First Trimester Prenatal Treatment and Molecular Genetic Diagnosis of Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency)*

Abstract

Prenatal treatment of pregnancies at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency was carried out in conjunction with chorionic villus sampling (CVS) in the first trimester for analysis of restriction fragment length polymorphisms. Fourteen families of a total of 49 families at risk for this disease elected to undergo both prenatal treatment and diagnosis via CVS. Dexamethasone administration to the pregnant woman was initiated at a mean gestational age of 7 weeks (range, 4-10 weeks) before testing to determine whether the fetus was affected with 21-hydroxylase deficiency, and CVS was performed at a gestational age of 8-10 weeks. Two affected female fetuses were identified by molecular genetic techniques among this group; neonatal physical examination demonstrated amelioration of the degree of genital ambiguity compared with both nonprenatally treated older sisters with 21-hydroxylase deficiency. The duration of unnecessary prenatal dexamethasone treatment for unaffected or male fetuses was substantially reduced in the CVS group compared with that in a cohort of 8 prenatally treated pregnancies in which amniocentesis was performed in the early second trimester. There were no major morbidities observed in the treated pregnancies. Postnatal confirmation of CVS diagnosis was obtained in all cases in which DNA from an affected sibling was available for comparative analysis with the DNA from chorionic villus tissue. We conclude based on these data that the benefit/risk ratio is favorable for prenatal administration of dexamethasone in pregnancies at risk for 21-hydroxylase deficiency. Treatment should be initiated during the first trimester in conjunction with diagnosis by CVS/molecular genetic techniques. Long term postnatal surveillance is recommended for all offspring of dexamethasone-treated pregnancies.

Prevention of Ambiguous Genitalia in Congenital Adrenal Hyperplasia

“…27 Dexamethasone, given antenatally to mothers who have children with congenital adrenal hyperplasia to prevent ambiguity of the genitalia, has been in use for a few years. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] The initial reports were rather discouraging, as the expected outcome of normal or near normal genitalia did not happen. 24 This was, however, most likely related to the fact that it was not used very early in pregnancy and the first trimester period was missed.…”

“…Using dexamethasone as early as possible, however, resulted in reducing the degree of virilization in at least two-thirds of reported cases. 18,21,23,28 The combination of a dedicated family and medical team is always needed for such a program. The medical team should include an obstetrician, radiologist, geneticist, biochemist, immunologist, nurses, pediatric surgeon, and a pediatrician or pediatric endocrinologist.…”

“…4 Advances in technology have made possible the prenatal diagnosis of CAH and subsequently, prenatal treatment with dexamethasone given to mothers throughout pregnancy and begun as early as possible has led to the prevention of virilization in at least three-fourths of affected infants. [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] In this article, prenatal dexamethasone therapy was given to a Saudi mother of children with CAH due to 21-hydroxylase deficiency. This has prevented ambiguity in the second daughter.…”

Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticoid excess

“…4) (50). Dexamethasone (20 g͞kg͞day in three divided doses) is administered to the pregnant mother beginning before 10 weeks gestation, blind to whether the fetus is female or is affected, to suppress excess adrenal androgen secretion and to prevent virilization should the fetus be an affected female (Fig.…”

Genetic Analysis of Classical 21-Hydroxylase Deficiency Using Polymerase Chain Reaction and Allele-Specific Oligonucleotide Hybridization

“…The methods described here can be used for genetic diagnosis and are applicable in the prenatal period. Prenatal diagnosis with the direct analysis of specific mutations has recently been reported [10], and its importance is amplified by the report of prenatal treatment with corticosteroid [16].…”