Biochemical and genetic diagnosis of 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is caused by mutations in the CYP21A2 gene and is often fatal in its classic forms if not treated with glucocorticoids. In contrast, non-classic CAH (NCCAH), with a prevalence from 0.1 % up to a few percentages in certain ethnic groups, only results in mild partial cortisol insufficiency and patients survive without treatment. Most NCCAH cases are never identified, but unnecessary suffering due to hyperandrogenism, especially in females, can be avoided by a correct diagnosis. A 17-hydroprogesterone (17OHP) level above 300 nmol/L indicates classic CAH while 30–300 nmol/L in adult males or females (follicular phase or if anovulatoric) indicates NCCAH. The gold standard for diagnosing NCCAH is the ACTH stimulation test. Deletion, large gene conversions, and nine microconversion-derived mutations are the most common CYP21A2 mutations. However, almost 200 rare mutations have been described. Since there is a good genotype–phenotype relationship, genotyping provides valuable diagnostic, as well as prognostic information. Neonatal screening for CAH is now performed in an increasing number of countries with the main goal of reducing mortality and morbidity due to salt-losing adrenal crises in the newborn period. In addition, screening may shorten the time to diagnosis in virilized girls. Neonatal screening misses some patients with milder classic CAH and most NCCAH cases. In conclusion, diagnosing classic CAH is life-saving, but diagnosing NCCAH is also important to prevent unnecessary suffering.