Ann Pediatr Endocrinol Metab.  2013 Sep;18(3):128-134. 10.6065/apem.2013.18.3.128.

Genotype-phenotype correlation in 27 pediatric patients in congenital adrenal hyperplasia due to 21-hydroxylase deficiency in a single center

• Yoo Y
• Chang MS
• Lee J
• Cho SY
• Park SW
• Jin DK
• Park HD

• KMID: 2266364
• DOI: http://doi.org/10.6065/apem.2013.18.3.128

Abstract

PURPOSE
The purpose of the study was to evaluate endocrine patterns of patients with congenital adrenal hyperplasia and each gene mutation and to analyze the correlation between each phenotype and genotype.
METHODS
This was a retrospective study of the patients with congenital adrenal hyperplasia in the pediatric outpatient clinic at the Samsung Medical Center from November 1994 to December 2012. We analyzed the medical records of 27 patients (male, 19; female, 8) with congenital adrenal hyperplasia who had been diagnosed by genetic testing to have 21-hydroxylase deficiency.
RESULTS
In genetic analysis of 54 alleles from 27 patients, 13 types of mutations were identified. The distribution of 21-hydroxylase deficiency gene mutations revealed that intron 2 splice site (c.293-13A/C>G) mutations and large deletions were the most common, at 31.5% and 22.2% respectively, followed by p.I173N, p.R356W, and p.I172N mutations at 11.1%, 9.3%, and 9.3%, respectively. Other mutations were observed at 1.9-3.7%. No novel mutations were detected.
CONCLUSION
The analysis of 54 alleles revealed 13 types of mutation. The salt wasting form showed a good correlation between genotype and phenotype, but the simple virilizing and nonclassic forms showed inconsistencies between genotype and phenotype. The distribution of CYP21A2 mutations was evaluated for 21-hydroxylase deficiency patients from a single center. This study provides limited data on mutation spectrum and genotype-phenotype correlation of 21-hydroxylase deficiency in Korea.

Keyword

21 hydroxylase deficiency; Human CYP21A2 protein; Genotype; Phenotype

MeSH Terms

Adrenal Hyperplasia, Congenital*
Alleles
Ambulatory Care Facilities
Female
Genetic Association Studies*
Genetic Testing
Genotype
Humans
Introns
Korea
Male
Medical Records
Phenotype
Retrospective Studies
Steroid 21-Hydroxylase*
Steroid 21-Hydroxylase

Reference

1. Krone N, Arlt W. Genetics of congenital adrenal hyperplasia. Best Pract Res Clin Endocrinol Metab. 2009; 23:181–192. PMID: 19500762.

2. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000; 21:245–291. PMID: 10857554.

3. Trakakis E, Basios G, Trompoukis P, Labos G, Grammatikakis I, Kassanos D. An update to 21-hydroxylase deficient congenital adrenal hyperplasia. Gynecol Endocrinol. 2010; 26:63–71. PMID: 19499408.

4. Pang S, Clark A. Newborn screening, prenatal diagnosis, and prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Trends Endocrinol Metab. 1990; 1:300–307. PMID: 18411135.

5. 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; 37:650–667. PMID: 9556656.

6. Raiti S, Newns GH. Congenital adrenal hyperplasia. Arch Dis Child. 1964; 39:324–333. PMID: 14206872.

7. Speiser PW, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna MT, et al. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest. 1992; 90:584–595. PMID: 1644925.

8. New MI. An update of congenital adrenal hyperplasia. Ann N Y Acad Sci. 2004; 1038:14–43. PMID: 15838095.

9. Kaplan SA. Diseases of the adrenal cortex: II. Congenital adrenal hyperplasia. Pediatr Clin North Am. 1979; 26:77–89. PMID: 223109.

10. Speiser PW. Nonclassic adrenal hyperplasia. Rev Endocr Metab Disord. 2009; 10:77–82. PMID: 18690539.

11. White PC, Grossberger D, Onufer BJ, Chaplin DD, New MI, Dupont B, et al. Two genes encoding steroid 21-hydroxylase are located near the genes encoding the fourth component of complement in man. Proc Natl Acad Sci U S A. 1985; 82:1089–1093. PMID: 2983330.

12. Wedell A, Thilen A, Ritzen EM, Stengler B, Luthman H. Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metab. 1994; 78:1145–1152. PMID: 8175971.

13. Lee HH. CYP21 mutations and congenital adrenal hyperplasia. Clin Genet. 2001; 59:293–301. PMID: 11359457.

14. The Human Cytochrome P450(CYP) Allele Nomenclature Committee. CYP21A2: CYP 21A1 allele nomenclature [Internet]. Stockholm: The Human Cytochrome P450(CYP) Allele Nomenclature Committee;c2013. cited 2013 Aug 19. Available from: http://www.cypalleles.ki.se/cyp21.htm.

15. Greulich WW, Pyle SI. Radiographic atlas of skeletal development of hand and wrist. 2nd ed. Redwood City: Stanford University Press;1959.

16. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003; 349:776–788. PMID: 12930931.

17. Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene. Proc Natl Acad Sci U S A. 1986; 83:2841–2845. PMID: 3486422.

18. 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 U S A. 1995; 92:10796–10800. PMID: 7479886.

19. Parajes S, Quinteiro C, Dominguez 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. PMID: 18478071.

20. Higashi Y, Hiromasa T, Tanae A, Miki T, Nakura J, Kondo T, et al. Effects of individual mutations in the P-450(C21) pseudogene on the P-450(C21) activity and their distribution in the patient genomes of congenital steroid 21-hydroxylase deficiency. J Biochem. 1991; 109:638–644. PMID: 1869518.

21. Amor M, Parker KL, Globerman H, New MI, White PC. Mutation in the CYP21B gene (Ile-172: Asn) causes steroid 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 1988; 85:1600–1604. PMID: 3257825.

22. Speiser PW, New MI. Genotype and hormonal phenotype in nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1987; 64:86–91. PMID: 3023431.

23. Tusie-Luna MT, Speiser PW, Dumic M, New MI, White PC. A mutation (Pro-30 to Leu) in CYP21 represents a potential nonclassic steroid 21-hydroxylase deficiency allele. Mol Endocrinol. 1991; 5:685–692. PMID: 2072928.

24. Nikoshkov A, Lajic S, Holst M, Wedell A, Luthman H. Synergistic effect of partially inactivating mutations in steroid 21-hydroxylase deficiency. J Clin Endocrinol Metab. 1997; 82:194–199. PMID: 8989258.

25. New MI, Gertner JM, Speiser PW, del Balzo P. Growth and final height in classical and nonclassical 21-hydroxylase deficiency. Acta Paediatr Jpn. 1988; 30(Suppl):79–88. PMID: 3146882.

26. Soliman AT, AlLamki M, AlSalmi I, Asfour M. Congenital adrenal hyperplasia complicated by central precocious puberty: linear growth during infancy and treatment with gonadotropin-releasing hormone analog. Metabolism. 1997; 46:513–517. PMID: 9160816.

27. Cornean RE, Hindmarsh PC, Brook CG. Obesity in 21-hydroxylase deficient patients. Arch Dis Child. 1998; 78:261–263. PMID: 9613359.

28. Manoli I, Kanaka-Gantenbein Ch, Voutetakis A, Maniati-Christidi M, Dacou-Voutetakis C. Early growth, pubertal development, body mass index and final height of patients with congenital adrenal hyperplasia: factors influencing the outcome. Clin Endocrinol (Oxf). 2002; 57:669–676. PMID: 12390343.

29. Wilkins L, Lewis RA, Klein R, Rosemberg E. The suppression of androgen secretion by cortisone in a case of congenital adrenal hyperplasia. Bull Johns Hopkins Hosp. 1950; 86:249–252. PMID: 15411555.

30. Bartter FC, Forbes AP, Leaf A. Congenital adrenal hyperplasia associated with the adrenogenital syndrome: an attempt to correct its disordered hormonal pattern. J Clin Invest. 1950; 29:797. PMID: 15436679.

31. Choi JH, Jin HY, Lee BH, Ko JM, Lee JJ, Kim GH, et al. Clinical phenotype and mutation spectrum of the CYP21A2 gene in patients with steroid 21-hydroxylase deficiency. Exp Clin Endocrinol Diabetes. 2012; 120:23–27. PMID: 22020670.

32. Finkielstain GP, Chen W, Mehta SP, Fujimura FK, Hanna RM, Van Ryzin C, 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–E172. PMID: 20926536.

33. Friães A, Rego AT, Aragues JM, Moura LF, Mirante A, Mascarenhas MR, et al. CYP21A2 mutations in Portuguese patients with congenital adrenal hyperplasia: identification of two novel mutations and characterization of four different partial gene conversions. Mol Genet Metab. 2006; 88:58–65. PMID: 16427797.

34. Ko JM, Choi JH, Kim GH, Yoo HW. Genotype of steroid 21-hydroxylase gene and clinical characteristics in patients with congenital adrenal hyperplasia 21-hydroxylase deficiency. J Korean Soc Pediatr Endocrinol. 2005; 10:57–63.

35. Jin DK, Kim JS, Song SM, Park SJ, Hwang HZ, On HY, et al. A study on the relationship between genotype and phenotype in korean patients with congenital adrenogenital syndrome caused by 21-hydroxylase deficiency. J Korean Soc Endocrinol. 2000; 15:237–247.

36. Asanuma A, Ohura T, Ogawa E, Sato S, Igarashi Y, Matsubara Y, et al. Molecular analysis of Japanese patients with steroid 21-hydroxylase deficiency. J Hum Genet. 1999; 44:312–317. PMID: 10496074.

37. Lee HH, Lee YJ, Wang YM, Chao HT, Niu DM, Chao MC, et al. Low frequency of the CYP21A2 deletion in ethnic Chinese (Taiwanese) patients with 21-hydroxylase deficiency. Mol Genet Metab. 2008; 93:450–457. PMID: 18039588.

38. Lee HH, Chao HT, Ng HT, Choo KB. Direct molecular diagnosis of CYP21 mutations in congenital adrenal hyperplasia. J Med Genet. 1996; 33:371–375. PMID: 8733045.

39. Schulze E, Scharer G, Rogatzki A, Priebe L, Lewicka S, Bettendorf M, et al. Divergence between genotype and phenotype in relatives of patients with the intron 2 mutation of steroid-21-hydroxylase. Endocr Res. 1995; 21:359–364. PMID: 7588399.