Genetic Heterogeneity in Adrenal Insufficiency

Genetic forms of primary adrenal insufficiency (AI) present clinical heterogeneity, variable modes of inheritance, and association with several clinical pictures. Congenital adrenal hyperplasia (CAH) comprises a wide group of autosomal recessive enzymatic disorders, impairing glucocorticoid, mineralocorticoid, and/or androgen biosynthesis. The most frequent form of CAH is due to 21-hydroxylase deficiency. Adrenoleukodystrophy is an X-linked progressive metabolic disorder, characterized by very long chain fatty acids accumulation with cytotoxic effects on adrenal and neural cells. Adrenal hypoplasia congenita is an X-linked disorder characterized by fetal alterations affecting adrenal glands, mainly leading to neonatal AI. Familial glucocorticoid deficiency is an autosomal recessive disease caused by multiple genetic alterations and characterized by unresponsiveness of the adrenal cortex to adrenocorticotropic hormone (ACTH) stimulation, with consequent isolated cortisol deficiency. Allgrove syndrome, a specific form of adrenal unresponsiveness to ACTH, is a rare autosomal recessive syndrome due to DNA repair defects, in which the triad AI, alachrymia, and achalasia are usually present. Aldosterone synthase deficiency is an autosomal recessive enzymatic disorder of the mineralocorticoid pathway, leading to mineralocorticoid deficiency. Primary generalized glucocorticoid resistance is a sporadic or familial form of peripheral insensitivity to glucocorticoids, either partial or generalized, caused by mutations in the glucocorticoid receptor. Type 1 pseudohypoaldosteronism is an inherited form of mineralocorticoid resistance, which can be generalized or limited to renal tissue. As far as secondary AI is concerned, ACTH deficiency may be isolated or, in the majority of cases, combined in the context of combined pituitary hormonal deficiency, with wide clinical spectrum and genetic heterogeneity, mainly related to mutations in genes expressed in the developing head, hypothalamus, and/or pituitary.