Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: a single centre experience

Objective: Donohue syndrome and Rabson-Mendenhall syndrome are extreme forms of insulin resistance caused by biallelic mutations in the insulin receptor gene. Recombinant human IGF1 (rhIGF-1) treatment is often used but its long-term benefits and risks are still poorly delineated. We describe rhIGF-I treatment outcomes of a cohort of patients with Donohue syndrome and Rabson-Mendenhall syndrome, and compare them to previously published patients. // Design: Single-centre retrospective observational study. // Methods: Case note review. Literature search for previously published Donohue syndrome and Rabson-Mendenhall syndrome patients treated with rhIGF-1. // Results: rhIGF1 outcomes beyond 4 months have been reported for only 11 patients with Donohue syndrome and Rabson-Mendenhall syndrome to date. We provide outcome data for three more males, and report the long-term clinical course of a patient already described. Metabolic benefits of rhIGF-1 included improved glycaemic control and fasting tolerance in early years of life, and some growth enhancement. Two patients exhibited poor response or intolerance to rhIGF-1 and died in infancy. The two longest-lived patients had progressive decompensation to diabetes mellitus, in one case despite long-term uninterrupted rhIGF-1 therapy. We also describe new features associated with severe insulin receptoropathies, such as cataract, liver haemangioma, and impaired hepatic protein synthesis. // Conclusion: The phenotypes of Donohue and Rabson-Mendenhall syndromes are heterogeneous. Current treatment options remain unsatisfactory as high dose rhIGF-1 exerts only limited beneficial effects and does not prevent decompensation to diabetes mellitus. More research is needed to identify alternative treatment strategies for extreme forms of insulin resistance.