BACKGROUNDWe determined the diagnosis of hereditary hemorrhagic telangiectasis (HHT) in a suspected HHT family, identified ALK1 gene mutation and established a gene diagnosis method of HHT. The level of related plasma proteins (transforming growth factor beta and thrombomodulin) were also analyzed.

METHODSBleeding history and family history were collected; Dilatant nasal mucosal capillaries in proband were observed under nasal cavity endoscope; exons 3, 7, 8 of ALK1 gene in proband and her family members were amplified with polymerase chain reaction (PCR), and the PCR products were analyzed. Using enzyme-linked immunosorbent assay (ELISA), plasma TGF-beta1 and TGF-beta2 concentrations were measured. Plasma thrombomodulin (TM) level was detected by Western blotting.

RESULTSOf all family members, four had epstaxis, two had evident telangiectases on skin or mucosa. Gene screening results showed that C to T substitution at position 1231 in exon 8 of ALK1 gene (CGG-->TGG) existed in proband, her affected brother and their father. The mutation did not exist in proband's sister-in-law and nephew. Plasma TGF-beta1 concentrations in the affected HHT was 20,538, 17,194, 13,131 pg/ml, while that of normal control and unaffected family members was 15,950, 20,297, 12,836 pg/ml, respectively. Plasma TGF-beta2 in HHT patients was 14,502, 9550, 10,592 and that of normal controls 8579, 20,297, 7680 pg/ml respectively. Level of plasma TM was in HHT subjects significantly lower than in normal subjects.

CONCLUSIONSChinese HHT individuals have mutant ALK1 gene, a C1231T variation on exon 8 of ALK1 is responsible for HHT clinical phenotypes in this family. ALK1 gene analysis, together with special clinical phenotypes and family history, provides a reliable method in diagnosing HHT. In affected HHT subjects, plasma TGFbeta levels were not obviously different from those of normal subject; while plasma TM concentration was significantly lower than that in normal subjects. The significance and mechanism remain to be elucidated.