Primary adrenal insufficiency: New genetic causes and their long‐term consequences

Abstract

Primary adrenal insufficiency (PAI) is a potentially life‐threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives. Here, we describe some recent insights into the genetics of adrenal insufficiency and associated molecular mechanisms. We discuss (a) the role of the nuclear receptors DAX‐1 (NR0B1) and steroidogenic factor‐1 (SF‐1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain‐of‐function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed‐onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine‐1‐phosphate lyase‐1 (SGPL1). Reaching a specific diagnosis can have life‐long implications for management. In some situations, milder or nonclassic forms of these conditions can first present in adulthood and may have been labelled, “Addison's disease.”

Hyperpigmentation and ACTH – an overview of literature

“…Addison's disease addison's disease is a rare, heterogeneous condition where the destruction of the adrenal glands is done mainly based on an autoimmune or tubecurculosis background (8). low cortisol causes an aCtH increase based on a feedback mechanism between pituitary and adrenal glands while hyperpigmentation at the level of skin (including scars) and mucosa is one of the main clinical features (9). Others skin conditions like vitiligo may be associated in cases with polyglandular autoimmune syndrome (10).…”

“…Others skin conditions like vitiligo may be associated in cases with polyglandular autoimmune syndrome (10). Primary adrenal insufficiency may be lethal if adequate substitution is not provided (9). More than 30 causes are described, including genetic types (9).…”

“…Primary adrenal insufficiency may be lethal if adequate substitution is not provided (9). More than 30 causes are described, including genetic types (9).…”

Current Insights Into Adrenal Insufficiency in the Newborn and Young Infant

“…However, monosomy 7 is linked to the development of myelodysplastic syndrome, which can lead to leukemia if other genetic changes occur. Interestingly, somatic loss-of-function (nonsense or frameshift) changes or uniparental disomy in cis can also “remove” the mutant allele and ameliorate the phenotype ( 5 , 62 – 64 ). Increasingly, children with milder MIRAGE-like features are being reported, many with normal adrenal function ( 65 ).…”

“…AI can be broadly divided into secondary causes, due to disruption of hypothalamic or pituitary (corticotrope) ACTH release, and primary causes, which affect the adrenal gland itself. Although some conditions have fairly typical presentation patterns and ages of onset, there is often a spectrum of features, and milder variants may produce partial or delayed onset forms of classic conditions ( 5 , 6 ). Associated features can sometimes give a clue to the diagnosis.…”