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

Abstract

Primary adrenal insufficiency (PAI) in pediatric age is a rare, but potentially fatal condition caused by diverse etiologies including biochemical defects of steroid biosynthesis, developmental abnormalities of the adrenal gland, or reduced responsiveness to adrenocorticotropic hormone. Compared to adult PAI, pediatric PAI is more often the result of genetic (monogenic, syndromic disorders) than acquired conditions. During the past decade, rare monogenic disorders associated with PAI have helped unravel the underlying novel molecular genetic mechanism. The diagnosis of adrenal insufficiency in children and young infancy is often challenging, usually based on clinical suspicion and endocrine laboratory findings. Pediatric endocrinologists sometimes encounter therapeutic difficulty in finding the balance between undertreatment and overtreatment, determining how to optimize the dose over the patient’s lifetime, and maximizing mimicry of normal cortisol secretion with glucocorticoid replacement therapy.

Adrenal Dysfunction in Mitochondrial Diseases

“…STAR is therefore essential for maintaining steroidogenesis in adrenal cells, with rare mutations that decrease or abolish STAR bioactivity highlighting this. The consequential decrease in steroid hormones increases intracellular lipids, eventually resulting in mitochondrial and cell death [ 2 , 3 , 8 ]. The resultant disease, known as congenital lipoid adrenal hyperplasia (lipoid CAH), is potentially fatal, presenting with critical adrenal failure in the first few months of life [ 18 , 19 ].…”

“…This non-functional MRAP cannot accompany MC2R out of the ER, decreasing membrane MC2R [ 15 ]. Both MC2R and MRAP mutations ultimately reduce ACTH signal transduction across the zF cell membrane [ 3 ]. Although MC2R and MRAP are expressed at low levels throughout the adrenals, they are particularly abundant in the zF [ 11 , 15 , 26 ].…”

“…However, there are a number of reports of partial loss-of-function STAR variants that also cause non-classical FGD (with preserved mineralocorticoid and androgen production) [ 15 ]. Mutations in CYP11A1 also typically produce a syndromic picture similar to lipoid CAH, with adrenal and gonadal steroid insufficiency and atypical sexual development [ 3 , 8 , 11 ]. However, multiple loss of function CYP11A1 mutations are also implicated in the development of isolated GC deficiency [ 11 , 15 , 28 , 29 ].…”

“…Both dysfunctional mitochondria and deranged steroidogenesis can precipitate fatal multi-system disorders. However, the exact role of mitochondria, particularly mitochondrial dysfunction, in the development of sterol insufficiency remains unclear [ 3 , 4 ].…”

Frequently Asked Questions in Patients With Adrenal Insufficiency in the Time of COVID-19

“…Then, in case of clinical deterioration (incoming hypotension, persistent cough, increased respiratory rate > 30 breaths/minute or SpO2 <93%), the self-administration of 100 mg HC and the contact with the emergency department are suggested (8,18). In children, 2 mg/kg or 50 mg/m 2 of HC every 6-8 h intramuscularly, subcutaneous or intravenous, combined with the correction of hypovolemia (0.9% up to 60 mL/kg within 1 hour) and hypoglycaemia, are suggested (6,30,31). Beyond the adjustment of GC therapy during COVID-19, patients with AI should reduce their risk to get the SARS-Cov-2 infection through social distancing, the use of masks, hands cleaning with dedicate gel, the choice of work-from-home if possible (18,32).…”