Key Points
Disease summary:
Hereditary hemorrhagic telangiectasia (HHT) is a disorder of vascular development that results in direct communication between arteries and veins.
Multiple organs are affected and the development of clinical features is age dependent. Telangiectases in the nose cause epistaxis severe enough to cause chronic anemia. Vascular anomalies in the brain and spinal column cause stroke or seizures. Pulmonary arteriovenous malformations (PAVMs) cause hypoxemia and high-output cardiac failure because of shunting and provide a conduit for clots and bacteria to cause embolic stroke and cerebral abscess. Hepatic AVMs cause high-output cardiac failure and cirrhosis. A late finding is gastrointestinal (GI) telangiectases that cause chronic blood loss.
While today mortality is only modestly increased, the clinical features cause considerable morbidity and diminished quality of life.
Hereditary basis:
HHT is an autosomal dominant condition of considerable variability found in all populations. Reproduction is little affected so sporadic cases are uncommon. Most cases (>80%) are due to mutations in either ENG or ACVRL1, the products of which function as cell surface receptors in the TGF-β/BMP signaling pathway. Mutations in SMAD4 cause HHT combined with juvenile polyposis. Some families show linkage to none of these loci.
Differential diagnosis:
A number of syndromes include cutaneous or sclera telangiectases (ataxia telangiectasia, CREST syndrome, chronic liver disease, hereditary benign telangiectasia, pregnancy) but not the visceral vascular anomalies.
An isolated PAVM can occur in the absence of other features of HHT.
Vascular dysplasias can accumulate in GI mucosa with age and cause chronic blood loss.
Diagnostic Criteria and Clinical Characteristics
The Curacao criteria have been expanded to include molecular genetic testing. In the absence of a mutation, three of the following four criteria are required to diagnose HHT:
Epistaxis
Visceral AVMs
Mucocutaneous telangiectases
A family history of documented HHT
Having two of these criteria qualify for possible HHT.
Having a pathogenic mutation in ENG, ACVRL1, or SMAD4 known to cause HHT in either the patient’s family of another individual with documented HHT qualifies for a diagnosis of HHT.
Patients present with recurrent epistaxis, anemia, cutaneous telangiectases, dyspnea due to hypoxemia or heart failure, liver failure, embolic or hemorrhagic stroke, or cerebral abscess.
Screening and Counseling
When HHT is suspected, such as in a relative of a person with documented HHT or in a person with one of the Curacao criteria, a protocol for establishing or discarding the diagnosis of HHT is as follows:
In a family in which the pathogenic mutation is known, DNA testing is the most effective and most economic method of screening.
Brain magnetic resonance imaging (MRI) to detect cerebral vascular anomalies and occult stroke(s) and cerebral abscess.
Contrast echocardiogram to detect elevated pulmonary artery pressure or delayed passage (4-8 cardiac cycles) of contrast from the right ventricle into the left atrium. Immediate passage of contrast suggests a cardiac septal defect, especially a patent foramen ovale, and no information about the integrity of the pulmonary capillary circulation can be inferred. In either case of contrast in the left atrium, a high-resolution computed tomographic angiogram (CTA) of the lungs is needed to determine whether a pulmonary AVM (PAVM) is present, how many, where, and the size of the feeding artery(ies).
Typically, the chest CT also visualizes much of the liver, so information about the presence of hepatic AVMs is also obtained. But if a chest CT is not needed, then screening of the liver is generally not needed for diagnostic purposes.
Upper and lower endoscopy of the GI tract can detect mucosal telangiectases; while the presence of such lesion may be useful for satisfying the Curacao criterion of visceral AVMs, such testing is generally not used for screening purposes.
