Hereditary Hemorrhagic Telangiectasia - HHT

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disorder characterized by multiple telangiectases in the skin and mucous membranes. Arteriovenous malformations (AVMs) also frequently occur in the lungs, liver, gastrointestinal tract, and brain, and may lead to serious complications. The most common symptom of HHT is recurrent nosebleeds (epistaxis). Pathogenic variants of the ACVRL1 (also known as ALK1) and ENG genes are the most common causes of HHT. Genetic testing is used to confirm a clinical diagnosis or to establish a diagnosis in symptomatic individuals, and to identify disease in family members of individuals with a known pathogenic variant.  

Quick Answers for Clinicians

What are the criteria for the diagnosis of hereditary hemorrhagic telangiectasia?

The diagnosis of hereditary hemorrhagic telangiectasia (HHT) is based on specific established clinical criteria. Criteria include (1) recurrent epistaxis (nosebleeds); (2) mucocutaneous telangiectases (specifically on the fingertips, lips, and oral cavity); (3) internal arteriovenous malformations (AVMs) of the lungs, liver, gastrointestinal tract, and brain; and (4) a first-degree relative with HHT. HHT is considered confirmed in individuals who meet three or more criteria, suspected in those who meet two criteria, and unlikely in those who meet a single criterion. It is of note, however, that these diagnostic criteria were established for adults and will lead to missed diagnoses if applied to children. This is due to the onset in later childhood, or even early adulthood, of some features of HHT, particularly epistaxis and cutaneous telangiectases. For this reason, establishing a diagnosis by genetic testing is recommended in children born to a parent with confirmed HHT and a known causative mutation.

How should the location and number of telangiectases guide laboratory testing for vascular malformation disorders?

Both hereditary hemorrhagic telangiectasia (HHT) and capillary-malformation–arteriovenous malformation syndrome (CM-AVM) may present with cutaneous vascular lesions. Aside from the lips, however, the locations of telangiectases are different in HHT and CM-AVM. If telangiectases are present on the fingertips or in the oral cavity, this suggests HHT; consider testing for HHT beginning with the ACVRL1 and ENG genes (see Test Selection). If telangiectases are present on the trunk and extremities other than hands, this suggests CM-AVM; consider testing the RASA1 and EPHB4 genes. Also, telangiectases “too numerous to count” at any location suggest CM-AVM rather than HHT. 

What are common differential diagnoses for hereditary hemorrhagic telangiectasia, and how can these disorders be distinguished?

Juvenile polyposis syndrome/hereditary hemorrhagic telangiectasia (JPS/HHT) is a syndrome marked by a combination of symptoms that meet criteria for both JPS and HHT. JPS/HHT is caused by variants in the SMAD4 gene and is characterized by multiple juvenile polyps of the upper and lower gastrointestinal tract with risk for becoming malignant.  SMAD4 variants are detected in a small percentage (~1-2%) of individuals with HHT. The HHT “features” of JPS/HHT syndrome are indistinguishable from those in individuals with HHT1 (caused by mutations in ENG) or HHT2 (caused by mutations in ACVRL1).

GDF2 (also known as BMP9) variants have been detected in a very small number of patients (fewer than 10 patients to date) who have an “HHT-like” syndrome but do not meet clinical criteria for HHT. Variants in RASA1 and EPHB4 cause a capillary-malformation–arteriovenous malformation syndrome (CM-AVM) that may be mistaken for HHT due to clinical overlap (cutaneous vascular lesions and brain AVM). Thus, use of a multigene panel that includes ACVRL1, ENG, SMAD4, GDF2, RASA1, and EPHB4 can be used to diagnose or confirm a causative variant in those with HHT or one of several other overlapping vascular malformation disorders.

Indications for Testing

Molecular genetic testing is used to confirm or establish a diagnosis of HHT or a disorder with clinical overlap in symptomatic individuals, to identify a causative variant in a known affected family proband, and for familial testing of at-risk relatives.

Laboratory Testing

Identification of a heterozygous pathogenic variant in ACVRL1, ENG, or SMAD4 establishes the diagnosis of HHT.  Identification of a heterozygous pathogenic variant in GDF2 (also known as BMP9) establishes the diagnosis of an HHT-like telangiectasia syndrome. Identification of pathogenic variants in RASA1 and EPHB4 may be used to rule out the diagnosis of HHT and establish the diagnosis of capillary malformation–arteriovenous malformation syndrome (CM-AVM).

Test Selection

For individuals who meet established diagnostic criteria for HHT, sequencing and deletion/duplication analysis of ACVRL1 and ENG is recommended, with reflex sequencing and deletion/duplication of SMAD4 if no pathogenic variant is identified in ACVRL1 and ENG. SMAD4 testing may be considered as a first test in individuals with suspected HHT and clinical findings suggestive of juvenile polyposis syndrome. If testing of ACVRL1, ENG, and SMAD4 fails to establish the diagnosis, sequencing of GDF2 can be considered.  

A multigene panel that includes analysis of genes that either cause HHT (ACVRL1 and ENG), or a disorder with clinical overlap (SMAD4, GDF2, and genes that cause CM-AVM) may be used if clinical findings are inconclusive.  Genes tested, clinical sensitivity, costs, and methodology vary between panels; clinical judgment is required to select the appropriate panel test.

Familial variant testing is useful to confirm or rule out a diagnosis in at-risk family members if a known familial variant exists. More comprehensive testing (eg, whole exome sequencing) may also be used if other techniques fail to confirm the diagnosis, or to identify a causative mutation in a patient in whom HHT or a disorder with an overlapping clinical presentation is strongly suspected. 

Genes Tested in HHT and Disorders with Clinical Overlap
Gene Condition Percentage of HHT Cases Inheritance De novo Variants
ACVRL1a HHT2 ~47 AD Rare
ENG HHT1 ~47 AD Rare
SMAD4 JPS with or without HHT 1-2 AD ~25%
GDF2b HHT type 5 <1 AD Unknown
RASA1 CM-AVM or RASA1-related disorder n/a AD ~25%
EPHB4 CM-AVM n/a AD Unknown

aAlso known as ALK1

bAlso known as BMP9

AD, autosomal dominant; JPS, juvenile polyposis syndrome; n/a, not applicable

Sources: McDonald, 2015 ; Wooderchak-Donahue, 2019 ; McDonald, 2017 ; Amyere, 2017 ; Wooderchak-Donahue, 2013 ; Boon, 2005 ; Eerola, 2003 

ARUP Laboratory Tests

Family Proband Testing

Consider for symptomatic individuals who meet 3 or 4 clinical criteria for HHT (recurrent epistaxis, mucocutaneous telangiectases, internal AVMs, or first-degree relative with HHT)

Reflex: If results of test do not explain clinical scenario, SMAD4 testing will be added

Consider for symptomatic individuals, particularly individuals suspected of having HHT who do not meet established clinical criteria

Genes tested: ACVRL1, ENG, EPHB4, GDF2, RASA1, SMAD4

Test for individuals with clinical features of HHT, if sequential testing is desired

Follow with SMAD4 testing if no causative variant is identified in ACVRL1 or ENG

Confirm JPS/HHT

Test for individuals suspected of having a telangiectasia syndrome without a variant in ACVRL1, ENG, or SMAD4 genes

Familial Variant Tests

Test for a known familial sequence variant previously identified in a family member

Fetal testing to detect a previously characterized variant in a family member

Medical Experts

Contributor
Contributor

McDonald

Jamie McDonald, MS, LGC
Co-Director, Hereditary Hemorrhagic Telangiectasia Center, Associate Professor of Clinical Pathology, University of Utah
Genetic Counselor, ARUP Laboratories

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®