebleeds, and mucocutaneous telangiectasias. If
three or more criteria are met, the diagnosis is considered to be
conclusive; if only two criteria are met, the diagnosis is considered to
be suspected HHT [10] [Table 1]. If less than two criteria are
met, the diagnosis is considered to be unlikely HHT.
Table 1 Curaçao diagnostic criteria for hereditary hemorrhagic
telangiectasias