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.
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References
White PC, New MI . Genetic basis of endocrine disease: congenital adrenal hyperplasia due to 21-hydroxylase deficiency J Clin Endocrinol Metab 1992 74: 6–11
Del Arbol J, Soto MJ, Fernandez AJ et al. Turner syndrome caused by deletion of long arm of the X chromosome associated with adrenogenital syndrome caused by partial deficiency of 21-hydroxylase Rev Clin Esp 1983 171: 67–71
Montemajor-Jauregui M, Ulloa-Gregori A, Flores-Briseno G . Associated adrenogenital and Turner's syndrome mosaicism Plastic & Reconstructive Surgery 1985 75: 877–881
Kuhnle U, Bidlingmaier F, Knorr D, Butenandt O, Peller P . Sex steroid dependent gonadotropin secretion in gonadal dysgenesis during early infancy: case study of an infant with gonadal dysgenesis (45.XO) and classical 21-hydroxylase deficiency J Ped Endocrinol 1989 3: 257–260
Maciel-Guerra AT, Guerra JG, Marini SHVL, Baptista MTM, Marques-de-Faria AP . Female pseudohermaphroditism due to classical 21-hydroxylase deficiency in a girl with Turner syndrome Clin Genet 1997 51: 351–353
Larizza D, Cuccia M, Martinetti M et al. Adrenocorticotrophin stimulation and HLA polymorphisms suggested a high frequency of heterozygosity for steroid 21-hydroxylase deficiency in patients with Turner's syndrome and their families Clin Endocrinol 1994 40: 39–45
Cuccia M, Blanche H, Dolzan V et al. Mutations of CYP21 gene (MHC class III) in pathologies other than congenital adrenal hyperplasia (CAH) In Charron D (ed) Genetic diversity of HLA. Functional and medical implication Paris: EDK 1997 vol 1: pp. 442–444
Cisternino M, Dondi E, Martinetti M et al. Exaggerated 17-hydroxyprogesterone response to short-term adrenal stimulation and evidence for CYP21B gene point mutations in true precocious puberty Clin Endocrinol 1998 48: 555–560
Blanchè H, Vexiau P, Clauin S et al. Exhaustive screening of the 21-hydroxylase gene in a population of hyperandrogenic women Hum Genet 1997 101: 56–90
Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI . High frequency of nonclassical steroid 21-hydroxylase deficiency Am J Hum Genet 1985 37: 650–667
Yamaguchi T, Abe H, Kuwano T, Sugimoto T, Chihara K . Congenital adrenal hyperplasia with 47, XXY Klinefelter syndrome Exp Clin Endocrinol 1994 102: 348–350
von Mülendahl KE, Heinrich U . Sexual precocity in Klinefelter syndrome: report on two new cases with idiopathic central precocious puberty Eur J Pediatr 1994 153: 322–324
Bertelloni S, Baroncelli GI, Battini R, Saggese G . Central precocious puberty in Klinefelter syndrome: a case report with longitudinal follow-up of growth pattern Am J Med Genet 1996 65: 52–55
White PC, Tusie-Luna MT, New MI, Speiser PW . Mutations in steroid 21-hydroxylase (CYP21) Hum Mutat 1994 3: 373–378
Nimkarn S, Cerame BI, Wei J et al. Congenital adrenal hyperplasia (21-hydroxylase deficiency) without demonstrable genetic mutations J Clin Endocrinol Metab 1999 84: 378–381
Carrera P, Bordone L, Azzani T et al. Point mutations in Italian patients with classic, non classic and cryptic forms of steroid 21-hydroxylase deficiency Hum Genet 1996 98: 662–665
Ezquieda B, Oliver A, Gracia R, Gancedo PC . Analysis of steroid 21-hydroxylase gene mutations in the Spanish population Hum Genet 1995 96: 198–204
Barbat B, Bogyo A, Raux-Demay MC et al. Screening of CYP21 gene mutations in 129 French patients affected by steroid 21-hydroxylase deficiency Hum Mutat 1995 5: 126–130
Guerneri S, Bettio D, Simoni G, Brambati B, Lanzani A, Fraccaro M . Prevalence and distribution of chromosome abnormalities in a sample of first trimester internal abortions Hum Reprod 1987 2: 735–739
Forbes LS . The evolutionary biology of spontaneous abortion in humans TREE 1997 12: 446–450
Hassold TY, Jacobs PA . Trisomy in man Annu Rev Genet 1984 18: 69–97
Witchel SF, Lee PA, Suda-Hartman M, Trucco M, Hoffman EP . Evidence for a heterozygote advantage in Congenital Adrenal Hyperplasia due to 21-Hydroxylase deficiency J Clin Endocrinol Metab 1997 82: 2097–2101
Raghupathy R . Th1-type immunity is incompatible with successful pregnancy Immunology Today 1997 18: 478–482
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Mantovani, V., Dondi, E., Larizza, D. et al. Do reduced levels of steroid 21-hydroxylase confer a survival advantage in fetuses affected by sex chromosome aberrations?. Eur J Hum Genet 10, 137–140 (2002). https://doi.org/10.1038/sj.ejhg.5200778
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DOI: https://doi.org/10.1038/sj.ejhg.5200778
