Endocrine Abstracts

Background: Type A insulin resistance syndrome (TAIRS) is rare (prevalence 1/100 000) and is caused by pathological mutations in the insulin receptor (INSR) gene. The clinical features tend to affect females more severely. Patients can present with severe hyperinsulinemia, hyperandrogenism and acanthosis nigricans. We report a case of a girl with symptoms initially suggestive of polycystic ovarian syndrome (PCOS) but also with asymptomatic diabetes mellitus.

Case: A 10-year-old female presented with severe hirsutism, acanthosis nigricans and glycosuria though asymptomatic for diabetes. At presentation the patient’s height was 149.2 cm (95th centile), weight 45.5 kg (91st centile) and body mass index (BMI) of 20 kg/m2. The HbA1c was elevated at 56 mmol/l but fasting glucose levels were in normal range (4.4 mmol/l). A serum insulin (2530pmol/L) and C-peptide levels (2806pmol/L) were markedly increased. Continuous glucose monitoring showed a profile of post-prandial hyperglycaemic but paradoxical hypoglycaemic episodes in the early mornings. Testosterone (9.8 mmol/l) and androstenedione (25.1 mmol/l) were extremely elevated. Pelvic ultrasound showed grossly enlarged ovaries with an appearance consistent with PCOS (right ovary: 51x21x27 mm, vol 15 ml; left ovary: 59x23x25 mm, vol 18ml). Genomic analysis revealed a heterozygous missense mutation in the INSR gene on chromosome 19 (Pro1205Leu), diagnostic of TAIRS. The patient was managed with Metformin 500 mg in the morning to which she was very sensitive and after 6 weeks of treatment had also halved her testosterone levels (4.7 mmol/l). However as this was still very high for a girl of her age, she was then also commenced on cyproterone acetate (50μg) daily.

Conclusions: An unusual but characteristic glycaemic pattern of both post-prandial hyperglycaemia and early morning hypoglycaemia (unlike type 1 and 2 diabetes), in combination with symptoms of severe hyperandrogenism is suggestive of TAIRS and would indicate the need for genetic testing. Currently there is no specific management to target the underlying genetic mutation and therefore management is symptomatic control. Pharmacological therapy for insulin resistance using Metformin may be very beneficial.