Primary Adrenal Insufficiency: New Genetic Causes and Their long-Term Consequences

Federica Buonocore; John C. Achermann


Clin Endocrinol. 2020;91(1):11-20. 

In This Article

Abstract and Introduction


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."


Primary adrenal insufficiency (PAI) is a relatively rare but potentially life-threatening condition that can result from a broad range of causes. In adulthood, the most common aetiologies include autoimmune "Addison's disease," haemorrhage, infiltrative disorders/metastases and infection, whereas congenital adrenal hyperplasia (usually due to 21-hydroxylase deficiency) affects approximately 1:18 000 infants and children.[1–3] In recent years, however, an ever-expanding list of genetic causes of PAI has been established (Table 1; see also International Classification of Pediatric Endocrine Diagnoses; These conditions can have different inheritance patterns and potentially important associated features. Furthermore, milder or nonclassic forms of some of these conditions may only first present in teenage years or adulthood.

Here, we review some recent insights into the genetics and molecular mechanisms of rare forms of PAI and show how reaching a specific diagnosis can have implications for management and long-term care. We will not discuss forms of CAH (including POR-related syndromes), or well-established adrenal insufficiency syndromes such as Triple A syndrome (achalasia, Addison's, alacrima) or X-linked adrenoleukodystrophy.