Endocrine Abstracts

Background: Monogenic insulin resistance syndromes are rare but important differential diagnoses in adolescents presenting with features of hyperandrogenism, particularly when obesity is absent. We present a case highlighting diagnostic challenges and the role of genetic testing in confirming a type A insulin resistance.

Case presentation: A 12-year-old female presented with progressive hirsutism, acne, and deepening of the voice. Her BMI was within the normal range (16.9 kg/m², 23rd centile), and her height was on the 88th centile. Initial laboratory investigations revealed elevated serum testosterone (2.4 nmol/l; reference <1.8), markedly raised C-peptide (7070 pmol/l; reference 174–960), and fasting insulin (554 pmol/l; reference 0–80), with adiponectin levels ranging between 8.3–9.9 μg/mL. Pelvic ultrasound demonstrated prepubertal uterine features without evidence of polycystic ovarian morphology. Over time, her hyperandrogenic features progressed, and she remained amenorrhoeic. Family history included maternal polycystic ovary syndrome (PCOS) diagnosed at age 20 and a half-sister with mild hirsutism. A comprehensive metabolic and endocrine work-up excluded adrenal pathology and lipodystrophy. Genetic testing identified a heterozygous, maternally inherited INSR likely pathogenic variant (c.3392C>G; p.Pro1131Arg), consistent with type A insulin resistance syndrome.

Discussion: Heterozygous INSR variants can present with variable phenotypic expression, ranging from asymptomatic carriers to adolescents with pronounced hyperandrogenism and insulin resistance. Unlike more severe biallelic INSR mutations, heterozygous variants are associated with milder metabolic derangements but have important implications for reproductive health, including an increased risk of gestational diabetes.

Conclusion: This case underscores the importance of considering monogenic insulin resistance in lean adolescents with hyperandrogenism and highlights how genetic diagnosis informs counselling and long-term management. Awareness of these rare presentations is crucial for early recognition and appropriate follow-up.

Keywords: Type A insulin resistance, INSR mutation, hyperandrogenism, adolescence, monogenic diabetes