A broken gene's inactive twin causes most congenital adrenal hyperplasia
Right beside the working gene for the enzyme 21-hydroxylase sits a nearly identical copy that does nothing. When the two swap stretches of DNA, the working copy can inherit the dud's flaws. That mix-up lies behind about 95 per cent of congenital adrenal hyperplasia, one of the most common recessive inherited disorders in humans.
The condition is a family of disorders, each caused by a shortfall in one of five enzymes the adrenal glands use to make cortisol from cholesterol. Because cortisol normally tells the brain to ease off a signalling hormone called ACTH, a shortage lets ACTH climb, and the constant stimulation makes the adrenal tissue overgrow, which gives the condition its name. The cortisol shortage itself is usually only partial.
The bigger trouble comes from shared chemistry. The same production line also makes aldosterone, which holds on to salt, and sex hormones. In about 75 per cent of severe cases too little aldosterone leads to dangerous salt loss in newborns. Excess male hormones before birth can make a girl's genitals look ambiguous; the 21-hydroxylase form is the most common cause of that in girls with typical chromosomes. Affected boys usually look unremarkable at birth. A milder, nonclassical form may only surface in late childhood or adulthood, through early growth spurts, acne or, in men, early balding and infertility. About 5 per cent of cases involve a different enzyme, 11β-hydroxylase.
In the United States and more than 40 other countries every newborn is screened, by measuring a hormone precursor called 17α-hydroxyprogesterone. The test casts a very wide net. One two-year study found just 111 true cases among 20,647 abnormal results, a hit rate of 0.53 per cent, the lowest of the conditions compared.
Naming has shifted too. Doctors used enzyme-based labels from the 1960s, and when the actual genes were pinned down in the 1980s most of the enzymes turned out to belong to the cytochrome P450 family and were renamed.
Source: Congenital adrenal hyperplasia
