Congenital adrenal hyperplasia, CYP21 deficiency, screening and clinical aspects

Abstract

Congenital adrenal hyperplasia (CAH) is a group of recessively inherited disorders. More than 90% of all cases of CAB are caused by 21-hydroxylase deficiency. This enzyme deficiency results in reduced ability to synthesize cortisol and aldosterone and at the same time increased secretion of androgens. There is a wide spectrum of severity of the disease. The most severe forms of CAH are life-threatening, with the risk of a salt crisis in the neonatal period. CAH has special implications for girls since it causes virilization of the external genitalia, sometimes to the extent that they are assigned the wrong gender. Patients with milder forms of the disease do not show signs of prenatal virilization at birth but develop symptoms of excess androgen production later in life. A limited number of mutations in the 21-hydroxylase gene (CYP21) are responsible for around 95% of all affected Scandinavian CYP21 alleles. There is a clear genotype-phenotype correlation.

Neonatal screening for CAH started in Sweden in 1986. Elevated blood levels of 17-hydroxy progesterone (17OHP) are used as an indicator of CAR The outcome for patients diagnosed with CAH before and after the screening program was initiated was studied. Screening resulted in earlier diagnoses and thereby prevented salt crises and led to earlier correct gender assignment in affected girls. We concluded that there are clear benefits of neonatal screening for CAR Neonatal screening is complicated by the fact that there is a spectrum of the severity of the disease. Screening 17-OHP levels were correlated with the CYP21 genotypes. We were able to show that the screening 17-OBP level provides some information on disease severity on a group level, but it cannot be used to predict disease severity in an individual case. Genotyping can be used to predict disease severity in children who are diagnosed through screening before any signs of salt loss have developed. In addition, genotyping can be used to distinguish between false and true positive cases with slightly elevated 17OHP.

In order to investigate whether the screening can be optimized for preterm infants, we correlated screening 17OHP levels with gestational age in pretem infants. We compared direct measurements of 17-OHP and values after ether extraction, and the number of recalls that would result from different putative cut-off levels were calculated. The possible effects of influencing factors, such as prenatal glucocorticoid treatment, mode of delivery, and neonatal asphyxia, on the screening results were studied. We concluded that with direct measurements of 17-OHP, we can detect patients with salt-wasting CAH born Preterm and obtain the results faster (which is essential to prevent salt crises) without increasing the number of recalls. New recall procedures for the screening of preterm infants were implemented in Sweden based on these findings.

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates cortisone to cortisol. A patient with insufficient response to treatment with cortisone-acetate was found to have an apparent 11beta-HSD1 deficiency with a greatly increased ratio of cortisone to cortisol metabolites. Treatment with hydrocortisone resulted in normalization of 17-OHP, reduced pregnanetriole excretion as well as the ratio of cortisone to cortisol metabolites. We could not detect any mutations in the 11 beta-HSD I gene. Some patients with CAH seem to be unable to activate cortisone to cortisol due to deficient 11beta-HSD1; hence, hydrocortisone should be the drug of choice in these patients. Further studies are needed to investigate the prevalence as well as the mechanisms behind the inter-individual differences in the activity of this enzyme.

Girls with CAH were studied in a structured play situation, using masculine, feminine, and neutral toys. They were videotaped when playing alone and when playing with a parent. CAH girls played more with masculine toys than the controls did. The degree of masculinization in toy play correlated with disease severity, i.e. the level of prenatal exposure to androgen, as assessed by CYP21 genotyping. The CAH girls played somewhat less with the masculine toys when a parent was present, indicating that the presence of the parent influenced them to behave in a less masculine fashion.

Our results point to a direct, causative effect of prenatal androgens as an explanation for the differences in sex-typed behavior that can be seen between girls affected with CAH and controls. An increased knowledge of the specific situation for girls with CAH is important for improving the care of the patients. An increased understanding of the girl's preferences is also valuable to the families.