Primary adrenal insufficiency (PAI) is a condition in which the capacity of adrenal glands to produce adrenocortical hormones (glucocorticoids and mineralocorticoids) is impaired.

It is a rare condition, with a prevalence of 82–144 cases per million inhabitants, an incidence of 4–6 cases per million inhabitants and a predominance of the female sex,1–3 and its incidence in children is unknown.

The most frequent cause of PAI present at birth is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. There are few case studies in children, like the one we present here, that analyse rare aetiologies, such as autoimmune forms, corticotropic resistance or other genetic disorders. To our knowledge, only one such study has been conducted before in Spain.4

Autoimmune adrenalitis is the most frequent cause of PAI in adults, accounting for 80% of cases, with a clear predominance of the female sex.5 It is much less frequent in the paediatric population, in which it accounts for only 10%–15% of cases.5

It can present in isolation or in association with other diseases such as hypoparathyroidism, mucocutaneous candidiasis or other autoimmune diseases as part of an autoimmune pluriglandular syndrome (APS).

X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder with an incidence of 1 in 14 700 births.6 It is caused by changes in the ABCD1 gene (Xq28) that encodes a transmembrane protein (ALDP) involved in the transport of very long chain fatty acids (VLCFAs) from the cytosol to the peroxisome, where they are degraded. The accumulation of VLCFAs compromises the structural integrity of the myelin sheath, which causes neurological manifestations, and causes damage to the adrenal cortex and hypogonadism as VLCFAs accumulate in Leydig cells.

Congenital adrenal hypoplasia is caused by changes in the NR0B1 gene, located in the Xp21.2 region, which encodes the DAX1 protein. It is a rare disorder with an incidence of less than 1 in 12 500 births.7 It manifests with primary adrenal insufficiency, delayed puberty and impaired spermatogenesis in adulthood.

This disorder should be suspected in male patients once CAH and X-ALD have been ruled out, especially if there is a family history of infertility in males.

Familial glucocorticoid deficiency (FGD) or ACTH resistance syndrome is a rare disease of unknown prevalence with an autosomal recessive pattern of inheritance. It manifests with isolated glucocorticoid deficiency due to a lack of response to ACTH by cells in the zona fasciculata of the adrenal cortex. It is due to defects in the ACTH receptor (MC2R) or its accessory protein (MRAP) necessary for transmitting the ACTH signal into the cell.8 It should be suspected in patients with recurrent hypoglycaemia and mucocutaneous hyperpigmentation. A family history of consanguinity or unexplained premature death supports the diagnosis.

Pearson syndrome is a rare disease caused by a deletion in mitochondrial DNA. Its incidence is 1 per million births.9 It is characterised by sideroblastic anaemia associated with neutropenia and thrombopenia, exocrine pancreatic dysfunction and renal tubulopathy. It may be associated with diabetes, primary adrenal insufficiency, hypoparathyroidism and growth delay.

Allgrove syndrome (AS), also known as triple A syndrome, is characterised by alacrima, achalasia and adrenal insufficiency secondary to ACTH resistance. It is associated with peripheral motor and sensory neuropathy, dysautonomia, optic atrophy and ataxia. Its prevalence is unknown. It is an autosomal recessive disorder caused by changes in the AAAS gene (12q13.13) encoding the ALADIN protein.10

In many cases, the clinical manifestations resulting from combined cortisol and mineralocorticoid deficiency develop gradually, and the nonspecificity of symptoms complicates the diagnosis.

Glucocorticoid deficiency manifests with asthenia, anorexia and a tendency toward hypoglycaemia due to the impact of the lack of cortisol on energy metabolism (decreased gluconeogenesis and glycogenolysis); it can also cause orthostatic hypotension due to decreased sensitivity to catecholamines and gastrointestinal symptoms due to an increase in hydrochloric acid and pepsin in the intestinal lumen. Weight loss is common.

The decrease in cortisol leads to an increase in corticotropin-releasing hormone (CRH), ACTH and other peptides derived from pro-opiomelanocortin, such as β-lipotropin, which has melanocyte-stimulating activity, causing hyperpigmentation of the skin and mucous membranes, a feature characteristic of Addison disease.

Mineralocorticoid deficiency is responsible for salt loss due to hypoaldosderonism, which in turn results in hypovolaemia, hyponatraemia with increased natriuresis, hyperkalaemia and metabolic acidosis. Salt craving is typical. Blood tests will show low aldosterone levels with a compensatory increase in renin.

Its suspicion is of vital importance, as any type of stress (infections, trauma, surgery, etc) can trigger an acute episode of adrenal insufficiency, referred to as an adrenal crisis, manifesting with hypovolaemic shock with hyponatraemia, hyperkalaemia, acidosis and hypoglycaemia.

The estimated incidence of adrenal crises in Europe is of 6–8 cases per 100 inhabitants per year, of which 70% occur in before age 10 years.11,12 The mortality rate is 0.5 deaths per 100 patients per year.2 Thus, it is a serious condition requiring urgent medical attention.

We consider this study to be of great interest, given the low prevalence in the paediatric population, the high level of suspicion required for diagnosis and the high mortality rate of adrenal crises.

The general objective was to identify the causes of primary adrenal insufficiency in paediatric patients. The specific objectives were to obtain epidemiological data on the different aetiologies, to gather data on the symptoms, signs and analytical findings present at onset, to determine the frequency of onset in the form of an adrenal crisis, to assess the value of ACTH measurement in treatment monitoring and to establish the number of patients that required combination therapy (glucocorticoids and mineralocorticoids).

Patients. We conducted a multicentre and descriptive case study including all patients who received a diagnosis of PAI during childhood in the past 30 years (from January 1990 to December 2020) in 5 Spanish hospitals.

The sample included all patients with suspected and subsequently confirmed PAI with onset from birth to age 18 years. Their medical history had to be compatible with PAI and include elevated serum ACTH levels and/or decreased cortisol levels.

We excluded all deceased patients for whom we were unable to collect data, cases of congenital adrenal hyperplasia and cases with a iatrogenic, neoplastic, infectious and/or traumatic aetiology.

Methods. We collected data from health records (paper and/or electronic format).

The data analysis was performed with the software SPSS version 25.0 (IBM, NY, USA). We expressed results as frequencies and percentages (qualitative variables) or as median and range (quantitative variables). We used the χ2 test or the Fisher exact test to compare proportions. We compared quantitative or ordinal variables in different groups by means of the Kruskal-Wallis test and the Mann-Whitney U test. P values of less than 0.05 were considered statistically significant.

Ethical considerations. The project was approved by the local clinical research ethics committee.

The most frequent causes of PAI in our study were X-linked adrenoleukodystrophy, autoimmune adrenalitis and congenital adrenal hypoplasia. In our series, X-linked adrenoleukodystrophy predominated, in agreement with a recently published article13; However, other studies continue to find that the most frequent type of aetiology is the autoimmune aetiology.14–16

We ought to highlight that congenital adrenal hypoplasia was the aetiology with the earliest onset (median age at diagnosis, 1.2 months), while the oldest age at diagnosis corresponded to autoimmune adrenalitis (median age at diagnosis, 11.2 years), which was consistent with the previous literature.7,15

The male/female ratio was 1/0.3, and the male predominance was consistent with other paediatric case series.4,13,14

In our study, asthenia, hyperpigmentation and hyponatraemia were the most frequent symptom, sign and electrolyte disturbance, respectively, although their absence does not rule out PAI.

Cutaneous hyperpigmentation is a cardinal sign that suggests the diagnosis, but it is not always present. Published studies show that hyperpigmentation is present in 90% of patients,17–19 although the frequency was lower in our series (62.1%). Hyperpigmentation can be very subtle at onset or in the first 6 weeks of life,17 which could explain its absence in 3 of our patients, who had onset at 7, 22 and 24 days post birth.

Hyponatraemia was present in 65.5% of patients, although this feature can be even more frequent (90%).20,21

Hyperkalaemia was infrequent in our sample (24.1%) compared to other published series, in which it was found in up to 50% of the cases.16,20 Its absence may be explained in patients with profuse vomiting, since the loss of hydrochloric acid causes metabolic alkalosis and, as a result, hypokalaemia, although we did not find an association between potassium levels and the presence of vomiting in our sample.

In this case series, 55.2% of the patients had onset with an acute adrenal crisis. In the paediatric population, adrenal crisis is defined as an acute deterioration in health status with haemodynamic changes (arterial hypotension, slow capillary refill or increased heart rate for age) or severe electrolyte disturbances (hyponatraemia or hyperkalaemia) or hypoglycaemia not attributable to any other cause. The diagnosis is confirmed when the disturbances are reversed after glucocorticoid administration.22

As this series demonstrates, arterial hypotension is not required for diagnosis of adrenal crisis, as more than half of our patients had onset with adrenal crisis but hypotension was only detected in 37.9%. Similarly, we should not wait for blood glucose, sodium and potassium levels to all be abnormal before suspecting an adrenal crisis.

The ACTH level is not a suitable marker for the purpose of treatment monitoring. Values of ACTH should remain elevated, as illustrated by our sample; if levels are within the normal range, the patient may be overtreated.3,17 Similarly, treatment should not be modified based on the degree of hyperpigmentation.17 The corticoid dose should be adjusted based on the assessment of weight gain, growth and clinical manifestations.

In this series, 69% of patients required combination therapy (glucocorticoid + mineralocorticoid). The rest of the patients did not show mineralocorticoid axis involvement, which can be explained by the fact that the zona glomerulosa of the adrenal cortex is usually less affected than the zona fasciculata and the zona reticularis.6

In conclusion, clinicians must be vigilant to recognise the signs and symptoms of primary adrenal insufficiency in order to achieve an early diagnosis and prevent the development of adrenal crises. Furthermore, knowledge of the different causes of PAI allows the clinician to narrow down the aetiological diagnosis.

This research did not receive any external funding.