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Prenatal diagnosis of 21-hydroxylase deficiency, the most common cause of congenital adrenal hyperplasia (CAH), has benefited from the advances in endocrinologic and molecular genetic studies. In 1976, prenatal diagnosis of the disease was first attempted by measuring 17-hydroxyprogesterone in the amniotic fluid in the second trimester of pregnancy. Discovery of a close linkage between HLA and the disease gave a second approach for prenatal diagnosis, the latter being made by linkage study of the haplotypes of the index case in a given family. Diagnosis was later made directly by molecular biology. Currently, the studies of the C4-CYP21B gene locus by Southern blotting and the CYP21B gene mutations by PCR methods simplify the diagnostic procedure of an early and accurate prenatal diagnosis in the first trimester. In these conditions all families are now informative. Moreover, using a direct genetic analysis associated with the possibility of detecting the heterozygotes in a non-related CAH population, a prenatal diagnosis can be done in a family without a previously CAH affected child. From our results in a series of 274 pregnancies at risk for CAH in whom prenatal diagnosis has been made by these different approaches, it can be concluded that steroid analysis in the amniotic fluid is an accurate method but provides only a late (second trimester) diagnosis, while an early and accurate diagnosis now relies on adequate molecular genetic studies on chorion villus biopsies. In the aim to prevent the virilization of the external genitalia in CAH female fetuses, prenatal treatment was instituted in our group in 1979 by giving dexamethasone to the mother. This prenatal treatment appears safe for the fetus and the child and is effective in preventing virilization of CAH affected females. Although the degree of prevention is not always complete in all cases, the advantages of prenatal treatment are prevailing over the complications observed in a few mothers.

A retrospective study of all Swedish patients with congenital adrenal hyperplasia (CAH) born 1969-1986, was conducted to elucidate possible benefits of neonatal screening for CAH. Information was obtained about 150 patients (67 male, 83 female). One hundred and forty-three cases were regarded as classical and seven as non-classical (symptoms after 5 years of age or cryptic). All but two (one girl with 11-hydroxylase deficiency and one boy with beta-hydroxysteroid-dehydrogenase deficiency) had 21-hydroxylase deficiency. The prevalence was 1:11,500. Ninety-three patients (48 male, 45 female) displayed salt loss, all before the age of 3 months. Two boys had died and many children had been critically ill during the first weeks of life. The median age at diagnosis for boys in this group was 21 days. Gender assignment was a major problem in 38 of 57 girls with ambiguous genitalia noticed during the first day. Fifteen of these girls were considered to be male for their first 40 days (median), before the CAH diagnosis was established. Patients in whom the first symptom was manifested after the age of one year often showed growth acceleration, which frequently was overlooked. Median diagnostic delay in this group was 17 months. Possible benefits of neonatal screening are: avoidance of a serious salt-loss crisis; earlier diagnosis and correct gender assignment in virilized girls; decreased virilization, growth acceleration and premature pubarche in prepubertal children; and reduced negative consequences for psycho-social development and final height.

A mother at risk for 21-hydroxylase deficiency was treated with oral dexamethasone (0.5 mg 12 hourly) from early pregnancy, in an attempt to prevent in utero virilization in case of a female fetus. Fetal karyotype was 46,XX, and because of a possible intra HLA recombination, treatment was continued to term. The newborn had a modest virilization and hormonal studies confirmed the diagnosis of congenital adrenal hyperplasia (CAH). This observation and review of the literature suggest that efficient prenatal treatment of CAH requires a higher and more frequent dosage of dexamethasone.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency can result in marked virilization of the external genitalia of affected female subjects. Theoretically, suppression of the fetal pituitary-adrenal axis with glucocorticoid during gestational weeks 9 to 17 should prevent the development of ambiguous genitalia in the female fetus. Prenatal diagnosis of congenital adrenal hyperplasia can be made on elevated amniotic fluid 17-hydroxyprogesterone and adrenal androgen concentrations, and HLA typing of cultured amniotic fluid cells. However, these tests cannot be completed before 16 to 17 weeks of gestation, and maternal therapy would have to be instituted before the exact genetic status of the fetus is known. Chorionic villus sampling during the first trimester provides an alternative to second trimester diagnosis in patients who are at risk for bearing offspring with congenital adrenal hyperplasia. We report the use of dexamethasone suppression at 8 weeks of gestation in a 34-year-old woman whose son had congenital adrenal hyperplasia due to severe salt-losing 21-hydroxylase deficiency and whose biopsy revealed a 46XX chromosomal pattern. Cultured cells from the biopsy confirmed the fetus to be of identical HLA haplotype to the previous affected sibling. At 41 weeks the patient delivered a female neonate with minimal prominence of the clitoris, mildly rugated labia, a single perineal opening and minimal posterior labial fusion. Postnatal tapering of maternal steroids was performed with no long-term sequelae.