Hereditary haemorrhagic telangiectasia I78.0

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 25.01.2023

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Familial hemorrhagic telangiectasia; hereditary hemorrhagic telangiectasia; HHT; HHTI; OMIM: 187300; OMIM: 600376; Osler M.; Osler's disease; Rendu-Osler syndrome; Rendu-Osler-Weber disease; Teleangiectasia hemorrhagica hereditaria; Teleangiectasia hereditaria hemorrhagica

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Sutton, 1864; Babington, 1865; Legg, 1876; Osler, 1901; Rendu, 1896

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Autosomal-dominant hereditary, hereditary systemic disease of increasing severity over the course of a lifetime with telangiectasia, arteriovenous aneurysms in the skin, mucous membrane and internal organs as well as recurrent bleeding. S.a. organoid naevi.

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Frequency 1:5000 - 1:40,000 depending on population group

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Type 1: autosomal-dominantly inherited mutations of the endoglin gene (HHT 1 gene or ENG gene; gene locus: 9q34.1; OMIM 187300) with consecutive disruption of endoglin.

Type 2: autosomal-dominantly inherited mutations of the activin A receptor, type II-like kinase 1 gene (HHT2 gene or ACVRLK1 gene; gene locus: 12q11 - 12q14; OMIM 600376) with consecutive disruption of activin A receptor-like kinase 1.

Type 3/4: other rare diseases are known. In familial juvenile polyposis, point mutations and large deletions in the SMAD4 gene (MADH4, DPC4 gene) are found in 30% of patients and in the BMPR1A gene in 20-25%. Patients with a SMAD4 germline mutation have an increased risk of developing gastric polyps and gastric cancer as well as hereditary hemorrhagic telangiectasia.

The individual phenotypes differ only slightly from each other, despite different genotypes. Type 1 is manifested earlier and shows AV shunts of the lung.

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Teleangiectasia is already possible in childhood, more pronounced and hemorrhagic diathesis in the 2nd or 3rd decade of life.

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Occurs mainly on the face (cheeks, zygomatic bone, auricles, lips, cheek and nose mucous membranes), chest, hands, feet, gastrointestinal tract (recurrent gastrointestinal bleeding), leptomeninx and retina.

Clinical features
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Teleangiectasia and angioma nodules: Blue-red to dark-red nodules, the size of a glass pinhead, protruding above the skin level in the shape of a dome, which can be pushed away with a glass spatula and are initially clinically noticeable on the lips and tongue.

Bleeding from the nose (recurrent spontaneous epistaxis in 70-90% of patients), mouth, gastrointestinal tract, and genitourinary tract is typical. Arterio-venous shunts may be present, possibly with large shunt volumes in the CNS and liver.

Rarely, paresthesias and Raynaud's-like circulatory disturbances occur.

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Hypochromic anemia.

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Ectatic, thin-walled capillaries, capillary neoplasms in the upper corium, dilated vessels in the deeper corium.

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The clinical diagnosis of HHT is made by the Curaçao criteria (see below) If at least three of the four criteria are met, the diagnosis of HHT is considered clinically confirmed.

  • Recurrent epistaxis
  • cutaneous and/or mucosal telangiectasia
  • visceral involvement
  • a first-degree family member with HHT

Clinical diagnosis is followed by human genetic counseling with molecular biology diagnostics to confirm the diagnosis.

After molecular biological confirmation, further investigations are aimed at identifying additional AV malformations typical for HHT.

  • Once a contrast-enhanced MRI of the neurocranium
  • Every 5 years a contrast-enhanced CT of the thorax
  • Every 5 years, a contrast-enhanced MRI or sonography of the liver or abdomen, respectively
  • Esophago-gastro-duodenoscopy and colonoscopy every 5 years

Differential diagnosis
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A causal therapy is not possible. In general, the therapy of HHT sets follows an individual concept which is adapted to the patient's needs and complaints.

For most patients, recurrent episodes of epistaxis are leading in terms of quality of life. Here, a meticulous mucosal care as well as regular nasal occlusions (1x daily 1-2h) are helpful. Furthermore, regular endonasal laser therapy by an experienced otolaryngologist can provide significant relief. Simple coagulation of the endonasal foci using bipolar forceps should be avoided because of the long-term consequences for the nasal mucosa and septum. In cases of pronounced epistaxis, the nasal valves can be surgically closed using "Young's procedure" - under this, epistaxis sits, but with loss of nasal breathing and part of the sense of smell.

Smaller cutaneous angiomas or possibly existing nevi aranei can be treated with laser treatment(argon, pulsed dye laser).

Gastrointestinal malformations should be treated endoscopically by laser, local sclerotherapy or argon plasma beam according to the experience of the respective center or endoscopist.

Larger malformations, especially of the liver and lungs, should be treated interventional if necessary.

Internal therapy
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Systemic therapies for HHT aim at inhibiting the underlying neoangiogenesis of the disease.

To date, all internal therapies for HHT are off-label - appropriate education and documentation are therefore essential. To date, all evidence is rather anecdotal literature; if necessary, an application for reimbursement has to be submitted to the responsible health insurance companies beforehand.

  • Bevacizumab (Avastin®) - target dose 10mg/kg bw every two weeks. Relatively high therapy costs are offset by comparatively good response rates.
  • Thalidomide/lenalidomide- Here, moderate success rates are offset by comparatively high dropout rates (up to 50% in the first year). CAVE: T prescriptions necessary.
  • Tacrolimus - Start with 1mg 1x tgl. for one week, then dosage according to serum level (target 2-3 µg/l). Comparatively low cost of therapy is offset by significant improvements in Hb, number of bleeds, and number of EC transfusions required, and relatively low dropout rates (20%).

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Patients with undiagnosed AV malformations in the CNS or gastrointestinal tract may develop severe, sometimes lethal hemorrhagic episodes. 1-2% of patients develop pulmonary hypertension due to pronounced pulmonary AV shunts, which is also regularly and rapidly lethal if left untreated. With adequate diagnosis, therapy and follow-up, life expectancy is not reduced compared to the normal population.

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  1. Babington BG (1865) Hereditary epistaxis.The Lancet (London) 2: 362-353
  2. Legg JW (1876) A case of haemophilia complicated with multiple naevi. Lancet 2: 856
  3. Long D, Marshman G (2004) Generalized essential telangiectasia. Australas J Dermatol 45: 67-69
  4. Ocran K et al (2003) Hereditary hemorrhagic teleangiectasia (Osler-Weber-Rendu disease). German Med Weekly 128: 2593-2597
  5. Osler WB (1901) On a family form of recurring epistaxis, associated with multiple telangiectases of the skin and mucous membranes. Johns Hopkins Hosp Bull 12: 333-337
  6. Rendu M (1896) Epistaxis répétés chez un sujet porteur de petits angiomes cutanés et muqueux.Lancette française: gazette des hôpitaux civils et militaires (Paris) 69: 1322-1323.
  7. Sadick H et al (2003) Argon plasma coagulation and topically applied estriol. Long-term results in the treatment of hereditary hemorrhagic telangiectasia of the nasal mucosa. HNO 51:118-124
  8. Sutton HG (1864) Epistaxis as an indication of impaired nutrition, and of degeneration of the vascular system Medical Mirror (London) 1: 769-781


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Last updated on: 25.01.2023