P3.267: Canary in the coal mine: Acanthosis nigricans as the early warning sign of severe insulin resistance in siblings with Rabson-Mendenhall Syndrome

Introduction: Acanthosis nigricans (AN) in children often signals insulin resistance in the setting of type 2 diabetes mellitus (DM), usually concomitant with obesity and typically presenting after initial puberty. However, for children with a normal BMI or presenting with AN pre-pubertally, alternative diagnoses should be considered. INSR-related severe insulin resistance syndrome (INSR-SIRS) results from mutations in the INSR gene, which encodes the insulin sensing receptor. Dysfunctional INSR leads to hyperinsulinemia, hyperglycemia, and severe insulin resistance with Donohue Syndrome, Rabson-Mendenhall Syndrome (RMS), and Type A insulin resistance representing decreasing severity across the phenotypic spectrum. We present a case of INSR-SIRS in two non-obese siblings who presented with AN, originally dismissed by their previous care teams, emphasizing the need for early recognition, thorough investigation, and genetic testing in atypical presentations.

Case Description: 14-year-old male with 22q11.2 deletion syndrome and his 9-year-old sister, both non-obese, presented with AN. The male’s AN, present since age 4, was deemed an isolated dermatologic issue due to a normal hemoglobin A1c (A1c) at presentation. Further investigation was limited, as subsequent care teams cited the previous A1c as adequate evaluation. Subsequently, the female’s AN was overlooked due to her brother’s history, attributed again to an isolated dermatologic condition. Upon transition of their medical care, the new pediatrician identified that AN in normal weight, pre-pubertal children was abnormal. Further evaluation revealed A1c of 8.9% and insulin of 699 µIU/mL in the male, and A1c of 7.2% and insulin of 248 µIU/mL in the female. Genetic testing confirmed INSR-SIRS (RMS phenotype), identifying maternally inherited duplication of exons 14-15 and paternally inherited Pro1013Leu mutation in the INSR gene. Both siblings started treatment with metformin, resulting in marked reduction in A1c (M 5.8%, F 5.4%).

Discussion: This case details the diagnosis of INSR-SIRS in siblings with atypical AN as identified by their pediatrician, highlighting the importance of considering AN as an indicator for uncommon systemic disease, particularly in non-obese and pre-pubertal children. Diagnostic overshadowing, particularly in the male with 22q11.2 syndrome, but also in his sister with presumed benign AN, delayed both diagnoses. INSR-SIRS of all phenotypes carries risks of both hyperglycemia and hypoglycemia, necessitating careful management with continuous glucose monitoring (CGM), insulin sensitizers, and eventual insulin to optimize therapy and prevent life-threatening hypoglycemia.

Conclusion: This case highlights AN as an indicator for systemic disease urging clinicians to consider diagnoses beyond type 2 DM. Pediatricians faced with abnormal physical findings must recognize clinical context in their assessment. Given the evolving understanding of INSR-SIRS, treatment should be patient-specific, addressing hypoglycemia and hyperglycemia risks. Future research is needed to improve diagnostic protocols and clinical guidelines.