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CAH, and genetic mutations are usually not required to confi rm the diagnosis of
CAH. Although, there is a good correlation between genotype and biochemical
phenotype, there is poor correlation between genotype and clinical phenotype in
terms of urogenital sinus virilization (severity of genital ambiguity). This is
probably due to variability in androgen sensitivity among individuals as a result
of differences in the number of CAG repeats in the androgen receptor. The num-
ber of CAG repeats has an inverse correlation with androgen sensitivity. In addi-
tion, the electron donor enzyme P450 oxidoreductase (POR) may also modulate
the clinical phenotype, as one variant of POR has been shown to reduce the
activity of 17α-hydroxylase, thereby decreasing the androgen biosynthesis.- What are the different types of mutations implicated in CAH due to
21 α - hydroxylase defi ciency?
The various types of mutations seen in patients with CAH due to 21α-hydroxylase
defi ciency include large base pair deletions, nonsense mutation, and missense
mutations. Large base pair deletions and nonsense mutations of CYP21A gene
manifest as salt-wasting form of CAH as these mutations result in <1 % residual
enzymatic activity. Missense mutations may result in either simple virilizing
forms of disease or in non-classical form based on the particular mutations.
Large base pair deletions are due to defects in genetic recombination during
meiosis and accounts for 20 % of mutations in patients with CAH, while trans-
fer of deleterious genetic material from pseudogene to active gene during mito-
sis occurs in 75 % of patients.- How does a child with salt - wasting crisis present?
A child with salt-wasting CAH manifests with failure to thrive, lethargy, recur-
rent vomiting, dehydration, and hypotension. The biochemical abnormalities
include hyperkalemia, hyponatremia, and metabolic acidosis.- Why does salt crisis in a patient with classical CAH develop 1 – 2 weeks after
birth?
The salt crisis in neonates with CAH usually manifests at 1–2 weeks of life
despite the enzyme defi ciency is present since birth. Progesterone plays a key
role in prevention of salt crisis in initial few days of life. Progesterone in high
concentration exerts agonistic activity at mineralocorticoid receptor in the pres-
ence of aldosterone defi ciency. Though progesterone has a weak mineralocorti-
coid receptor agonistic activity, in aldosterone-suffi cient state, it exerts
anti- mineralocorticoid activity. As infants with salt-wasting CAH have aldoste-
rone defi ciency, transplacental passage of maternal progesterone in newborn
prevents salt crisis by mineralocorticoid activity of progesterone.10 Congenital Adrenal Hyperplasia