Genetics and pathophysiology: Most severe insulin receptoropathies follow an autosomal recessive inheritance pattern, with affected individuals carrying pathogenic mutations in both INSR alleles. Mutations disrupt insulin receptor synthesis, trafficking, or signaling, particularly via the PI3K-AKT and MAPK pathways. The result is impaired cellular glucose uptake and dysregulated carbohydrate, lipid, and protein metabolism. Compensatory hyperinsulinemia is common, but high circulating insulin cannot achieve normal metabolic effects.
Clinical features: Presentation varies by mutation and severity. Congenital forms typically show growth retardation, dysmorphic features, and marked insulin resistance in infancy. Rabson–Mendenhall syndrome may include coarse facial features, dental abnormalities, acanthosis nigricans, and progressive metabolic complications. Milder forms, such as some cases of type A insulin resistance, may present later with severe insulin resistance, hirsutism, and acanthosis nigricans, but with variable growth effects.
Diagnosis and management: Diagnosis is based on clinical suspicion and confirmation by genetic testing for INSR mutations, supported by profiles of resistant hyperinsulinemia with hyperglycemia or hypoglycemia risk. Management is supportive and multidisciplinary, as there is no cure. Treatments may include insulin-sensitizing agents (e.g., metformin) and, in selected cases, insulin therapy at high doses; recombinant IGF-1 (mecasermin) has been used in some patients to improve growth and metabolic control. Regular monitoring for metabolic complications and genetic counseling are recommended.
Prognosis and research: Prognosis depends on severity and timing of onset. Severe neonatal forms can be life‑limiting, while milder cases may survive into adulthood with ongoing metabolic management. Research continues into targeted therapies and potential gene-based approaches, along with registries to better characterize the condition.