Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes.
Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes.
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DOI：
10.2337/dc08-1188
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发表时间：
2009-01
期刊：
影响因子：
16.2
通讯作者：
Hattersley, Andrew T.
中科院分区：
文献类型：
--
作者：
Rubio-Cabezas, Oscar;Minton, Jayne A. L.;Caswell, Richard;Shield, Julian P.;Deiss, Dorothee;Sumnik, Zdenek;Cayssials, Amely;Herr, Mathias;Loew, Anja;Lewis, Vaughan;Ellard, Sian;Hattersley, Andrew T.
目的免疫失调、多内分泌疾病、肠病、X连锁(IPEX)综合征是由FOXP3突变引起的。我们的目标是确定FOXP3突变在永久性新生儿糖尿病(PNDM)大队列中的患病率、遗传学和临床表型。10名受试者至少有一种额外的免疫相关疾病，其余16名受试者单独患有糖尿病。新突变V408M发现于两个无血缘关系的家系中的3例患者，表现为轻度甲状腺功能减退和自身免疫性肠病(n=2)或肾病综合征(n=1)，存活12~15年。结论：在6个月前确诊的男性永久性糖尿病患者中，FOXP3基因突变导致4%的∼。患者不仅有典型的IPEX综合征，而且出乎意料的是，可能有更良性的表型。
OBJECTIVE—Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM). RESEARCH DESIGN AND METHODS—The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes. RESULTS—We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes (P = 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n = 2) or nephrotic syndrome (n = 1) and survival to 12–15 years. CONCLUSIONS—FOXP3 mutations result in ∼4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome.
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