medwireNews: Italian researchers report presenting characteristics and outcomes for children with primary adrenal insufficiency (PAI) not caused by 21-hydroxylase deficiency (OHD) congenital adrenal hyperplasia (CAH).

The team identified 803 children diagnosed with PAI in eight Italian centres over the previous 20 years, the majority (85%) of whom had 21-OHD CAH and were not assessed further for this study.

For the remaining 121 children, the most common cause of PAI was a rare inherited condition, accounting for 73.5% of these cases.

The most frequent of these were X-linked adrenoleukodystrophy (X-ALD) in 25 boys, autoimmune polyglandular syndrome type 1 (APS-1) in 25 children (nine boys) and adrenal hypoplasia congenital (AHC) caused by mutations in NR0B1 in 16 boys.

In addition, 10 children (eight boys) had other forms of CAH, most commonly 3β-hydroxysteroid dehydrogenase or 11-hydroxylase deficiency.

Five children (three boys) had familial glucocorticoid deficiency (FGD), most often due to an MC2R gene mutation, and for the remaining eight children, PAI was a component of a rare syndrome – Allgrove syndrome for seven children (five boys) and Pearson syndrome for one girl.

The second most common category was autoimmune PAI, which was diagnosed in 20 children, to account for 16.5% of the 121 cases. Twelve of these children had isolated autoimmune PAI and eight had it in the setting of APS-2.

A further three children had acquired forms of PAI, while the aetiology was not determined in the other nine.

Mariacarolina Salerno (University Federico II of Naples) and co-researchers found that the children’s signs and symptoms at presentation were “highly dependent on the underlying etiology.”

The most common symptom at the point of diagnosis was fatigue, in 67.0% of the children, followed by hyperpigmentation in 50.4%, dehydration in 33.0%, compensated hypotension in 31.0% and gastrointestinal symptoms, particularly vomiting, which occurred in 30.7% of the children.

Nearly a quarter of the children had failure to thrive and a similar proportion had neurological symptoms that were related to the specific underlying disease.

Age at diagnosis was also related to the underlying aetiology. Children with FGD, non–21-OHD CAH, AHC or rare genetic syndromes were diagnosed when very young (average 1.0 to 3.7 years), whereas those with X-ALD, APS-1 or autoimmune PAI were diagnosed at an average of 8.6 to 10.7 years of age.

“An acute onset was more frequently reported in children with AHC or FGD, whereas nonspecific signs may dominate the clinical picture in children with autoimmune PAI or X-ALD”, the researchers write in The Journal of Clinical Endocrinology & Metabolism.

And they note that there was a longer duration of symptoms before a diagnosis was made in this latter group, “pointing attention on the importance of increasing awareness in older children in which nonspecific symptoms may dominate the clinical picture for long-time.”

During an average follow-up of 8.7 years, 23.0% of the cohort experienced one adrenal crisis, 4.9% had two and 4.1% had three, with these being most frequent in children with autoimmune disease (60.0% of events). Three children died from complications related to the underlying disease; two had X-ALD and one had APS-1.

By Eleanor McDermid

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J Clin Endocrinol Metab 2020; doi:10.1210/clinem/dgaa881

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