Primary Adrenal Insufficiency in Childhood: Data From a Large Nationwide Cohort

Abstract

Context Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition, poorly characterized in children. Objective to describe causes, presentation, auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI. Patients and methods data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected. Results the following etiologies were reported: 85% (n=682) Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n=25) X linked Adrenoleukodystrophy; 3.1% (n=25) Autoimmune Polyglandular syndrome type 1; 2.5% (n=20) autoimmune AI; 2% (n=16) Adrenal Hypoplasia Congenital; 1.2% (n=10) CAH non 21-OHD; 1% (n=8) rare syndromes; 0.6% (n=5) Familial Glucocorticoid Deficiency; 0.4% (n=3) acquired AI; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis different from 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%) and hypotension (31%). Elevated ACTH (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%) and hypoglycemia (33.7%). The median age at presentation was 6.5±5.1 years (0.1-17.8 years) and the mean length of symptoms before diagnosis was 5.6±11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patients years. Three patients died for the underlying disease. Adult height, evaluated in 70 patients, was -0.70±1.20 SDS. Conclusions we characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.

Case Report: Neonatal Cholestasis as Early Manifestation of Primary Adrenal Insufficiency

“…FGD is a group of rare conditions characterized by a lack of response to ACTH and the presence of isolated glucocorticoid deficiency. FGD usually presents in the early period of life with hypoglycemia, convulsions, prolonged jaundice, and marked skin hyperpigmentation ( 6 , 11 , 14 ). Several defects in MC2R, MRAP, MCM4, NNT, and TXNRD2 genes are related to FGD or related conditions, and MC2R variants cause about 25% of all cases of FGD ( 15 , 16 ).…”

“…Several studies have shown that the pituitary-adrenal axis affects the synthesis of bile acids and that cortisol deficiency may have a role in inducing cholestasis (2)(3)(4)(5). Primary adrenal insufficiency (PAI) is a potentially life-threatening disease characterized by impaired secretion of glucocorticoids eventually associated with mineralocorticoid and adrenal androgen deficiency or excess (6,7). Although PAI is known to be a possible cause of NC, cholestasis has not been reported as its isolated clinical manifestation so far.…”

“…Although PAI is known to be a possible cause of NC, cholestasis has not been reported as its isolated clinical manifestation so far. In children, PAI is mainly due to inherited disorders of steroidogenesis, including familial glucocorticoid deficiency (FGD), which is characterized by isolated glucocorticoid deficiency ( 6 ). Here, we report the case of an infant with prolonged cholestatic jaundice due to PAI suspected because of a single episode of hypoglycemia occurring at birth in the absence of other clinical signs of adrenal insufficiency.…”

Diverse etiologies, diagnostic approach, and management of primary adrenal insufficiency in pediatric age

“…The most common cause of pediatric PAI is congenital adrenal hyperplasia (CAH) of 21-hydroxylase deficiency (21OHD). 1) During the past decade, a number of rare monogenic disorders with PAI have been reported. The diagnosis of AI in children and young infants is frequently delayed because it has nonspecific, vague clinical symptoms.…”

Delayed pubarche

“…Impaired adrenal steroidogenesis, adrenal dysgenesis and adrenal destruction are the most common causes of primary adrenal insufficiency in children, with congenital adrenal hyperplasia (CAH) and autoimmune destruction being the most frequent [ 17 ]. Symptoms of adrenal insufficiency range from insidious to severe and include fatigue, weakness, weight loss, nausea, abdominal pain, vomiting, severe dehydration unresponsive to intravenous fluid, and coma [ 18 ]. Infants may also show poor feeding and impaired growth.…”