There are many genetic causes of secondary adrenal insufficiency broadly categorized into those involved in pituitary development and genes involved in pro- opiomelanocortin (POMC) cell maturation and POMC synthesis and processing (Table 1). Defects in genes involved in pituitary development give rise to combined pituitary hormone deficiency. Often there is relative sparing of corticotroph function in these disorders, which are described in more detail in Chapter 2.3.1 (‘Development of the Pituitary and Genetic Forms of Hypopituitarism’). Here we will focus on the few genes, in which alterations give rise to isolated ACTH deficiency.
Table1. Genetic causes of secondary adrenal insufficiency
Disorders of PoMc Synthesis and Processing
The paraventricular nucleus of the hypothalamus secretes vasopressin and CRH, which regulate the synthesis of the precursor protein pro- opiomelanocortin (POMC) in the corticotropic cells of the anterior pituitary gland. POMC is then cleaved to produce ACTH, which binds to its unique receptor the ACTH receptor (also known as the melanocortin 2 receptor, MC2R) on the surface of adrenocortical cells to stimulate glucocorticoid secretion. POMC is also expressed in the arcuate nucleus of the hypothalamus where it is processed to generate melanocortin peptides, most importantly α- MSH. Central melanocortin signalling through the melanocortin 3 and 4 receptors (MC3R and MC4R) regulates energy balance and satiety. Peripheral melanocortin signalling through the melanocortin 1 receptor (MC1R) is involved in pigment production in melanocytes. Biallelic loss- of- function mutations in POMC in humans have been demonstrated to lead to adrenal deficiency in the first few months of life. Hyperphagia, early onset obesity and hypopigmentation of skin and hair are invariably also present. Mutations in proprotein convertase 1 (PC1), a subtilisin- like enzyme responsible for the cleavage of POMC, gives rise to a related phenotype of secondary ad renal insufficiency associated with obesity.
POMC Lineage Differentiation and transcription Defects
Autosomal recessive genetic variants in the gene T-box 19 (TBX19), which encodes a transcription factor, which is involved in the development of the POMC expressing cells of the anterior pituitary and the transcription of POMC, have been identified in patients with isolated ACTH deficiency, typically presenting with hypoglycaemia, seizures and prolonged jaundice in the neonatal period.
