Investigations for Premature Adrenarche
In children presenting with premature adrenarche, measure basal 17-hydroxyprogesterone (17-OHP) first—if it is ≥2 ng/mL, proceed with an ACTH stimulation test to exclude late-onset congenital adrenal hyperplasia (LO-CAH); if basal 17-OHP is <2 ng/mL, no further hormonal testing is needed as this threshold has 100% sensitivity and 99% specificity for ruling out LO-CAH. 1
Initial Clinical Assessment
When evaluating a child with premature adrenarche (pubic/axillary hair before age 8 in girls or age 9 in boys), distinguish between typical presentation (isolated pubic/axillary hair with body odor) versus atypical presentation (pubic hair plus genital enlargement or clitoromegaly). 2, 3 This distinction matters because 45% of children with atypical features have underlying steroidogenic defects compared to only 12% with typical features. 3
First-Line Laboratory Investigations
Essential Initial Tests
- Basal (morning) 17-hydroxyprogesterone (17-OHP): This is the critical screening test. 1
- Serum androgens: Measure DHEA-S, androstenedione, and testosterone to confirm androgen excess and assess severity. 2
- Bone age radiograph: Assess for skeletal advancement, which suggests significant androgen exposure. 2
The 2 ng/mL Rule for 17-OHP
A basal 17-OHP <2 ng/mL effectively rules out LO-CAH with 99% specificity, eliminating the need for ACTH stimulation testing in the vast majority of children. 1 This selective strategy would avoid 99% of unnecessary ACTH tests. 1
Second-Line Testing (When Indicated)
ACTH Stimulation Test
Perform this test only if basal 17-OHP is ≥2 ng/mL. 1
Protocol:
- Administer 0.25 mg cosyntropin (tetracosactide) IV or IM 4, 5
- Measure 17-OHP at baseline and 30 minutes post-stimulation 1, 3
- Diagnostic threshold: Post-ACTH 17-OHP >10 ng/mL confirms LO-CAH 1
- Also measure progesterone, 17-hydroxypregnenolone, DHEA, androstenedione, 11-deoxycortisol, and cortisol to identify other steroidogenic enzyme defects 3
Genetic Confirmation
If ACTH stimulation test is positive, confirm with CYP21A2 gene mutational analysis to definitively diagnose 21-hydroxylase deficiency. 1, 6
Third-Line Imaging (Rarely Needed)
Adrenal ultrasound is indicated only if: 2
- Markedly elevated androgens suggest adrenal tumor
- Rapid progression of virilization
- Atypical features not explained by enzyme defects
Common Pitfalls to Avoid
Don't Overtest
The traditional approach of performing ACTH stimulation tests on all children with premature adrenarche is outdated, stressful, and expensive. 1 Using the basal 17-OHP threshold of 2 ng/mL safely avoids unnecessary testing in >95% of cases. 1
Don't Miss LO-CAH in Atypical Cases
Children with genital enlargement (clitoromegaly in girls, penile growth in boys) in addition to pubic hair have a 45% prevalence of steroidogenic defects versus 12% in typical cases. 3 These children warrant more aggressive investigation regardless of basal 17-OHP if clinical suspicion is high. 3
Don't Ignore Metabolic Screening in High-Risk Groups
While not part of the diagnostic workup for premature adrenarche itself, children with low birth weight and premature adrenarche have increased risk of insulin resistance and metabolic syndrome. 2, 7 Consider fasting glucose, insulin, and lipid screening in this subgroup, as metformin intervention may be warranted on a case-by-case basis. 2
When Reassurance Alone is Appropriate
If basal 17-OHP is <2 ng/mL, androgens are mildly elevated (consistent with early adrenarche), and bone age is not significantly advanced, no treatment is needed—this represents benign premature adrenarche. 2 Reassure families that this is a normal variant of development that does not affect final height or pubertal timing. 2, 7
However, counsel families that some populations show association with later polycystic ovary syndrome (PCOS) and metabolic abnormalities, particularly in girls with low birth weight. 2, 7 Long-term monitoring for these complications may be warranted in selected cases. 7