Spotlight on a Rare Hematologic Disorder: Hereditary Hemorrhagic Telangiectasia

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Hematologists and oncologists are uniquely poised to aid in the identification of patients with hereditary hemorrhagic telangiectasia and assist in their care, and it is important for the practicing clinician to familiarize oneself with the symptoms of hereditary hemorrhagic telangiectasia to avoid overlooking the diagnosis.

Jennifer R. Green, MD

Jennifer R. Green, MD

Hereditary hemorrhagic telangiectasia (HHT), synonymous with Osler-Weber-Rendu Syndrome, is an inherited vascular disorder which affects multiple organ systems. HHT patients often have significant delays in diagnosis due to phenotypically variable and heterogeneous medical presentations.1 Hematologists and oncologists are uniquely poised to aid in the identification of these patients and assist in their care, and it is important for the practicing clinician to familiarize oneself with the symptoms of HHT to avoid overlooking the diagnosis. These patients may seek medical attention from the development of iron deficiency anemia (IDA) or may be referred to a hematologist for evaluation for a bleeding disorder due to epistaxis or gastrointestinal (GI) bleeding. Without an accurate diagnosis, patients can experience morbidity and mortality arising from untreated HHT.

Of note, the autosomal dominant inheritance pattern2,3 of HHT can affect multiple generations in the same family and has an estimated prevalence of 1 in 5000.3,4 Therefore, it stands to reason that identification of patients with HHT may also render a benefit to their affected biological relatives through detection of this inherited disorder. This underscores the importance of taking a careful family history. To best assist these patients and their families, clinicians must learn to recognize HHT.

HHT should typically be considered in adults with recurrent epistaxis, iron deficiency, telangiectasias, or arteriovenous malformations (AVMs) identified upon routine imaging or procedures, but other presentations are also possible. This multi-system disorder causes abnormal vasculature in multiple anatomic locations and can differ significantly in individual patients. Common sites for AVMs include the lungs, skin, liver, GI tract, nose, and brain with variability in the location, number, and sizes of AVMs. Patients commonly have visible telangiectasias in mucocutaneous locations such as the mouth or lips, or cutaneous locations such as the fingertips or face. Bleeding may manifest at the location of AVMs, and the bleeding phenotype ranges from mild to severe. Indeed, there may be variability in bleeding phenotypes in members of the same family.

Over 90% of HHT patients in adulthood will experience epistaxis, and most of these patients will also develop cutaneous telangiectasias, so these 2 features provide a useful clue to the diagnosis on an initial history and exam.5 Recurrent gastrointestinal (GI) bleeding can also occur in up to 30% of these patients5,6 related to visceral AVMs. Manifestations in the cardiopulmonary system and central nervous system (CNS) may include high output cardiac failure, pulmonary hypertension, cerebrovascular accident, headaches, seizures, or even CNS abscesses. Some patients with HHT unfortunately may have both bleeding and thrombosis as well.

An additional challenge for the hematologist could include the recognition of a small subset of HHT patients within the large number of patients with IDA non-related to HHT. With such potentially for variability, the Curacao Criteria aids clinicians as the consensus diagnostic criteria for HHT.3,5

The criteria include recurrent epistaxis, telangiectasias in classical locations (such as lips, tongue, fingertips, ears), the presence of visceral AVMs (hepatic, pulmonary, cerebral), and a confirmed first degree relative with HHT. Scoring of the criteria range from “0” to “≥3” and rate the likelihood of HHT as “unlikely” to “definite” respectively based on the number of criteria present. Diagnosis may be established either by the Curacao Criteria or by the identification of a pathogenic mutation.1,3,4

Pathogenic mutations in the genes ENG, ACVRL1, or SMAD4 are causative of a majority of HHT cases, however rarely GDF2 or RASA1 mutations may also cause HHT.2,6,7 Multigene panel testing is available to evaluate the most common mutations.7 The identification of a familial mutation can aid other biological relatives in diagnosis through targeted testing of first-degree relatives in the setting of a known pathogenic mutation. Genetic testing may be particularly useful in younger family members with a milder bleeding phenotype, since the bleeding symptoms of HHT often develop later in life, typically beginning at a median age of 12 years with high rates of epistaxis by age 40.3,5

Once the diagnosis of HHT has been established, additional resources become available for specialized clinical care at HHT Centers of Excellence (COE) nationally and internationally.1 Referral to COE provides access to multidisciplinary expertise in management of HHT. These centers have received certification for the knowledge and resources they provide for patients. They typically have experience in the management of HHT with multiple specialty approaches. There are 31 COE in North America currently.1 To learn more or to locate the nearest COE, please visit:

In summary, HHT may cause significant morbidity and mortality in multiple generations within families, many of whom do not yet have an identified name for their underlying diagnosis. Hematologists and oncologists should consider this not uncommon bleeding disorder for applicable patients with the goals of alleviation of the suffering associated with untreated HHT and to assist the patient in establishing care at a COE if possible.

Jennifer R. Green, MD, is director of the Hematology/Oncology Fellowship Program at Vanderbilt University Medical Center in Nashville, Tennessee.


  1. Signs & Symptoms. CureHHT. Accessed March 9, 2023.
  2. HHT Mutation Database. University of Utah. Accessed March 9, 2023.
  3. Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genetics. 2011;48(2):73-87. doi:10.1136/jmg.2009.069013
  4. Faughnan ME, Mager JJ, Hetts SW, et al. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med. 2020;173(12):989-1001. doi:10.7326/M20-1443.
  5. Diagnosis of HHT. International HHT Guidelines. Accessed March 9, 2023.
  6. Al-Samkari H. Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care. Blood. 2021;137(7):888-895. doi:10.1182/blood.2020008739
  7. Hammill AM, Wusik K, Kasthuri RS. Hereditary hemorrhagic telangiectasia (HHT): a practical guide to management. ASH Hematol Educ Program. 2021(1):469-477. doi:10.1182/hematology.2021000281
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