Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterised by unresponsiveness to ACTH and isolated cortisol deficiency. FGD is caused by mutations in genes encoding the ACTH receptor (melanocortin 2 receptor (MC2R)), its accessory protein (MRAP) or the steroidogenic acute regulatory protein (StAR). One significant feature is generalized skin hyperpigmentation which is thought to be due to elevated ACTH acting on the melanocortin 1 receptor (MC1R). MC1R plays a central role in the regulation of skin pigmentation, is expressed in melanocytes and binds α-MSH and ACTH with similar affinity. MC1R activation increases the ratio of black, strongly photoprotective eumelanins to reddish, poorly photoprotective pheomelanins. Several MC1R variants are associated with red hair/fair skin.
The index case presented aged 4 years with hypoglycaemia after prolonged fasting during a respiratory tract infection. She had further hypoglycaemic attacks and was diagnosed with hypocortisolemia at 6 years (14 nmol/l during hypoglycaemia) and hypercorticotropinemia (ACTH >1250 pg/ml). Her parents were consanguineous and she had one unaffected sister. Her physical examination was normal except her height and weight were greater than the 97th centile for age. Interestingly, she had no hyperpigmentation despite very high ACTH levels. Nucleotide sequence analysis revealed homozygous mutations c.478C>T in MC1R and c.455C>A in MC2R leading to R160W and T152K changes in the proteins respectively.
The R160W MC1R change has previously been implicated in a red hair/pale skin phenotype and the T152K change in MC2R is novel. Both parents were heterozygous for the mutations and her unaffected sister was heterozygous for the MC1R mutation and had a wild-type MC2R.
We report an unusual case of FGD without hyperpigmentation due to co-existent MC1R/MC2R mutations. This case is important as it clearly demonstrates for the first time that the assumption that skin pigmentation is caused by the action of ACTH on the MC1R is correct.