Childhood primary adrenal insufficiency diagnosis pattern changes with age

medwireNews: A study of children in Finland reveals that diagnosis of primary adrenal insufficiency (PAI) is most common shortly after birth and related to congenital adrenal hyperplasia (CAH), but after age 4 years, autoimmune-related diagnoses become more frequent.

“It is important to recognize these differences in PAI etiology in different ages since the cause of PAI affects the diagnostic measures, treatment, and follow-up of the patient”, say Joonatan Borchers (University of Helsinki, Finland) and co-authors in The Journal of Clinical Endocrinology & Metabolism.

The team collated medical records for 97 children included in the Finnish National Care Register for Health Care between 1996 and 2016 as having a diagnosis of chronic PAI before the age of 21 years and requiring glucocorticoid replacement therapy. The majority of patients were boys (64%) and the median age at diagnosis was 3 years.

The highest incidence of PAI occurred before the age of 1 year, at a rate of 3.4 cases per 100,000 person–years, and this was more common in boys than girls at this time (4.0 vs 2.7 cases per 100,000 person–years).

The incidence fell to 0.4 cases per 100,000 person–years between the ages of 1 and 15 years; however, the cumulative incidence was 10 and 13 cases per 100,000 person–years at ages 15 and 20 years, respectively. And the incidence continued to be higher in boys than girls up to age 20 years (17 vs 9 cases per 100,000 person–years).

CAH was the most common cause of PAI, affecting 57% of patients including 35 boys and 20 girls. This was followed by autoimmune disease in 29% of cases, affecting 16 boys and 12 girls.

A further 6% of patients were diagnosed with X-linked adrenoleukodystrophy (XALD) and 6% with other rare genetic causes, including two patients with MRAP alteration-related adrenocorticotropic hormone resistance and single cases of NR0B1 alteration-related adrenal hypoplasia, triple A syndrome with an AAS mutation and TRIM37 defect-related Mulibrey nanism. One patient was diagnosed with adrenal aplasia before birth, but genetic testing was not performed, and two patients had PAI of unknown aetiology.

CAH accounted for 88% of PAI cases in children aged up to 1 year and remained the most common cause until age 4 years. The majority (65%) of patients with CAH were diagnosed by age 1 year, including 75% of girls and 60% of boys.

By contrast, the median age at diagnosis for other forms of PAI was 8 years, rising to 11 years for children with isolated autoimmune PAI (n=13) and autoimmune polyendocrine syndrome (APS, n=15). Autoimmune disease was the most common PAI aetiology after age 5 years, with 95% of new PAI cases after age 8 years attributed to this cause, mirroring the autoimmune aetiology of PAI in adults, the researchers observe.

Further analysis of the children with autoimmune PAI revealed that eight were diagnosed with APS type 1 – also known as autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy – and all but one of these children carried two pathogenic variants of AIRE, with one mutated form reported in the remaining child.

Seven patients were diagnosed with APS type 2, including three with type 1 diabetes, one with autoimmune hypothyroidism, two patients with both diagnoses and one patient with autoimmune hypogonadism. None of the patients with isolated autoimmune PAI were diagnosed with another autoimmune disease during follow-up.

“Our findings indicate that in Finland PAI is more prevalent in males than in females during childhood”, write Borchers et al, partially because of male-only XALD diagnoses, and partially because of the “clear difference between the sexes in the number of patients with CAH”, despite the autosomal recessive inheritance of the disease meaning a sex balance would be expected.

Noting that families in Finland with a child affected by CAH are offered genetic counselling and prenatal diagnosis is available, the researchers question whether the virilising impact of CAH on girls may lead to more induced abortions in girls than boys.

“The effect of genetic counseling should be further analyzed by studying the sex ratio of affected siblings in families with more than 1 child with CAH”, the authors suggest. “So far, there are no studies on the effects of genetic counseling and prenatal diagnostics on diseases like CAH and our cohort size unfortunately did not allow such an analysis”, they say.

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

J Clin Endocrinol Metab; doi: 10.1210/clinem/dgad283
Martin Savage
Programme Director
Sign up for eAlerts
Be the first to hear about new resources and content by signing up to receive our eAlerts.

We'd love your feedback!

Please complete this short 5-question survey to help improve the content offered on this website.
Please rank the following aspects of the program from best [1] to worst [4].