Clinical and Translational Research Center, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, 3615 Civic Center Boulevard, Abramson Research Center Room 802A, Philadelphia, Pennsylvania 19104, USA.
J Clin Endocrinol Metab. 2012 Oct;97(10):E2026-30. doi: 10.1210/jc.2012-1356. Epub 2012 Jul 16.
Inactivating mutations in HNF1A and HNF4A cause the maturity-onset diabetes of youth (MODY)-3 and MODY1 forms of monogenic diabetes, respectively. Children carrying HNF4A (MODY1) mutations can present in early infancy with macrosomia and diazoxide-responsive hyperinsulinism.
Our objective was to describe three novel cases of hyperinsulinism associated with MODY1 and MODY3 mutations.
Clinical data were obtained from chart review. Gene sequencing was performed on genomic DNA.
Case 1 was diagnosed at 20 months with persistent hyperinsulinemic hypoglycemia and was found to have a novel MODY3 HNF1A mutation, carried by her father who had diabetes. Case 2 was diagnosed with diazoxide-responsive hyperinsulinism at 3 months of age and had complete resolution of hyperinsulinism by 4 yr. She was found to have a novel MODY3 HNF1A missense mutation, also carried by her father. Case 3 presented as a newborn with diazoxide-responsive hyperinsulinism and later developed renal Fanconi syndrome, hypophosphatemic rickets, and hepatic glycogenosis. Although the latter's features suggested Fanconi-Bickel syndrome, sequencing of the SLC2A2 gene was normal. The patient was found to have a known MODY1 mutation in HNF4A. In all cases, the hyperinsulinism improved with age.
The first two cases demonstrate that mutations in HNF1A (MODY3) can cause hyperinsulinism early in life and diabetes later, similar to the phenotype recently reported for HNF4A (MODY1) mutations. Case 3 indicates that the effects of HNF4A mutations in infancy may extend beyond pancreatic β-cells to produce a disorder similar to glucose transporter 2 deficiency involving both liver glycogen metabolism and renal tubular transport.
HNF1A 和 HNF4A 的失活突变分别导致青年发病的成年型糖尿病（MODY）-3 和 MODY1 形式的单基因糖尿病。携带 HNF4A（MODY1）突变的儿童可能在婴儿期表现为巨大儿和二氮嗪反应性高胰岛素血症。
本研究旨在描述与 MODY1 和 MODY3 突变相关的 3 例新的高胰岛素血症病例。
通过病历回顾获取临床数据。对基因组 DNA 进行基因测序。
病例 1 在 20 个月时被诊断为持续性高胰岛素血症低血糖，发现携带父亲的 MODY3 HNF1A 突变，该突变导致糖尿病。病例 2 在 3 个月时被诊断为二氮嗪反应性高胰岛素血症，4 岁时高胰岛素血症完全缓解。她携带一种新的 MODY3 HNF1A 错义突变，也由其父亲携带。病例 3 为新生儿，表现为二氮嗪反应性高胰岛素血症，后来发展为范可尼氏综合征、低磷性佝偻病和肝糖原贮积症。尽管后者的特征提示范可尼-比克尔综合征，但 SLC2A2 基因测序正常。该患者发现有 HNF4A 已知的 MODY1 突变。在所有病例中，高胰岛素血症随年龄增长而改善。
前两例表明，HNF1A（MODY3）突变可导致婴儿期发生高胰岛素血症，随后发生糖尿病，与最近报道的 HNF4A（MODY1）突变表型相似。病例 3 表明，HNF4A 突变在婴儿期的影响可能超出胰腺β细胞，导致类似于葡萄糖转运蛋白 2 缺乏症的疾病，涉及肝脏糖原代谢和肾小管转运。
