Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management

Abstract

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.

Keywords: CYP21A2; 21-hydroxylase deficiency; Steroid biosynthesis; aldosterone; cortisol; glucocorticoid; mineralocorticoid.

Graphical Abstract

Figure 1.

Adrenal steroidogenesis. Enzymes are boxed with dotted lines extending to arrows denoting each enzymatic conversion; 2 enzymes, CYP11B2 and CYP17, catalyze several successive enzymatic conversions. Accessory proteins required for activity of cytochrome P450 enzymes are shown next to each such enzyme: POR, P450 oxidoreductase, required by CYP enzymes in the endoplasmic reticulum; FDXR/FDX1, ferredoxin reductase and ferredoxin, required by mitochondrial CYP enzymes. Cytochrome B5 (CYP5A) 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 21OHD, 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: gray, 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; magenta; steps in the zona reticularis and extra-adrenal tissues leading to androgens; purple, the “backdoor” or alternate pathway from 17-OH progesterone to dihydrotestosterone (for clarity, the alternative pathway from progesterone is not shown); green, conversions leading to 11-oxo androgens.

Figure 2.

Genetics of the CYP21 genes. (A) the genetic region 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. (B) An illustration of unequal meiotic crossing-over generating a deletion representing a salt-wasting 21-hydroxylase deficiency allele. The other chromosome has 3 copies of the RCCX tandem and is not associated with disease. The scale is expanded from Fig. 1A. For clarity, only the C4 and CYP21 genes are illustrated.

Figure 3.

(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.

Figure 4.

Genital development. Top, Differentiation of male and female reproductive systems are illustrated in schematic cross-section (not to scale). Bottom, the Prader scale of genital virilization.

Figure 5.

New therapeutic approaches target different aspects of the pathophysiology of CAH. Circadian cortisol replacement with a modified-release glucocorticoid or subcutaneous hydrocortisone infusion aim to control corticotropin-driven hyperandrogenism by replacing cortisol in a physiological manner. Other approaches to reduce androgen production without chronic supraphysiological glucocorticoid exposure include corticotropin-releasing hormone receptor-1 antagonists, adrenocorticotropic hormone (corticotropin, ACTH) antibodies, adrenocorticotropic hormone receptor (MC2R) antagonists, adrenolytic agents, adrenalectomy, and pharmacological inhibition of steroidogenic enzymes or steroid receptors in the adrenal or peripheral tissues. Since CAH owing to 21OHD is a monogenic disorder, gene therapy with cell-based and gene-editing technologies may be able to restore defective steroidogenesis. CRH denotes corticotropin-releasing hormone (sometimes referred to as corticotropin-releasing factor [CRF]). From New England Journal of Medicine, Merke DP, Auchus RJ, Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency, Volume 83, Page 1258. Copyright © (2020) Massachusetts Medical Society. Reprinted with permission.