Skip to main content
SpringerLink
Log in

Genotype in the diagnosis of 21-hydroxylase deficiency: Who should undergo CYP21A2 analysis?

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Aims: to confirm the diagnosis of 21-hydroxylase deficiency (21-OHD) by the analysis of CYP21A2 gene in infants with clinical and/or biochemical features of 21-OHD in order to clarify which patients to submit to genetic analysis; to analyze the genotype-phenotype concordance in these infants. Subjects and methods: We studied 25 children with clinical and/or biochemical features of 21-OHD. All of them and their parents were submitted to genetic analysis of CYP21A2. Patients were classified in 3 groups according to mutations’ severity: severe (group A), moderate (group B) or mild (group C). Results: CYP21A2 gene mutations were found in 17 children. Whereas all infants of groups A and B presented a classical form of 21-OHD, children of group C had a non-classical form of 21-OHD. Four infants resulted heterozygotes and 4 children were wild-type. A girl clinically presenting a non-classical form of 21-OHD resulted compound heterozygote with one of the mutations not described in literature (R25W) and whose residual enzymatic activity is not already known. All affected children presented a 17-OHP level after ACTH stimulation greater than 100 nmol/l. We found an optimal concordance between 17-OHP levels after ACTH test and genotype. Conclusions: CYP21A2 analysis permitted to confirm the diagnosis of 21-OHD in 68% of our children. To improve this percentage we suggest to perform the CYP21A2 analysis only when 17-OHP after ACTH test is greater than 100 nmol/l. Moreover, we found an optimal genotype-phenotype concordance in the 21-OHD patients.

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

Similar content being viewed by others

References

  1. Hughes IA. Congenital adrenal hyperplasia — a continuum of disorders. Lancet 1998, 352: 752–4.

    Article  PubMed  CAS  Google Scholar 

  2. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med 2003, 349: 776–88.

    Article  PubMed  CAS  Google Scholar 

  3. Riepe FG, Sippell WG. Recent advances in diagnosis, treatment, and outcome of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Rev Endocr Metab Disord 2007, 8: 349–63.

    Article  PubMed  CAS  Google Scholar 

  4. Speiser PW, Azziz R, Baskin LS, et al. Endocrine Society: Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010, 95: 4133–60.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  5. Speiser PW. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Endocrinol Metab Clin North Am 2001, 30: 31–59.

    Article  PubMed  CAS  Google Scholar 

  6. New MI. Nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 2006, 91: 4205–14.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  8. 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 

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

    PubMed  CAS  Google Scholar 

  10. Speiser PW, Dupont J, Zhu D, et al. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxilase deficiency. J Clin Invest 1992, 90: 584–95.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  11. 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 

  12. Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 1995, 80: 2322–9.

    PubMed  CAS  Google Scholar 

  13. Torresani T, Biason-Lauber A. Congenital adrenal hyperplasia: diagnostic advances. J Inherit Metab Dis 2007, 30: 563–75.

    Article  PubMed  CAS  Google Scholar 

  14. New MI, Carlson A, Obeid J, et al. Prenatal diagnosis for congenital adrenal hyperplasia in 532 pregnancies. J Clin Endocrinol Metab 2001, 86: 5651–7.

    Article  PubMed  CAS  Google Scholar 

  15. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 2002, 87: 4048–53.

    Google Scholar 

  16. Nordenström A, Thilén A, Hagenfeldt L, Larsson A, Wedell A. Genotyping is a valuable diagnostic complement to neonatal screening for congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab 1999, 84: 1505–9.

    PubMed  Google Scholar 

  17. Pinto G, Tardy V, Trivin C, et al. Follow up of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: relevance of genotype for management. J Clin Endocrinol Metab 2003, 88: 2624–33.

    Article  PubMed  CAS  Google Scholar 

  18. Merke DP, Bornstein SR. Congenital adrenal hyperplasia. Lancet 2005, 365: 2125–36.

    Article  PubMed  Google Scholar 

  19. Bachega TA, Brenlha EM, Billerbeck AE, et al. Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations. J Clin Endocrinol Metab 2002, 87: 786–90.

    Article  PubMed  CAS  Google Scholar 

  20. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of the hand and wrist. 2nd Edition Stanford: Stanford University Press. 1959.

    Google Scholar 

  21. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988, 16: 1215.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  22. Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G. Relative quantification of 40 nucleic acid sequenze by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002, 30: e57.

    Article  PubMed Central  PubMed  Google Scholar 

  23. New MI, Lorenzen F, Lerner AJ, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Met 1983; 57: 320–6.

    Article  CAS  Google Scholar 

  24. Azziz R, Hincapie LA, Knochenhauer ES, Dewailly D, Fox L, Boots LR. Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertil Steril 1999, 72: 915–25.

    Article  PubMed  CAS  Google Scholar 

  25. Armengaud JB, Charkaluk ML, Trivin C, et al. Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrinol Metab 2009, 94: 2835–40.

    Article  PubMed  CAS  Google Scholar 

  26. Ghizzoni L, Cappa M, Vottero A, et al. Relationship of CYP21A2 genotype and serum 17-hydroxyprogesterone and cortisol levels in a large cohort of Italian children with premature pubarche. Eur J Endocrinol 2011, 165: 307–14.

    Article  PubMed  CAS  Google Scholar 

  27. Azziz R, Dewailly D, Owerbach D. Clinical review 56: nonclassic adrenal hyperplasia: current concepts. J Clin Endocrinol Metab 1994, 78: 810–5.

    PubMed  CAS  Google Scholar 

  28. Bidet M, Bellanné-Chantelot C, Galand-Portier MB, et al. Clinical and molecular characterization of a cohort of 161 unrelated women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency and 330 family members. J Clin Endocrinol Metab 2009, 94: 1570–8.

    Article  PubMed  CAS  Google Scholar 

  29. Cavarzere P, Samara-Boustani D, Flechtner I, et al. Transient hyper-17-hydroxyprogesteronemia: a clinical subgroup of patients diagnosed at neonatal screening for congenital adrenal hyperplasia. Eur J Endocrinol 2009, 161: 285–92.

    Article  PubMed  CAS  Google Scholar 

  30. Honour JW, Torresani T. Evaluation of neonatal screening for congenital adrenal hyperplasia. Horm Res 2001, 55: 206–11.

    Article  PubMed  CAS  Google Scholar 

  31. Nomura S. Immature adrenal steroidogenesis in preterm infants. Early Hum Dev 1997, 49: 225–33.

    Article  PubMed  CAS  Google Scholar 

  32. Ng PC, Wong GW, Lam CW, et al. Pituitary-adrenal response in preterm very low birth weight infants after treatment with antenatal corticosteroids. J Clin Endocrinol Metab 1997, 82: 3548–52.

    Article  PubMed  CAS  Google Scholar 

  33. Arafah BM. Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. J Clin Endocrinol Metab 2006, 91: 3725–45.

    Article  PubMed  CAS  Google Scholar 

  34. 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: 650–67.

    PubMed Central  PubMed  CAS  Google Scholar 

  35. Knochenhauer ES, Cortet-Rudelli C, Cunnigham RD, Conway-Myers BA, Dewailly D, Azziz R. Carriers of 21-hydroxylase deficiency are not at increased risk for hyperandrogenism. J Clin Endocrinol Metab 1997, 82: 479–85.

    PubMed  CAS  Google Scholar 

  36. Escobar-Morreale HF, San Millán JL, Smith RR, Sancho J, Witchel SF. The presence of the 21-hydroxylase deficiency carrier status in hirsute women: phenotype-genotype correlations. Fertil Steril 1999, 72: 629–38.

    Article  PubMed  CAS  Google Scholar 

  37. Admoni O, Israel S, Lavi I, Gur M, Tenenbaum-Rakover Y. Hyperandrogenism in carriers of CYP21 mutations: the role of genotype. Clin Endocrinol 2006; 64: 645–51.

    Article  CAS  Google Scholar 

  38. Witchel SF, Lee PA, Suda-Hartman M, Hoffman EP. Hyperandrogenism and manifesting heterozygotes for 21-hydroxylase deficiency. Biochem Mol Med 1997; 62: 151–8.

    Article  PubMed  CAS  Google Scholar 

  39. Napolitano E, Manieri C, Restivo F, et al. Correlation between Genotype and Hormonal Levels in Heterozygous Mutation Carriers and Non Carriers of 21 -OH Deficiency. J Endocrinol Invest 2011, 34: 498–501.

    PubMed  CAS  Google Scholar 

  40. 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 

  41. Finkielstain GP, Chen W, Mehta SP, et al. 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 Central  PubMed  CAS  Google Scholar 

  42. 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 

  43. Day DJ, Speiser PW, Schulze E, et al. Identification of non-amplifying CYP21 genes when using PCR-based diagnosis of 21-hydroxylase deficiency in congenital adrenal hyperplasia (CAH) affected pedigrees. Hum Mol Genet 1996; 5: 2039–48.

    Article  PubMed  CAS  Google Scholar 

  44. 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 Central  PubMed  CAS  Google Scholar 

  45. Concolino P, Mello E, Toscano V, Ameglio F, Zuppi C, Capoluongo E. Multiplex ligation-dependent probe amplification (MLPA) assay forthe detection of CYP21A2 gene deletions/duplications in congenital adrenal hyperplasia: first technical report. Clin Chim Acta 2009, 402: 164–70.

    Article  PubMed  CAS  Google Scholar 

  46. Ezquieta B, Oliver A, Gracia R, Gancedo PG. Analysis of steroid 21-hydroxylase gene mutations in the Spanish population. Hum Genet 1995, 96: 198–204.

    Article  PubMed  CAS  Google Scholar 

  47. Balsamo A, Cacciari E, Baldazzi L, et al. CYP21 analysis and phenotype/genotype relationship in the screened population of the Italian Emilia-Romagna region. Clin Endocrinol 2000, 53: 117–25.

    Article  CAS  Google Scholar 

  48. Deneux C, Tardy V, Dib A, et al. Phenotype-genotype correlation in 56 women with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Endocrinol Metab 2001, 86: 207–13.

    Article  PubMed  CAS  Google Scholar 

  49. Speiser PW, New MI. Genotype and hormonal phenotype in non-classical 21-hydroxylase deficiency. J Clin Endocrinol Metab 1987, 64: 86–91.

    Article  PubMed  CAS  Google Scholar 

  50. Bachega TA, Billerbeck AE, Marcondes JA, Madureira G, Arnhold IJ, Mendonca BB. Influence of different genotypes on 17-hydroxyprogesterone levels in patients with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin Endocrinol 2000, 52: 601–7.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Pediatric Clinic, Department of Life and Reproduction Sciences, University of Verona, Verona, Italy

    P. Cavarzere MD, Ph, M. Vincenzi, F. Teofoli, R. Gaudino, S. Lauriola, E. Maines, M. Camilot & F. Antoniazzi

Authors
  1. P. Cavarzere MD, Ph
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Vincenzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. Teofoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. R. Gaudino
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Lauriola
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. E. Maines
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Camilot
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Antoniazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. Cavarzere MD, Ph.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cavarzere, P., Vincenzi, M., Teofoli, F. et al. Genotype in the diagnosis of 21-hydroxylase deficiency: Who should undergo CYP21A2 analysis?. J Endocrinol Invest 36, 1083–1089 (2013). https://doi.org/10.3275/9096

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.3275/9096

Key-words

Search

Navigation