Female Preponderance in Congenital Adrenal Hyperplasia due to CYP21 Deficiency in England: Implications for Neonatal Screening

Abstract

Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase (CYP21) deficiency causes symptoms ranging from life-threatening neonatal adrenal crises to minimal virilization in adulthood. The relationship between CYP21 genotype and phenotypic markers in a non-screened population of 73 CAH children (44 female, 29 male; 54 white, 19 Asian) treated at the Royal Manchester Children’s Hospital was investigated and ethnic and sex differences assessed. The patients were categorized according to the mutation on the mildest allele. The age at the time of diagnosis differed significantly between the groups (p = 0.02): all 25 Null and 25 of 26 of the I2 splice patients were diagnosed during the neonatal period, whereas 7 of 11 I172N patients were diagnosed late. Degree of female genital virilization, 17-hydroxyprogesterone level at diagnosis, and fludrocortisone requirement during the 1st year of treatment correlated with the genotype, although Asian Null patients required more fludrocortisone than their white counterparts (p = 0.055). There was an equal sex ratio in both the I2 splice (12 female/14 male) and I172N (5 female/6 male) groups. However, in the Null group, the ratio was 4.0 (20 female/5 male; p = 0.003), suggesting that some Null male infants perish before being clinically detected to have CYP21 deficiency. Our findings strongly support the need for implementation of a neonatal screening programme for CAH in the UK which may reduce the male infant mortality.

Subjective health status in men and women with congenital adrenal hyperplasia: a population-based survey in Norway

“…Notably, we identified fewer adult men than women with classical CAH, which was also reported in England (22). Before newborn screening started in Sweden in 1986, the prevalence of CAH was also higher for girls than for boys (21,23).…”

“…Before newborn screening started in Sweden in 1986, the prevalence of CAH was also higher for girls than for boys (21,23). This is intriguing, since CAH is an autosomal recessive trait with expected equal sex ratio, and may be interpreted as increased neonatal male mortality because of adrenal crises, as male infants are less readily diagnosed and treated than female infants (22). Another explanation may be that some boys with the SV form of CAH remain undiagnosed in adult age (24).…”

Ten-year evaluation of a Neonatal Screening Program for Congenital Adrenal Hyperplasia

“…The mortality rate associated with a saltloss crisis in CAH is 4 to 10% (8). In our study, no cases of adrenal crisis or death were observed, despite the fact that 37 children presented the salt-wasting form of the disease.…”

“…Girls with classic CAH have ambiguous genitalia at birth and may be registered and raised improperly as boys (8). We observed in our study that 6% of the children had improper gender identification, hence the importance of early diagnosis and confirmation with karyotype for early correction of the error in establishing the correct gender in affected girls.…”

“…However, when based on a clinical diagnosis, girls predominate over boys (4:1) since in them, the changes in the external genitalia make the diagnosis more evident. In contrast, boys with the salt-wasting form of the disease generally die without a diagnosis (8).…”