Endocrine Abstracts

JOINT812

Three cases of Donohue syndrome, a rare disorder of severe congenital insulin resistance due to INSR gene mutations, are presented. All patients exhibited severe intrauterine growth restriction (IUGR), failure to thrive (FTT), dysmorphic features, extremely high insulin and C-peptide levels at birth.

Case 1: A 7-month-old male infant had metformin initiated at 50 mg/kg/day at three weeks. He developed severe hypertrophic cardiomyopathy, requiring beta-blocker therapy, and was treated with ursodiol for cholestatic liver disease. Frequent enteral feedings enriched with polycose via gastrostomy were provided to prevent hypoglycemia. Continuous glucose monitoring (CGM) indicated 80% time in range (55-180 mg/dL), 18% above range (>180 mg/dL), and 2% below 55 mg/dL. Last measured length and weight SDS were -5.0 and -4.0, respectively. Despite treatment, he died at seven months, with a hypoglycemia episode near the time of death.

Case 2: A 13-month-old female infant had metformin initiated at 50 mg/kg/day at one month, along with continuous PZ feedings and MCT oil due to recurrent hypoglycemia. The CGM was unreliable, and metformin did not improve HbA1c or C-peptide levels, leading to its discontinuation. Liver dysfunction with cholestasis and synthetic impairment was treated with ursodiol, vitamin K, and ADEK. She experienced ovarian torsion at six months, hyperandrogenism, respiratory distress managed with Vapotherm, nephrocalcinosis, and difficulty to mange central hypothyroidism. Current length SDS is -5.0, weight SDS is -4.5.

Case 3: A 21-month-old female infant had metformin started at 40 mg/kg/day at one month, with recombinant IGF-1 (0.2 mg/kg/day) added at 11 months. Glycemic control improved: 84% time in range 55-180 mg/dL, yet growth parameters remained poor (weight -9.8 SDS, length -5.5 SDS). Current IGF-1 levels are measurable, and C-peptide levels have decreased, but insulin levels remain extremely high. She presented with enlarged ovaries, hyperandrogenism, cardiomyopathy (beta-blocker treated), restrictive lung disease requiring ventilation, and well-managed central hypothyroidism.

Differences: While all patients exhibited significant challenges, the specific manifestations and responses to treatment varied. Case 1 presented cardiac complications earlier and had a fatal outcome. Case 2 involved significant liver dysfunction. Case 3 demonstrated some improvement in glucose control using multiple treatments, but persistent growth failure, and respiratory difficulty.

Conclusion: Donohue syndrome presents significant diagnostic and therapeutic challenges. The variability in presentation and treatment response underscores the need for individualized management, close monitoring, and multidisciplinary care. Further research into this rare syndrome is crucial for improving outcomes and understanding its pathophysiology.