Variable Phenotypes of Individual and Family Monogenic Cases with Hyperinsulinism and Diabetes: a Systematic Review

Maturity-Onset Diabetes of the Youth (MODY) diabetes remains commonly misdiagnosed. A monogenic form should be suspected in individuals presenting hyperinsulinemic hypoglycemia (HH) associated with, either later development of MODY (hypoglycemia-remission-diabetes sequence), or with first/second-degree family history of diabetes. Herein, we aimed to describe this individual or family monogenic association between HH and diabetes, and identify potential genotype-phenotype correlations. We conducted a systematic review of 26 studies, including a total of 67 patients with this association resulting from variants in GCK (n = 5 cases), ABCC8 (n = 29), HNF1A (n = 5), or HNF4A (n = 28). A family history of hypoglycemia and/or diabetes was present in 91% of cases (61/67). Median age at first hypoglycemia was 24 h after birth. Diazoxide was initiated in 46 children (46/67-69%); responsiveness was found in 91% (42/46). Median HH duration was three years (1 day-25 years). Twenty-three patients (23/67-34%) later developed diabetes (median age: 13 years; range: 8-48); more frequently in those untreated with diazoxide. This association was most commonly inherited in an autosomal dominant manner (43/48-90%). Some genes were associated with less severe initial hypoglycemia (HNF1A), shorter duration of HH (HNF4A), and more maternal (ABCC8) or paternal (HNF4A) transmission. This study illustrates that the same genotype can give a biphasic phenotype in the same person or a reverse phenotype in the same family. Wider awareness of this association is necessary in pediatrics to establish annual monitoring of patients who have presented HH, and during maternity to screen diabetes and optimize genetic counseling and management of pregnancy, childbirth, and the newborn.PROSPERO registration: CRD42020178265.