The clinical and biochemical spectrum of congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency

Abstract

21-Hydroxylase Deficiency (21-OH Deficiency) represents the most common form of Congenital Adrenal Hyperplasia (CAH), a complex and heterogenous group of conditions, characterised by defects in one of the five enzymes involved in adrenal steroidogenesis. Defects in this steroidogenic enzyme, the product of the CYP21A2 gene, cause disruption in the pathway involved in cortisol and aldosterone production and consequently, the accumulation of their steroid precursors as well as a resulting adrenocorticotrophic hormone (ACTH)-driven overproduction of adrenal androgens. Treatment with glucocorticoid, with or without mineralocorticoid and salt replacement, is directed at preventing adrenal crises and ensuring normal childhood growth by alleviating hyperandrogenism. Conventionally, two clinical forms of 21-OH Deficiency are described - the classical form, separated into salt-wasting and simple-virilising phenotypes, and the non-classical form. They are differentiated by their hormonal profile, predominant clinical features and age of presentation. A greater understanding of the genotype-phenotype correlation supports the view that 21-OH Deficiency is a continuum of phenotypes as opposed to a number of distinct phenotypical entities. Significant advancements in technologies such as Tandem Mass Spectrometry (TMS) and improvements in gene analysis, such as complete PCR-based sequencing of the involved gene, have resulted in remarkable developments in the areas of diagnosis, treatment and treatment monitoring, neonatal screening, prenatal diagnosis and prenatal therapy.

Figure 1

Steroidogenesis in the three zones of the adrenal cortex. Shaded boxes represent the five enzyme defects described in the various types of Congenital Adrenal Hyperplasia. Boxes with dashed lines indicate enzymes involved in androgen biosynthesis which have extra-adrenal activity. 3β-HSD = 3β-Hydroxysteroid dehydrogenase; 17β-HSD = 17β-Hydroxysteroid dehydrogenase; StAR = Steroidogenic Acute Regulatory protein.

Figure 2

Schematic representation of the CYP21A2 gene with microconversions causing 21-OH Deficiency, and the frequency (%) of mutations found in a cohort of Australian patients compared with those described in worldwide studies (reference 27). *Mutation associated with both simple-virilising and salt-wasting phenotypes.

Figure 3

Simplified nomogram illustrating the relationship between basal 17-OHP levels and 17-OHP levels at 60 minutes following stimulation with synthetic ACTH (250 μg intravenous). Differentiation of normal individuals from carriers is complicated by a degree of overlap. NC21OHD = Non-classic 21-Hydroxylase Deficiency; C21OHD = Classic 21-Hydroxylase Deficiency.