medwireNews: Next-generation sequencing can identify a genetic cause of primary adrenal insufficiency (PAI) in around eight in 10 children, research suggests.

For the study, Tulay Guran (Marmara University, Istanbul, Turkey) and co-researchers assessed 95 children with PAI drawn from 19 centres across Turkey.

The aetiology was unknown for all these patients, but using next-generation sequencing of 160 known and candidate genes involved in adrenal development and function, the team made a genetic diagnosis for 77 (81%) patients, including 18 with familial PAI and 59 with sporadic PAI.

The patients had a total of 43 mutations in nine genes, with missense mutations being the most common (n=24). Twenty-one of the mutations had been previously reported, but 22 were novel. The researchers considered these novel variants the cause of the patients’ PAI because they explained particular phenotypes, were predicted to be damaging in bioinformative models and were not present in databases or healthy controls.

The most commonly affected gene was MC2R (26%), which encodes the adrenocorticotropic hormone (ACTH) receptor, mutations in which are an established cause of familial glucocorticoid deficiency (FGD). Thirteen of the 25 children with MC2R mutations had severely disruptive mutations and were clinically diagnosed before the age of 6 months because of hypoglycaemic convulsions, respiratory distress or both.

However, salt loss is not typical in patients with FGD, and in fact just five of the children had evidence of hyponatremia, of whom only two were receiving long-term fludrocortisone replacement. “On the basis of the genetic diagnosis it is likely the need for this treatment can be reviewed”, the team writes in The Journal of Clinical Endocrinology & Metabolism.

The second-most commonly affected gene was NR0B1 (13%), which encodes the nuclear receptor DAX-1. All 12 affected patients were boys who had salt loss and presented either before 1 month of age or after 18 months. Guran et al note that diagnosis during childhood is important for these patients, to plan for probable hypogonadotropic hypogonadism and infertility later in life.

Other commonly affected genes were STAR (12.0%), leading to disrupted cholesterol transport into the mitochondria and therefore congenital lipoid adrenal hyperplasia; CYP11A1 (9.5%), affecting the conversion of cholesterol to pregnenolone; and MRAP (9.5%), impairing the trafficking of the ACTH receptor to the cell membrane.

The team also identified mutations in NNT (7%), and in ABCD1NR5A1 and AAAS (1–2%).

“This nationwide cohort study of high throughput genetic screening of children with rare causes of PAI has provided many novel and supportive clinical and molecular insights and has significant impact on the management of these patients and their families”, conclude the researchers.

By Eleanor McDermid, Senior medwireNews Reporter

J Clin Endocrinol Metab 2015; Advance online publication

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