FaCD Online Syndrome Fact Sheet

Last updated: 28 Feb 2008

Name: Hereditary Hemorrhagic Telangiectasia

Synonym: HHT, Rendu-Osler-Weber disease, incl.: Pulmonary arteriovenous malformations, hypertrophic osteoarthropathy and juvenile polyposis,

Mode of Inheritance: AD

Genes

ACVRL1/ALK1, mapped to 12q11-q14
ENG, mapped to 9q34.1
SMAD4/DPC4, mapped to 18q21.1

Tumor features

colorectal cancer
gastrointestinal hamartomas
gastrointestinal polyps, juvenile type

Tumor features (possible)

hepatocellular cancer (hepatoma)

Non-tumor features

arteriovenous malformation, cerebral
arteriovenous malformation, pulmonary
mucocutaneous telangiectasia

Comment

HHT is characterized by mucocutaneous telangiectasia (epistaxis is a common symptom) and arteriovenous malformations in the brain and lungs (associated with digital clubbing and hypertrophic osteoarthropathy). Spinal and hepatic AVMs may occur as well. Hepatocellular cancer has been observed in 2 HHT patients, 1 with a cirrhotic and 1 with a non-cirrhotic liver[1]. In a few patients/families with this disorder an association with juvenile polyposis and early-onset colorectal cancer[2] has been observed[3-6]. In one family, the combination of juvenile polyposis with hypertrophic osteoarthropathy without pulmonary arteriovenous malformations has been observed[7]. The HHT-juvenile polyposis combination is associated with germline SMAD4 mutations. Some HHT patients without signs of juvenile polypsis have been shown to carry SMAD4 mutations as well[9].

Diagnostic criteria[8] (the Curaçao Criteria):
HHT diagnosis definite if 3 criteria are met
HHT diagnosis possible or suspected if 2 criteria are met
HHT is unlikely if less than 2 criteria are met

criteria:
1. Epistaxis (spontaneous, recurrent)
2. Telangiectases (multiple at characteristic sites: lips, oral, fingers, nose)
3. Visceral lesions (incl.: gastrointestinal telangiectasia, pulmonary/hepatic/cerebral/spinal arteriovenous malformations)
4. Family history (1 first-degree relative with definite diagnosis of HHT)

References

[1] Jameson CF. Primary hepatocellular carcinoma in hereditary haemorrhagic telangiectasia: a case report and literature review. Histopathology 1989; 15(5):550-552.
[2] Conte WJ, Rotter JI, Schwartz AG, Conqleton JE. Hereditary generalized juvenile polyposis, arteriovenous malformations and colonic carcinoma. Clin.Res. 30[1], 93A. 1982.
[3] Cox KL, Frates RCJr, Wong A, Gandhi G. Hereditary generalized juvenile polyposis associated with pulmonary arteriovenous malformation. GASTROENTEROLOGY 1980; 78:1566-1570.
[4] Desai DC, Murday V, Phillips RKS, Neale KF, Milla P, Hodgson SV. A survey of phenotypic features in juvenile polyposis. J Med Genet 1998; 35:476-481.
[5] Inoue S, Matsumoto T, Iida M, Hoshika K, Shimizu M, Hisamoto N, Kihara T. Juvenile polyposis occurring in hereditary hemorrhagic telangiectasia. Am J Med Sci 317[1], 59-62. 1999.
[6] Baert AL, Casteels-van Daele M, Broeckx J, Wijndaele L, Eggermont E. Generalized juvenile polyposis with pulmonary arteriovenous malforamtions and hypertrophic osteoarthro[athy. Am J Roentgenol 1983; 141:661-662.
[7] Simpson EL, Dalinka MK. Association of hypertrophic osteoarthropathy with gastrointestinal polyposis. Am J Roentgenol 1984; 144:983-984.
[8] Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJJ, Kjeldsen AD, Plauchu H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet 2000; 91:66-67.
[9] Gallione CJ, Richards JA, Letteboer TG, Rushlow D, Prigoda NL, Leedom TP, Ganguly A, Castells A, Ploos van Amstel JK, Westermann CJ, Pyeritz RE, Marchuk DA. SMAD4 mutations found in unselected HHT patients. Journal of medical genetics 2006; 43(10):793-7.
[10] Abdalla SA, Letarte M. Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. Journal of medical genetics 2006; 43(2):97-110.