Late onset congenital adrenal hyperplasia (LOCAH), also known as nonclassic congenital adrenal hyperplasia (NCCAH or NCAH), is a milder form of congenital adrenal hyperplasia (CAH), a group of autosomal recessive disorders characterized by impaired cortisol synthesis that leads to variable degrees of postnatal androgen excess.The causes of LOCAH are the same as of classic CAH, and in the majority of the cases are the mutations in the CYP21A2 gene resulting in corresponding activity changes in the associated P450c21 (21-hydroxylase) enzyme which ultimately leads to excessive androgen production. Other causes, albeit less frequent, are mutations in genes affecting other enzymes involved in steroid metabolism, like 11β-hydroxylase or 3β-hydroxysteroid dehydrogenase. It has a prevalence between 0.1% and 2% depending on population, and is one of the most common autosomal recessive genetic diseases in humans. The pathophysiology is complex and not all individuals are symptomatic. Presentation
Patients with LOCAH usually present with signs of hyperandrogenism, rather than of glucocorticoid deficiency, a condition characterized by inadequate cortisol production. Cortisol synthesis impairment is mild but clinically silent. LOCAH patients usually have the same baseline but lower peak cortisol levels comparing to healthy controls.
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.