Current Insights Into Adrenal Insufficiency in the Newborn and Young Infant

Abstract

Adrenal insufficiency (AI) is a potentially life-threatening condition that can be difficult to diagnose, especially if it is not considered as a potential cause of a child's clinical presentation or unexpected deterioration. Children who present with AI in early life can have signs of glucocorticoid deficiency (hyperpigmentation, hypoglycemia, prolonged jaundice, poor weight gain), mineralocorticoid deficiency (hypotension, salt loss, collapse), adrenal androgen excess (atypical genitalia), or associated features linked to a specific underlying condition. Here, we provide an overview of causes of childhood AI, with a focus on genetic conditions that present in the first few months of life. Reaching a specific diagnosis can have lifelong implications for focusing management in an individual, and for counseling the family about inheritance and the risk of recurrence.

Genetic Analysis of Pediatric Primary Adrenal Insufficiency of Unknown Etiology: 25 Years’ Experience in the UK

“…Several “hotspots” of other forms of CAH exist (eg, 11β-hydroxylase deficiency in Jewish populations from Morocco); indeed, congenital lipoid adrenal hyperplasia due to disruption of STAR is particularly prevalent in South Korea and Japan [ 2 , 6 ]. Other well-recognized causes of PAI include autoimmune disorders (eg, autoimmune polyglandular syndrome type 1/ AIRE ; autoimmune Addison disease in teenagers) and established but rare metabolic disorders (eg, Wolman disease, Zellweger spectrum, mitochondrial disorders, adrenoleukodystrophy) [ 4 ]. Of these metabolic conditions, X-linked adrenoleukodystrophy is an important diagnosis to make in boys, and very-long change fatty acid analysis should be considered.…”

“…The past 25 years have seen significant progress in our understanding of the genetic causes of PAI, especially for conditions presenting in children or in young people [ 4-8 ]. More than 30 different single gene disorders have now been reported with a diverse range of genetic inheritance patterns (recessive, dominant/de novo, X-linked, or even imprinted).…”

Non-Canonical Effects of ACTH: Insights Into Adrenal Insufficiency

“…Generally, the presenting signs and symptoms are hypoglycemia and jaundice due to AI, usually developing during the neonatal period or infancy although the age of onset is variable ( 119 ). Failure to thrive, seizures, and frequent infections are also common features.…”

“…Interestingly, TPIT disruption only affects POMC production from the pituitary gland, whereas other sites of synthesis, such as the skin and hypothalamus, seem preserved ( 121 ); affected patients lack other signs and symptoms that are present in POMC defects. In fact, patients with monogenic POMC and PC1 defects show altered pigmentation and auburn hair, due to the lack of α-melanocyte-stimulating hormone, and hyperphagic obesity usually presenting during infancy, due to defective POMC hypothalamic signaling ( 119 ).…”

Society for Endocrinology UK Guidance on the initial evaluation of a suspected difference or disorder of sex development (Revised 2021)

“…In the presence of a poor testosterone response following hCG stimulation, assessment of adrenal function by a standard short synacthen stimulation test should be considered. There is currently insufficient evidence to recommend that everybody with XY DSD should have a ACTH stimulation test but clinicians should be aware of the clear association between some forms of DSD and primary adrenal insufficiency and should consider thorough assessment of adrenal function in those diagnoses where an association has already been described 85 and in those with any clinical suspicion of adrenal insufficiency, especially those with low steroid precursors on USP.…”