341- Why is 21α - hydroxylase defi ciency the most common cause of CAH?
Humans have two CYP21A genes, a pseudogene (CYP21A1P) and the active
gene (CYP21A2), which are located on the short arm of chromosome 6. The
active gene encodes for 21α-hydroxylase enzyme, while pseudogene produces
a truncated protein without any enzymatic activity. The presence of >95 %
homology between functional gene and pseudogene allows recombination
between these two genes. CYP21A genes are located on the short arm of chro-
mosome 6 within the region of major histocompatibility locus (HLA class III),
a site with very high rate of recombination. The genetic recombination is an
event that occurs during meiosis as well as during mitosis and produces a new
combination of alleles in the offspring which is different from each parent. The
presence of >95 % homology between active gene and pseudogene, and loca-
tion at a site with high rate of recombination, explains the increased prevalence
of CAH due to 21α-hydroxylase defi ciency.- What is the difference between homozygote , heterozygote, and compound
heterozygote?
An individual who has same mutation in each allele of a gene is said to be
homozygote, while an individual with a mutation in one allele of a gene (and
the other allele is normal) is said to be heterozygote. An individual with differ-
ent mutation in each allele of a gene is said to be compound heterozygote.- What is the importance of compound heterozygosity in CAH?
Compound heterozygosity is present in the majority (60–75 %) of patients with
CAH. The clinical phenotype of a compound heterozygote individual with
CAH is determined by the less severely mutated allele. For example, if an indi-
vidual receives different mutation from each parent (e.g., exon 1 mutation from
father and exon 8 mutation from mother), the individual is said to be compound
heterozygote for that disease. Assuming that mutation in exon 1 allele is a
severe mutation (known to be associated with salt-wasting) and mutation in
exon 8 allele is a mild mutation (known to be associated with non-classical
CAH), the individual will manifest as non-classical phenotype of CAH.- What is the genotype – phenotype correlation in patients with CAH due to
21 α - hydroxylase defi ciency?
The genotype–phenotype correlation in CAH can be considered in terms of bio-
chemical or clinical phenotype. There is a good correlation between genotype
and biochemical phenotype as patients with severe mutations have <5 % resid-
ual enzyme activity with stimulated serum 17α-hydroxyprogesterone 17(OH)P
level >100 ng/ml, whereas those with less severe mutations have 20–50 % resid-
ual enzyme activity with stimulated serum 17(OH)P level 10–100 ng/ml. Hence,
stimulated serum 17(OH)P is an excellent test to establish the diagnosis of10 Congenital Adrenal Hyperplasia