Important note: This background is “as is” from the First HHT Guidelines. To access references or the complete manuscript, refer to the First Guidelines.

Making the diagnosis of HHT in a patient allows the appropriate screening and preventive treatment to be undertaken in the patient and their affected family members. HHT has traditionally been diagnosed on the basis of its clinical features, but can now also be diagnosed using genetic testing. We reviewed the evidence and expert experience for clinical and genetic diagnosis in HHT.

The clinical diagnostic features of HHT have been identified by describing the clinical presentation of patients who have known or suspected HHT and their close relatives. The average age of onset for epistaxis is 12 years, with nearly 100% affected by age 40 years(2,8-10). Most patients report the appearance of telangiectasia of the mouth, face or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade. Unfortunately, there are no longitudinal natural history studies of HHTclinical manifestations and how these might vary with genotype. 

In 2000, consensus clinical diagnostic criteria known as the Curaçao Criteria were published (11) (table 2). Using these criteria, a diagnosis of HHT is considered ‘definite’ if three or more criteria are present, ‘possible or suspected’ if two criteria are present, and ‘unlikely’ if 0 or 1 criterion is present.

There have been no studies reporting sensitivity and specificity of the Curaçao Criteria, but the expert panel agreed that the Curaçao Criteria are particularly helpful in two situations: (1) discriminating affected from non-affected older adults and (2) ruling-in the diagnosis in younger adults and children. The expert panel was specifically concerned about the risk of missing diagnoses in children and young adults, who might have no epistaxis or visible telangiectases, yet have undiagnosed PAVMs or CVMs (12).  It is in these groups that genetic testing should be most useful. 

The goal of genetic testing for HHT is to clarify the specific HHT mutation in an HHT family, allowing diagnosis among those relatives (often children and young adults) who do not meet clinical diagnostic criteria. Genetic testing is performed first on the index case in the family and involves DNA sequencing and deletion/duplication analysis of the coding exons of the endoglin gene (ENG, HHT1) and the activin A receptor type II-like 1 gene (ACVRL1, HHT2). Mutations in these genes account for the majority of cases of HHT. At least two other HHT loci have been described, although specific genes at these loci are not yet identified (13,14). Mutations in the SMAD4 gene can cause a rare syndrome which combines juvenile polyposis and HHT(15). Genetic testing in HHT is complex relative to many other genetic conditions because a mutation in one of multiple genes can cause the condition, not all genes that can cause HHT have been discovered, and there are no ‘common mutations’, with most families having their own ‘private’ HHT mutation. 

Several authors have reported (16,17) a clinical sensitivity/ mutation detection rate of ~75% for sequence analysis of ENG and ACVRL1. Use of an additional method to detect large deletion/duplication mutations increases the detection rate by ~10% (16,17). Recent reports suggest that about 1-3% of patients clinically diagnosed with HHTwill have a mutation detected in the SMAD4 gene, or about 10% of those who test negative for ENG and ACVRL1 mutations (17-19). There is considerable clinical overlap between patients/families with ENG mutation and those with ACVRL1 mutation, with VMs reported in similar organs in both types (20-22). The expert panel agreed that ENG versus ACVRL1 genotype should not significantly influence screening recommendations for VMs. Most HHT patients/families with SMAD4 mutation reported to date have juvenile polyposis and are therefore at risk of GI malignancy (15-18).

There is currently no evidence about the effect of prenatal testing for HHT and no consensus among experts about how fetal diagnosis might alter pregnancy or delivery management. Expert experience is that prenatal diagnosis is not commonly sought in HHT, and is most often requested as an alternative to postnatal diagnostic testing when there is already another reason for performing prenatal testing.

Important note: this background is “as is” from the First HHT Guidelines. To access references or the complete manuscript, refer to the First Guidelines.