Prenatal Diagnosis Of
Congenital Adrenal Hyperplasia

Congenital Adrenal Hyperplasia is a genetic condition. It is inherited when each parent passes an abnormal gene, which encodes the 21-Hydroxylase enzyme, to their offspring. This pair of abnormal genes is on the short arm of chromosome 6. This condition does not appear if one of the genes is normal. This explains why parents can be carriers of only one mutant or abnormal gene, but appear completely normal.

If both parents are carriers of the mutant gene, with each pregnancy, there is a 1 in 4 chance of a child inheriting both mutant genes, one from each parent. This child will then inherit Congenital Adrenal Hyperplasia (CAH).

The prenatal diagnosis of a fetus with Congenital Adrenal Hyperplasia (CAH), in a family with an affected child, is important, because the family can be psychologically prepared, and a potentially life threatening post-natal adrenal crisis can be prevented, by instituting early hormone replacement. More importantly, recent research has demonstrated that prenatal treatment of affected females with CAH, can also prevent the genital ambiguity associated with virilisation at the critical embryological period of genital development. This would eliminate the need for post-natal cosmetic surgery, with the occasional poor result after surgical reconstruction.

Previous screening for affected CAH fetuses involved a procedure called amniocentesis, which essentially is a technique to sample a small amount of amniotic fluid in early pregnancy, between 15 to 18 weeks of gestation. The precursor metabolite, 17-Hydroxyprogesterone (17OHP) is measured in the amniotic fluid. This would be elevated if the fetus had CAH. However, this test is not very specific, as the levels of 17OHP may be normal for the non-salt wasters, and the milder types of CAH.

Pregnancies at risk could have the amniotic cells assessed for the HLA genotype. The HLA gene locus is situated close to the gene encoding the 21-Hydroxylase enzyme. By applying the concept of linkage, which means that there is a high chance that two genes which are closely located will be inherited together, a fetus sharing both HLA genotypes as the affected child would be predicted to be affected. A fetus sharing only one HLA genotype with the affected child, is a carrier. If no HLA
genotypes are shared, the fetus is generally predicted to be unaffected. However, this technique still provides indirect and circumstantial evidence for the diagnosis of CAH in the fetus.

With recent advances in medical genetics, the gene mutations for the 21-Hydroxylase deficient form of CAH have now been well characterized. In families with a child affected with CAH, in whom the mutation for CAH has already been determined, it is now possible to screen the fetuses in subsequent pregnancies for the CAH gene directly. Genetic determination of the fetus uses the technique called Chorionic Villous Sampling (CVS), which can be performed much earlier in pregnancy, at 9 to 10 weeks of gestation. A sample of the chorionic villous which contains fetal tissue is removed, and the genetic material called deoxyribonucleic acid (DNA) is extracted. This is then amplified by the technique called Polymerase Chain Reaction (PCR) and the CAH gene can be screened by direct sequencing. This method is more accurate than the previous techniques, which can still be used as adjuncts in the prenatal diagnosis of CAH.

With both amniocentesis and chorionic villous sampling, the sex of the fetus can be determined. This is important in prenatal treatment, because only affected females will develop genital ambiguity.

In prenatal treatment, the mother is treated with a potent steroid called dexamethasone, which is commenced once the pregnancy is confirmed, even though it has not been determined whether the fetus is affected or not. This is because the chorionic villous sampling cannot be performed earlier than 9 weeks gestation, and the external genitalia of the fetus develops very early at 9 to 12 weeks of gestation. As such, it is not possible to wait for the diagnosis of the fetus, or treatment will be too late to prevent the accumulation of adrenal androgens, which would virilise the genitals of the affected female fetus. Once the fetus is confirmed to be a male, or a female who is not affected, the mother can stop taking dexamethasone. Treatment is only continued in affected females to prevent or reduce the genital ambiguity. There are risks to the mother of steroid excess, including the features of Cushing’s syndrome (go read Effects of Steroid Medication). There are also concerns regarding potential risks to the fetus.

Prenatal techniques have a reasonably low procedural risk for fetal death. It is  0.3 percent for amniocentesis, and 0.8 percent for the chorionic villous sampling. Although there have been increasing reports of the efficacy of prenatal therapy for CAH in the prevention of genital ambiguity, all cases of prenatal treatment for CAH must be very closely monitored, and are at best performed on the basis of a research trial by trained, committed and responsible specialists.