Clinical Guidance

Essentially all known HHT pathogenic variants are null alleles, and no absolute genotype-phenotype correlations exist between clinical phenotypes and specific pathogenic variants or types of variants .

Source: GeneReviews — "Hereditary Hemorrhagic Telangiectasia"

Penetrance

The average age of onset is late childhood for epistaxis and early adulthood for mucocutaneous telangiectases. HTT is near fully penetrant by late adulthood .

Source: GeneReviews — "Hereditary Hemorrhagic Telangiectasia"

Diagnostic Criteria

Consensus clinical diagnostic criteria (Curaao criteria) for hereditary hemorrhagic telangiectasia (HHT) are available with proposed updates .

Suggestive Findings

HHT should be considered in an individual with any of the following revised Curaao criteria:

Source: GeneReviews — "Hereditary Hemorrhagic Telangiectasia"

Differential Diagnosis

Recurrent epistaxis can be a sign of various bleeding diatheses including von Willebrand disease , but may also be seen in otherwise healthy individuals. Telangiectases occur in a number of conditions:

Source: GeneReviews — "Hereditary Hemorrhagic Telangiectasia"

Management Guidelines

Guidelines for management of hereditary hemorrhagic telangiectasia (HHT) have been published . They should be considered supplementary to those recommended by an expert in clinical management of HHT as typically seen at HHT Centers of Excellence.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with HHT, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended .

Table 4.

Hereditary Hemorrhagic Telangiectasia: Recommended Evaluations Following Initial Diagnosis

System/Concern | Evaluation | Comment

Epistaxis/

Other bleeding/

Anemia

| • Assess for history of epistaxis GI bleeding.

• Nasal, oral, cutaneous exam for telangiectases

| Also consider other causes of anemia if disproportionate to the amount of epistaxis; medical problems unrelated to HHT (e.g., ulcers, colon cancer) can cause GI blood loss.

Complete blood count to assess for anemia /or polycythemia | Polycythemia raises suspicion for large pulmonary AVMs.

Ferritin level to assess for iron deficiency |

Pulmonary AVMs/

Pulmonary arterial

hypertension | • Assess for history of TIA, stroke, dyspnea, migraines, or hemoptysis.

Source: GeneReviews — "Hereditary Hemorrhagic Telangiectasia"

Clinical Guidance

Individuals with significant epistaxis are advised to avoid vigorous nose blowing, lifting of heavy objects, straining during bowel movements, and finger manipulation in the nose. Some individuals with HHT experience increased epistaxis after drinking alcohol. Anticoagulants including aspirin and nonsteroidal anti-inflammatory agents such as ibuprofen that interfere with normal clotting should be avoided unless required for treatment of other medical conditions. However, HHT is not an absolute contraindication for anticoagulation (prophylactic or therapeutic) or antiplatelet therapy. It is recommended that individuals with HHT receive these therapies when there is an indication, with consideration of their individualized bleeding risks . Two case series demonstrated that anticoagulation or antiplatelet therapy is well tolerated by most individuals with HHT . Note: A nonsteroidal anti-inflammatory drug that does not inhibit platelet aggregation may be preferred (e.g., celecoxib). When anticoagulation is pursued, unfractionated heparin, low-molecular-weight heparin, and vitamin K antagonists are preferred over direct-acting oral anticoagulants, which are less well tolerated in individuals with HHT . In individuals with atrial fibrillation, if anticoagulation is not tolerated, alternate approaches can be considered, such as left atrial appendage closure .

Source: GeneReviews — "Hereditary Hemorrhagic Telangiectasia"

Therapies Under Investigation

Newer therapies designed to interfere with the development of abnormal vascular connections are being investigated; while numerous case reports, small uncontrolled series, and small randomized clinical trials indicate promise, results from larger controlled trials are needed. Specific agents under various stages of study include the following:

Source: GeneReviews — "Hereditary Hemorrhagic Telangiectasia"

Surveillance Guidelines

The evaluations summarized in are recommended for all individuals with an established diagnosis of HHT and for all individuals at risk for HHT based on family history in whom HHT has not been ruled out by molecular genetic testing .

Table 7.

Hereditary Hemorrhagic Telangiectasia: Recommended Surveillance

System/Concern | Evaluation | Frequency

General

| Eval by health care provider familiar w/HHT, incl interval history for epistaxis, other bleeding, shortness of breath, reduced exercise tolerance, headache, other neurologic symptoms | Annually

Anemia

| • Hematocrit/Hgb

• Ferritin

Pulmonary AVMs

| • In adults: TCE w/agitated saline contrast if previous TCE did not reveal evidence of significant right-to-left shunt

• In children: TCE w/agitated saline contrast OR chest radiograph w/pulse oximetry1

| • TCE should generally be done every 5 yrs in those w/normal TCE.

• Some HHT centers recommend continued surveillance w/TCE for those w/mild shunt2 proceed to chest CT if shunt worsens to moderate or severe. Other centers perform chest CT in all persons w/abnormal findings on TCE (even mild shunt), then monitor by chest CT every 5 yrs.

Cerebral AVMs

| Brain MRI (w/ w/o contrast using sequences that detect blood products) | • Repeat MRI by age 18-20 yrs is routinely done in the US3 if initial MRI was done in childhood, as development or evolution of cerebral AVMs in 1st 2 decades of life has been reported.4

Source: GeneReviews — "Hereditary Hemorrhagic Telangiectasia"