Family with two novel in cis INSR gene variants: Phenotypic evolution with age.

Authors

Georgia Sotiriou, Anny Mertzanian, Maria Eleni Raptopoulou, Amalia Sertedaki, Maria Tsirevelou, Eftychia Drogouti, Christina Kanaka Gantenbein, Christos Tsakalidis, Athanasios Christoforidis

Published in

Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology. Volume 35. Issue 4. Pages 351-356. Epub May 21, 2026.

Abstract

Pathogenic variants in the insulin receptor gene (INSR) cause a broad spectrum of metabolic disorders, from severe insulin resistance to milder phenotypes such as hyperinsulinemic hypoglycemia. We describe a preterm female neonate with persistent, asymptomatic hyperinsulinemic hypoglycemia, characterized by markedly elevated insulin and C-peptide levels with suppressed ketones. Genetic testing revealed two novel, maternally inherited heterozygous INSR variants in cis, c.3541A>C p.(Thr1181Pro) and c.3566A>C p.(Tyr1189Ser), located in the tyrosine kinase domain. The infant remains clinically stable without pharmacological treatment and demonstrates normal growth and development. Her 7-yr-old brother, carrying the same variants, is asymptomatic but shows relatively increased insulin responses during oral glucose tolerance testing, while the mother developed insulin-resistant diabetes in early adulthood. This family highlights the age-dependent phenotypic variability associated with the same INSR variants, ranging from neonatal hyperinsulinemic hypoglycemia to childhood hyperinsulinemia with euglycemia and adult insulin resistance. These observations expand the clinical spectrum of heterozygous INSR variants and underscore the influence of residual receptor activity, age, and metabolic demands on disease expression. Early genetic testing in infants with even mild hyperinsulinemic hypoglycemia is important for prognosis, family screening, and long-term follow-up to detect evolving insulin resistance.

PMID:
42825299
Bibliographic data and abstract were imported from PubMed on 02 Oct 2026.

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