Journal List > J Korean Endocr Soc > v.22(4) > 1003379

Kim, Choi, Bai, Rha, Jo, and Shong: Two Cases of Simple Virilizing Congenital Adrenal Hyperplasia with Compound Heterozygous Mutations of CYP21 Gene


Steroid 21-hydroxylase deficiency is the most frequent cause of congenital adrenal hyperplasia (CAH), which is an inherited inability to synthesize cortisol. Actually, CAH is caused by mutations in the CYP21 gene encoding the steroid 21-hydroxylase enzyme. In some cases, discordance has been observed between the genotype and the phenotype. We recently experienced two cases of simple virilizing congenital adrenal hyperplasia with compound heterozygous mutations of the CYP21 gene. The patients had primary amenorrhea and showed virilization. We have described these two cases along with a review of the literature.

Figures and Tables

Fig. 1
Pictures of patient 1 showed virilization, brownish skin (A), and external genital ambiguity (B).
Fig. 2
Sequences of parts of CYP21 genes of patient 1 (amplification of CYP21 and CYP21P genes using allele-specific primer, ref. 3,6,13). Thin boxes show the mutations leading to steroid 21-hydroxylase deficiency.
Fig. 3
Pictures of patient 2 showed virilization and hirsutism (A & B).
Fig. 4
Sequences of parts of CYP21 genes of patient 2 (amplification of CYP21 and CYP21P genes using same method applied to patient 1). Thin box and circle shows the mutations leading to steroid 21-hydroxylase deficiency.


1. Speiser PW, White PC. Congenital adrenal hyperplasia. N Engl J Med. 2003. 349:776–788.
2. White PC, Speiser PW. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr Rev. 2000. 21:245–291.
3. Jin DK, Kim JS, Song SM, Park SJ, Hwang HZ, On HY, Oh PS, Koh SW, Uhm MR, Lee DH, Shin JH, Han HS, Kim HS, Ko CW, Yoo HW, Lee JS, Kim DH. 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.
4. Speiser PW, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna MT, Lesser M, New MI, White PC. Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest. 1992. 90:584–595.
5. 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. 85:1059–1065.
6. Lee H. CYP21 mutations and congenital adrenal hyperplasia. Clin Genet. 2001. 59:293–301.
7. Pinto G, Tardy V, Trivin C, Thalassinos C, Lortat-Jacob S, Nihoul-Fekete C, Morel Y, Brauner R. Follow-up of 68 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency: relevance of genotype for management. J Clin Endocrinol Metab. 2003. 88:2624–2633.
8. Dolzan V, Solyom J, Fekete G, Kovacs J, Rakosnikova V, Votava F, Lebl J, Pribilincova Z, Baumgartner-Parzer SM, Riedl S, Waldhauser F, Frisch H, Stopar-Obreza M, Krzisnik C, Battelino T. Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia. Eur J Endocrinol. 2005. 153:99–106.
9. Heo Jun, Yu Jae Hong, Jeong Dong Ki. Three cases of congenital adrenal hyperplasia owing to multiple mutations of CYP21 Gene. J Korean Soc Pediatr Endocrinol. 2001. 6:176–181.
10. Stikkelbroeck NM, Hoefsloot LH, de Wijs IJ, Otten BJ, Hermus AR, Sistermans EA. CYP21 gene mutation analysis in 198 patients with 21-hydroxylase deficiency in the Netherlands: six novel mutations and a specific cluster of four mutations. J Clin Endocrinol Metab. 2003. 88:3852–3859.
11. Liao XY, Zhang YF, Gu XF. CYP21 gene point mutations study in 21-hydroxylase deficiency patients. Zhonghua Er Ke Za Zhi. 2003. 41:670–674.
12. Wilson RC, Mercado AB, Cheng KC, New MI. Steroid 21-hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Meta. 1995. 80:2322–2329.
13. Wedell A, Ritzen EM, Haglund-Stengler B, Luthman H. Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype -genotype relationships of common mutations. Proc Natl Acad Sci U S A. 1992. 89:7232–7236.
14. Cargill M, Altshuler D, Ireland J, Sklar P, Ardlie K, Patil N, Shaw N, Lane CR, Lim EP, Kalyanaraman N, Nemesh J, Ziaugra L, Friedland L, Rolfe A, Warrington J, Lipshutz R, Daley GQ, Lander ES. Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nat Gene. 1999. 22:231–238.
15. Bojunga J, Welsch C, Antes I, Albrecht M, Lengauer T, Zeuzem S. Structural and functional analysis of a novel mutation of CYP21B in a heterozygote carrier of 21-hydroxylase deficiency. Hum Genet. 2005. 117:558–564.
16. Speiser PW, Agdere L, Ueshiba H, White PC, New MI. Aldosterone synthesis in salt-wasting congenital adrenal hyperplasia with complete absence of adrenal 21-hydroxylase. N Engl J Med. 1991. 324:145–149.
17. Chemaitilly W, Betensky BP, Marshall I, Wei JQ, Wilson RC, New MI. The natural history and genotype-phenotype nonconcordance of HLA identical siblings with the same mutations of the 21-hydroxylase gene. J Pediatr Endocrinol Metab. 2005. 18:143–153.
18. Porzio O, Cunsolo V, Malaponti M, De Nisco E, Acquafredda A, Cavallo L, Andreani M, Giardina E, Testi M, Cappa M, Federici G. Divergent phenotype of two siblings human leukocyte antigen identical, affected by nonclassical and classical congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. J Clin Endocrinol Metab. 2006. 91:4510–4513.
19. Zucker KJ, Bradley SJ, Oliver G, Blake J, Fleming S, Hood J. Psychosexual development of women with congenital adrenal hyperplasia. Horm Beha. 1996. 30:300–318.
20. Kharrat M, Tardy V, M'Rad R, Maazoul F, Jemaa LB, Refai 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. 89:368–374.
Similar articles