Residency · Residency · Pediatrics

Adrenal Insufficiency and Congenital Adrenal Hyperplasia

Introduction

Adrenal insufficiency (AI) in children can be primary (adrenal gland failure), secondary (pituitary ACTH deficiency), or tertiary (hypothalamic CRH deficiency). Congenital adrenal hyperplasia (CAH) is the most common cause of primary AI in children and the most frequent cause of ambiguous genitalia in 46,XX newborns. Both conditions can present as life-threatening adrenal crisis if unrecognized. Understanding the cortisol synthesis pathway is essential for diagnosis and management.

Adrenal Physiology

The adrenal cortex has three zones: the zona glomerulosa (producing mineralocorticoids, primarily aldosterone), the zona fasciculata (producing glucocorticoids, primarily cortisol), and the zona reticularis (producing androgens, including DHEA and androstenedione). Cortisol follows a diurnal rhythm with a peak in the early morning and is regulated by the HPA axis (CRH, ACTH). Aldosterone is regulated primarily by the renin-angiotensin-aldosterone system (RAAS) and potassium levels. Cortisol functions include the stress response, glucose homeostasis, immune modulation, blood pressure support, and anti-inflammatory effects.

Congenital Adrenal Hyperplasia

21-Hydroxylase Deficiency (Greater Than 90% of CAH Cases)

This is an autosomal recessive disorder caused by mutations in the CYP21A2 gene. Impaired cortisol synthesis leads to elevated ACTH, which drives adrenal hyperplasia and shunts precursors toward androgen production. The incidence is approximately 1 in 15,000 live births for the classic form, with a carrier frequency of about 1 in 60.

Clinical Forms

The classic salt-wasting form (75% of classic cases) involves both cortisol and aldosterone deficiency. In 46,XX neonates, excess androgens cause ambiguous genitalia (clitoromegaly, labial fusion, urogenital sinus), classified on the Prader scale. In 46,XY neonates, the genitalia appear normal at birth, and these infants may present with a salt-wasting crisis at 1-3 weeks of life characterized by hyponatremia, hyperkalemia, dehydration, vomiting, and shock.

The classic simple-virilizing form (25% of classic cases) features cortisol deficiency with sufficient aldosterone. Girls show virilization at birth. Boys may go undetected until signs of androgen excess appear, including accelerated growth, premature pubarche, and advanced bone age.

The non-classic (late-onset) form involves mild enzyme deficiency and presents later in childhood or adolescence with premature adrenarche, acne, hirsutism, menstrual irregularities, or subfertility. It is not detected by newborn screening.

Other Enzyme Deficiencies

11-beta-hydroxylase deficiency is the second most common (5-8%) and causes virilization plus hypertension because excess 11-deoxycorticosterone has mineralocorticoid activity. 3-beta-HSD deficiency, 17-alpha-hydroxylase deficiency, and lipoid CAH (StAR mutations) are rare with variable presentations.

<image>Steroidogenesis pathway diagram showing enzymatic steps from cholesterol to cortisol, aldosterone, and androgens, with 21-hydroxylase and 11-beta-hydroxylase blocks highlighted and the resulting accumulation of precursors and shunting toward androgens</image>

Newborn Screening and Diagnosis

Newborn screening measures 17-hydroxyprogesterone (17-OHP), which is markedly elevated in classic 21-hydroxylase deficiency. False positives are common in premature and low birth weight infants. Confirmatory testing includes serum 17-OHP (drawn after 24-48 hours of life), electrolytes (sodium, potassium), plasma renin activity, cortisol, and ACTH. The ACTH stimulation test is the gold standard for confirming AI and diagnosing non-classic CAH, with a stimulated 17-OHP greater than 1,500 ng/dL being diagnostic. Karyotype and pelvic ultrasound are performed in neonates with ambiguous genitalia. CYP21A2 genotyping provides confirmation and supports genetic counseling.

Management of CAH

Glucocorticoid replacement uses hydrocortisone at 10-15 mg/m2/day divided three times daily, preferred in growing children due to its short half-life and growth-sparing properties. The goal is to suppress excess androgens while avoiding overtreatment (Cushingoid features, growth suppression). Mineralocorticoid replacement for the salt-wasting form uses fludrocortisone at 0.05-0.2 mg/day, with sodium supplementation in infancy (1-2 g NaCl/day).

Stress dosing involves tripling the glucocorticoid dose during illness, surgery, or significant physiological stress. Monitoring includes 17-OHP, androstenedione, testosterone, renin, electrolytes, growth velocity, and bone age every 3-6 months. Surgical considerations regarding feminizing genitoplasty in severely virilized 46,XX patients remain ethically debated in terms of timing and approach, and multidisciplinary team involvement is essential.

<image>Clinical illustration showing the spectrum of genital ambiguity in 46,XX neonates with classic CAH using the Prader staging system (stages I-V) alongside a diagram of the HPA axis feedback loop showing ACTH-driven adrenal hyperplasia</image>

Other Causes of Adrenal Insufficiency in Children

Primary Adrenal Insufficiency

Autoimmune adrenalitis (Addison disease) is the most common acquired cause in older children and may be isolated or part of autoimmune polyendocrine syndrome (APS). APS type 1 features hypoparathyroidism, mucocutaneous candidiasis, and adrenal insufficiency (AIRE gene mutation). APS type 2 features adrenal insufficiency, autoimmune thyroid disease, and T1DM. Adrenal hemorrhage or infarction occurs in Waterhouse-Friderichsen syndrome (meningococcal sepsis). Adrenoleukodystrophy is an X-linked peroxisomal disorder, and very long-chain fatty acids should always be checked in boys with primary AI. Tuberculosis remains the most common cause globally.

Secondary/Tertiary Adrenal Insufficiency

The most common cause in pediatrics is iatrogenic: chronic exogenous glucocorticoid use (oral, inhaled, topical) with abrupt withdrawal. Other causes include pituitary or hypothalamic tumors (craniopharyngioma), surgery, radiation, and isolated ACTH deficiency (rare).

Adrenal Crisis -- Emergency Management

Signs include hypotension, shock, hypoglycemia, hyponatremia (with or without hyperkalemia), lethargy, and abdominal pain. Immediate treatment involves hydrocortisone IV or IM at 50-100 mg/m2 bolus (or age-based: 25 mg for infants, 50 mg for children, 100 mg for adolescents), normal saline bolus with dextrose (D5NS or D10NS) for volume resuscitation and hypoglycemia correction, and close monitoring of electrolytes, glucose, and hemodynamics. All patients with AI must have an emergency action plan, injectable hydrocortisone at home, and medical alert identification.

<image>Emergency management algorithm for adrenal crisis in children showing recognition of signs (hypotension, hypoglycemia, hyponatremia), immediate interventions (stress-dose hydrocortisone, IV fluids), and monitoring parameters</image>

Clinical Pearls

Any neonate with ambiguous genitalia should be evaluated urgently for CAH because a salt-wasting crisis can be fatal within the first weeks of life. Boys with classic salt-wasting CAH appear phenotypically normal at birth and may present with life-threatening adrenal crisis before newborn screening results return, so a high index of suspicion must be maintained. Boys with primary adrenal insufficiency should always be screened for adrenoleukodystrophy with very long-chain fatty acids. Chronic glucocorticoid use (even inhaled corticosteroids at high doses) can suppress the HPA axis, so tapering should be gradual and cosyntropin stimulation testing performed before discontinuation. Stress dosing instructions must be reviewed at every visit because families forget, and failure to stress dose is the most common cause of adrenal crisis in known AI patients.

References

1. Speiser PW, Arlt W, Auchus RJ, et al. Congenital Adrenal Hyperplasia Due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088.
2. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389.
3. White PC, Speiser PW. Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency. Endocr Rev. 2000;21(3):245-291.
4. Hsieh S, White PC. Presentation of Primary Adrenal Insufficiency in Childhood. J Clin Endocrinol Metab. 2011;96(6):E925-E928.

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