Enhanced Islet Cell Nucleomegaly Defines Diffuse Congenital Hyperinsulinism in Infancy but Not Other Forms of the Disease.

Congenital hyperinsulinism in infancy (CHI) is the most common cause of persistent or recurrent hypoglycemia in early childhood and infancy. CHI is broadly characterized by the inappropriate release of insulin from pancreatic β cells for the level of glycemia and is associated with hypoglycemia-induced brain injury and adverse long-term neurologic outcomes in more than one-third of cases.1-3 The hypoglycemia can be unresponsive to diazoxide, somatostatin analogues, and other medications, necessitating partial or near-total pancreatectomy.1‐3 Defects in several genes are identifiable causes of CHI,4‐6 but for many cohorts of patients with persistent disease, the genetic basis of disease is unknown,7‐11 ranging from 18% in Saudi Arabia12 to greater than 60% in Australia13 and China.14 The most common origins of drug-unresponsive disease are due to inactivating mutations in either the ABCC8 or KCNJ11 genes. These encode subunits of adenosine triphosphate (ATP)–sensitive K+ channels in β cells and result in loss of channel function, leading to inappropriate changes in the β-cell membrane potential, calcium influx, and insulin release.15 In addition to a spectrum of severities and genetic causes, CHI also has anatomopathologic diversity,16 which means that surgical management can be selectively deployed if affected parts of the pancreas can be identified. In patients with diffuse CHI (CHI-D), all islets throughout the pancreas are affected,16 whereas in patients with focal CHI (CHI-F), β-cell defects are localized to a topographical region caused by hyperplasia due to the loss of maternally imprinted genes.17 Recently, a third form of the condition has been described, accounting for approximately 10% to 15% of patients undergoing pancreatectomy: atypical CHI (CHI-A). Patients with CHI-A normally seek treatment later in the childhood period, have no known genetic cause of disease, and exhibit none of the histopathologic hallmarks of CHI-D or CHI-F.18 In CHI treatment centers with access to genotype screening facilities, genetic diagnosis of CHI can be helpful in distinguishing CHI-F from CHI-D prior to surgery because CHI-F is associated with a paternally inherited ABCC8/KCNJ11 defect.7 Current techniques of imaging, including positron emission tomography–computed tomography (PET-CT) using 6-L-18F-fluorodihydroxyphenylalanine (18F-DOPA), can also be used to differentiate between CHI-F and CHI-D,19,20 but these are not widely available. For CHI-A, although measurements of serum incretin peptides may be of value,21 there is currently no preoperative investigation for the detection of this form of disease. Intraoperative and postoperative diagnosis of CHI-F is based on the appearance of adenomatous hyperplasia of β cells within the focal lesion and is a clearly identifiable feature in cases of localized focal domains.16,22,23 In CHI-D, the islet architecture takes the form of ductal-insular complexes (nesidioblastosis) and has been reported to be associated with the appearance of nuclear enlargement in some islet cells.24,25 However, nesidioblastosis is a normal developmental feature of the early postnatal pancreas,25,26 and the detection of islet cell nucleomegaly is subjective and has not always been reported as pathognomonic of CHI-D.24,27‐29 With increased numbers of nontypical cases of CHI being encountered and reported in the literature,18,21,23,30‐32 we have investigated islet cell nucleomegaly in the postnatal pancreas and quantified the incidence of nucleomegaly in cases of CHI-F, CHI-D, and CHI-A. Our data have been generated using a combination of high-content analysis of postoperative tissues and serial block-face scanning electron microscopy to quantify nuclear volume changes in CHI and to identify the source of cells displaying islet cell nucleomegaly.