eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Adrenal Hypoplasia: Differential Diagnoses & Workup

Author: Thomas A Wilson, MD, Professor of Clinical Pediatrics, Department of Pediatrics; Director of Pediatric Endocrinology, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York at Stony Brook
Contributor Information and Disclosures

Updated: Feb 18, 2009

Differential Diagnoses

Other Problems to Be Considered

Addison disease
Adrenoleukodystrophy
Bilateral adrenal hemorrhage
Congenital unresponsiveness to adrenocorticotropic hormone (ACTH)
Hypoaldosteronism
Renal tubular disorders
46,XY sex reversal due to mutations in genes SRY, SOX9, WT1 (Denys-Drash Syndrome), and SF1

Workup

Laboratory Studies

The most difficult aspect of adrenal hypoplasia is clinical suspicion because signs and symptoms can be insidious and subtle.

• When adrenal insufficiency is suspected, promptly obtain the following laboratory values:
  • Electrolytes
  • Blood sugar
  • Serum adrenocorticotropic hormone (ACTH)
  • Plasma-renin activity
  • Serum cortisol
  • Aldosterone
  • 17-hydroxyprogesterone
  • High-resolution karyotype
• When hyponatremia or hyperkalemia are found, a spot urine test or a 24-hour urine test for sodium, potassium, and creatinine (along with simultaneous serum sodium concentrations and creatinine concentrations) determine whether inappropriate natriuresis is occurring (fractional excretion of sodium >1% in the face of hyponatremia). This occurs with mineralocorticoid deficiency when renal function is otherwise normal. A plasma renin activity (PRA)–to–aldosterone ratio of more than 30 is suggestive of inadequate mineralocorticoid production.
• Random serum cortisol concentrations must be interpreted within the context in which they were obtained.
  • For example, in a healthy individual, an 8:00 am serum cortisol concentration higher than 10 mcg/dL makes adrenal insufficiency unlikely.
  • A serum cortisol concentration less than 18 mcg/dL in a sick and stressed patient is highly suggestive of adrenal insufficiency.
  • A serum cortisol concentration less than 18 mcg/dL in the presence of an elevated serum ACTH concentration and plasma renin activity confirms adrenal insufficiency. Serum cortisol less than 18 mcg/dL obtained 30-60 minutes following cosyntropin is confirmatory.¹⁷
  • These guidelines do not apply to premature infants and infants with low birth weight who have lower cortisol secretion and, most likely, decreased cortisol binding to carrier proteins.¹⁸ The diagnosis of adrenal insufficiency in premature infants remains problematic.
• Measure a panel of adrenal cortical hormones either with or without prior cosyntropin stimulation to exclude the various forms of congenital adrenal hyperplasia.
• A cosyntropin stimulation test can confirm the diagnosis of adrenocortical insufficiency.
  • Controversy surrounds whether the best dose of cosyntropin is the standard dose (250 mcg for an adult) or the low dose (1 mcg or 0.5 mcg/m²), which some have advocated as more sensitive for central adrenal insufficiency. A meta-analysis suggested that the low dose cosyntropin stimulation test is superior, but the difference was small.¹⁹  This issue remains unresolved in the pediatric age group. 
  • Because dilution of cosyntropin to 1 mcg is cumbersome and prone to error, and because all the above doses are probably supraphysiologic, the author generally uses the standard dose or empirically adjusts the dose for patient size (25 mcg for an infant, 50 mcg for a young child, 100 mcg for an older child, and 250 mcg for an adolescent or adult).
  • When a patient's serum cortisol response to cosyntropin is subnormal but his or her serum ACTH level is not elevated, the possibility of central adrenal insufficiency should be considered. Other indications of pituitary dysfunction such as prior glucocorticoid exposure (suggesting a suppressed hypothalamic-pituitary-adrenal axis) or evidence of other pituitary dysfunction are helpful clues suggesting ACTH deficiency. 
  • In central adrenal insufficiency, 3 days of stimulation with ACTH produces a normal cortisol response, indicating intact adrenal glands and implying that the initial low cortisol response to cosyntropin was related to chronic ACTH deficiency. ACTH gel (ACTHar Gel) is administered at 25 U/m² every 12 hours for 3 days. Plasma cortisol levels should increase to more than 40 mcg/dL in response. This procedure is now seldom performed
• The standard ovine corticotropin-releasing hormone (CRH) stimulation test (1 mcg/kg over 1 min) may be helpful in the differential diagnosis of adrenal insufficiency. 
  • A lack of a 2-fold increase in serum ACTH concentration indicates pituitary dysfunction. A 2-fold or greater rise in ACTH levels without a concomitant rise in serum cortisol to more than 18-20 mcg/dL implies primary adrenal insufficiency.²⁰
  • Ovine CRH is difficult to obtain, and this test is mainly done for research purposes.
• In the most common form of congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, serum 17-hydroxyprogesterone is markedly elevated.
• Consider adrenoleukodystrophy (OMIM 300100) in older boys with evidence of adrenal insufficiency. Both males and females may be affected with autoimmune Addison disease, another important diagnostic consideration.
  • Adrenal leukodystrophy is also X-linked and can be diagnosed by demonstrating elevated concentrations of very–long-chain fatty acids (>24 carbon) in serum.
  • Autoimmune Addison disease is confirmed by the demonstration of antiadrenal antibodies in the serum.
• Karyotype, fluorescent in situ hybridization (FISH) or microarray analysis may reveal the gene deletion involving DAX1.
• Prenatal diagnosis is possible.²¹

Imaging Studies

• CT is the best imaging study for the adrenal gland. It excludes the possibility of bilateral adrenal hemorrhage, which can present with an identical clinical picture. However, CT cannot exclude congenital adrenal hypoplasia due to a DAX1 deletion in an infant because the fetal adrenal zone is preserved in this condition.
• Abdominal ultrasonography identifies adrenal glands in infants due to the large fetal zone; however, it usually is not helpful in older children.

Other Tests

• Gene studies of the DAX1 gene on the X chromosome or fluorescent in situ hybridization (FISH), using an appropriate complimentary DNA (cDNA) probe to the region containing DAX1, confirms the existence of a deletion in the DAX1 region of the X chromosome.

Histologic Findings

• The 2 described forms of congenital adrenal hypoplasia differ in anatomic findings.
  • The X-linked form is associated with hypoplasia of the definitive adult zone of the adrenal cortex with preservation of the fetal zone. Histologically, the adrenal cortex is disorganized and the cells are cytomegalic.
  • The autosomal recessive form is associated with absence of the fetal zone and severe hypoplasia of the definitive adult adrenal zone. This is often referred to as the miniature type because of the hypoplastic adrenal cortex.
• Congenital adrenal hypoplasia due to SF1 defect is associated with gonadal dysgenesis (streak gonad, gonad replaced by fibrous material).

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