Familial glucocorticoid deficiency (FGD), also known as isolated glucocorticoid deficiency or hereditary unresponsiveness to ACTH, is a subtype of primary adrenal insufficiency characterized by ad renal resistance to ACTH. The hallmark of FGD is low to absent serum cortisol in the presence of preserved mineralocorticoid production and extremely high levels of plasma ACTH. FGD classically presents in the neonatal period or infancy with symptoms of hypocortisolaemia leading to hypoglycaemia, failure to thrive, coma, susceptibility to infections, and death if untreated. Intense hyperpigmentation is a feature of FGD due to the action of ACTH on MC1R in skin.
FGD is a rare autosomal recessive disorder, first described by Shepherd et al. in 1959, who reported siblings with ‘familial Addison’s disease’. This prompted subsequent reports of individuals with isolated glucocorticoid deficiency and normal aldosterone production. The first inactivating mutation in the ACTH receptor was described some 30 years later, made possible by the cloning of the receptor, the second melanocortin receptor to be cloned— hence the alternative name MC2R. Since 1993 over 40 variants have been described, predominantly missense mutations spread throughout the length of the receptor. Nonsense MC2R variants are less frequent and have been associated mild disturbance of the renin- angiotensin- aldosterone system. Mutations in MC2R account for approximately 25% of cases of FGD (FGD type 1). Tall stature has been associated with FGD type 1; it is unclear whether this is due to ACTH action on bone or to hypocortisolaemia, it is not seen in all FGD type 1 individuals. Absent adrenarche, i.e. loss of accelerating adrenal androgen pro duction at age 6– 9 years, has also been described, demonstrating the importance of ACTH in this process.
In 2005, homozygosity mapping using SNP arrays in consanguineous FGD families without causative mutations in MC2R enabled the identification of MRAP, melanocortin 2 receptor accessory protein. It had long been suggested that the MC2R required an adrenal specific factor to enable expression at the cell surface. MRAP proved to be this factor. A small single transmembrane do main protein expressed in adrenal cells, MRAP was shown to be essential for the functional expression of the MC2R at the cell sur face. Intriguingly, it has now been shown that this protein adopts an antiparallel dimer conformation— the only eukaryotic protein, except for its paralogue MRAP2, to do this. Approximately 20% of cases of FGD are now known to be due to mutations in MRAP (FGD type 2). Unlike mutations in MC2R, MRAP mutations are usually nonsense or splice- site variations resulting in truncation or complete absence of the protein. As such, individuals with mutations in MRAP present earlier than those with defects in MC2R. Rare MRAP missense mutations have been described and are associated with milder, late onset disease.
Studying FGD type 3 and beyond, i.e. those individuals without mutations MC2R and MRAP, has identified novel genes and path ways in adrenal gland physiology (described next). Such gen etic discoveries have highlighted great phenotypic heterogeneity, prompting increased awareness of overlap in classical categorizations of primary adrenal insufficiency disorders.
