The McCune-Albright syndrome is characterized by the classic triad of polyostotic fibrous dysplasia of bone, irregular caf´e-au-lait spots on the skin, and GnRH-independent sexual precocity. The caf´e-au-lait spots are usually large, do not cross the midline, and have irregular “coast of Maine” margins. They are often located on the same side as the bony lesions. Sexual precocity often begins in the first 2 years and usually presents with menstrual bleeding. Girls develop sexual precocity as a result of functioning ovarian cysts. Serum estradiol is elevated. Other endocrinopathies may include hyperthyroidism, hypercortisolism, hyperprolactinemia, acromegaly, and hyperparathyroidism. Osteomalacia, hepatic abnormalities, and cardiac arrhythmia may occur. Mutations of the Gsα subunit of the G protein, which couples extracellular hormonal signals to the activation of adenylate cyclase, are responsible for the autonomous hyperfunction of the endocrine glands and, presumably, for the other defects present in this disorder (82). Treatment with a GnRH agonist is not effective because the precocious pubertal development is GnRH independent. Treatment with aromatase inhibitors, such as testolactone and fadrozole, has mixed results. A multicenter trial showed that tamoxifen decreases vaginal bleeding, growth rate, and the rate of bone age advancement (83).
21-Hydroxylase Deficiency Most patients with classic CAH have 21-hydroxylase deficiency (Fig. 29.19). All forms of 21-hydroxylase deficiency are caused by homozygous or compound heterozygous mutations in the human CYP21A2 gene, which encodes the 21-hydroxylase enzyme; in the carrier, heterozygote state, only one allele is mutated (85). Two CYP21A2 genes, a3 CYP21A2B gene encoding the functional enzyme and a pseudogene termed CYP21A2A, are situated very close to each other within the major histocompatibility locus on the short arm of chromosome 6. At least one-fourth of cases of 21-hydroxylase deficiency result from unequal crossover and genetic recombination between the two genes during meiosis. Severe mutations do not correlate with severe phenotype, and phenotypic variability likely depends on the activity of other interacting genes.
Neonatal screening suggests an incidence of about 1 in 15,000 births. Because of the location of the gene within the major histocompatibility locus, siblings with 21-hydroxylase deficiency usually have identical human leukocyte antigen (HLA) types. There are various forms of 21-hydroxylase deficiency, including simple virilizing (typically identified at birth because of genital ambiguity), salt-wasting (in which there is impairment of mineralocorticoid and glucocorticoid secretion), and late-onset or nonclassic (in which heterosexual development occurs at the expected age of puberty). The so-called classic form includes the simple virilizing and salt-wasting forms. The nonclassic form is discussed in the following section on heterosexual pubertal development.