Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype.
ABSTRACT Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) is an autosomal dominant disease characterized by arteriovenous malformations ranging from cutaneous and mucous membrane telangiectasias to more severe pulmonary, gastrointestinal, and cerebral arteriovenous malformations (AVMs). Acute complications from bleeding or pulmonary shunting may be catastrophic. However, when diagnosed early, the complications can usually be prevented. Mutations in two genes, Endoglin (ENG) and activin receptor-like kinase 1 (ACVRL1 or ALK1) have been associated with HHT. We describe the results of mutation analysis on a consecutive series of 200 individuals undergoing clinical genetic testing for HHT. The observed sensitivity of mutation detection was similar to that in other series with strict ascertainment criteria. A total of 127 probands were found, with sequence changes consisting of 103 unique alterations, 68 of which were novel. In addition, eight intragenic rearrangements in the ENG gene and two in the ACVRL1 gene were identified in a subset of coding sequence mutation-negative individuals. Most individuals tested could be categorized by the number of HHT diagnostic criteria present. Surprisingly, almost 50% of the cases with a single symptom were found to have a significant sequence alteration; three of these reported only nosebleeds. Genetic testing can confirm the clinical diagnosis in individuals and identify presymptomatic mutation carriers. As many of the complications of HHT disease can be prevented, a confirmed molecular diagnosis provides an opportunity for early detection of AVMs and management of the disease.
- SourceAvailable from: Branislav Belić[Show abstract] [Hide abstract]
ABSTRACT: Hereditary hemorrhagic telangectasia (HHT) or Rendu-Osler-Weber syndrome, is a rare genetic disorder with autosomal dominance and variable penetrance. The typical findings of the disease are telangiectasias in skin and mucous membranes, and arteriovenous malformations presenting in the organs like lung, intestine, brain and liver. It is characterized by the classic triad of recurrent epistaxis, mucocutaneous telangiectasias and visceral hemorrhages, with familial occurrence. This article describes a case of HHT of an adult patient, associated with multiple angiodysplasic injuries in the nasal mucosa, upper gastrointestinal tract, lungs and who presents continuous blood loss, resulting iron deficiency anemia. Based on clinical and diagnostic findings, we diagnosed this case as HHT, which has rarely been reported in our literature.Macedonian Journal of Medical Sciences 09/2014;
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ABSTRACT: Hereditary hemorrhagic telangiectasia (HHT), also known by the eponym Osler-Weber-Rendu syndrome, is a group of related disorders inherited in an autosomal dominant fashion and characterized by the development of arteriovenous malformations (AVM) in the skin, mucous membranes, and/or internal organs such as brain, lungs, and liver. Its prevalence is currently estimated at one in 5,000 to 8,000. Most cases are due to mutations in the endoglin (HHT1) or ACVRLK1 (HHT2) genes. Telangiectasias in nasal and gastrointestinal mucosa generally present with recurrent/chronic bleeding and iron deficiency anemia. Larger AVMs occur in lungs (~40%-60% of affected individuals), liver (~40%-70%), brain (~10%), and spine (~1%). Due to the devastating and potentially fatal complications of some of these lesions (for example, strokes and brain abscesses with pulmonary AVMs), presymptomatic screening and treatment are of utmost importance. However, due to the rarity of this condition, many providers lack an appreciation for the whole gamut of its manifestations and complications, age-dependent penetrance, and marked intrafamilial variation. As a result, HHT remains frequently underdiagnosed and many families do not receive the appropriate screening and treatments. This article provides an overview of the clinical features of HHT, discusses the clinical and genetic diagnostic strategies, and presents an up-to-date review of literature and detailed considerations regarding screening for visceral AVMs, preventive modalities, and treatment options.Hematology Research and Reviews 01/2014; 5:191-206.