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The prevalence of heterozygous CYP21A2 deficiency in patients with idiopathic acne, hirsutism, or both

  • Yinjie Gao
  • Bingqing Yu
  • Jiangfeng Mao
  • Xi Wang
  • Min NieEmail author
  • Xueyan WuEmail author
Original Article



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.


Acne 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.

Author contributions

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.

Ethical approval

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

Informed consent was obtained from all individual participants included in the study.

Supplementary material

12020_2019_2104_MOESM1_ESM.docx (14 kb)
Supplementary Information


  1. 1.
    G. Tilles, Acne pathogenesis: history of concepts. Dermatology. 229(1), 1–46 (2014). CrossRefPubMedGoogle Scholar
  2. 2.
    C.N. Collier, J.C. Harper, J.A. Cafardi, W.C. Cantrell, W. Wang, K.W. Foster, B.E. Elewski, The prevalence of acne in adults 20 years and older. J. Am. Acad. Dermatol. 58(1), 56–59 (2008). CrossRefPubMedGoogle Scholar
  3. 3.
    D. Ferriman, J.D. Gallwey, Clinical assessment of body hair growth in women. J. Clin. Endocrinol. Metab. 21, 1440–1447 (1961). CrossRefPubMedGoogle Scholar
  4. 4.
    J.J. Heidelbaugh, Endocrinology. Update.: Hirsutism. FP Essent. 451, 17–24 (2016)PubMedGoogle Scholar
  5. 5.
    R. Podgorski, D. Aebisher, M. Stompor, D. Podgorska, A. Mazur, Congenital adrenal hyperplasia: clinical symptoms and diagnostic methods. Acta Biochimica Polonica 65(1), 25–33 (2018). CrossRefPubMedGoogle Scholar
  6. 6.
    D. Lizneva, L. Gavrilova-Jordan, W. Walker, R. Azziz, Androgen excess: Investigations and management. Best practice & research. Clin. Obstet. Gynaecol. 37, 98–118 (2016). CrossRefGoogle Scholar
  7. 7.
    F. Cordera, C. Grant, J. van Heerden, G. Thompson, W. Young, Androgen-secreting adrenal tumors. Surgery 134(6), 874–880 (2003). discussion 880CrossRefPubMedGoogle Scholar
  8. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    P.C. White, P.W. Speiser, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr. Rev. 21(3), 245–291 (2000). CrossRefPubMedGoogle Scholar
  10. 10.
    R. Azziz, D. Dewailly, D. Owerbach, Clinical review 56: Nonclassic adrenal hyperplasia: current concepts. J. Clin. Endocrinol. Metab. 78(4), 810–815 (1994). CrossRefPubMedGoogle Scholar
  11. 11.
    M.L. Narasimhan, A. Khattab, Genetics of congenital adrenal hyperplasia and genotype-phenotype correlation. Fertil. Steril. 111(1), 24–29 (2019). CrossRefPubMedGoogle Scholar
  12. 12.
    S.F. Witchel, P.A. Lee, M. Suda-Hartman, E.P. Hoffman, Hyperandrogenism and manifesting heterozygotes for 21-hydroxylase deficiency. Biochemical Mol. Med. 62(2), 151–158 (1997)CrossRefGoogle Scholar
  13. 13.
    F. Paris, V. Tardy, A. Chalancon, M.C. Picot, Y. Morel, C. Sultan, Premature pubarche in Mediterranean girls: high prevalence of heterozygous CYP21 mutation carriers. Gynecol. Endocrinol. 26(5), 319–324 (2010). CrossRefPubMedGoogle Scholar
  14. 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). CrossRefPubMedGoogle Scholar
  15. 15.
    O. Admoni, S. Israel, I. Lavi, M. Gur, Y. Tenenbaum-Rakover, Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin. Endocrinol. 64(6), 645–651 (2006). CrossRefGoogle Scholar
  16. 16.
    R. Azziz, D. Owerbach, Molecular abnormalities of the 21-hydroxylase gene in hyperandrogenic women with an exaggerated 17-hydroxyprogesterone response to short-term adrenal stimulation. Am. J. Obstet. Gynecol. 172(3), 914–918 (1995)CrossRefGoogle Scholar
  17. 17.
    L.S. Ostlere, G. Rumsby, P. Holownia, H.S. Jacobs, M.H. Rustin, J.W. Honour, Carrier status for steroid 21-hydroxylase deficiency is only one factor in the variable phenotype of acne. Clin. Endocrinol. 48(2), 209–215 (1998)CrossRefGoogle Scholar
  18. 18.
    H.F. Escobar-Morreale, J.L. San Millan, R.R. Smith, J. Sancho, S.F. Witchel, The presence of the 21-hydroxylase deficiency carrier status in hirsute women: phenotype-genotype correlations. Fertil. Steril. 72(4), 629–638 (1999)CrossRefGoogle Scholar
  19. 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
  20. 20.
    K. Sardana, C. Singh, I. Narang, S. Bansal, V.K. Garg, The role of antimullerian hormone in the hormonal workup of women with persistent acne. J. Cosmet. Dermatol. 15(4), 343–349 (2016). CrossRefPubMedGoogle Scholar
  21. 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). CrossRefPubMedGoogle Scholar
  22. 22.
    M. Wong, X. Zhao, Y. Hong, D. Yang, Semiquantitative assessment of hirsutism in 850 PCOS patients and 2,988 controls in China. Endokrynol. Pol. 65(5), 365–370 (2014). CrossRefPubMedGoogle Scholar
  23. 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. 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).
  25. 25.
    W. Wang, H.W. Wu, J.F. Liu, Cow milk induced allergies (CMA) and asthma in new born. Eur. Rev. Med. Pharmacol. Sci. 20(6), 1008–1014 (2016)PubMedGoogle Scholar
  26. 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). CrossRefPubMedGoogle Scholar
  27. 27.
    S. Israel, L. Weinrib, N. Weintrob, K. Miller, C. Brautbar, Distribution of the V281L mutation of the CYP21 gene in Israeli congenital adrenal hyperplasia patients and its association with HLA- B14. Pediatr. Endocrinol. Rev.: PER 3(Suppl 3), 447–450 (2006).PubMedGoogle Scholar
  28. 28.
    S.F. Witchel, Congenital adrenal hyperplasia. J. Pediatr. Adolesc. Gynecol. 30(5), 520–534 (2017). CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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. 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). CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    J. Mihailidis, R. Dermesropian, P. Taxel, P. Luthra, J.M. Grant-Kels, Endocrine evaluation of hirsutism. Int. J. Women’s. Dermatol. 3(1 Suppl), S6–S10 (2017). CrossRefGoogle Scholar
  32. 32.
    W.D. James, Clinical practice. Acne. New Engl. J. Med. 352(14), 1463–1472 (2005). CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.NHC key laboratory of Endocrinology, Department of EndocrinologyPeking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical SciencesBeijingChina

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