Primary adrenal insufficiency (PAI) is an important diagnosis to make as it is potentially life-threatening and requires urgent treatment. Although most paediatric endocrinologists have experience of more common conditions such as congenital adrenal hyperplasia (CAH) and autoimmune adrenal insufficiency, more than 30 other genetics causes of PAI exist, as well as physical causes such as haemorrhage. Reaching a specific diagnosis for some of these rarer conditions can have important management implications, such as the need to assess potential associated features (or syndromes), modifying treatment approaches, counselling families about recurrence risk and identifying presymptomatic family members. New high-throughput sequencing approaches are increasing our knowledge in this area and are helping in the discovery of new genetic causes of PAI. Here, I will review several recent insights into the genetics of adrenal insufficiency and related molecular mechanisms, including: 1) the role of the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human adrenal and reproductive function; 2) non-classic forms of STAR and CYP11A1 insufficiency that present with delayed-onset PAI and are surprisingly common; 3) defects in SGPL1 causing a new sphingolipidosis that affects multiple systems; and 4) growth restriction syndromes affecting adrenal development such as gain-of-function of the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1. The relative prevalence of some of these genetic causes of PAI in large cohort studies will also be discussed.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology