The mutated enzyme protein is synthesized, but is less efficient than the wild type. Another mechanism resulting in excessive adrenal androgen secretion especially in NCAH results from the alteration in enzyme kinetics due to the CYP21A2 missense mutations. In fact, some have an over-responsive glucocorticoid response to ACTH stimulation, possibly reflective of subtle adrenal hyperplasia. For example, patients with NCAH usually have no evidence of ACTH or CRH excess. Unfortunately, the pathophysiology of NCAH (and CAH) is more complicated than this description would suggest. Individuals with NCAH generally have adequate mineralocorticoid secretion. The excessive ACTH stimulation also results in fasciculata-reticularis zone hypertrophy, resulting in the adrenal hyperplasia typical of the syndrome, and possibly increased adrenocortical nodularity. Elevated 17-OHP, P4, and androstenedione concentrations are typically found. With decreased P450c21 activity, conversions of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol, and progesterone (P4) to deoxycorticosterone, are impaired. The resulting loss of cortisol negative feedback inhibition leads to increased hypothalamic corticotrophin releasing hormone (CRH) and pituitary adrenocorticotrophic hormone (ACTH) secretion. In broad terms, the virilizing forms (simple virilizing, salt-wasting, and nonclassic) of CAH are characterized by mutations that significantly impair cortisol biosynthesis and lead to the accumulation of steroid intermediates proximal to the deficient enzyme. Nevertheless, utilizing rigid criteria to distinguish among salt wasting, simple virilizing and NCAH can be problematic because impaired 21-hydroxylase function represents a continuum of decreased enzyme activity. Roughly, phenotype correlates with molecular genotype and reflects the residual activity of the milder mutation. One-half to two-thirds of individuals with NCAH carry one allele encoding for a severe defect in enzyme function (which would result in classic CAH if present on both alleles) and an allele encoding a mild defect in enzyme function on the other allele. Novel mutations associated with NCAH include R369W and I230T. Other missense mutations associated with NCAH include P30L, P453S, and R339H. This genetic variant is commonly identified among Eastern Europeans especially those of Ashkenazi Jewish descent. The missense mutation, V281L, accounts for at least one of the CYP21A2 alleles for most patients with NCAH. Individuals with NCAH are generally compound heterozygotes bearing different CYP21A2 mutations on each allele. įunctional analysis of mutations associated with NCAH generally indicates a 50–80% loss of enzymatic (21-hydroxylase) function. Functional studies indicate that these mutations result in 0–5% residual enzymatic function. The majority of the CYP21A2 mutations reported to date are associated with simple virilizing or salt-wasting classic congenital adrenal hyperplasia (CAH). Nevertheless, approximately 10–12 mutations account for the majority of the affected alleles. Most of the mutations result from recombination between the active gene, CYP21A2, and its highly homologous non-functional pseudogene, CYP21A1P (i.e., gene conversion), which is located in close proximity within the HLA region on chromosome 6p21.3. To date, 127 mutations have been reported in CYP21A2 ( ) these mutations range from complete loss of enzyme function to partial enzyme activity.
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