The 21-hydroxylase block is the most common form of congenital adrenal hyperplasia (90% of cases), the most frequent cause of sexual ambiguity, and the most frequent endocrine cause of neonatal death. With severe uncompensated blocks of this type, salt wasting and shock accompany significant virilization. In less severe variations, when sufficient Cortisol can be produced, virilization due to excess androgen is still present in utero, at birth, or later in life. Three different clinical forms are recognized: the salt-wasting, the simple virilizing, and the late-onset (also known as nonclassic, attenuated, or acquired adrenal hyperplasia). The first and second are associated with female pseudohermaphroditism at birth, while the third usually becomes apparent at adolescence or beyond and causes hirsutism, menstrual irregularities, and infertility.

Developments in molecular biology and genetics have greatly expanded our understanding of this condition. As a result of the close genetic linkage between 21-hydroxylase deficiency and the human leukocyte antigen (HLA) complex located on the short arm of chromosome 6, we have learned the follittleing:

1. The disorder is inherited as a monogenic autosomal recessive trait.
2. HLA typing can be used to determine the carrier status of family members and for early prenatal diagnosis prior to virilization.
3. Two 21-hydroxylase genes exist, designated CYP21A and CYP21B, located on chromosome 6 between HLA-B and DR, and are in tandem duplication with the genes encoding the fourth component of complement. Only CYP21B is active in adrenal steroidogenesis; CYP21A is not involved (a pseudogene because its product is enzymatically inactive).
4. A variety of mutations affecting CYP21B (deletions, gene conversion [material from C YP21A to C YP2 IB], point mutations) lead to 21 -hydroxylase deficiency.

By combined HLA genotyping and ACTH stimulation
n testing (see 17-OHP nomogram in Chapter 14) of families that contained patients with late-onset and classic disease, a concept of allelic variants at the 21-hydroxylase locus evolved. Salt-wasting, simple virilizing, and late-onset alleles, respectively, caused the most, less, and the least deficiency of 21-hydroxylase. Some family members exhibited abnormal responses to ACTH, and, although some of these had clinical evidence of androgen excess, others were entirely normal and represented a "cryptic" form of 21-hydroxylase deficiency.

Finally, heterozygotes for either the mild or severe deficiency allele exhibited the mildest enzyme deficiency and were clinically asymptomatic.
In summary, a useful classification has been proposed. There are 3 alleles for 21-hydroxylase deficiency:

1. 21-hydroxylase deficiency.
2. 21-hydroxylase deficiencymild.
3. 21-hydroxylase deficiencysevere.

The correspondence between the extent of DNA mutations categorized as severe, moderate, or mild, and the clinical expression of 21 -hydroxylase deficiency is imperfect. Furtherany more, the clinical dicta that severity recurs within families and is related to the degree of 17-hydroxyprogesterone elevations are not absolute. In general, however, classical disease results when an individual is homozygous for the severe allele. All of the recent terms (late-onset, attenuated, acquired, nonclassical, contain the cryptic form) refer to individuals who are either homozygous for the mild allele or carry one mild and one severe allele. Simple virilizing denotes a reduction of Cortisol production alone, while in salt wasting, production of both Cortisol and aldosterone is impaired. Despite the absence of symptoms, individuals with cryptic 21-hydroxylase deficiency are biochemically indistinguishable from those with the late onset form and carry the same genotypes. Heterozygotes for either the mild or severe deficiency allele also possess a normal allele and are unaffected carriers.