Congenital adrenal hyperplasia (CAH) diagnosis is critical, particularly when ambiguous genitalia are observed in newborns. Prompt diagnosis is essential to initiate appropriate therapy and guide crucial decisions regarding sex assignment. This process relies on determining the genetic sex, identifying the specific enzyme deficiency through hormonal analysis, understanding the genotype, and evaluating the infant’s potential for future sexual function and fertility.
As detailed in Table 1, each form of CAH presents a unique hormonal profile, characterized by elevated levels of hormone precursors and altered levels of adrenal steroid products. Biochemical evaluation plays a vital role in confirming 21-hydroxylase deficiency (21-OHD) CAH, the most common type. A random blood sample revealing a high concentration of 17-hydroxyprogesterone (17-OHP), a precursor of the deficient enzyme, strongly indicates classical 21-OHD. This measurement forms the basis of newborn screening programs designed to identify infants at risk of life-threatening salt-wasting crises.
Alt text: Table outlining different types of congenital adrenal hyperplasia emergencies, detailing their respective deficient enzymes, key hormonal precursors like 17-hydroxyprogesterone, and adrenal steroid product levels for diagnostic reference.
It’s important to note that newborn screening can yield false-positive results, especially in premature infants. Consequently, screening programs often utilize weight and gestational age-adjusted reference ranges. False-negative results can also occur if blood samples are drawn late in the day due to the diurnal variation of adrenal hormones.
The corticotropin stimulation test is considered the gold standard for hormonal diagnosis. This test involves administering 250 μg of cosyntropin intravenously and measuring 17-OHP and Δ4 androstenedione levels at baseline and 60 minutes. The resulting values are then compared against established nomograms to determine disease severity. It is crucial to avoid performing this test within the first 24 hours of life, as hormone levels are naturally elevated in all newborns during this period, potentially leading to false-positive results.
Genetic diagnosis is equally important for understanding genotype-phenotype correlations and providing genetic counseling for families regarding future pregnancies and the patient’s reproductive prospects. For 21-OHD CAH, genetic analysis of the CYP21A2 gene can offer further insights into predicting the severity of the condition. While genotype-phenotype correlations exist for approximately 50% of causative genotypes, phenotypic variability can occur, particularly in the simple virilizing form, across different populations. Comprehensive gene sequencing is recommended to identify rare mutations when genotype-phenotype discrepancies arise in CAH patients.
Newborn screening programs utilizing 17-hydroxyprogesterone levels are invaluable for the early detection of CAH, enabling timely intervention before adrenal crises develop in affected neonates. However, the high rate of false positives associated with prematurity and birth weight necessitates a multi-tiered screening approach. Molecular genetics, specifically CYP21A2 gene genotyping, is increasingly considered a beneficial second-tier screening test in newborn screening programs to improve accuracy and reduce false positives.
Prenatal testing for CAH has evolved significantly. Historically, invasive procedures like amniocentesis and chorionic villus sampling were used, but these could not be performed before 14 weeks of gestation. To prevent genital ambiguity in affected female fetuses, prenatal dexamethasone treatment, if chosen, must commence before genital formation at approximately 9 weeks. Recent advances in non-invasive prenatal diagnosis have emerged. Massive parallel sequencing using hybridization probes on cell-free fetal DNA in maternal plasma has demonstrated the ability to accurately determine fetal CAH status as early as 5 weeks and 6 days of gestation. This non-invasive technique offers the potential for accurate and early CAH diagnosis before the critical ninth week of gestation.
