Lesca Gaëtan, Olivieri Carla, Burnichon Nelly, Pagella Fabio, Carette Marie-France, Gilbert-Dussardier Brigitte, Goizet Cyril, Roume Joelle, Rabilloud Muriel, Saurin Jean-Christophe, Cottin Vincent, Honnorat Jerome, Coulet Florence, Giraud Sophie, Calender Alain, Danesino Cesare, Buscarini Elisabetta, Plauchu Henri
Service de Génétique Moléculaire et Médicale, Hôpital Edouard Herriot, Lyon, France, and Genetica Medica, Università di Pavia and IRCCS S. Matteo, Pavia, Italy.
Genet Med. 2007 Jan;9(1):14-22. doi: 10.1097/gim.0b013e31802d8373.
Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder characterized by arteriovenous malformations (AVM), mostly cutaneous and mucous (telangiectases), but also involving the lungs (PAVM), liver (HAVM) and brain (CAVM). We studied the relationship between the phenotype and genotype in patients with a proven mutation in either ENG (HHT1) or ACVRL1 (HHT2).
Clinical features and their age of onset were compared between HHT1 and HHT2. The type of mutation was also analyzed. Clinical manifestations were distinguished from lesions found by screening.
Ninety-three HHT1 patients and 250 HHT2 patients were included. Epistaxis occurred later in HHT2, with incomplete penetrance (P<0.0001). Symptomatic PAVMs were more frequent in HHT1 (34.4 vs. 5.2%, P<0.001), as were cerebral abscesses (7.5 vs. 0.8%, P=0.002). Gastrointestinal bleeding occurred more frequently in HHT2 (16.4 vs. 6.5%, P=0.017). Symptomatic hepatic involvement was only seen in HHT2 patients. PAVMs were more frequently detected in asymptomatic HHT1 patients (54 vs. 12.8%, P<0.0001). PAVMs and HAVMs were often family clustered in HHT1 and HHT2, respectively. Truncating mutations were associated with a higher frequency of epistaxis and telangiectasis, in HHT2.
This study shows major differences between HHT1 and HHT2 phenotypes, which should be taken into account for future clinical studies.
遗传性出血性毛细血管扩张症是一种常染色体显性疾病，其特征为动静脉畸形（AVM），主要发生于皮肤和黏膜（毛细血管扩张），但也可累及肺（肺动静脉畸形，PAVM）、肝脏（肝动静脉畸形，HAVM）和脑（脑动静脉畸形，CAVM）。我们研究了ENG（HHT1）或ACVRL1（HHT2）基因发生已证实突变的患者的表型与基因型之间的关系。
比较HHT1和HHT2患者的临床特征及其发病年龄。还分析了突变类型。将临床表现与筛查发现的病变区分开来。
纳入了93例HHT1患者和250例HHT2患者。鼻出血在HHT2患者中出现较晚，且外显不全（P<0.0001）。有症状的PAVM在HHT1患者中更常见（34.4%对5.2%，P<0.001），脑脓肿也是如此（7.5%对0.8%，P=0.002）。胃肠道出血在HHT2患者中更常见（16.4%对6.5%，P=0.017）。有症状的肝脏受累仅见于HHT2患者。无症状的HHT1患者中PAVM检出率更高（54%对12.8%，P<0.0001）。PAVM和HAVM在HHT1和HHT2患者中常呈家族聚集性。在HHT2中，截短突变与鼻出血和毛细血管扩张的较高发生率相关。
本研究显示了HHT1和HHT2表型之间的主要差异，未来临床研究应予以考虑。
