We report a non-obese 14-year old white female who initially presented to the paediatric endocrine service aged 7 years with adrenarche. She was born small for gestational age (2nd centile) but was otherwise developmentally normal with no significant past medical history. There was maternal history of polycystic ovarian syndrome (PCOS) but no family history of type 2 diabetes (T2DM). A GnRH test showed a pre-pubertal response and she was discharged after 1 year of follow-up with a normal pre-pubertal growth pattern.
Four years later, she represented with hyperandrogenism (hirsutism, acne, mild Acanthosis nigricans and serum testosterone 3.4 nmol/l) suggestive of PCOS. Late onset congenital adrenal hyperplasia was excluded by normal peak 17-hydroxyprogesterone and 11-deoxycortisol response to synacthen stimulation. Ultrasound scan revealed bulky ovaries with small ovarian cysts.
Oral glucose tolerance testing was undertaken, showing both T2DM (glucose 3.9 and 15.1 mmol/l at 0 and 120 min respectively) and severe hyperinsulinism (insulin 263 and >1000 mIU/l). Metformin and home glucose monitoring were initiated, following which the patient noticed frequent mid-morning hypoglycaemia. Continuous glucose monitoring confirmed persistent hypoglycaemia with most levels 2.33.2 mmol/l, maximum 4.2 mmol/l and postprandial hypoglycaemia.
Further investigations showed normal leptin but inappropriately high adiponectin for the degree of insulin resistance, recently shown to be diagnostic of insulin receptor dysfunction. Genetic analysis showed the patient to be heterozygous for the P1178L mutation in the insulin receptor (INSR), the most frequent INSR mutation identified to date in the UK. Primary disorders of insulin action due to inherited abnormalities of the INSR are rare causes of extreme insulin resistance, while adrenarche and PCOS are relatively common endocrine entities. This case remind us INSR defects in females most commonly present with an aggressive PCOS-like picture, which can be identified in puberty. Severe clinical or biochemical abnormalities, particularly in non-obese PCOS patients, should alert clinicians to the likelihood of extreme insulin resistance. Improved biochemical triage now allows expeditious identification of those patients with underlying insulin receptor defects.
05 - 07 Nov 2008
British Society for Paediatric Endocrinology and Diabetes