Janecke Andreas R, Heinz-Erian Peter, Müller Thomas
*Department of Pediatrics I, Medical University of Innsbruck †Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
J Pediatr Gastroenterol Nutr. 2016 Aug;63(2):170-6. doi: 10.1097/MPG.0000000000001139.
Congenital diarrheal disorders (CDDs) represent a group of challenging clinical conditions for pediatricians because of the severity of the presentation and the broad range of possible differential diagnoses. CDDs arise from alterations in the transport of nutrients and electrolytes across the intestinal mucosa, from enterocyte and enteroendocrine cell differentiation and/or polarization defects, and from the modulation of the intestinal immune response. Advances were made recently in deciphering the etiology and pathophysiology of one of these disorders, congenital sodium diarrhea (CSD). CSD refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. A syndromic form of CSD features choanal and intestinal atresias as well as recurrent corneal erosions. Small bowel histology frequently detects an epithelial "tufting" dysplasia. It is autosomal recessively inherited, and caused by SPINT2 mutations. The nonsyndromic form of CSD can be caused by dominant activating mutations in GUCY2C, encoding intestinal receptor guanylate cyclase C (GC-C), and by autosomal recessive SLC9A3 loss-of-function mutations. SLC9A3 encodes Na/H antiporter 3, the major intestinal brush border Na/H exchanger, and a downstream target of GC-C. A number of patients with GUCY2C and SLC9A3 mutations developed inflammatory bowel disease. Both the number of recognized CDD forms as well as the number of underlying disease genes are gradually increasing. Knowledge of these CDD genes enables noninvasive, next-generation gene panel-based testing to facilitate an early diagnosis in CDD. Primary Na/H antiporter 3 and GC-C malfunction is implicated as a predisposition for inflammatory bowel disease in subset of patients.
先天性腹泻疾病（CDDs）对儿科医生而言是一组具有挑战性的临床病症，这是因为其临床表现严重且可能的鉴别诊断范围广泛。CDDs源于营养物质和电解质跨肠黏膜转运的改变、肠上皮细胞和肠内分泌细胞分化及/或极化缺陷，以及肠道免疫反应的调节。最近在解读这些疾病之一——先天性钠腹泻（CSD）的病因和病理生理学方面取得了进展。CSD指宫内发病且粪便钠丢失量高的难治性腹泻。CSD在临床和遗传上具有异质性。CSD的综合征形式的特征为后鼻孔和肠道闭锁以及复发性角膜糜烂。小肠组织学检查常发现上皮“簇状”发育异常。它是常染色体隐性遗传，由SPINT2突变引起。CSD的非综合征形式可由编码肠受体鸟苷酸环化酶C（GC-C）的GUCY2C中的显性激活突变以及常染色体隐性SLC9A3功能丧失突变引起。SLC9A3编码钠/氢逆向转运蛋白3，即主要的肠刷状缘钠/氢交换体，也是GC-C的下游靶点。许多携带GUCY2C和SLC9A3突变的患者患上了炎症性肠病。已认识到的CDD形式数量以及潜在疾病基因数量都在逐渐增加。了解这些CDD基因可实现基于新一代基因panel的非侵入性检测，以促进CDD的早期诊断。原发性钠/氢逆向转运蛋白3和GC-C功能异常被认为是部分患者发生炎症性肠病的一个易患因素。
