The diagnostic approach to monogenic very early onset inflammatory bowel disease.
The diagnostic approach to monogenic very early onset inflammatory bowel disease.
复制标题
DOI：
10.1053/j.gastro.2014.07.023
复制
发表时间：
2014-11
期刊：
影响因子：
29.4
通讯作者：
COLORS in IBD Study Group and NEOPICS
中科院分区：
文献类型：
--
作者：
Uhlig HH;Schwerd T;Koletzko S;Shah N;Kammermeier J;Elkadri A;Ouahed J;Wilson DC;Travis SP;Turner D;Klein C;Snapper SB;Muise AM;COLORS in IBD Study Group and NEOPICS
患有多种罕见遗传性疾病的患者可能会出现炎症性肠病（单基因IBD）。患有这些疾病的患者通常在婴儿期或幼儿期出现症状，沿着克罗恩病、溃疡性结肠炎或IBD的内窥镜或组织学特征未分类。白细胞介素10信号传导缺陷具有孟德尔遗传模式，可完全避免肠道炎症。一些干扰肠上皮屏障功能或影响先天性和适应性免疫功能的遗传缺陷具有IBD样表型的不完全转化。这些单基因疾病中的几种对常规治疗没有反应，并且与高发病率和死亡率相关。由于这些极其罕见的疾病的范围很广，正确的诊断往往是一个挑战，而且往往会延误。在许多情况下，这些疾病不能根据IBD的标准组织学和免疫学特征进行分类。需要进行遗传分析以确定疾病的原因，并为患者提供适当的治疗选择，包括药物治疗，手术或异基因造血干细胞移植。此外，基于遗传分析的诊断可以为患者的家庭成员提供遗传咨询。我们描述了与IBD样肠道炎症相关的50种遗传变异的关键肠道、肠外和实验室特征。我们提供了识别可能患有这些疾病的患者的方法。我们讨论了经典的方法来确定这些变异的患者，从表型和功能评估，导致候选基因的分析。作为一种补充方法，我们讨论了使用下一代测序的并行遗传筛查，然后对遗传缺陷进行功能确认。
Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel diseases (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histologic features of Crohn’s disease, ulcerative colitis or IBD unclassified. Defects in interleukin 10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histologic and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extra-intestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. We provide approaches for identifying patients likely to have these disorders. We discuss classical approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.