背景:青少年息肉病综合征(JPS),一种罕见的常染色体显性综合征,影响到每10万新生儿中的一个,终生癌症风险增加9-50%。大约40-60%的JPS病例是由SMAD4或BMPR1A基因的致病变异(DCV)引起的。其中SMAD4占20-30%。
目的:为了表征SMAD4与JPS表型的位点和变异类型之间的基因型-表型相关性,告知诊断,筛选,和JPS的管理。
方法:使用的在线搜索数据库包括OvidMEDLINE,Embase经典+Embase和PubMed,使用按MeSHonDemand分类的搜索词。邻接运算符,采用了词截断和布尔运算符。110篇文章被纳入审查,从文献中整理291个变体。
结果:在SMAD4+JPS患者中,大多数变体位于SMAD4的MH2域(3'端)周围。结肠外受累,大量胃息肉病和更具侵袭性的表型与SMAD4+JPS相关,易患胃癌.与其他导致JPS的基因相比,这导致了胃肠道癌症的总体发病率更高。DCV大部分都在MH2域内。SMAD4的遗传相关等位基因疾病在该区域也有变异,包括遗传性出血性毛细血管扩张症(HHT)以及SMAD4+JPS,和Myhre综合征,独立于JPS。同样,与MH2域中的DCV,Ménétrier病,肥大性骨关节病和幼年特发性关节炎已经在这个人群中看到,而心脏病变与SMAD4+JPS同时发生和独立发生,DCV在MH1域。
结论:SMAD4的MH2区域周围的截短和错义变异是最普遍和致病的,因此应该进行仔细的监视。考虑到结肠外息肉病和较高的胃肠道癌症风险,与其他致病基因的患者相比,SMAD4+JPS患者的内镜筛查应更频繁且年龄更早,在上消化道内窥镜检查中考虑到Ménétrier病。此外,HHT应在诊断后6个月内进行评估,与SMAD4+JPS相关的肠外表现的针对性临床检查。这篇综述可能有助于修改SMAD4+JPS患者的临床诊断和管理,并通过更好地了解表型来帮助SMAD4DCV的致病性分类。
BACKGROUND: Juvenile polyposis syndrome (JPS), a rare autosomal dominant syndrome, affects one per 100 000 births, increasing lifetime cancer risk by 9 - 50%. Around 40-60% of JPS cases are caused by disease-causing variants (DCV) in SMAD4 or BMPR1A genes, of which SMAD4 accounts for 20-30%.
OBJECTIVE: To characterise genotype-phenotype correlations between sites and types of variants within SMAD4 to JPS phenotypes, to inform diagnosis, screening, and management of JPS.
METHODS: Online search databases utilised included Ovid MEDLINE, Embase Classic + Embase and PubMed, using search terms classified by MeSH on Demand. Adjacency operators, word truncation and Boolean operators were employed. 110 articles were included in the review, collating 291 variants from the literature.
RESULTS: In SMAD4 + JPS patients, most variants are located around SMAD4\'s MH2 domain (3\' end). Extracolonic involvement, massive gastric polyposis and a more aggressive phenotype have been associated with SMAD4 + JPS, predisposing to gastric cancer. This has contributed to an overall higher incidence of GI cancers compared to other genes causing JPS, with DCVs mostly all within the MH2 domain. Genetically related allelic disorders of SMAD4 also have variants in this region, including hereditary haemorrhagic telangiectasia (HHT) alongside SMAD4 + JPS, and Myhre syndrome, independent of JPS. Similarly, with DCVs in the MH2 domain, Ménétrier\'s disease, hypertrophic osteoarthropathy and juvenile idiopathic arthritis have been seen in this population, whereas cardiac pathologies have occurred both alongside and independently of SMAD4 + JPS with DCVs in the MH1 domain.
CONCLUSIONS: Truncating and missense variants around the MH2 region of SMAD4 are most prevalent and pathogenic, thus should undergo careful surveillance. Given association with extracolonic polyposis and higher GI cancer risk, endoscopic screening should occur more frequently and at an earlier age in SMAD4 + JPS patients than in patients with other causative genes, with consideration of Ménétrier\'s disease on upper GI endoscopy. In addition, HHT should be evaluated within 6 months of diagnosis, alongside targeted clinical examination for extraintestinal manifestations associated with SMAD4 + JPS. This review may help modify clinical diagnosis and management of SMAD4 + JPS patients, and aid pathogenicity classification for SMAD4 DCVs through a better understanding of the phenotypes.