Last update: 05/06/2006
Background to disease
OMIM # 201910
Congenital adrenal hyperplasia (CAH) results from a deficiency in the enzymes or cortisol biosynthesis. 21-hydroxylation is impaired in the zona fasciculate of the adrenal cortex in 95% of cases, preventing the conversion of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol. The overproduction and accumulation of cortisol precursors, particularly 17-OHP, proximal to the block are a result of defective cortisol synthesis and increases in ACTH levels. This causes excessive production of androgens, resulting in virilization.
There are 4 recognized clinical forms of congenital adrenal hyperplasia, the majority of cases being associated with 21-hydroxylase deficiency: salt-wasting (SW), simple virilizing (SV), nonclassic (NC) late-onset (also called attenuated and acquired), and cryptic. All 4 forms are closely linked to HLA and represent the effects of various combinations of alleles.
Congenital adrenal hyperplasia due to 21-OH deficiency is an autosomal recessive disorder, mapping to the class III region of the major histocompatibility complex on chromosome 6p21.3
Estimates for the incidence of classical CAH are in the region of 1 in 10,000 - 14,000 with a carrier frequency of 1 in 50 or 1 in 60. These figures can vary with ethnicity and we estimates a prior carrier risk of 1 in 50 when an individual at population risk requests carrier testing. The incidence of non-classical CAH is generally estimated at 1 in 1000.
There are two 21-hydroxylase loci at 6p21.3, a functional gene (variously termed P450c21B, CYP21B and CYP21) and a non-functional pseudogene (variously termed P450c21A, CYP21A and CYP21P). In order to avoid confusion, the functional gene is now commonly symbolized simply as CYP21, and the nonfunctional gene is symbolized CYP21P (for pseudogene). CYP21 encodes a protein predicted to contain 494 amino acids with a molecular weight of 55,000. The enzyme is at most 28% homologous to other cytochrome P450 enzymes that have been studied.
Laboratory Analysis
Contact scientist: Ian Berry
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Test |
Target reporting time (working days) |
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1. |
MLPA for dosage changes & point mutations |
20 |
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2. |
ARMS test for common point mutations |
20 |
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3. |
Bi-directional sequencing of exons 6 & 7 |
40 |
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4. |
Linked markers |
40 |