ESPE Abstracts

Introduction: Donohue syndrome (DS) is presenting as the most severe form of insulin resistance. Most of the patients are dying within the first two years of life. As potential treatment has been described the administration of rhIGF1 (Mecasermin) to stimulate the pathway of insulin-like action. An improved metabolic control was reported with continuous subcutaneous administration of rhIGF1 instead of twice daily injections [Plamper 2018].

Case report: At birth our female patient (38⁺² weeks of gestation) presented the following clinical features: large ears, thick lips, acanthosis nigricans, hyperplasia of nipples, decreased subcutaneous fat mass, small toenails, abdominal distension and clitoris hypertrophy. The girl was small for gestational age (1,820g birth weight) and appeared in the first days with hypoglycemia (min. 37 mg/dl). A first episode of hyperglycemia (343 mg/dl) was seen on 13^th day of life. We noticed the absence of ketoacidosis. The patient received treatment with i.v. insulin, max. at 0.6 IE/kg/h. Laboratory showed an extremely elevated c-peptide (>30.0 µg/l) and insulin levels (max. 2,640 mU/l). Further signs of the patient were hypertrophic cardiomyopathy, extremely enlarged polycystic ovaries and renal tubular dysfunction with nephrocalcinosis grade III. Due to the suspicion of an insulin resistance syndrome we started a modified ketogenic diet to achieve sufficient energy gain in the event of insufficient glucose metabolism. It was possible to establish reliable continuous blood glucose measurement with a Dexcom® sensor despite the very small subcutaneous fat tissue. Genetic testing confirmed DS (compound heterozygous mutation of the INSR gene: c.1610+1G>A paternal and c.32_52del (Ala11_Ala17del) maternal). Our primary treatment approach was a significant reduction in hyperinsulinemia to reduce the life-limiting factor of progressive hypertrophic cardiomyopathy (HCM). Therefore, we started administration of diazoxide, which did not significantly improve hyperinsulinemia and severe HCM. After switching to subcutaneous administration of octreotide HCM improved rapidly and insulin level fell down (min. 15 mU/l). Our current goal is sufficient thriving of the patient which is challenging. At the age of one month we started continuous subcutaneous administration of rhIGF1. We also gradually modified the ketogenic diet to avoid hypoglycemic events and to improve the disturbed enteral absorption of food.

Conclusion: Severe neonatal DS is challenging. One main goal seems to be to reduce the massive hyperinsulinemia causing life-limiting hypertrophic cardiomyopathy.