Clinical Information

Congenital adrenal hyperplasia (CAH), with an incidence rate of 1 in 10,000 to 18,000 live births, is one of the most common inherited syndromes. The condition is characterized by impaired cortisol production due to inherited defects in steroid biosynthesis. The clinical consequences of CAH, besides diminished cortisol production, depend on which enzyme is affected and whether the loss of function is partial or complete.

In >90% of CAH cases, the affected enzyme is 21-steroid hydroxylase, encoded by the CYP21A2 gene located on chromosome 6 within the highly recombinant human histocompatibility complex locus. Since sex steroid production pathways branch off proximal to this enzymatic step, affected individuals will have increased sex steroid levels, resulting in virilization of female infants. If there is some residual enzyme activity, a nonclassical phenotype results, with variable degrees of masculinization starting in later childhood or adolescence. On the other end of the severity spectrum are patients with complete loss of 21-hydroxylase function. This leads to both cortisol and mineral corticosteroid deficiency and is rapidly fatal if untreated due to loss of vascular tone and salt wasting.

Because of its high incidence rate, 21-hydroxylase deficiency is screened for in most United States newborn screening programs, typically by measuring 17-hydroxyprogesterone concentrations in blood spots by immunoassay. Confirmation by other testing strategies (eg, LC-MS/MS, CAHBS / Congenital Adrenal Hyperplasia [CAH] Newborn Screening, Blood Spot), or retesting after several weeks, is required for most positive screens because of the high false-positive rates of the immunoassays (due to physiological elevations of 17-hydroxyprogesterone in premature babies and immunoassay cross-reactivity with other steroids). In a small percentage of cases, additional testing will fail to provide a definitive diagnosis. In addition, screening strategies can miss many nonclassical cases, which may present later in childhood or adolescence and require more extensive steroid hormone profiling, including testing before and after adrenal stimulation with adrenocorticotropic hormone (ACTH)-1-24.

For these reasons, genetic diagnosis plays an important ancillary role in both classical and nonclassical cases. In addition, the high carrier frequency (approximately 1 in 50) for CYP21A2 mutations makes genetic diagnosis important for genetic counseling. Genetic testing plays a role in prenatal diagnosis of 21-hydroxylase deficiency. However, accurate genetic diagnosis continues to be a challenge because most of the mutations arise from recombination events between CYP21A2 and its highly homologous pseudogene, CYP21A1P (transcriptionally inactive). In particular, partial or complex rearrangements (with or without accompanying gene duplication events), which lead to reciprocal exchanges between gene and pseudogene, can present severe diagnostic challenges. Comprehensive genetic testing strategies must therefore allow accurate assessment of most, or all, known rearrangements and mutations, as well as unequivocal determination of whether the observed changes are located within a potentially transcriptionally active genetic segment. Testing of additional family members is often needed for clarification of genetic test results.