Molecular Diagnosis & Therapy

, Volume 22, Issue 3, pp 261–280 | Cite as

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

Review Article


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

Compliance with Ethical Standards

Conflict of interest

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

Supplementary material

40291_2018_319_MOESM1_ESM.doc (93 kb)
Supplementary material 1 (DOC 93 kb)
40291_2018_319_MOESM2_ESM.doc (27 kb)
Supplementary material 2 (DOC 27 kb)
40291_2018_319_MOESM3_ESM.doc (26 kb)
Supplementary material 3 (DOC 26 kb)


  1. 1.
    El-Maouche D, Arlt W, Merke DP. Congenital adrenal hyperplasia. Lancet. 2017;17:31431–9.Google Scholar
  2. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 4.
    Parsa AA, New MI. Steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia. J Steroid Biochem Mol Biol. 2017;165:2–11.CrossRefPubMedGoogle Scholar
  5. 5.
    White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000;21:245–91.PubMedGoogle Scholar
  6. 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.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 8.
    Wedell A. Molecular genetics of 21-hydroxylase deficiency. Endocr Dev. 2011;20:80–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009;23:181–92.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 14.
    Balsamo A, Baldazzi L, Menabò S, Cicognani A. Impact of molecular genetics on congenital adrenal hyperplasia management. Sex Dev. 2010;4:233–48.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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.CrossRefPubMedGoogle Scholar
  19. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci USA. 1986;83:5111–5.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Lee HH. CYP21 mutations and congenital adrenal hyperplasia. Clin Genet. 2001;59:293–301.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 33.
    Lee HH. Variants of the CYP21A2 and CYP21A1P genes in congenital adrenal hyperplasia. Clin Chim Acta. 2013;418:37–44.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 35.
    Tsai LP, Lee HH. Analysis of CYP21A1P and the duplicated CYP21A2 genes. Gene. 2012;506:261–2.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.CrossRefPubMedGoogle Scholar
  39. 39.
    Kaufman CS, Butler MG. Mutation in TNXB gene causes moderate to severe Ehlers–Danlos syndrome. World J Med Genet. 2016;6:17–21.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.CrossRefPubMedGoogle Scholar
  42. 42.
    Lee HH. Chimeric CYP21P/CYP21 and TNXA/TNXB genes in the RCCX module. Mol Genet Metab. 2005;84:4–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Lee HH. The chimeric CYP21P/CYP21 gene and 21-hydroxylase deficiency. J Hum Genet. 2004;49:65–72.CrossRefPubMedGoogle Scholar
  44. 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.CrossRefPubMedGoogle Scholar
  45. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.CrossRefPubMedGoogle Scholar
  49. 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.CrossRefPubMedGoogle Scholar
  50. 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.CrossRefPubMedGoogle Scholar
  51. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 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.CrossRefPubMedGoogle Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. 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.CrossRefPubMedGoogle Scholar
  56. 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.CrossRefPubMedGoogle Scholar
  57. 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.CrossRefPubMedGoogle Scholar
  58. 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.CrossRefPubMedGoogle Scholar
  59. 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.CrossRefPubMedGoogle Scholar
  60. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Database of CY21A2 by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee: Accessed 14 Feb 2018.
  69. 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.CrossRefPubMedGoogle Scholar
  70. 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. 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.CrossRefPubMedGoogle Scholar
  72. 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.CrossRefPubMedGoogle Scholar
  73. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 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.CrossRefPubMedGoogle Scholar
  75. 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.CrossRefPubMedGoogle Scholar
  76. 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.CrossRefPubMedGoogle Scholar
  77. 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.CrossRefPubMedGoogle Scholar
  78. 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.CrossRefPubMedGoogle Scholar
  79. 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.PubMedGoogle Scholar
  80. 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.CrossRefPubMedGoogle Scholar
  81. 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.CrossRefPubMedGoogle Scholar
  82. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Polo Scienze per Immagini, di Laboratorio e Infettivologiche, Università Cattolica del Sacro CuoreFondazione Policlinico Universitario Agostino GemelliRomeItaly
  2. 2.Institute of Biochemistry and Clinical BiochemistryCatholic University of RomeRomeItaly

Personalised recommendations