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
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 and lips and in the 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. However, these diagnostic criteria were established for adults and will lead to missed diagnoses if applied to children because some features of HHT, particularly epistaxis and cutaneous telangiectases, do not develop until later childhood or even early adulthood. For this reason, establishing a diagnosis by genetic testing is recommended in children born to a parent with confirmed HHT and a known causative variant.
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. Telangiectases on the fingertips or in the oral cavity are suggestive of HHT, and testing for HHT beginning with the ACVRL1 and ENG genes should be considered (see Test Selection). Telangiectases on the trunk and extremities other than hands are suggestive of CM-AVM, and RASA1 and EPHB4 gene testing should be considered. Telangiectases “too numerous to count” at any location suggest CM-AVM rather than HHT.
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 (approximately 1-2%) of individuals with HHT. The HHT “features” of JPS/HHT syndrome are indistinguishable from those in individuals with HHT1 (caused by pathogenic variants in ENG) or HHT2 (caused by pathogenic variants in ACVRL1).
GDF2 (also known as BMP9) pathogenic 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. Pathogenic 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.
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 can be used to rule out the diagnosis of HHT and establish the diagnosis of capillary malformation-arteriovenous malformation syndrome (CM-AVM).
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 or ENG. SMAD4 testing can be considered as a first test in individuals with suspected HHT and clinical findings suggestive of juvenile polyposis syndrome (JPS). 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 cause either HHT (ACVRL1 and ENG) or a disorder with clinical overlap (SMAD4, GDF2, and genes that cause CM-AVM) can 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. Genetic testing should be offered to children of parents with HHT, even in the absence of symptoms. More comprehensive testing (eg, whole exome sequencing) can also be used if other techniques fail to confirm the diagnosis, or to identify a pathogenic variant in a patient in whom HHT or a disorder with an overlapping clinical presentation is strongly suspected.
|Gene||Condition||Percentage of HHT Cases||Inheritance||De novo Variants|
|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%|
aAlso known as ALK1.
bAlso known as BMP9.
AD, autosomal dominant; n/a, not applicable
All adult and pediatric patients with HHT who experience recurring bleeding or symptoms of anemia should be assessed for iron deficiency anemia; evaluation includes CBC and ferritin testing and may include serum iron and iron-binding capacity testing.
If anemia is present and persists in spite of iron replacement therapy, testing for other causes of anemia should be considered. For more information, see the ARUP Consult Anemia topic.
ARUP Laboratory Tests
Consider for symptomatic individuals who meet 3 or 4 clinical criteria for HHT (recurrent epistaxis, mucocutaneous telangiectases at characteristic sites, internal AVMs, or first-degree relative with HHT)
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray
Genes tested: ACVRL1, ENG, EPHB4, GDF2, RASA1, SMAD4
Use for individuals suspected of having a telangiectasia syndrome without a variant in ACVRL1, ENG, or SMAD4 genes
Polymerase Chain Reaction/Sequencing
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
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