Rare forms of genetic paediatric adrenal insufficiency: Excluding congenital adrenal hyperplasia

Abstract

Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.

Familial Glucocorticoid Deficiency: the changing landscape of an eponymous syndrome

“…A significant number of patients (8 out of 15) presented with sequelae of hypoglycaemia. A further study noted that some patients were mineralocorticoid deficient highlighting a degree of phenotypic variability (46,72).…”

“…The majority of variants are splice site/nonsense that ultimately lead to a truncated and nonfunctional receptor. Patients generally present at an earlier age (median age of 0.08 years at diagnosis) with normal stature when compared to subjects with MC2R variants (37,45,46). This suggests reduced exposure to the unfettered actions of ACTH on the growth plate seen in FGD Type 1.…”