The gene encoding the enzyme 21-hydroxylase, CYP21, is a microsomal cytochrome P450 located on the short arm of chromosome 6 (46) in the human lymphocyte antigen (HLA) complex. (47.) CYP21 and its homologue, the pseudogene CYP21P, alternate with two genes called C4B and C4A (48, 49) that encode the two isoforms of the fourth component (C4) of serum complement. (50) CYP21 and CYP21P, which each contain 10 exons, share 98% sequence homology in exons and approximately 96% sequence homology in introns. (51, 52)

Approximately 60 mutations in the CYP21 gene causing 21-OHD have been identified thus far. (53) The most common mutations appear to be the result of either of two types of meiotic recombination events between CYP21 and CYP21P: 1) misalignment and unequal crossing over, resulting in large-scale DNA deletions, and 2) apparent gene conversion events that result in the transfer to CYP21 of smaller-scale deleterious mutations present in the CYP21P pseudogene.

Both classical and nonclassical 21-hydroxylase deficiency are inherited in a recessive manner as allelic variants. Classical 21-hydroxylase deficiency results from the presence of two severely affected alleles and nonclassical 21-hydroxylase deficiency results from the presence of either two mild 21-hydroxylase deficiency alleles or one severe and one mild allele. A list of common CYP21 mutations causing the different forms of CAH is listed in Table 2. It is important to note, however, that the 10 most common mutations observed in CYP21 cause variable phenotype effects and are not always concordant with genotype. (54, 55)

In the three major publications on the issue of nonconcordance, (54, 56-58) it is clear that although there is nonconcordance of phenotype to genotype, it is rare (~10%). It is true that this rare nonconcordance of genotype to phenotype complicates prenatal diagnosis and parents must be alerted to this possibility. In our extensive experience with prenatal diagnosis and treatment, we have not encountered the problem of genotype not predicting phenotype to date. (54) We are, however, prepared to deal with it as caveats are added to the consent forms and letters. Oftentimes, the indication for prenatal diagnosis is an affected sibling. Thus, we have an opportunity to examine genotype-phenotype correlations in living family members.

In recent years, 21-hydroxylase deficiency has been added to the newborn screening panels in 31 states. It is an ideal disorder for newborn screening as the salt-wasting form has a high mortality and morbidity in the neonatal period and can be treated easily with replacement medication. Detection is usually accomplished by measurement of 17-OHP levels on day 2 or 3 of life.