Do reduced levels of steroid 21-hydroxylase confer a survival advantage in fetuses affected by sex chromosome aberrations?

Abstract

We investigated whether molecular defects in the CYP21 gene were detectable in two common sex chromosome aberrations, the Turner and the Klinefelter syndromes. We found abnormal 17-hydroxyprogesterone levels after adrenal stimulation in 26/60 (43.3%) patients affected by these chromosome aberrations, as compared with only 11/68 (16.2%) normal controls (P=0.0014, odds ratio 4.0). Screening of the CYP21 gene identified a single Val281Leu missense mutation in exon 7 in 9/63 (14.3%) of the patients, all nine of whom were heterozygote carriers; the mutation frequency was significantly higher than in the general population (P=0.007, odds ratio=3.5). The hormonal and molecular data indicate that these common sex chromosome aberrations are associated with a remarkably high frequency of steroidogenic defects. It may be hypothesised that reduced levels of steroid 21-hydroxylase could confer a survival advantage, leading to a successful pregnancy.

New concepts in Klinefelter syndrome

“…Cortisol levels should be routinely measured, because there is growing evidence that adrenal steroidogenic deficiency may be seen in 47% of men with Klinefelter syndrome [33]. Because decreased testosterone significantly increases the risk of osteopenia and osteoporosis, bone density is routinely performed to diagnose these conditions.…”

Autoimmune stigmata in Turner syndrome: When lacks an X chromosome

“…Nowadays we know that these alleles and especially B38, mainly in the haplotypic combination with HLA-DRB1 * 13 allele variant, mark florid newborns with high birth weight [35]. Therefore, it is conceivable that Turner babies survive in spite of their genetic abnormalities also thanks to their immunogenetic phenotype containing genes favoring foetus' survival [36].…”

A Rare Combination: Congenital Adrenal Hyperplasia Due To 21 Hydroxylase Deficiency and Turner Syndrome

“…Mantovani et al (9) also reported that the frequencies of both abnormal 17-OHP response to ACTH stimulation test and CYP21 gene mutation carriers were prominently higher in patients with TS than in healthy controls. They speculated that while more than 90% of conceptions with 45X0 karyotype normally resulted in spontaneous abortion, certain endocrine signals originating from embryos with decreased 21-OH activities may lead to relaxation of maternal screening, and so provide survival advantage for heterozygote patients with 21-OH deficiencies (9).…”