A 45-year-old woman presents with enlarging blood vessels on her tongue that recently have increased in size and number. Numerous 1- to 2-mm discrete red macules and papules are seen on her tongue, oral mucosa, nose, lower lip, and fingertips. She has had frequent nosebleeds since childhood as well as iron-deficiency anemia that has not responded to iron supplementation. Her father, who died at the age of 50, had similar symptoms.
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The diagnosis of hereditary hemorrhagic telangiectasia (HHT) syndrome, also known as Osler-Weber-Rendu disease, was made based on the patient’s medical and family history and characteristic clinical findings.
An autosomal dominant disease, HHT is a vascular disorder that manifests with telangiectases of the oral mucosa, lips, nose, and fingertips, as well as arteriovenous malformations (AVMs) affecting multiple organs, including the lungs, brain, and kidneys.1 HHT typically presents with a familial pattern of epistaxis and iron deficiency due to chronic gastrointestinal blood loss in the setting of telangiectasia.2
Henry Sutton, Benjamin Babington, and John Legg were the first to describe this familial syndrome of recurrent nosebleeds in the late 19th century.3-5 However, the disorder was named for 3 other 19th century physicians, William Osler, Henri Jules Louis Marie Rendu, and Frederick Parkes Weber, after they further characterized the syndrome and reported the association between epistaxis, mucocutaneous lesions, and visceral AVMs.6-8 In 1909, Frederic Hanes was the first to coin the term hereditary hemorrhagic telangiectasia, as the syndrome is called today.9
The current diagnostic criteria for HHT were established by international consensus in 2000.10 They are based on the Curaçao Criteria, which delineate a scoring system evaluating 4 features: spontaneous and recurrent epistaxis; multiple telangiectases at characteristic sites (lips, oral cavity, nose, and fingers); visceral involvement (eg, gastrointestinal telangiectasia; pulmonary, cerebral, or hepatic AVMs); and a first-degree relative with either the same clinical criteria or in whom HHT has been diagnosed genetically.3 If at least 3 of these criteria are present, a definite diagnosis of HHT can be made; if 2 criteria are present, a probable diagnosis can be considered; and if one or no criterion is present, a diagnosis of HHT is unlikely. Genetic testing is available to confirm the diagnosis but usually is not necessary.10
Mucocutaneous telangiectases are visible in about 75% to 90% of those with HHT.11 These appear as thin spider web-like red macules and papules with dilated superficial blood vessels (capillaries, venules, or arterioles) that blanch with pressure.11 Rare at birth, telangiectases normally develop by the third decade of life and increase in size and number with age.11 When telangiectases are present in the pediatric population, they often are found in places other than those listed as characteristic sites in the Curaçao criteria.12
Most clinical manifestations of HHT are due to mucocutaneous telangiectases. Their presence in the nose results in spontaneous and recurrent epistaxis, the most common presentation of HHT.11 Epistaxis tends to occur early in life, even before telangiectases become apparent.11 Telangiectases and small AVMs subsequently develop throughout the gastrointestinal tract, especially the stomach and duodenum; this can result in hemorrhage, most commonly in the fourth and fifth decades of life.11 Although 75% of patients have gastric or small intestinal telangiectases, only 33% have gastrointestinal bleeding.11
HHT occurs in approximately 1 in 5,000 to 8,000 live births.1 Although HHT is inherited in an autosomal dominant fashion, disease penetrance and expression vary greatly. These variations likely contribute to the low number of reported cases worldwide, since many cases are undiagnosed.1
Mutations causing HHT were detected as early as 1994.13 A total of 85% to 90% of cases studied have a mutation in either endoglin (ENG) or activin A receptor type II-like1 (ACVRL1), genes within a signaling pathway that regulates cell proliferation, differentiation, apoptosis, and migration.13 Mutations in SMAD4, which has a role in the same signaling pathway, account for about 10% of patients with HHT.14 Yet, there are a significant number of patients in whom the genetic abnormality has yet to be determined.13.14
HHT is not the only disorder to present with vascular dysplasia. Other conditions to consider in the differential diagnosis include benign and malignant tumors, vascular hemorrhage, and other systemic disorders that present with telangiectases, such as ataxia-telangiectasia, Bloom syndrome, cirrhosis of the liver, and various connective tissues diseases. Distinguishing these from HHT depends on vascular morphology as well various clinical indicators.
The cerebellar ataxia and immune deficiency associated with ataxia-telangiectasia and the anatomic abnormalities of Bloom syndrome allow for differentiation of these syndromes quickly. The classic spider angioma of cirrhosis has a distinct appearance, with a central perforating vessel and a surrounding array of capillaries. In lupus, dermatomyositis, and scleroderma, telangiectases typically affect the nail folds, not the nail beds, and facial and mucosal telangiectasia may be present. These conditions can be distinguished from HHT by their myriad other clinical and laboratory parameters.
After a diagnosis of HHT is made, practitioners can review consensus guidelines such as the International Guidelines for the Diagnosis and Management of HHT for information about how to screen for silent features of HHT.15 All individuals should be screened for pulmonary AVMs with chest computed tomography (CT); evidence suggests that identifying AVMs early may reduce the risk for stroke and brain abscess in patients older than 16 years of age.16 Iron status and complete blood counts should be assessed and monitored regularly. Screening for cerebral AVMs is controversial and depends on physician and patient preferences. It is important to refer patients to genetic counselors for education about the natural history of this disease and the benefits of screening family members.15
Treatments for HHT are focused on monitoring and ameliorating the signs and symptoms of the disease. However, recent preclinical studies have identified molecular targets directed at the signaling pathways of the disease that may offer future treatment options.14
Our patient was screened with a chest CT that revealed no pulmonary AVMs, and she opted to forego further imaging. Her blood count and iron stores will be monitored regularly, and gastrointestinal bleeding will be addressed as needed. In addition, she is working with a genetic counselor to consider genetic testing and screening for her 2 adolescent daughters.
Kelly McCoy, BS, MA, is a medical student at Virginia Commonwealth University, and Julia R. Nunley, MD, is a professor of dermatology at Virginia Commonwealth University in Richmond, Virginia.
1. Shovlin CL, Buscarini E, Kjeldsen AD, et al. European Reference Network For Rare Vascular Diseases (VASCERN) outcome measures for hereditary haemorrhagic telangiectasia (HHT). Orphanet J Rare Dis. 2018;13(1):136.
2. Fuchizaki U, Miyamori H, Kitagawa S, Kaneko S, Kobayashi K. Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease). Lancet. 2003;362(9394):1490-1494.
3. Sutton HG. Epistaxis as an indication of impaired nutrition and of degeneration of the vascular system. Med Mirror. 1864;1:769-781.
4. Babington BG. Hereditary epistaxis. Lancet. 1865;86(2195):362-363.
5. Legg JW. A case of haemophilia complicated with multiple naevi. Lancet. 1876;108(2781):856-857.
6. Rendu HJ. Épistaxis répétées chez un sujet porteur de petits angiomes cutanés et muqueux. Gaz Hop Paris. 1896;135:1322-1323.
7. Osler W. On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes. Bull Johns Hopkins Hosp. 1901;12:333-337.
8. Weber FP. Multiple hereditary developmental angiomata (telangiectases) of the skin and mucous membranes associated with recurring haemorrhages. Lancet. 1907;170(4377):160-162.
9. Hanes FM. Multiple hereditary telangiectasis causing hemorrhage (hereditary hemorrhagic telangiectasia). Bull Johns Hopkins Hosp. 1909;20:63-73.
10. Shovlin CL, Guttmacher AE, Buscarini E, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1):66-67.
11. Garg N, Khunger M, Gupta A, Kumar N. Optimal management of hereditary hemorrhagic telangiectasia. J Blood Med. 2014;5:191–206.
12. Gonzalez CD, Cipriano SD, Topham CA, et al. Localization and age distribution of telangiectases in children and adolescents with hereditary hemorrhagic telangiectasia: a retrospective cohort study. J Am Acad Dermatol. 2019;81(4):950-955.
13. McDonald J, Wooderchak-Donahue W, VanSant WC, et al. Hereditary hemorrhagic telangiectasia: genetics and molecular diagnostics in a new era. Front Genet. 2015;6:1
14. Robert F, Desroches-Castan A, Bailly S, Dupuis-Girod S, Feige JJ. Future treatments for hereditary hemorrhagic telangiectasia. Orpanet J Rare Dis. 2020;15(1):4.
15. Faughnan ME, Palda VA, Garcia-Tsao G, et al. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia. J Med Genet. 2011;48(2):73-87.
16. Shovlin CL, Jackson JE, Bamford KB, et al. Primary determinants of ischaemic stroke/brain abscess risks are independent of severity of pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia. Thorax. 2008;63(3):259-266.