Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome
Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome
复制标题
DOI：
10.1007/s00125-004-1576-3
复制
发表时间：
2004-12-01
期刊：
影响因子：
8.2
通讯作者：
Polychronakos, C
中科院分区：
文献类型：
--
作者：
Mitchell, J;Punthakee, Z;Polychronakos, C
目的/假设。新生儿糖尿病是一种罕见的疾病，有几个确定的分子病因。尽管与其他畸形，新生儿糖尿病肠道和胆道异常尚未被描述。目前的研究旨在描述一种新的综合征，并检查与已知引起新生儿糖尿病的三种基因之一的可能联系。五个临床病例进行了描述。对其中三名婴儿进行了胰岛激素免疫组织化学染色。对一名婴儿的DNA进行PLAGL-1（ZAC）、葡萄糖激酶和PDX-1（IPF-1）基因异常分析。五名婴儿（来自两个家庭的两对兄弟姐妹和一个孤立的病例）表现为新生儿糖尿病，胰腺发育不全或环状胰腺，空肠闭锁，十二指肠闭锁和胆囊发育不全或发育不全。其中一对兄弟姐妹的父母是近亲。一名病情较轻的患者在没有胰岛素的情况下存活下来。尽管进行了积极的医疗管理，但有四名儿童在出生后的第一年死亡。胰腺免疫组化显示，一些分散的嗜铬粒蛋白-A阳性细胞簇，但完全没有胰岛素，胰高血糖素和生长抑素。外分泌组织学是可变的。在1例来自血缘家系的病例中，分子分析显示PLAGL-1在6 q24没有重复或单亲同二体，没有涉及葡萄糖激酶基因的连续基因缺失，PDX-1的编码序列或剪接位点没有突变。这种多种先天性异常的组合以前没有被描述过，可能代表了一种新的常染色体隐性遗传综合征，涉及干扰正常胰岛发育的遗传异常，其病因尚不清楚。
Aims/hypothesis. Neonatal diabetes is a rare disease with several identified molecular aetiologies. Despite associations with other malformations, neonatal diabetes with intestinal and biliary anomalies has not been described. The current study aims to describe a new syndrome, and to examine a possible link with one of three genes known to cause neonatal diabetes.Methods. Five clinical cases are described. Immunohistochemical staining for pancreatic islet hormones was performed on three of the infants. DNA from one infant was analysed for abnormalities of the PLAGL-1 (ZAC), glucokinase and PDX-1 (IPF-1) genes.Results. Five infants ( two sibling pairs from two families, and an isolated case) presented with neonatal diabetes, hypoplastic or annular pancreas, jejunal atresia, duodenal atresia and gall bladder aplasia or hypoaplasia. One sibling pair was born to consanguineous parents. One patient with a milder form is surviving free of insulin. Four children died in the first year of life despite aggressive medical management. Pancreatic immunohistochemistry revealed few scattered chromogranin-A-positive cell clusters but complete absence of insulin, glucagon and somatostatin. Exocrine histology was variable. In one case from the consanguineous family, molecular analysis showed no duplication or uniparental isodisomy of PLAGL-1 at 6q24, no contiguous gene deletion involving the glucokinase gene, and no mutation in the coding sequences or splice sites of PDX-1.Conclusions/interpretation. This combination of multiple congenital abnormalities has not been previously described and probably represents a new autosomal recessive syndrome involving a genetic abnormality that interferes with normal islet development and whose aetiology is as yet unknown.