Current Screening Strategies for the Diagnosis of Adrenal Insufficiency in Children

Figures & data

Table 1 Conditions Associated with Adrenal Insufficiency (AI) in Children

Primary Adrenal Insufficiency
Etiologies	Clinical Characteristics	Laboratory Characteristics (all with ↓ cortisol)
Genetic disorders
● Congenital adrenal hyperplasia (CAH)
o 21-hydroxylase deficiency (95% of CAH)	-Salt-wasting (75%), non salt-wasting (25%) -Newborn girls with ambiguous genitalia or virilizing females, premature pubarche, hirsutism -Neonates with abnormal newborn screening for CAH	↑ 17-OH progesterone, ↑androgens, ↑ACTH, ↑PRA, ↓aldosterone ↓Na, ↑K (in salt-wasting)
o 3β- hydroxysteroid dehydrogenase deficiency	Salt-wasting in severe form, male and female disorder of sexual development (DSD), premature pubarche, hirsutism	↑17-OH pregnenolone, ↑DHEA, ↑PRA, ↓aldosterone
o 11β-hydroxylase deficiency	Virilizing females, premature pubarche in male and females, Hypertension due to ↑ deoxycorticosterone level	↑ deoxycorticosterone, ↑compound S, ↑ACTH. ↓PRA, ↓potassium
o 17-alpha-hydroxylase/17,20 lyase deficiency	Male DSD, sexual infantilism, primary amenorrhea, hypertension	↑DOC, ↑corticosterone, ↑ACTH ↓PRA, ↓potassium
o P450 oxidoreductase (POR) deficiency	Virilizing females, under virilized males, ± skeletal malformations (similar to Antley-Bixler syndrome)	↑17-OH progesterone, ↑17-OH pregnenolone, nl/↓androgens
● Congenital lipoid adrenal hyperplasia (StAR)	Female phenotype in 46, XY and 46, XX, neonatal salt wasting (classic)	↓adrenal and gonadal steroids, ↑PRA, ↑LH
● P450 side-chain-cleavage deficiency	Similar to lipoid adrenal hyperplasia, atrophic adrenal glands	↓adrenal and gonadal steroids, ↑PRA, ↑LH
● Adrenal hypoplasia congenita	Severe AI and salt-wasting in males, hypogonadotropic hypogonadism	↓adrenal androgens, ↑ACTH, ↑PRA
● ACTH insensitivity syndrome
o Familial glucocorticoid deficiency 1	Failure to thrive, hyperpigmentation, hypoglycemia, tall stature	↑ACTH, normal electrolytes, PRA
o Familial glucocorticoid deficiency 2	Failure to thrive, hyperpigmentation, hypoglycemia	↑ACTH, normal electrolytes, PRA
o Triple A (Allgrove) syndrome (alacrimia, achalasia, adrenal insufficiency)	Achalasia, alacrima, adrenal insufficiency, failure to thrive, developmental delay, neurological symptoms	↑ACTH, aldosterone deficiency in 10–15%
● Peroxisome defects: Adrenoleukodystrophy	Males: AI precedes neurological symptoms	↑ACTH, ↑PRA, ↓aldosterone ↑VLCFA
Adrenal damage
● Autoimmune adrenalitis (Addison’s disease)	Weight loss, fatigue, salt craving, hyperpigmentation. Can be isolated or part of autoimmune polyglandular syndrome 1 and 2	↑ACTH, ↑PRA, ↓aldosterone
● Bilateral adrenal hemorrhage of the newborn	Risk factors: traumatic delivery, birth asphyxia, sepsis. May present in shock.	Suprarenal cystic mass on ultrasound
● Adrenal hemorrhage of acute infection (Waterhouse-Friderichsen syndrome, tuberculosis, bacterial, viral and fungal infections, human immunodeficiency virus, cytomegalovirus)	Hypotension, shock in the setting of infection, fever, fatigue, weakness, abdominal or flank pain, nausea, vomiting, confusion, delirium. Petechial rash (in meningococcemia)	↑ACTH, ↑PRA, ↓aldosterone, ↓Na, ↑K
Drug effects:	Mechanism
● Ketoconazole, fluconazole, etomidate	Reduces endogenous cortisol production by inhibiting cortisol-synthesis enzyme (P-450 cytochrome enzyme)
● Anticoagulants (heparin, warfarin)	Increases risk of adrenal hemorrhage
● Phenytoin, phenobarbital, rifampin	Increases cortisol metabolism by induction of P450 cytochrome enzyme
Central adrenal insufficiency
Etiologies	Clinical characteristics	Comments
Congenital
● Septo-optic dysplasia (HESX1)	At least 2 of the following: optic nerve hypoplasia, midline forebrain defects, pituitary hypoplasia	Variable hypopituitarism.
● Pituitary aplasia/hypoplasia	Neonatal hypoglycemia, prolonged jaundice, micropenis	Multiple pituitary hormone deficiencies
● Congenital isolated ACTH deficiency	Neonatal onset adrenal insufficiency	↓ACTH
● POMC deficiency	Early-onset obesity, hyperphagia, red hair	↓ACTH; may have other pituitary hormone deficiencies
Acquired
● Brain tumor	Suprasellar tumors	May have other pituitary hormone deficiencies
● Traumatic brain injury, surgery, cranial radiation	Can be late onset after injury or radiation
● Lymphocytic hypophysitis	Symptoms related to mass effect from pituitary gland enlargement and pituitary dysfunction. Headache, visual symptoms due to optic nerve compression.	ACTH and TSH deficiencies are very frequent in early stages; diabetes insipidus
● Hemochromatosis	Patients with Thalassemia major receiving chronic blood infusions	Begin screening biannually at age 5 years with 1 µg ACTH stimulation test
Drug effects	Mechanism
● Corticosteroid withdrawal after prolonged administration ● Opiate, megestrol acetate, medroxyprogesterone	Suppresses hypothalamic-pituitary-adrenal axis

Abbreviations: ACTH, adrenocorticotropic hormone; PRA, plasma renin activity; DHEA, dehydroepiandrosterone; DOC, deoxycorticosterone; VLCFA, very long chain free fatty acids; POMC, proopiomelanocortin.

Table 2 Clinical and Laboratory Findings for Adrenal Insufficiency

	Primary Adrenal Insufficiency	Central Adrenal Insufficiency
Clinical signs and symptoms	Fatigue Postural dizziness/orthostatic hypotension Weakness Nausea, vomiting Salt craving Abdominal pain Diarrhea Weight loss Hyperpigmentation of skin	Similar to those of primary AI Absence of hyperpigmentation
Laboratory findings	Hyponatremia Hyperkalemia (50%) or normal potassium Hypoglycemia Low cortisol Elevated ACTH Low aldosterone Elevated plasma renin activity Mild metabolic acidosis Hypercalcemia (rare) Mild normocytic anemia Lymphocytosis Eosinophilia Neutropenia	Hyponatremia Normal potassium Hypoglycemia Low cortisol Low or normal ACTH Normal aldosterone Normal Plasma renin activity Possible other pituitary hormone deficiency (central hypothyroidism, growth hormone deficiency, or diabetes insipidus)

Note: Bold text indicates the important and unique clinical and lab findings.

Figure 1 Skin hyperpigmentation in primary adrenal insufficiency. (A) Hyperpigmentation at axillary and nipples in a 10-day-old male infant with salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency. (B) Skin hyperpigmentation in a 10-year-old Caucasian male with autoimmune adrenalitis (Addison’s disease).

Notes: (A) Reprinted from Bowden SA, Henry R. Pediatric adrenal insufficiency: diagnosis, management, and new therapies. Int J Pediatr. 2018;2018;1,739,831. Creative Commons.⁵

Figure 2 Diagnostic approach for patients with suspected primary adrenal insufficiency.

Abbreviations: ACTH, adrenocorticotropic hormone; VLCFA, very long chain fatty acids; CAH, congenital adrenal hyperplasia; 21-OHD CAH, congenital adrenal hyperplasia due to 21-hydroxylase deficiency; AHC, adrenal hypoplasia congenita.

Figure 3 Screening and assessment of recovery of the hypothalamic-pituitary-adrenal axis after corticosteroid withdrawal. After reaching half the physiologic dose of hydrocortisone (≤5 mg/m²/day), obtain morning serum cortisol to determine if daily and stress dose hydrocortisone can be discontinuation. *Serum cortisol cutoff values are assay dependent and may be lower with newer cortisol assays. Reprinted from Bowden SA, Connolly AM, Kinnett K, Zeitler PS. Management of adrenal insufficiency risk after long-term systemic glucocorticoid therapy in Duchenne muscular dystrophy: clinical practice recommendations. J Neuromuscular Dis. 2019;6(1):31–41, with permission from IOS Press. The publication is available at IOS Press through http://dx.doi.org/doi: 10.3233/JND-180346.⁵³

Bowden SA, Henry R. Pediatric adrenal insufficiency: diagnosis, management, and new therapies. Int J Pediatr. 2018;2018:87.

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Bowden SA, Connolly AM, Kinnett K, Zeitler PS. Management of adrenal insufficiency risk after long-term systemic glucocorticoid therapy in Duchenne muscular dystrophy: clinical practice recommendations. J Neuromuscular Dis. 2019;6(1):31–41. doi:10.3233/JND-180346

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