ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Clin Endocrinol (Oxf). 2020; 92(1): 11–20. PMID: 31610036.

Primary adrenal insufficiency (PAI) is a relatively rare but potentially life?threatening condition that requires urgent diagnosis and treatment (1). Although the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, there is an ever-expanding list of rare genetic causes (2). These genetic causes frequently have variable inheritance patterns, while some milder or non-classical forms of these conditions may present for the first time in adolescence or adulthood (2). In some situations, patients may have been labelled as having ‘Addison’s’ disease and more detailed genetic investigations to find a specific cause have not been undertaken.

In this narrative review, the authors present the recent insights into the genetics and molecular mechanisms of rare forms of PAI and show how reaching a specific diagnosis benefit for management and long-term care. Specifically, they discuss the role of the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human adrenal and reproductive dysfunction (3, 4); multisystem growth restriction syndromes due to gain-of-function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1 (5, 6, 7); non-classical forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed-onset predominantly adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI or resembling familial glucocorticoid deficiency (FGD) (8, 9); and a new sphingolipidosis causing PAI due to defects in sphingosine-1-phosphate lyase-1 (SGPL1) (10, 11).

Reaching a genetic diagnosis of PAI in childhood can have important implications for counselling and management, while clinical monitoring for the emergence of potential associated features and devising of treatment strategies is of paramount importance in this diverse group of patients. Detecting affected family members before the onset of disease is also important. When presented with a child or young person with newly diagnosed adrenal insufficiency, several aspects of the history, clinical features or focused tests may give a clue to the underlying cause. The suggested approach is for single gene testing in conditions such as 21-hydroxylase deficiency or X-linked adrenoleukodystrophy, where there are diagnostic biochemical markers. Focused panels are also available that include many of the genetic causes of PAI. Ultimately, in the future, whole exome or whole genome sequiencing with targeted analysis of relevant genes will likely be the best approach, as all known genes can be reviewed initially and, if the cause is not found, data can subsequently be reanalysed as new genetic causes are identified or the relevance becomes established of intronic changes that may affect splicing. In addition, knowledge of geographical hotspots is potentially important to implement targeted genetic testing quickly and cost-effectively, especially in resource-limited settings. The authors finally offer insights in gene discovery approaches using genome wide analysis that have the potential to give better understanding of human adrenal development and function.

References:

1. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2016; 101(2):364–389.

2. Flück CE. Mechanisms in endocrinology: update on pathogenesis of primary adrenal insufficiency: beyond steroid enzyme deficiency and autoimmune adrenal destruction. Eur J Endocrinol. 2017;177(3): R99–R111.

3. Muscatelli F, Strom TM, Walker AP, et al. Mutations in the DAX?1 gene give rise to both X?linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism. Nature. 1994;372(6507):672–676.

4. Suntharalingham JP, Buonocore F, Duncan AJ, Achermann JC. DAX?1 (NR0B1) and steroidogenic factor?1 (SF?1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015;29(4):607–619.

5. Kerns SL, Guevara?Aguirre J, Andrew S, et al. A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early?adulthood?onset diabetes. J Clin Endocrinol Metab. 2014;99(10):E2117–E2122.

6. Narumi S, Amano N, Ishii T, et al. SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet. 2016;48(7):792–797.

7. Logan CV, Murray JE, Parry DA, et al. DNA polymerase epsilon deficiency causes IMAGe syndrome with variable immunodeficiency. Am J Hum Genet. 2018;103(6):1038–1044.

8. Achermann JC, Ito M, Ito M, Hindmarsh PC, Jameson JL. A mutation in the gene encoding steroidogenic factor?1 causes XY sex reversal and adrenal failure in humans. Nat Genet. 1999;22(2):125–126.

9. Sahakitrungruang T, Tee MK, Blackett PR, Miller WL. Partial defect in the cholesterol side?chain cleavage enzyme P450scc (CYP11A1) resembling nonclassic congenital lipoid adrenal hyperplasia. J Clin Endocrinol Metab. 2011;96(3):792–798.

10. Prasad R, Hadjidemetriou I, Maharaj A, et al. Sphingosine?1?phosphate lyase mutations cause primary adrenal insufficiency and steroid?resistant nephrotic syndrome. J Clin Invest. 2017;127(3):942–953.

11. Lovric S, Saba JD, Hildebrandt F, et al. Mutations in sphingosine?1?phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. J Clin Invest. 2017;127(3):912–928.