Endocrine Abstracts

Introduction: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease characterised by ACTH resistance and isolated glucocorticoid deficiency. Mutations of ACTH receptor, known as melanocortin-2 receptor (MC2R), and melanocortin-2 receptor accessory protein (MRAP) account for approximately 25 and 15 to 20% of cases respectively. To date there is no strong evidence that heterozygous carriers have abnormal cortisol secretion.

Case: We studied a pedigree with a MC2R mutation where the index case presented with severe hypoglycaemia at three years of age in 1970s and was subsequently diagnosed with adrenal insufficiency. Of eight siblings, two brothers died as neonates, with hindsight due to adrenal insufficiency and a third brother was diagnosed with adrenal insufficiency when he presented comatose at two months and remained profoundly handicapped and later died. The index case was found to have a homozygous missense mutation c.221G>T, leading to p.S74I (substitution of serine with isoleucine at position 74) in the MC2R gene. We studied three of her siblings with the heterozygous S74I mutation in the MC2R gene. The mean age of heterozygous carriers was 31.3±2.5 years. They had generalised slightly tanned skin, but no significant hyperpigmentation. They were normotensive and had no symptoms suggestive of glucocorticoid deficiency. Short synacthen testing with 250 μg tetracosactide in heterozygous carriers showed baseline ACTH levels of 53.7±31.9 ng/l (normal range <46 ng/l), 0 min cortisol levels of 506±168 nmol/l, 30 min cortisol levels of 952±85 nmol/l, and 60 min cortisol levels of 953±36 nmol/l.

Conclusion: The study of heterozygous MC2R mutation carriers demonstrated slightly elevated baseline ACTH levels with a relatively high baseline cortisol level and an exaggerated cortisol response to synacthen test. These findings suggest there is no evidence of glucocorticoid deficiency despite elevated ACTH levels in heterozygous carriers with MC2R mutations.