Hereditary haemorrhagic telangiectasia I78.0

Autosomal dominant, hereditary, systemic disease that increases in severity over the course of life with telangiectasias, arteriovenous aneurysms in the skin, mucous membranes and internal organs as well as recurrent bleeding. See also organoid nevi.

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

Type 1: autosomal dominant inherited mutations of the endoglin gene(ENG gene; gene locus: 9q34.1; OMIM 187300) with consecutive disruption of endoglin.Detected in around 44%. The ENG gene, also known as the HHT1 gene, is a protein-coding gene located on chromosome 9q34.11.

Type 2: autosomal dominant inherited mutations in the ACVRL1 gene (also known as HHT2), which codes for the Activin A receptor, type II-like kinase. Detectable in around 52%. Gene locus: 12q11 - 12q14; OMIM 600376) with consecutive disruption of activin A receptor-like kinase 1. The ACVRL1 gene encodes a type I cell surface receptor for the TGF-beta superfamily of ligands. It shares a high degree of similarity with other type I receptors in the serine-threonine kinase subdomains, a glycine- and serine-rich region (the so-called GS domain) that precedes the kinase domain, and a short C-terminal tail.

Type3/4: Mutations in the SMAD4 gene. Detected in around 1%. Patients with an SMAD4 germline mutation have an increased risk of developing gastric polyps and gastric cancer.

The individual phenotypes differ only slightly from one another, despite the different genotypes. Type 1 manifests earlier and shows AV shunts of the lung.

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.

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.

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

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.

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%).

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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