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.”
Highlights
Primary adrenal insufficiency (PAI) is a relatively rare but po‐ tentially life‐threatening condition that can result from a broad range of causes
Genetic analysis has revealed that many European individuals and families of European ancestry with this condition are compound heterozygous for a c.940G > A variant on one al‐ lele of CYP11A1 and a severely disruptive change on the other allele (Figure 3A).[64]
The c.940G>A variant is predicted to cause a be‐ nign protein change (p.E314K), detailed molecular studies have shown that it generates a novel splice site so that missplicing occurs.[64,65]. This variant is carried by approximately 1:140 people of European descent, but is likely to cause adrenal insufficiency only when inherited with a very rare disruptive change on the other allele
Summary
Primary adrenal insufficiency (PAI) is a relatively rare but po‐ tentially life‐threatening condition that can result from a broad range of causes. Targeted deletion of the gene encoding Nr5a1 in the mouse causes adrenal and gonadal dysgenesis; children with a similar phenotype of adrenogonadal dysfunction were first reported in 1999 and 2002.1719 These individuals had variants affecting key DNA‐binding regions of SF‐1 (P‐box and A‐box).[20]
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