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

A New Sphingolipidosis: SGPL1

Another recent discovery is the association of PAI with steroid-resistant nephrotic syndrome, due to homozygous or compound heterozygous variants in sphingosine-1-phosphate lyase-1 (SGPL1).[67–69]

SGPL1 is an enzyme that catalyses the breakdown of sphingolipids by cleaving sphingosine-1-phosphate.[67] Disruption of this enzyme can lead to an accumulation of sphingolipids and ceramide and represents a novel sphingolipidosis (similar to Fabry disease, Gaucher disease and Niemann-Pick disease; Figure 4A). Other clinical features reported in these patients include ichthyosis, neurological dysfunction, dyslipidaemia, lymphopaenia and other endocrine features such as primary hypothyroidism and cryptorchidism.[67] The adrenal features are not invariable at presentation and may be masked by steroid treatment for nephrotic syndrome or precipitated by steroid withdrawal. Some children have mineralocorticoid insufficiency and Sgpl1 knockout mice have depleted lipid in zona glomerulosa cells (Figure 4B). In patients, adrenal calcifications can sometimes be seen on imaging.[69]

Figure 4.

Sphingosine-1-phosphate lyase-1 (SGPL1) disruption causes adrenal insufficiency. (A) SGPL1 regulates breakdown of ceramide, a pathway associated with several established metabolic disorders (sphingolipidoses). (B) The Sgpl1−/− knockout mouse has an adrenal phenotype including depleted lipid in zona glomerulosa cells. Panels (A) and (B) modified from 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 © 2017 The Authors (

SGPL1-deficiency is an important diagnosis to make as it is a potentially progressive, multisystem disorder. Future therapies could target this pathway to restore function. Of note, SGPL1 antagonists have been trialled for the treatment of multiple sclerosis; initial data suggest these do not affect adrenal function but more information about the role of this pathway in the adrenal gland is needed.[70]

Genetic Testing for PAI

Reaching a genetic diagnosis of PAI in childhood can have important implications for counselling and management, especially as inheritance patterns are variable, important potential associated features might need monitoring and treatment strategies can differ. Detecting affected family members before the onset of features can be 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. For example:

  1. Some more common causes of PAI such as congenital adrenal hyperplasia (CAH), autoimmune Addison's disease and some metabolic causes (eg X-linked adrenal leukodystrophy) can be diagnosed by focused biochemical testing backed up (where relevant) by single gene testing. Features such as hyperandrogenism (CAH) or other autoimmune conditions may help;

  2. Family history may point to an X-linked condition (eg NR0B1/hypoplasia; ABCD1/adrenoleukodystrophy) if boys are affected in the maternal family, or a recessive condition if there is known consanguinity (Table 1);

  3. Known associated features can be highly informative if present at diagnosis (eg hypogonadotropic hypogonadism and NR0B1/hypoplasia, steroid-resistant nephrotic syndrome and SGPL1; IUGR/FGR and IMAGe/MIRAGE);

  4. Ancestral background may be important as founder effects and geographical hotspots for some conditions are known.

In the absence of the potential features listed above, many forms of PAI have a similar biochemical profile (ie, elevated ACTH, low cortisol or poor cortisol response to stimulation, with or without mineralocorticoid insufficiency). Additional "clues" such as age of presentation and presence of salt-loss can sometimes help with a likely broad diagnosis, but are not specific on their own. Therefore, next-generation sequencing approaches using targeted panels of known genes or exomes are being increasing used in both research and clinical practice.

The diagnostic rate for known genes using some of these approaches is surprisingly high. In a national multicentre study of 95 children with PAI of unknown aetiology (non-CAH, nonautoimmune, nonmetabolic) in Turkey, a genetic diagnosis was made in almost 90% of individuals, with variants in just 10 genes (eg MC2R, NR0B1 (DAX-1), STAR, CYP11A1, MRAP, NNT, ABCD1, NR5A1, AAAS, SGPL1).[37] Key founder effects and geographical hot spots were seen, such as a recurrent MRAP slice variant in Western Turkey and partial loss-of-function variant in CYP11A1 in Central regions. Obviously, high consanguinity rates would have enriched for recessively inherited conditions in this cohort, but even in an analysis of our data for young people presenting with PAI in the United Kingdom, a genetic diagnosis was reached in more than 60% of children and young people (unpublished data). Thus, genetic analysis seems worthwhile.

So, what is the best approach to clinical genetic analysis? This is a difficult question as access to genetic testing varies in different countries and policies change rapidly as technologies improve and costs reduce. In England, the "National Genomic Test Directory" was launched in March 2019 to provide guidance on commissioned genetic testing for rare and inherited diseases ( At the time of writing, we would suggest that single gene testing is still preferred for 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, clinical exomes or genomes 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. Finally, knowledge of geographical hotspots can be very important for targeting genetic testing quickly and cost-effectively, especially in resource-limited settings.

As well as the known causes described here, gene discovery approaches using genome wide analysis, better understanding of human adrenal development and function, and newer genetic approaches should help in the discovery of additional causes of PAI in the future.[71] Where no genetic cause is identified, other physical causes may have been overlooked. Finally, in a small but important group, adrenal insufficiency resolves and no specific cause is found.