Clinical spectrum of extreme insulin resistance syndromes treated with rhIGF-1: A single-center experience

CONTEXT: Donohue syndrome (DS) and Rabson-Mendenhall syndrome (RMS) are extreme forms of insulin resistance (IR) caused by biallelic mutations in the insulin receptor gene. Recombinant human insulin-like growth factor-1 (rhIGF-1) treatment is often used but its long-term benefits and risks are still poorly delineated. OBJECTIVE: We describe rhIGF-1 treatment outcomes of a cohort of patients with DS and RMS, and compare them to previously published patients. METHODS: A single-center retrospective observational study with case note review was conducted. A literature search was performed for previously published DS and RMS patients treated with rhIGF-1. RESULTS: rhIGF-1 outcomes beyond 4 months have been reported for only 11 patients with DS and RMS to date. We provide outcome data for 3 more males, and report the long-term clinical course of a patient already described. Metabolic benefits of rhIGF-1 included improved glycemic 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 2 longest-lived patients had progressive decompensation to diabetes mellitus, in 1 case despite long-term uninterrupted rhIGF-1 therapy. We also describe new features associated with severe insulin receptoropathies, such as cataract, liver hemangioma, and impaired hepatic protein synthesis. CONCLUSION: The phenotypes of DS and RMS 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 IR.