Genetics and Pathophysiology of Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Abstract

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease that manifests clinically in varying forms depending on the degree of enzyme deficiency. CAH is most commonly caused by 21-hydroxylase deficiency (21OHD) due to mutations in the CYP21A2 gene. Whereas there is a spectrum of disease severity, 21OHD is generally categorized into 3 forms. The classic form encompasses salt-wasting and simple virilizing CAH and the least affected form is termed nonclassic CAH. The classic form of 21OHD occurs in ∼1 in 16 000 births with the most severe salt-wasting cases presenting in the neonatal period with cortisol and aldosterone deficiencies and virilization of external female genitalia. Cortisol deficiency removes normal feedback on the hypothalamic-pituitary-adrenal axis leading to elevations in ACTH and adrenal androgen levels, which often accelerate skeletal maturation, leading to premature epiphyseal growth plate closure. Additionally, supraphysiologic doses of glucocorticoids are necessary to suppress androgen levels, adversely affecting final adult height. This paper highlights a brief history of 21OHD and provides an overview of the genetic basis and pathophysiology of 21OHD.

Keywords: CYP21A2; aldosterone; androgens; cortisol; cytochrome P450.

Figure 1.

Adrenal steroidogenesis. Enzymes are boxed with dotted lines extending to arrows denoting each enzymatic conversion; 2 enzymes, CYP11B2 and CYP17A1, catalyze several successive enzymatic conversions. Accessory proteins required for activity of cytochrome P450 enzymes are shown next to each such enzyme: POR is required by CYP enzymes in the endoplasmic reticulum; FDXR/FDX1 are required by mitochondrial CYP enzymes. Cytochrome B5 is required for full 17,20-lyase activity of CYP17A1. There are 2 11β-hydroxysteroid dehydrogenase isozymes: HSD11B1, expressed mainly in the liver, catalyzes reduction (eg, cortisone to cortisol), whereas HSD11B2, expressed mainly in the kidney, catalyzes oxidation (eg, cortisol to cortisone). The steps affected by 21-hydroxylase deficiency, including steroids secreted in increased amounts in this disease, are denoted by red lines and red lettering. Steps taking place only in the adrenal glands are in unshaded boxes; steps taking place partly or predominantly outside the adrenal cortex are denoted by shaded boxes. Planar structures of cholesterol, aldosterone, cortisol, and testosterone are illustrated; the position of the 11-oxo (11-keto) group in 11-ketotestosterone is illustrated in green. Colored rectangles indicate the following: grey, early steps of steroidogenesis common to all zones of the cortex; orange, steps in the zona glomerulosa leading to aldosterone; blue, steps in the zona fasciculata leading to cortisol; pink; steps in the zona reticularis and extra-adrenal tissues leading to androgens; purple, the “backdoor” or alternative pathway from 17-OH progesterone to dihydrotestosterone (for clarity, the alternative pathway from progesterone is not shown); green, conversions leading to 11-oxo androgens. Reproduced from Claahsen-van der Grinten HL et al, Endo Rev, 2022; 43(1): 91-159. © The Endocrine Society (3). Abbreviations: FDX1, ferredoxin; FDXR, ferredoxin reductase; POR, P450 oxidoreductase.

Figure 2.

Genetics of the CYP21 genes on chromosome 6p21.3, using data from the Human Genome database (http://genome.ucsc.edu/). The location of this region is indicated on a schematic of the entire chromosome. A scale is marked every 10 kb, with positions in the genome assembly numbered every 0.1 Mb. Genes transcribed in the telomeric-to- centromeric direction (left to right) are on the strand denoted by a right-facing arrow: SKIV2L, Ski2 like RNA helicase; STK19, serine/threonine kinase 19; C4A, complement component C4A; CYP21A1P, cytochrome P450 family 21 subfamily A member 1 (21-hydroxylase) pseudogene; STK19B, serine/threonine kinase 19 pseudogene; C4B, complement component C4B, CYP21A2, cytochrome P450 family 21 subfamily A member 2 (21-hydroxylase). Genes transcribed from the opposite strand (right to left in the figure) are immediately below: ATF6B, activating transcription factor 6 beta; TNXB, tenascin XB; TNXA, tenascin XA pseudogene; DXO, decapping and exoribonuclease protein. ZA and ZB are adrenal-specific noncoding transcripts overlapping the C4 genes in the sense direction (141, 142); additional transcripts exist but are not shown. The 30 kb duplication of part of STK19, all of C4, all of CYP21, and part of TNX (a so-called RCCX module) is indicated. Adapted from Claahsen-van der Grinten HL et al, Endo Rev, 2022; 43(1): 91-159. © The Endocrine Society (3).

Figure 3.

An illustration of unequal meiotic crossing-over generating a deletion representing a salt-wasting 21-hydroxylase deficiency (21-OHD) allele. The other chromosome has 3 copies of the CYP21 gene and is not associated with disease. For clarity, only the C4 and CYP21 genes are illustrated. Adapted from Claahsen-van der Grinten HL et al, Endo Rev, 2022; 43(1): 91-159. © The Endocrine Society (3).

Figure 4.

(A) Structure of the CYP21 genes. Exons are numbered. Mutations affecting enzymatic function that are normally present in the CYP21A1P pseudogene are shown. They are positioned vertically to show the severity of CAH they cause when transferred to CYP21A2 in gene conversion events. These are grouped into 4 mutation groups (0, A-C) and are associated with particular forms of CAH, as indicated. (B) Associations between mutation groups and forms of CAH. These are displayed in tabular form on the left and as histograms on the right. Reproduced from Claahsen-van der Grinten HL et al, Endo Rev, 2022; 43(1): 91-159. © The Endocrine Society (3). Abbreviation: CAH, congenital adrenal hyperplasia.