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Adrenal insufficiency

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Endocrine & Reproductive Presentations/Adrenal

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A patient with deficient adrenal cortex output: glucocorticoid (cortisol) deficiency with or without mineralocorticoid (aldosterone) and adrenal sex hormone defects. Presentation ranges from a neonate in salt-wasting crisis (hyponatremia, hyperkalemia, hypoglycemia, shock) to an older child or adult with insidious fatigue, hyperpigmentation, weight loss, and orthostasis. The clinical posture is two-fold: treat empirically with stress-dose hydrocortisone the moment crisis is suspected (you can confirm later; you cannot resuscitate a dead patient), and localize the lesion (primary adrenal versus secondary pituitary/hypothalamic; congenital versus acquired) to drive the genetic work-up.

Three sorting axes:

  1. Primary versus secondary: primary (adrenal-level) shows low cortisol + high ACTH + hyperpigmentation + often mineralocorticoid deficiency (salt wasting). Secondary (pituitary or hypothalamic) shows low cortisol + low or normal ACTH + no hyperpigmentation + mineralocorticoid axis preserved (renin-angiotensin still intact).
  2. Congenital versus acquired: congenital usually declares in the first weeks (CAH, adrenal hypoplasia, lipoid CAH) or first decade (Triple A, X-ALD onset, familial glucocorticoid deficiency); acquired in older children/adults includes autoimmune Addison disease, tuberculosis, and infiltrative or hemorrhagic causes.
  3. Salt-wasting versus not: salt-wasting flags 21-hydroxylase CAH (the dominant cause), 3β-HSD CAH, lipoid CAH, adrenal hypoplasia congenita, and aldosterone synthase deficiency.

Primary, congenital

  • Congenital adrenal hyperplasia is the dominant cause and the first diagnosis to rule out in any neonate with adrenal insufficiency or ambiguous genitalia.
    • 21-hydroxylase deficiency (CYP21A2, AR, ~95% of CAH): elevated 17-hydroxyprogesterone on newborn screen. Salt-wasting form presents day 7-14 with hyponatremia, hyperkalemia, hypoglycemia, shock; non-salt-wasting (simple virilizing) presents with virilization without electrolyte crisis. Treatment: hydrocortisone + fludrocortisone.
    • 11β-hydroxylase deficiency (CYP11B1): virilization + hypertension (deoxycorticosterone excess) instead of salt wasting; ~5% of CAH.
    • 3β-hydroxysteroid dehydrogenase 2 deficiency (HSD3B2): ambiguous genitalia in both sexes, salt-wasting; rare.
    • 17α-hydroxylase / 17,20-lyase deficiency (CYP17A1): hypertension + sexual infantilism (no androgens, no estrogens); 46,XY undervirilization; rare.
    • Lipoid CAH (STAR, also CYP11A1): all steroidogenesis blocked, with massively enlarged lipid-laden adrenals. Severe salt-wasting; 46,XY presents as phenotypically female (no androgens); profound.
  • Adrenal hypoplasia congenita (NR0B1/DAX1, X-linked recessive): boys present in infancy or childhood with primary adrenal failure (salt-wasting crisis) followed in adolescence by hypogonadotropic hypogonadism (failure to enter puberty). Discriminating clue: family history pattern + adolescent failure to virilize.
  • Triple A / Allgrove syndrome (AAAS, AR): the triad of Adrenal insufficiency + Achalasia + Alacrima (often with progressive neurologic features). Alacrima often the earliest sign; tear-test on Schirmer paper is the bedside clue.
  • Familial glucocorticoid deficiency (MC2R / ACTH receptor, MRAP, also MCM4, NNT, TXNRD2): isolated cortisol deficiency with preserved mineralocorticoid axis. Tall stature is described with MC2R defects. Marked hyperpigmentation from very high ACTH.

Primary, peroxisomal or storage

  • X-linked adrenoleukodystrophy (ABCD1, X-linked): the second most common cause of primary adrenal insufficiency in males (after autoimmune Addison disease). Phenotype ranges from childhood cerebral form (rapid neurodegeneration in school-age boys) to adrenomyeloneuropathy in adults to isolated adrenal insufficiency. Very-long-chain fatty acids (VLCFAs) elevated in plasma is the screen; ABCD1 confirms. Any male with primary adrenal insufficiency without antibodies gets VLCFAs.
  • Wolman disease / cholesteryl ester storage disease (LIPA): infant with hepatosplenomegaly + adrenal calcifications + malabsorption + failure to thrive.

Primary, acquired

  • Autoimmune Addison disease: the most common cause of primary adrenal insufficiency in adults; isolated or as part of APS-1 (AIRE; mucocutaneous candidiasis + hypoparathyroidism + Addison) or APS-2 (Addison + type 1 diabetes + autoimmune thyroid disease).
  • Tuberculosis, histoplasmosis, HIV-related, hemorrhage (Waterhouse-Friderichsen from meningococcemia), bilateral metastasis: acquired etiologies that come up in older patients.

Secondary (pituitary or hypothalamic)

  • Congenital hypopituitarism (PROP1, POU1F1, LHX3, LHX4, HESX1, SOX2, SOX3, others): multiple anterior pituitary deficiencies (often growth hormone + TSH + LH/FSH + ACTH); neonates with hypoglycemia, prolonged jaundice, micropenis.
  • Septo-optic dysplasia (HESX1 classic): midline defects + optic nerve hypoplasia + hypopituitarism. Look for septum pellucidum absence on MRI and pendular nystagmus on exam.
  • Craniopharyngioma in older children: panhypopituitarism plus visual field defects.
  • Iatrogenic chronic glucocorticoid use: the most common cause of suppressed HPA axis in clinical practice; not a genetic question but always on the differential.
  • Any salt-wasting neonate gets 17-OHP today and empiric hydrocortisone + fludrocortisone before the result returns. Salt-wasting CAH can kill in the second week of life.
  • Any male with primary adrenal insufficiency without antibodies gets VLCFAs to rule out X-ALD. Early identification matters because hematopoietic stem cell transplant for the cerebral form works only before the brain inflammation is established.
  • Adrenal insufficiency in a boy + failure to enter puberty → adrenal hypoplasia congenita (NR0B1/DAX1).
  • Triad of alacrima + achalasia + adrenal insufficiency → Allgrove (Triple A) syndrome.
  • Hyperpigmentation + isolated cortisol deficiency with preserved mineralocorticoid axis → familial glucocorticoid deficiency (MC2R, MRAP).
  • Neonate with hypoglycemia + prolonged cholestasis + micropenis + nystagmus → septo-optic dysplasia or congenital hypopituitarism; secondary adrenal insufficiency from ACTH deficiency.
  • Adrenal insufficiency + mucocutaneous candidiasis + hypoparathyroidism → APS-1 (AIRE).
  1. Cortisol + ACTH (paired): distinguishes primary (high ACTH) from secondary (low or inappropriately normal ACTH).
  2. Electrolytes, glucose, renin, aldosterone: salt-wasting signal + renin-aldosterone axis assessment.
  3. 17-hydroxyprogesterone: 21-hydroxylase CAH; on newborn screen but repeat serum if clinically suspicious.
  4. VLCFAs (very-long-chain fatty acids): mandatory for any male with primary adrenal insufficiency without antibodies; screens for X-ALD.
  5. 21-hydroxylase antibodies + adrenal cortex antibodies: autoimmune Addison.
  6. ACTH stimulation test (cosyntropin / Synacthen): cortisol < 18 µg/dL at 30-60 min is consistent with adrenal insufficiency.
  7. Anterior pituitary panel (free T4, TSH, IGF-1, LH, FSH, prolactin) if secondary is suspected.
  8. Pituitary MRI for secondary causes (look for absent posterior pituitary bright spot, ectopic neurohypophysis, septo-optic dysplasia, mass).
  9. Adrenal imaging (ultrasound in neonates, CT in older patients): bilateral enlargement (CAH, lipoid CAH), atrophy (autoimmune), calcifications (Wolman, TB), hemorrhage.
  10. Targeted gene panel based on phenotype: CAH panel, adrenal insufficiency panel, hypopituitarism panel; or exome if syndromic and unclear.
  • Salt-wasting CAH is treatable and tracked on newborn screening; the deaths in the literature are the ones where the screen was missed, came back late, or the family was lost to follow-up between the screen and the salt-wasting crisis at day 10-14.
  • Any boy with primary adrenal insufficiency gets VLCFAs. The diagnostic delay between adrenal failure and cerebral X-ALD onset is the window where transplant works.
  • Adrenal crisis is the differential's lethal endpoint regardless of etiology. Stress-dose hydrocortisone + fluids + glucose first, work-up second.
  • Always check the mother of a boy with X-linked adrenal hypoplasia congenita. Carrier identification informs counseling and reproductive planning.
  • An "Addison patient" who develops other autoimmune disease is APS-2 (Schmidt syndrome); the dyad of Addison + type 1 diabetes is the recognition pattern. APS-1 (AIRE, recessive) is the rare childhood-onset triad with candidiasis and hypoparathyroidism.