A 2021 study showed that mild genotypes associated with LOCAH have a low concordance rate with those phenotypes, probably due to the complex characteristics of 21-hydroxylase genotyping and the limitation of using massive parallel sequencing alone without combining with other comprehensive methods.The following three mutations to the CYP21A2 gene have been found to result in a moderate reduction in enzyme activity associated with that allele (20–60% residual activity), and are associated with LOCAH:
p.V281L (rs6471, c.844G>C, CYP21A2*15);
p.P453S (rs6445, c.1360C>T, CYP21A2*19);
p.P30L (rs9378251, c.92C>T, CYP21A2*8).A point mutation in exon 7 of CYP21A2, (p.V281L), is commonly found in LOCAH-associated alleles. Carriers for this mutation retain 20%–50% of 21-hydroxylase activity, but are at higher risk of symptoms of androgen excess than carriers of the severe mutations and had higher adrenocorticotropic hormone (ACTH) stimulated 17α-hydroxyprogesterone, suggesting heterozygous mutations on CYP21A2 play an important role in disease.The particularly mild clinical symptoms of LOCAH such as hyperandrogenism, hirsutism and acne or infertility overlap with other diseases such as polycystic ovary syndrome. Biochemical parameters like 17α-hydroxyprogesterone may not be elevated in very mild cases of LOCAH, and may vary between labs that makes interpretation difficult. It may not be possible to perform ACTH stimulation tests in all institutions, depending on the availability of the injectable adrenocorticotropic hormone medication. This is why a comprehensive CYP21A2 genotyping (rather than variant-specific assays alone) is a good way to exclude/confirm 21-hydroxylase deficiency and heterozygosity (carrier) status.
From the clinical perspective, LOCAH is not an intersex condition and including LOCAH in intersex prevalence estimates has been cited as an example of dubious statistical practice. See also
Congenital adrenal hyperplasia due to 17α-hydroxylase deficiency
Lipoid congenital adrenal hyperplasia

References


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