Hereditary hemorrhagic telangiectasia
|Hereditary hemorrhagic telangiectasia|
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Kiran Singh, M.D. 
Synonyms and keywords: HHT, Osler-Weber-Rendu syndrome
Hereditary hemorrhagic telangiectasia (HHT), also known as Osler-Weber-Rendu syndrome, is an autosomal dominant genetic disorder that leads to vascular malformations.
Signs and symptoms
HHT is characterised by telangiectasia (small vascular malformations) on the skin and mucosal linings, epistaxis (nosebleeds), and arteriovenous malformations (AVMs) in various internal organs. Skin and mucosa telangiectasias are most remarkable on the tongue, hands/fingers, nose, lips, mouth/throat and conjunctiva.
The internal organs that can harbor AVMs often include the brain and lungs. In both, bleeding can seriously endanger life. Anemia may occur due to bleeding from digestive tract AVMs. Congestive cardiac failure (high-output heart failure) may develop in the presence of marked shunting arterial blood to the venous circulation, e.g. when AVMs are present in the liver.
There are four diagnostic criteria. If three or four are met, a patient has definite HHT, while two gives a possible diagnosis:
- Spontaneous recurrent epistaxis
- Multiple teleangiectasias on typical locations (see above)
- Proven visceral AVM (lung, liver, brain, spine)
- First-degree family member with HHT
When HHT is suspected, physical examination focuses on inspecting the whole skin for teleangiectasias, auscultation of the lungs and liver, and neurological examination.
Pulmonary AVMs can be anticipated by measuring oxygen levels and performing arterial blood gas (ABG) sampling. An X-ray of the chest can show susceptible lesions; in addition, low oxygen tension (<96% or a 2% decrease upon standing) or low blood oxygen levels on ABG are required for a diagnosis.
HHT is a genetic disorder by definition. It is inherited in an autosomal dominant manner. Four forms have been described:
- HHT1: mutation of the endoglin gene (ninth chromosome). Endoglin is a receptor of TGFβ1 (transforming growth factor beta 1) and TGFβ3. It also interacts with zyxin and ZRP-1 with its intracellular domain, to control composition of focal adhesions and regulate organization of actin filaments. This form predisposes for pulmonary AVMs and early nosebleeds.
- HHT2: mutation in the alk1 gene (12th chromosome). Alk-1 (activin receptor-like kinase 1) is a TGFβ1 receptor. Less pulmonary AVMs and later nosebleeds, but an increased risk of pulmonary hypertension (supposedly due to altered TGFβ signalling or other related pathways which may lead to vascular malformations).
- HHT3: a third form has been suspected to exist, but has not yet been linked to a defective gene. Current research is focused upon chromosome 5.
- Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome is caused by mutations in the gene SMAD4
- HHT4 has been identified in September 2006. The search for the gene associated with HHT4 is ongoing, with current research focused upon chromosome 7. 
It is possible to test patients for the presence of mutations in endoglin, ALK-1 and SMAD4. When the mutation in an affected family member has been found it is possible to test other family members and identify those people not at risk for developing the disease.
The mechanism underlying the formation of vascular malformations is not completely understood, but signalling of transforming growth factor-β1 is most likely to be involved. Possibly, connective tissue is required to support and guide proliferating blood vessels during angiogenesis, and defects in TGF-β signalling adversely affect connective tissue and matrix production.
There is no specific treatment for the condition. Anemia due to bleeding from digestive tract AVMs often necessitates repeated blood transfusions. AVMs in critical organs often necessitates surgery.If major AVMs are all the patient has in terms of long-term problems, the surgery performed will block the malformed arteries, ruling out the risk for stroke and blood-clots. This surgery will hopefully lead to a normal life for the patient, and also help doctors diagnose patients with HHT more easily around the globe.
HHT occurs mainly in whites (1:5,000), more in certain areas of France, but much less in blacks (1 in million). It is found in all continents throughout the world. It is also seen with increased frequency in Mormon families from Utah.
- ↑ Template:WhoNamedIt
- ↑ Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJJ, Kjeldsen AD, and Plauchu H. Diagnostic Criteria For Hereditary Hemorrhagic Telangiectasia (Rendu-Osler-Weber Syndrome). Am J Med Genet 2000:91:66-7. PMID 10751092.
- ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 3.19 "Dermatology Atlas".
- ↑ Cole SG, Begbie ME, Wallace GM, Shovlin CL (2005). "A new locus for hereditary haemorrhagic telangiectasia (HHT3) maps to chromosome 5". J. Med. Genet. 42 (7): 577–82. doi:10.1136/jmg.2004.028712. PMID 15994879.
- ↑ Bayrak-Toydemir P, McDonald J, Akarsu N; et al. (2006). "A fourth locus for hereditary hemorrhagic telangiectasia maps to chromosome 7". Am. J. Med. Genet. A. 140 (20): 2155–62. doi:10.1002/ajmg.a.31450. PMID 16969873.
- Guttmacher AE, Marchuk DA, White RI Jr. Hereditary hemorrhagic telangiectasia. N Engl J Med 1995;333:918-24. PMID 7666879.
- Online Mendelian Inheritance in Man (OMIM) 187300 (HHT1), Online Mendelian Inheritance in Man (OMIM) 600376 (HHT2), Online Mendelian Inheritance in Man (OMIM) 601101 (HHT3)
- Information about Hereditary Hemorrhagic Telangiectasia from Children's Hospital, Seattle.
de:Morbus Osler nl:Ziekte van Rendu-Osler-Weber