Ciężki wrodzony hiperinsulinizm z postępującym pogorszeniem stanu neurologicznego spowodowany nowymi digenicznymi mutacjami HADH-GHSR: pierwszy opis przypadku

Congenital hyperinsulinism (CHI) represents a complex group of genetic disorders causing inappropriate insulin secretion. We report the first case of severe CHI caused by a novel combination of HADH and GHSR mutations, leading to an unusually severe neurological phenotype. A male infant presented at 24 days of life with severe hypoglycemic seizures (0.3 mmol/l), inappropriate hyperinsulinemia (10.31 µUI/ml), and elevated C-peptide (2.64 µg/l). His clinical course was marked by progressive neurological deterioration, evolving from neonatal seizures to West syndrome at 12 months, and subsequently to Lennox-Gastaut syndrome at 3 years. Genetic analysis revealed a previously undescribed combination of a homozygous HADH deletion (5.25 kb, exons 3–4) and a heterozygous GHSR missense variant (c.611C>A, p.Ala204Glu). Therapeutic management was particularly challenging in a resource-limited setting, with unavailability of essential medications such as diazoxide. Despite intensive management with medium-chain triglyceride-enriched formula, levocarnitine, and nocturnal cornstarch, glycemic control remained suboptimal. At 7 years, the patient presents severe psychomotor delay (–4 SD for weight and height) and drug-resistant epilepsy. This case highlights the potential for severe phenotypes in digenic CHI and suggests synergistic effects between fatty acid metabolism and hormonal signaling pathways in glucose homeostasis, opening new perspectives for understanding complex forms of CHI.