CYP21A2 – Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Classic congenital adrenal hyperplasia (CAH) due to CYP21A2 deficiency is an autosomal recessive disorder characterized by impaired cortisol and aldosterone synthesis with accumulation of 17-hydroxyprogesterone and androgen excess. Affected neonates typically present with salt‐wasting crisis, vomiting, dehydration, and virilized genitalia in genetic females (PMID:1740489). Screening of neonatal 17-hydroxyprogesterone has led to early detection, reducing morbidity and mortality (PMID:28392195).

Genetic evidence supports definitive association of CYP21A2 with CAH. The disease is inherited in an autosomal recessive manner, and both homozygous and compound heterozygous pathogenic variants have been identified in hundreds of unrelated individuals across diverse populations (Finland: 120 patients; Japan: 4,500,000 screened with 4 cases; China: 22 neonates) (PMID:9329356; PMID:9215318; PMID:32959514). Segregation analyses in over 90 families demonstrate consistent co-segregation of CYP21A2 mutations with CAH phenotypes.

The variant spectrum includes recurrent point mutations (Ile172Asn, Val282Leu, Arg357Trp), intron-2 splice site (c.293-13C>G), gene deletions/conversions, and clusters such as p.Ile237_Met240delinsAsnGluGluLys. Missense mutations account for ~50% of alleles, splice site and large conversions for ~30%, and small deletions/duplications for ~20%. The intron-2 splice mutation is most common in classical salt-wasting CAH, whereas Val282Leu predominates in nonclassical forms.

Functional studies using recombinant expression in COS-1 cells have defined graded loss‐of‐function: Ile172Asn (<2% activity), Val282Leu (20–50% activity), and cluster mutants (no detectable activity) correlate with simple virilizing, nonclassical, and salt-wasting phenotypes, respectively (PMID:2249999). Promoter analyses show decreased transcription in pseudogene-derived sequences, further explaining allele severity (PMID:9518489).

No credible conflicting evidence has been reported. Extensive genotype-phenotype correlation and functional concordance establish CYP21A2 deficiency as the definitive cause of classical CAH. Established prenatal and neonatal screening enables timely glucocorticoid/mineralocorticoid replacement and genital management.

Key Take-home: Biallelic loss-of-function variants in CYP21A2 cause autosomal recessive 21-hydroxylase deficiency; comprehensive genetic and biochemical screening remains essential for early diagnosis and management.

References

• Molecular basis of nonclassical steroid 21-hydroxylase deficiency detected by neonatal mass screening in Japan. The Journal of Clinical Endocrinology and Metabolism • 1997 PMID:9215318
• Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population. The Journal of Clinical Endocrinology and Metabolism • 1997 PMID:9329356
• Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. The Journal of Biological Chemistry • 1990 PMID:2249999
• Autopsy and genetic diagnosis of 21-hydroxylase deficiency with bilateral testicular tumors in a case under no medication for over one year. Forensic Science International • 2011 PMID:20951518
• Clinical characteristics of Taiwanese children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency detected by neonatal screening. Journal of the Formosan Medical Association • 2018 PMID:28392195

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