Familial glucocorticoid deficiency type 1 (FGD1) is a rare autosomal recessive disease resulting from resistance to the action of adrenocorticotropin (ACTH) on the adrenal cortex. The impairment of the adrenal response to ACTH leads to deficient secretion of cortisol and adrenal C19 androgen precursors. By contrast, mineralocorticoid production, regulated by the renin-angiotensin system, is normal. All the signs and symptoms seen in FGD1 patients are the result of either low levels of plasma cortisol or elevated ACTH levels. They are usually observed during the first year of life and can also appear during infancy or later childhood. These symptoms include, prolonged jaundice, hypoglycemia or hypoglycemic convulsions, failure to thrive, skin hyperpigmentation and sepsis. The symptoms may be lethal in some children. Tall stature has also been reported in a subset of individuals with FGD1, especially prior to glucocorticoid treatment, but the pathogenic basis of this feature is not clear.
Early intervention and constant care are crucial for affected individuals. Treatment consists of replacement therapy with oral hydrocortisone.
Inactivating mutations in the ACTH receptor (melanocortin-2-receptor, MC2R) are well described and account for approximately 25% of cases of FGD1. MC2R encodes a member of the five-member G-protein associated melanocortin receptor family. The interaction of ACTH with its receptor (MC2-R) on the adrenal cortex stimulates glucocorticoid production. Mutations in the MC2R gene affect this interaction, leading to the severe deficiency of glucocorticoids. The combination of low cortisol levels paired with extremely high plasma ACTH levels represent the hallmark features in the pathogenesis of FGD1.