SAT-160 - A Shared Homozygous INSR Variant Causing Type A Insulin Resistance Syndrome in Members of A Single Tribe: Longitudinal Response to Recombinant IGF-1 and Insulin-Sensitizing Therapies

Background:
Type A insulin resistance syndrome (TAIRS) is a rare genetic disorder caused by pathogenic variants in the insulin receptor (INSR) gene, characterized by severe insulin resistance, hyperinsulinemia, and hyperandrogenism, typically in individuals with normal body mass index (BMI). Most reported cases involve heterozygous INSR variants, while homozygous mutations are extremely rare.

Discussion:
We describe four Saudi unrelated individuals (three females and one male, age range 14-24 years) from the same tribe diagnosed with TAIRS, all harboring identical homozygous pathogenic INSR variant (c.433C>T; p.Arg145Cys). Clinical characteristics, biochemical profiles, and longitudinal responses to treatment modalities were reviewed, including recombinant insulin-like growth factor-1 (IGF-1; mecasermin), insulin-sensitizing agents, and anti-androgen therapy. All patients had normal BMI, coarse and acromegaloid facial features, and acanthosis nigricans. All female patients fulfilled diagnostic criteria for polycystic ovary syndrome, with significant hyperandrogenism and menstrual dysfunction. The two pediatric patients received IGF-1 therapy for three years. In Patient 1, IGF-1 led to an approximately 90% reduction in fasting insulin levels (peak 951 μIU/mL, nadir 34.9 μIU/mL) and improvement in HbA1c from 7.5% to < 6.5%, with minimal improvement in androgenic features. Glycemic control was stable after IGF-1 discontinuation on metformin alone. Patient 2 demonstrated excellent glycemic control during IGF-1 therapy (HbA1c nadir 5.3%); however, following discontinuation, HbA1c rose to 13%, requiring escalation to insulin and pioglitazone, with persistent amenorrhea. The male patient exhibited variable glycemic control related to adherence and ultimately required basal insulin in addition to oral agents, including pioglitazone, achieving HbA1c improvement to 7.2%. The fourth female patient demonstrated marked reductions in insulin levels (peak 431 μIU/mL, nadir 51–61 μIU/mL) and improved HbA1c with pioglitazone alone, although hyperandrogenism and menstrual irregularity persisted.

Conclusion:
This case series highlights a shared homozygous INSR mutation causing TAIRS within a single Saudi tribe and underscores the metabolic benefits of IGF-1 in selected pediatric patients. Insulin sensitizers, particularly pioglitazone, improved glycemic control; however, hyperandrogenism and reproductive dysfunction remained challenging. A high index of clinical suspicion, early genetic diagnosis, and multimodal treatment strategies are essential. Future studies are needed to define the role of IGF-1 therapy in TAIRS, considering its high cost and limited accessibility.

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