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Variable phenotypes of individual and family monogenic cases with hyperinsulinism and diabetes: a systematic review

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Abstract

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.

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All data generated or analyzed during this study are included in the published article [and its supplementary information files].

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  1. Service d’Endocrinologie Pédiatrique Et Pédiatrie Générale, Hospices Civils de Lyon, Hôpital Femme Mère Enfant, 59 Boulevard Pinel, 69677, Bron, France

    Kevin Perge & Marc Nicolino

  2. Université Claude Bernard, Lyon 1, 8 Avenue Rockefeller, 69008, Lyon, France

    Kevin Perge & Marc Nicolino

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KP performed the literature search, preparation of figures, data collection, data analysis, data interpretation, and writing of the initial manuscript. MN initiated the study and proposed the study design, literature search, preparation of figures, data collection, data analysis, data interpretation, and writing. All the authors reviewed the final manuscript, endorsed the findings and the scientific content.

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11154_2022_9749_MOESM1_ESM.xlsx

Supplementary file1 Online Resource 1: Demographic, clinical, laboratory, genetic, and treatment features of individual or family monogenic association between HH and diabetes in GCK subgroup (XLSX 13 KB)

11154_2022_9749_MOESM2_ESM.xlsx

Supplementary file2 Online Resource 2: Demographic, clinical, laboratory, genetic, and treatment features of individual or family monogenic association between HH and diabetes in ABCC8 subgroup (XLSX 22 KB)

11154_2022_9749_MOESM3_ESM.xlsx

Supplementary file3 Online Resource 3: Demographic, clinical, laboratory, genetic, and treatment features of individual or family monogenic association between HH and diabetes in HNF1A subgroup (XLSX 17 KB)

11154_2022_9749_MOESM4_ESM.xlsx

Supplementary file4 Online Resource 4: Demographic, clinical, laboratory, genetic, and treatment features of individual or family monogenic association between HH and diabetes in HNF4A subgroup (XLSX 20 KB)

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Perge, K., Nicolino, M. Variable phenotypes of individual and family monogenic cases with hyperinsulinism and diabetes: a systematic review. Rev Endocr Metab Disord 23, 1063–1078 (2022). https://doi.org/10.1007/s11154-022-09749-2

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