Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency.
Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency.
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DOI：
10.1097/md.0000000000002918
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发表时间：
2016-03
期刊：
影响因子：
1.6
通讯作者：
Ou LS
中科院分区：
文献类型：
--
作者：
Lee WI;Huang JL;Chen CC;Lin JL;Wu RC;Jaing TH;Ou LS
补充数字内容可在文本中找到。 综合征性腹泻/毛肝肠综合征 (SD/THE) 是一种罕见的常染色体隐性遗传性严重肠道疾病，主要由四肽重复结构域 37 (TTC37) 基因突变引起，该基因作为异四聚体辅助因子增强异常 mRNA 的衰减。 SD/THE 的表型和免疫特征与原发性免疫缺陷疾病 (PID) 重叠。患有顽固性腹泻的新生儿接受了免疫学评估，包括免疫球蛋白水平、淋巴细胞亚群、淋巴细胞增殖、超氧化物产生和 IL-10 信号功能。本研究对易患炎症性肠病的 PID 候选基因进行了测序。两名非近亲出生的新生儿因肝硬化或伴随年龄增长而出现的结节性毛裂导致顽固性腹泻、反复感染和食管静脉曲张导致大量吐血，从而指导诊断与 TTC37 突变（纯合子 DelK1155H、Fs*2；杂合子 Y1169Ter 和InsA1143，Fs*3)。他们的免疫学评估显示，丝裂原刺激的淋巴细胞增殖、超氧化物产生和 IL-10 信号传导正常，但 IgG 水平较低，乙型肝炎表面抗原抗体检测不到，抗原刺激的淋巴细胞增殖减少。 PubMed 对双等位基因 TTC37 突变和表型的搜索记录在 14 名亚洲病例和 12 名非亚洲病例中。他们有类似的婴儿期难治性腹泻、面部畸形、头发异常、低 IgG、低出生体重和近亲结婚的表现。与非亚洲患者相比，亚洲患者心脏异常（8/14 vs 2/12；P = 0.0344，卡方）、无义突变（28 个等位基因中有 19 个）和热点突变（W936Ter、2779-2G>A 和 Y1169Ter）的发生率更高。尽管其中 20 名患者接受了免疫球蛋白治疗，但仍有 4 名患者死于肝硬化，1 名患者死于败血症。具有结节性T细胞、肝硬化和顽固性肠病特征三联征的SD/THE的所有种族患者均具有低IgG、疫苗反应差和/或抗原刺激的淋巴细胞增殖减少。现在，在更新的 PID 分类中，与“主要抗体缺陷”相比，这种情况更好地归类为“明确定义的免疫缺陷综合征”（更新称为“具有相关或综合征特征的联合免疫缺陷”）亚组，并且需要最佳干预措施。
Supplemental Digital Content is available in the text Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare, autosomal recessive and severe bowel disorder mainly caused by mutations in the tetratricopeptide repeat domain 37 (TTC37) gene which act as heterotetrameric cofactors to enhance aberrant mRNAs decay. The phenotype and immune profiles of SD/THE overlap those of primary immunodeficiency diseases (PIDs). Neonates with intractable diarrhea underwent immunologic assessments including immunoglobulin levels, lymphocyte subsets, lymphocyte proliferation, superoxide production, and IL-10 signaling function. Candidate genes for PIDs predisposing to inflammatory bowel disease were sequencing in this study. Two neonates, born to nonconsanguineous parents, suffered from intractable diarrhea, recurrent infections, and massive hematemesis from esopharyngeal varices due to liver cirrhosis or accompanying Trichorrhexis nodosa that developed with age and thus guided the diagnosis of SD/THE compatible to TTC37 mutations (homozygous DelK1155H, Fs∗2; heterozygous Y1169Ter and InsA1143, Fs∗3). Their immunologic evaluation showed normal mitogen-stimulated lymphocyte proliferation, superoxide production, and IL-10 signaling, but low IgG levels, undetectable antibody to hepatitis B surface antigen and decreased antigen-stimulated lymphocyte proliferation. A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases. They had similar presentations of infantile onset refractory diarrhea, facial dysmorphism, hair anomalies, low IgG, low birth weight, and consanguinity. A higher incidence of heart anomalies (8/14 vs 2/12; P = 0.0344, Chi-square), nonsense mutations (19 in 28 alleles), and hot-spot mutations (W936Ter, 2779-2G>A, and Y1169Ter) were found in the Asian compared with the non-Asian patients. Despite immunoglobulin therapy in 20 of the patients, 4 died from liver cirrhosis and 1 died from sepsis. Patients of all ethnicities with SD/THE with the characteristic triad of T nodosa, hepatic cirrhosis, and intractable enteropathy have low IgG, poor vaccine response and/or decreased antigen-stimulated lymphocyte proliferation. This is now better classified into the subgroup of “well-defined syndromes with immunodeficiency” (the update termed as “combined immunodeficiencies with associated or syndromic features”) than “predominantly antibody deficiencies” in the update PIDs classification, and requires optimal interventions.