背景:已知遗传性出血性毛细血管扩张症(HHT)和青少年息肉病综合征(JPS)均由SMAD4致病变异引起,一些患者的两种疾病的症状重叠。还报道了其他结缔组织疾病。这里,我们在HHT参考中心描述了SMAD4变异的携带者,以进一步描述表型.
方法:基于从Rendu-Osler队列数据库的临床调查收集的数据的观察性研究。
结果:来自15个家庭的33名参与者,在1114例HHT患者中,有一个SMAD4变体(3%)。关于HHT,33名参与者中有26名(88%)根据库拉索岛标准进行了明确的临床诊断。并发症频率如下:鼻出血(n=27/33,82%),皮肤毛细血管扩张酶(n=19/33,58%),肺动静脉畸形(n=17/32,53%),肝动静脉畸形(AVM)(n=7/18,39%),消化性血管发育不良(n=13/22,59%)。未诊断为脑AVM。关于青少年息肉病,31名参与者中有25名(81%)符合Jass等人定义的青少年息肉病综合征标准。7例患者(21%)因广泛的胃息肉病与内镜随访不相容而进行了预防性胃切除术,4名患者(13%)发展为消化道癌。关于结缔组织疾病,20(61%)有至少一种症状,4例(15%)接受超声心动图检查的参与者有主动脉扩张.
结论:我们在HHT的背景下描述了大量SMAD4变异携带者。消化系统并发症很常见,早期和弥漫性,每2年进行一次内镜检查。HHT表型,肺和肝AVM相关,需要系统筛查。结缔组织疾病扩大了与SMAD4基因变异相关的表型,证明了系统心脏超声和骨骼并发症筛查的合理性。
BACKGROUND: Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of SMAD4 variants followed in an HHT reference centre to further delineate the phenotype.
METHODS: Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database.
RESULTS: Thirty-three participants from 15 families, out of 1114 patients with HHT, had an SMAD4 variant (3%).Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Curaçao criteria. Complication frequencies were as follows: epistaxis (n=27/33, 82%), cutaneous telangiectases (n=19/33, 58%), pulmonary arteriovenous malformations (n=17/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7/18, 39%), digestive angiodysplasia (n=13/22, 59%). No cerebral AVMs were diagnosed.Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass et al for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer.Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation.
CONCLUSIONS: We describe a large cohort of SMAD4 variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with SMAD4 gene variants and justify systematic cardiac ultrasound and skeletal complications screening.