The prevalence of heterozygous CYP21A2 deficiency in patients with idiopathic acne, hirsutism, or both
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The purpose of this study is to assess the prevalence of heterozygous CYP21A2 mutation and analyze its correlation with clinical manifestation in patients with acne, hirsutism, or both.
Clinical evaluation, hormone testing, and genetic analysis of the CYP21A2 gene were performed in 60 female patients who visited department of endocrinology of Peking Union Medical College Hospital (PUMCH) for acne, hirsutism, or both from May to November of 2018. The average age of the patients was 26.72 ± 5.73 years. ACTH, Plasma cortisol, LH, FSH, PRL, estradiol, progesterone, testosterone, 17-hydroxyprogesterone (17-OHP), and dehydroepiandrosterone sulfate (DHEA-S) were measured in all participants. Polymerase chain reaction (PCR) combined with sequencing and multiplex ligation dependent probe amplification (MLPA) technique were used to detect the mutation of the CYP21A2 gene. The prevalence of CYP21A2 mutation was compared between the patients and 60 controls, as well as the data in different genetic variant database.
A total of 8.3% (5/60) of individuals with acne, hirsutism, or both in this study were found to harbor heterozygotic CYP21A2 mutation, and the frequency was significantly higher than that in public databases. Identified mutations included V282L (n = 2), I173N (n = 1), E6 cluster [I237N, V238E, and M240K (n = 1)] and large deletion (n = 1). There was no significant difference in hormone levels between heterozygous carriers and subjects with normal CYP21A2 genes.
The prevalence of heterozygous CYP21A2 mutation detected in patients with acne, hirsutism, or both was significantly higher than in the general population. Whether the heterozygous mutation of CYP21A2 is the cause of clinical symptoms needs further assessment.
KeywordsAcne Hirsutism Heterozygosity 21-Hydroxylase deficiency Congenital adrenal hyperplasia CYP21A2 gene
This work was supported by the National Natural Science Foundation of China (Grant No. 81971375 and 81270879) and National Key Research and Development Program of China (2016YFC0905100) and CAMS Innovation Fund for Medical Sciences (2016-I2M-1–002). We thank all subjects for their participation in the research.
Conceived and designed the experiments: MN and XW; collected clinical data: XW, JM; analyzed data: BY, YG; write the paper: MN, YG; revise the paper: XW, JM. All authors have approved the final draft of the paper.
Compliance with ethical standards
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Ethics committee of Peking Union Medical College Hospital; S-K159) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 8.H. Raff, S.T. Sharma, L.K. Nieman, Physiological basis for the etiology, diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, adrenal insufficiency, and congenital adrenal hyperplasia. Compr. Physiol. 4(2), 739–769 (2014). https://doi.org/10.1002/cphy.c130035 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.E.S. Knochenhauer, C. Cortet-Rudelli, R.D. Cunnigham, B.A. Conway-Myers, D. Dewailly, R. Azziz, Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism. J. Clin. Endocrinol. Metab. 82(2), 479–485 (1997). https://doi.org/10.1210/jcem.82.2.3759 CrossRefPubMedGoogle Scholar
- 19.X. Felix-Lopez, L. Riba, M.L. Ordonez-Sanchez, S. Ramirez-Jimenez, J.L. Ventura-Gallegos, A. Zentella-Dehesa, M.T. Tusie-Luna, Steroid 21-hydroxylase (P450c21) naturally occurring mutants I172N, V281L and I236n/V237E/M239K exert a dominant negative effect on enzymatic activity when co-expressed with the wild-type protein. J. Pediatr. Endocrinol. Metab. 16(7), 1017–1024 (2003)CrossRefGoogle Scholar
- 21.K.A. Martin, R.R. Anderson, R.J. Chang, D.A. Ehrmann, R.A. Lobo, M.H. Murad, M.M. Pugeat, R.L. Rosenfield, Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J. Clin. Endocrinol. Metab. 103(4), 1233–1257 (2018). https://doi.org/10.1210/jc.2018-00241 CrossRefPubMedGoogle Scholar
- 23.X.M. Zhao, R.M. Ni, J. Huang, L.L. Huang, S.M. Du, M.J. Ma, D.Y. Lin, D.Z. Yang, [Study on the facial and body terminal hair growth in women in Guangdong by using modified Ferriman-Gallwey scoring system]. Zhonghua fu chan ke za zhi 48(6), 427–431 (2013)Google Scholar
- 24.Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertility and sterility 81(1), 19-25 (2004). https://doi.org/10.1016/j.fertnstert.2003.10.004
- 26.Y.J. Gao, B.Q. Yu, L. Lu, A.L. Tong, S. Chen, J.F. Mao, X. Wang, X.Y. Wu, M. Nie, [Diagnostic value of multiplex ligation dependent probe amplification combined with Sanger sequencing in 21-hydroxylase deficiency]. Zhonghua yi xue za zhi 99(6), 432–437 (2019). https://doi.org/10.3760/cma.j.issn.0376-2491.2019.06.010 CrossRefPubMedGoogle Scholar
- 29.D. Knorr, F. Bidlingmaier, W. Holler, U. Kuhnle, B. Meiler, A. Nachmann, Is heterozygosity for the steroid 21-hydroxylase deficiency responsible for hirsutism, premature pubarche, early puberty, and precocious puberty in children? Acta endocrinologica. Supplementum 279, 284–289 (1986)Google Scholar
- 30.V. Neocleous, C. Shammas, A.A. Phedonos, L.A. Phylactou, N. Skordis, Phenotypic variability of hyperandrogenemia in females heterozygous for CYP21A2 mutations. Indian J. Endocrinol. Metab. 18(Suppl 1), S72–S79 (2014). https://doi.org/10.4103/2230-8210.145077 CrossRefPubMedPubMedCentralGoogle Scholar