Skip to main content
SpringerLink
Log in

Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene

  • Review Article
  • Published:
Molecular Diagnosis & Therapy Aims and scope Submit manuscript

Abstract

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders caused by complete or partial defects in one of the several steroidogenic enzymes involved in the synthesis of cortisol from cholesterol in the adrenal glands. More than 95–99% of all cases of CAH are caused by deficiency of steroid 21-hydroxylase, an enzyme encoded by the CYP21A2 gene. Currently, CYP21A2 genotyping is considered a valuable complement to biochemical investigations in the diagnosis of 21-hydroxylase deficiency. More than 200 mutations have been described in literature reports, and much energy is still focused on the clinical classification of new variants. In this review, we focus on molecular genetic features of 21-hydroxylase deficiency, performing an extensive survey of all clinical pathogenic variants modifying the whole sequence of the CYP21A2 gene. Our aim is to offer a very useful tool for clinical and genetic specialists in order to ease clinical diagnosis and genetic counseling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Reference

  1. El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet. 2017;17:31431–9.

    Google Scholar 

  2. Arlt W, Willis DS, Wild SH, Krone N, Doherty EJ, Hahner S, Han TS, Carroll PV, Conway GS, Rees DA, Stimson RH, Walker BR, Connell JM, Ross RJ, United Kingdom Congenital Adrenal Hyperplasia Adult Study Executive (CaHASE). Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J Clin Endocrinol Metab. 2010;95:5110–21.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Gidlöf S, Falhammar H, Thilén A, von Döbeln U, Ritzén M, Wedell A, Nordenström A. One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study. Lancet Diabetes Endocrinol. 2013;1:35–42.

    Article  PubMed  Google Scholar 

  4. Parsa AA, New MI. Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2017;165:2–11.

    Article  PubMed  CAS  Google Scholar 

  5. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21:245–91.

    PubMed  CAS  Google Scholar 

  6. Falhammar H, Nordenström A. Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome. Endocrine. 2015;50:32–50.

    Article  PubMed  CAS  Google Scholar 

  7. Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, Witchel SF, Azziz R. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: an update with a special focus on adolescent and adult women. Hum Reprod Update. 2017;23:580–99.

    Article  PubMed  Google Scholar 

  8. Wedell A. Molecular genetics of 21-hydroxylase deficiency. Endocr Dev. 2011;20:80–7.

    Article  PubMed  CAS  Google Scholar 

  9. Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009;23:181–92.

    Article  PubMed  CAS  Google Scholar 

  10. New MI, Abraham M, Gonzalez B, Dumic M, Razzaghy-Azar M, Chitayat D, Sun L, Zaidi M, Wilson RC, Yuen T. Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc Natl Acad Sci USA. 2013;110:2611–6.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Krone N, Braun A, Roscher AA, Knorr D, Schwarz HP. Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany. J Clin Endocrinol Metab. 2000;85:1059–65.

    Article  PubMed  CAS  Google Scholar 

  12. Marino R, Ramirez P, Galeano J, Perez Garrido N, Rocco C, Ciaccio M, Warman DM, Guercio G, Chaler E, Maceiras M, Bergadá I, Gryngarten M, Balbi V, Pardes E, Rivarola MA, Belgorosky A. Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype-phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2011;75:427–35.

    Article  PubMed  CAS  Google Scholar 

  13. Khattab A, Yuen T, Malki AS, Yau M, Kazmi D, Sun L, Harbison M, Haider S, Zaidi M, New MI. A rare CYP21A2 mutation in a congenital adrenal hyperplasia kindred displaying genotype-phenotype nonconcordance. Ann N Y Acad Sci. 2016;1364:5–10.

    Article  PubMed  CAS  Google Scholar 

  14. Balsamo A, Baldazzi L, Menabò S, Cicognani A. Impact of molecular genetics on congenital adrenal hyperplasia management. Sex Dev. 2010;4:233–48.

    Article  PubMed  CAS  Google Scholar 

  15. Choi JH, Kim GH, Yoo HW. Recent advances in biochemical and molecular analysis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann Pediatr Endocrinol Metab. 2016;21(1):1–6.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Concolino P, Mello E, Zuppi C, Capoluongo E. Molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an update of new CYP21A2 mutations. Clin Chem Lab Med. 2010;48:1057–62.

    Article  PubMed  CAS  Google Scholar 

  17. White PC, Grossberger D, Onufer BJ, Chaplin DD, New MI, Dupont B, Strominger JL. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci USA. 1985;82:1089–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Yang Z, Mendoza AR, Welch TR, Zipf WB, Yu CY. Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations. J Biol Chem. 1999;274:12147–56.

    Article  PubMed  CAS  Google Scholar 

  19. Haglund-Stengler B, Martin Ritzen E, Gustafsson J, Luthman H. Haplotypes of the steroid 21-hydroxylase gene region encoding mild steroid 21-hydroxylase deficiency. Proc Natl Acad Sci USA. 1991;88:8352–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Blanchong CA, Zhou B, Rupert KL, Chung EK, Jones KN, Sotos JF, Zipf WB, Rennebohm RM, Yung YuC. Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease. J Exp Med. 2000;191:2183–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci USA. 1986;83:5111–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ezquieta B, Beneyto M, Muñoz-Pacheco R, Barrio R, Oyarzabal M, Lechuga JL, Luzuriaga C, Hermoso F, Quinteiro S, Martinez S. Gene duplications in 21-hydroxylase deficiency: the importance of accurate molecular diagnosis in carrier detection and prenatal diagnosis. Prenat Diagn. 2006;26:1172–8.

    Article  PubMed  CAS  Google Scholar 

  23. Kharrat M, Riahi A, Maazoul F, M’rad R, Chaabouni H. Detection of a frequent duplicated CYP21A2 gene carrying a Q318X mutation in a general population with quantitative PCR methods. Diagn Mol Pathol. 2011;20:123–7.

    Article  PubMed  Google Scholar 

  24. Parajes S, Quinteiro C, Domínguez F, Loidi L. High frequency of copy number variations and sequence variants at CYP21A2 locus: implication for the genetic diagnosis of 21-hydroxylase deficiency. PLoS One. 2008;3:e2138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Wedell A, Stengler B, Luthman H. Characterization of mutations on the rare duplicated C4/CYP21 haplotype in steroid 21-hydroxylase deficiency. Hum Genet. 1994;94:50–4.

    Article  PubMed  CAS  Google Scholar 

  26. Kleinle S, Lang R, Fischer GF, Vierhapper H, Waldhauser F, Födinger M, Baumgartner-Parzer SM. Duplications of the functional CYP21A2 gene are primarily restricted to Q318X alleles: evidence for a founder effect. J Clin Endocrinol Metab. 2009;94:3954–8.

    Article  PubMed  CAS  Google Scholar 

  27. Koppens PF, Hoogenboezem T, Degenhart HJ. CYP21 and CYP21P variability in steroid 21-hydroxylase deficiency patients and in the general population in the Netherlands. Eur J Hum Genet. 2000;8:827–36.

    Article  PubMed  CAS  Google Scholar 

  28. Concolino P, Mello E, Minucci A, Giardina B, Capoluongo E. Genes, pseudogenes and like genes: the case of 21-hydroxylase in Italian population. Clin Chim Acta. 2013;424:85–9.

    Article  PubMed  CAS  Google Scholar 

  29. Werkmeister JW, New MI, Dupont B, White PC. Frequent deletion and duplication of the steroid 21-hydroxylase genes. Am J Hum Genet. 1986;39:461–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. Lee HH. CYP21 mutations and congenital adrenal hyperplasia. Clin Genet. 2001;59:293–301.

    Article  PubMed  CAS  Google Scholar 

  31. Tusié-Luna MT, White PC. Gene conversions and unequal crossovers between CYP21 (steroid 21-hydroxylase gene) and CYP21P involve different mechanisms. Proc Natl Acad Sci USA. 1995;92:10796–800.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Concolino P, Mello E, Zuppi C, Toscano V, Capoluongo E. CYP21A2 p. E238 deletion as result of multiple microconversion events: a genetic study on an Italian congenital adrenal hyperplasia (CAH) family. Diagn Mol Pathol. 2013;22:48–51.

    Article  PubMed  CAS  Google Scholar 

  33. Lee HH. Variants of the CYP21A2 and CYP21A1P genes in congenital adrenal hyperplasia. Clin Chim Acta. 2013;418:37–44.

    Article  PubMed  CAS  Google Scholar 

  34. Tsai LP, Cheng CF, Chuang SH, Lee HH. Analysis of the CYP21A1P pseudogene: indication of mutational diversity and CYP21A2-like and duplicated CYP21A2 genes. Anal Biochem. 2011;413:133–41.

    Article  PubMed  CAS  Google Scholar 

  35. Tsai LP, Lee HH. Analysis of CYP21A1P and the duplicated CYP21A2 genes. Gene. 2012;506:261–2.

    Article  PubMed  CAS  Google Scholar 

  36. Cantürk C, Baade U, Salazar R, Storm N, Pörtner R, Höppner W. Sequence analysis of CYP21A1P in a German population to aid in the molecular biological diagnosis of congenital adrenal hyperplasia. Clin Chem. 2011;57:511–7.

    Article  PubMed  CAS  Google Scholar 

  37. Concolino P, Mello E, Minucci A, Zuppi C, Capoluongo E. Multiplex ligation-dependent probe amplification analysis is useful for diagnosing congenital adrenal hyperplasia but requires a deep knowledge of CYP21A2 genetics. Clin Chem. 2011;57:1079–80.

    Article  PubMed  CAS  Google Scholar 

  38. Koppens PF, Hoogenboezem T, Degenhart HJ. Carriership of a defective tenascin-X gene in steroid 21-hydroxylase deficiency patients: TNXB -TNXA hybrids in apparent large-scale gene conversions. Hum Mol Genet. 2002;11:2581–90.

    Article  PubMed  CAS  Google Scholar 

  39. Kaufman CS, Butler MG. Mutation in TNXB gene causes moderate to severe Ehlers–Danlos syndrome. World J Med Genet. 2016;6:17–21.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, van Haren B, Miller WL, Bristow J. A recessive form of the Ehlers–Danlos syndrome caused by tenascin-X deficiency. N Engl J Med. 2001;345:1167–75.

    Article  PubMed  CAS  Google Scholar 

  41. Lee HH, Lee YJ, Lin CY. PCR-based detection of the CYP21 deletion and TNXA/TNXB hybrid in the RCCX module. Genomics. 2004;83:944–50.

    Article  PubMed  CAS  Google Scholar 

  42. Lee HH. Chimeric CYP21P/CYP21 and TNXA/TNXB genes in the RCCX module. Mol Genet Metab. 2005;84:4–8.

    Article  PubMed  CAS  Google Scholar 

  43. Lee HH. The chimeric CYP21P/CYP21 gene and 21-hydroxylase deficiency. J Hum Genet. 2004;49:65–72.

    Article  PubMed  CAS  Google Scholar 

  44. Chen W, Xu Z, Sullivan A, Finkielstain GP, Van Ryzin C, Merke DP, McDonnell NB. Junction site analysis of chimeric CYP21A1P/CYP21A2 genes in 21-hydroxylase deficiency. Clin Chem. 2012;58:421–30.

    Article  PubMed  CAS  Google Scholar 

  45. Concolino P, Mello E, Minucci A, Giardina E, Zuppi C, Toscano V, Capoluongo E. A new CYP21A1P/CYP21A2 chimeric gene identified in an Italian woman suffering from classical congenital adrenal hyperplasia form. BMC Med Genet. 2009;10:72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Vrzalová Z, Hrubá Z, Hrabincová ES, Vrábelová S, Votava F, Koloušková S, Fajkusová L. Chimeric CYP21A1P/CYP21A2 genes identified in Czech patients with congenital adrenal hyperplasia. Eur J Med Genet. 2011;54:112–7.

    Article  PubMed  Google Scholar 

  47. Chu X, Braun-Heimer L, Rittner C, Schneider PM. Identification of the recombination site within the steroid 21-hydroxylase gene (CYP21) of the HLA-B47, DR7 haplotype. Exp Clin Immunogenet. 1992;9:80–5.

    PubMed  CAS  Google Scholar 

  48. Helmberg A, Tabarelli M, Fuchs MA, Keller E, Dobler G, Schnegg I, Knorr D, Albert E, Kofler R. Identification of molecular defects causing congenital adrenal hyperplasia by cloning and differential hybridization of polymerase chain reaction-amplified 21-hydroxylase (CYP21) genes. DNA Cell Biol. 1992;11:359–68.

    Article  PubMed  CAS  Google Scholar 

  49. Lee HH, Lee YJ, Chan P, Lin CY. Use of PCR-based amplification analysis as a substitute for the Southern blot method for CYP21 deletion detection in congenital adrenal hyperplasia. Clin Chem. 2004;50:1074–6.

    Article  PubMed  CAS  Google Scholar 

  50. Lee HH, Chang SF, Lee YJ, Raskin S, Lin SJ, Chao MC, Lo FS, Lin CY. Deletion of the C4-CYP21 repeat module leading to the formation of a chimeric CYP21P/CYP21 gene in a 9.3-kb fragment as a cause of steroid 21-hydroxylase deficiency. Clin Chem. 2003;49:319–22.

    Article  PubMed  CAS  Google Scholar 

  51. White PC, New MI, Dupont B. HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation. Proc Natl Acad Sci USA. 1984;81:7505–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. L’Allemand D, Tardy V, Grüters A, Schnabel D, Krude H, Morel Y. How a patient homozygous for a 30-kb deletion of the C4-CYP 21 genomic region can have a nonclassic form of 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2000;85:4562–7.

    Article  PubMed  Google Scholar 

  53. Lekarev O, Tafuri K, Lane AH, Zhu G, Nakamoto JM, Buller-Burckle AM, Wilson TA, New MI. Erroneous prenatal diagnosis of congenital adrenal hyperplasia owing to a duplication of the CYP21A2 gene. J Perinatol. 2013;33:76–8.

    Article  PubMed  CAS  Google Scholar 

  54. Sani I, Rossodivita AN, Mariani M, Costella A, Molinario R, Concolino P, Capoluongo E. CYP21A2 genetics: When genotype does not fit phenotype. Clin Biochem. 2016;49:524–5.

    Article  PubMed  CAS  Google Scholar 

  55. Robins T, Bellanne-Chantelot C, Barbaro M, Cabrol S, Wedell A, Lajic S. Characterization of novel missense mutations in CYP21 causing congenital adrenal hyperplasia. J Mol Med (Berl). 2007;85:247–55.

    Article  PubMed  CAS  Google Scholar 

  56. Krone N, Riepe FG, Grötzinger J, Partsch CJ, Sippell WG. Functional characterization of two novel point mutations in the CYP21 gene causing simple virilizing forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2005;90:445–54.

    Article  PubMed  CAS  Google Scholar 

  57. Concolino P, Vendittelli F, Mello E, Minucci A, Carrozza C, Rossodivita A, Giardina B, Zuppi C, Capoluongo E. Functional analysis of two rare CYP21A2 mutations detected in Italian patients with a mildest form of congenital adrenal hyperplasia. Clin Endocrinol (Oxf). 2009;71:470–6.

    Article  PubMed  CAS  Google Scholar 

  58. Concolino P, Vendittelli F, Mello E, Carelli Alinovi C, Minucci A, Carrozza C, Santini SA, Zuppi C, Capoluongo E. Two novel CYP21A2 missense mutations in Italian patients with 21-hydroxylase deficiency: Identification and functional characterisation. IUBMB Life. 2009;61:229–35.

    Article  PubMed  CAS  Google Scholar 

  59. Robins T, Carlsson J, Sunnerhagen M, Wedell A, Persson B. Molecular model of human CYP21 based on mammalian CYP2C5: structural features correlate with clinical severity of mutations causing congenital adrenal hyperplasia. Mol Endocrinol. 2006;20:2946–64.

    Article  PubMed  CAS  Google Scholar 

  60. Pey AL, Stricher F, Serrano L, Martinez A. Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. Am J Hum Genet. 2007;81:1006–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Alibés A, Nadra AD, De Masi F, Bulyk ML, Serrano L, Stricher F. Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: the Pax6 example. Nucleic Acids Res. 2010;38:7422–31.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Minutolo C, Nadra AD, Fernández C, Taboas M, Buzzalino N, Casali B, Belli S, Charreau EH, Alba L, Dain L. Structure-based analysis of five novel disease-causing mutations in 21-hydroxylase-deficient patients. PLoS One. 2011;6:e15899.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Worth CL, Preissner R, Blundell TL. SDM—a server for predicting effects of mutations on protein stability and malfunction. Nucleic Acids Res. 2011;39:W215–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Zhao B, Lei L, Kagawa N, Sundaramoorthy M, Banerjee S, Nagy LD, Guengerich FP, Waterman MR. Three-dimensional structure of steroid 21-hydroxylase (cytochrome P450 21A2) with two substrates reveals locations of disease-associated variants. J Biol Chem. 2012;287:10613–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Pallan PS, Wang C, Lei L, Yoshimoto FK, Auchus RJ, Waterman MR, Guengerich FP, Egli M. Human Cytochrome P450 21A2, the major steroid 21-hydroxylase: structure of the enzyme progesterone substrate complex and rate-limiting C-H bond cleavage. J Biol Chem. 2015;290:13128–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Haider S, Islam B, D’Atri V, Sgobba M, Poojari C, Sun L, Yuen T, Zaidi M, New MI. Structure-phenotype correlations of human CYP21A2 mutations in congenital adrenal hyperplasia. Proc Natl Acad Sci USA. 2013;110:2605–10.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Bruque CD, Delea M, Fernández CS, Orza JV, Taboas M, Buzzalino N, Espeche LD, Solari A, Luccerini V, Alba L, Nadra AD, Dain L. Structure-based activity prediction of CYP21A2 stability variants: a survey of available gene variations. Sci Rep. 2016;6:39082.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Database of CY21A2 by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee: https://www.pharmvar.org/htdocs/archive/cyp21.htm. Accessed 14 Feb 2018.

  69. Araújo RS, Mendonca BB, Barbosa AS, Lin CJ, Marcondes JA, Billerbeck AE, Bachega TA. Microconversion between CYP21A2 and CYP21A1P promoter regions causes the nonclassical form of 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2007;92:4028–34.

    Article  PubMed  CAS  Google Scholar 

  70. Menabò S, Balsamo A, Baldazzi L, Barbaro M, Nicoletti A, Conti V, Pirazzoli P, Wedell A, Cicognani A. A sequence variation in 3′UTR of CYP21A2 gene correlates with a mild form of congenital adrenal hyperplasia. J Endocrinol Investig. 2012;35:298–305.

    Google Scholar 

  71. Concolino P, Rizza R, Costella A, Carrozza C, Zuppi C, Capoluongo E. CYP21A2 intronic variants causing 21-hydroxylase deficiency. Metabolism. 2017;71:46–51.

    Article  PubMed  CAS  Google Scholar 

  72. Nermoen I, Brønstad I, Fougner KJ, Svartberg J, Øksnes M, Husebye ES, et al. Genetic, anthropometric and metabolic features of adult Norwegian patients with 21-hydroxylase deficiency. Eur J Endocrinol. 2012;167:507–16.

    Article  PubMed  CAS  Google Scholar 

  73. Brønstad I, Breivik L, Methlie P, Wolff AS, Bratland E, Nermoen I, Løvås K, Husebye ES. Functional studies of novel CYP21A2 mutations detected in Norwegian patients with congenital adrenal hyperplasia. Endocr Connect. 2014;3:67–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Barbaro M, Baldazzi L, Balsamo A, Lajic S, Robins T, Barp L, Pirazzoli P, Cacciari E, Cicognani A, Wedell A. Functional studies of two novel and two rare mutations in the 21-hydroxylase gene. J Mol Med (Berl). 2006;84:521–8.

    Article  PubMed  CAS  Google Scholar 

  75. Nunez BS, Lobato MN, White PC, Meseguer A. Functional analysis of four CYP21 mutations from spanish patients with congenital adrenal hyperplasia. Biochem Biophys Res Commun. 1999;262:635–7.

    Article  PubMed  CAS  Google Scholar 

  76. Kirby-Keyser L, Porter CC, Donohoue PA. E380D: a novel point mutation of CYP21 in an HLA-homozygous patient with salt-losing congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum Mutat. 1997;9:181–2.

    Article  PubMed  CAS  Google Scholar 

  77. Hsu NC, Guzov VM, Hsu LC, Chung BC. Characterization of the consequence of a novel Glu-380 to Asp mutation by expression of functional P450c21 in Escherichia coli. Biochim Biophys Acta. 1999;1430:95–102.

    Article  PubMed  CAS  Google Scholar 

  78. Kharrat M, Tardy V, M’Rad R, Maazoul F, Jemaa LB, Refaï M, Morel Y, Chaabouni H. Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation. J Clin Endocrinol Metab. 2004;89:368–74.

    Article  PubMed  CAS  Google Scholar 

  79. Jiang L, Song LL, Wang H, Wang JL, Wang PP, Zhou HB, Zhang XL. Identification and functional characterization of a novel mutation P459H and a rare mutation R483W in the CYP21A2 gene in two Chinese patients with simple virilizing form of congenital adrenal hyperplasia. J Endocrinol Invest. 2012;35:485–9.

    PubMed  CAS  Google Scholar 

  80. Nikoshkov A, Lajic S, Vlamis-Gardikas A, Tranebjaerg L, Holst M, Wedell A, Luthman H. Naturally occurring mutants of human steroid 21-hydroxylase (P450c21) pinpoint residues important for enzyme activity and stability. J Biol Chem. 1998;273:6163–5.

    Article  PubMed  CAS  Google Scholar 

  81. Finkielstain GP, Chen W, Mehta SP, Fujimura FK, Hanna RM, Van Ryzin C, McDonnell NB, Merke DP. Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2011;96:E161–72.

    Article  PubMed  CAS  Google Scholar 

  82. Krone N, Rose IT, Willis DS, Hodson J, Wild SH, Doherty EJ, Hahner S, Parajes S, Stimson RH, Han TS, Carroll PV, Conway GS, Walker BR, MacDonald F, Ross RJ, Arlt W, United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE). Genotype-phenotype correlation in 153 adult patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: analysis of the United Kingdom Congenital adrenal Hyperplasia Adult Study Executive (CaHASE) cohort. J Clin Endocrinol Metab. 2013;98:E346–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Kazmi D, Bailey J, Yau M, Abu-Amer W, Kumar A, Low M, Yuen T. New developments in prenatal diagnosis of congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2017;165:121–3.

    Article  PubMed  CAS  Google Scholar 

Download references

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Polo Scienze per Immagini, di Laboratorio e Infettivologiche, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, Largo Francesco Vito 1, 00168, Rome, Italy

    Paola Concolino & Alessandra Costella

  2. Institute of Biochemistry and Clinical Biochemistry, Catholic University of Rome, Largo A. Gemelli 8, 00168, Rome, Italy

    Paola Concolino

Authors
  1. Paola Concolino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alessandra Costella
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paola Concolino.

Ethics declarations

Conflict of interest

The authors (PC and AC) declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Concolino, P., Costella, A. Congenital Adrenal Hyperplasia (CAH) due to 21-Hydroxylase Deficiency: A Comprehensive Focus on 233 Pathogenic Variants of CYP21A2 Gene. Mol Diagn Ther 22, 261–280 (2018). https://doi.org/10.1007/s40291-018-0319-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40291-018-0319-y

Search

Navigation