Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.
Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.
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DOI：
10.1530/eje-21-1095
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发表时间：
2022-08-01
影响因子：
5.8
通讯作者：
De Leon, Diva D.
中科院分区：
文献类型：
--
作者：
Boodhansingh, Kara E.;Yang, Zhongying;Li, Changhong;Chen, Pan;Lord, Katherine;Becker, Susan A.;States, Lisa J.;Adzick, N. Scott;Bhatti, Tricia;Shyng, Show-Ling;Ganguly, Arupa;Stanley, Charles A.;De Leon, Diva D.
先天性高胰岛素血症（HI）是儿童持续性低血糖的最常见原因。除了典型的局灶性或弥漫性 HI 之外，一些对二氮嗪无反应的先天性高胰岛素血症 (HI) 病例还具有非典型胰腺组织学，称为局限性胰岛核肿大 (LINE) 或马赛克 HI，其组织学特征与弥漫性 HI 类似，但仅限于胰腺的某个区域。我们的目标是表征 LINE-HI 儿童的表型和基因型。对12例胰腺组织学符合LINE-HI的儿童的表型和基因型特征进行了检查。我们收集了 12 名 LINE-HI 儿童的临床特征，并对其中 8 名儿童的胰腺标本进行了下一代测序 (NGS)，以寻找已知与二氮嗪无反应 HI 相关的基因（ABCC8、KCNJ11 和 GCK）中的嵌合突变。与典型局灶性或弥漫性 HI 儿童相比，LINE-HI 儿童出生体重较低且发病年龄较晚。 LINE-HI 病例中的部分胰腺切除术导致 75% 的病例血糖正常；没有病例发展为糖尿病。在 6 例 LINE-HI 病例的胰腺中发现了低水平嵌合突变（3 例在 ABCC8，3 例在 GCK）。表达研究证实所有新突变都是致病性的。这些结果表明，已知 HI 基因的合子后低水平嵌合突变是导致某些缺乏可识别种系突变的 LINE-HI 病例的原因，部分胰腺切除术可能对这些病例有疗效。
Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital hyperinsulinism (HI) have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI. The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined. We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing (NGS) on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK). Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic. These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI which lack an identifiable germline mutation and that partial pancreatectomy may be curative for these cases.