Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Journal of Clinical Endocrinology and Metabolism

Volumn 96, Issue 1, 2011, Pages

  Finkielstain, Gabriela P ^a   Chen, Wuyan ^c   Mehta, Sneha P ^b   Fujimura, Frank K ^d   Hanna, Reem M ^b   Van Ryzin, Carol ^b   McDonnell, Nazli B ^c   Merke, Deborah P ^a,b  

^a NATIONAL INSTITUTES OF HEALTH   (United States)

^b EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT   (United States)

^c NATIONAL INSTITUTE ON AGING   (United States)

^d Esoterix Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450; CYTOCHROME P450 21A1; UNCLASSIFIED DRUG;

ACNE; ADOLESCENT; ADRENAL CORTEX INSUFFICIENCY; ADULT; AGED; AMBIGUOUS GENITALIA; ARTICLE; CHILD; CLINICAL ASSESSMENT; CONGENITAL ADRENAL HYPERPLASIA; DIAGNOSTIC TEST ACCURACY STUDY; DNA EXTRACTION; EXON; FAMILY HISTORY; FEMALE; GENE DELETION; GENE MUTATION; GENE SEQUENCE; GENETIC ANALYSIS; GENOTYPE PHENOTYPE CORRELATION; GROWTH ACCELERATION; HAPLOTYPE; HIRSUTISM; HUMAN; INFANT; INFERTILITY; MAJOR CLINICAL STUDY; MALE; MENSTRUAL IRREGULARITY; MUTATIONAL ANALYSIS; NEWBORN SCREENING; PRESCHOOL CHILD; PRIORITY JOURNAL; SCHOOL CHILD; SOUTHERN BLOTTING; STEROID 21 MONOOXYGENASE DEFICIENCY;

EID: 78650878748     PISSN: 0021972X     EISSN: 0021972X     Source Type: Journal    
DOI: 10.1210/jc.2010-0319     Document Type: Article

References (54)

1. Merke DP, Bornstein SR 2005 Congenital adrenal hyperplasia. Lancet 365:2125-2136
2. Therrell Jr BL, Berenbaum SA, Manter-Kapanke V, Simmank J, Korman K, Prentice L, Gonzalez J, Gunn S 1998 Results of screening 1.9 million Texas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics 101:583-590
3. van der Kamp HJ, Wit JM 2004 Neonatal screening for congenital adrenal hyperplasia. Eur J Endocrinol 151(Suppl 3):U71-U75
4. Fitness J, Dixit N, Webster D, Torresani T, Pergolizzi R, Speiser PW, Day DJ 1999 Genotyping of CYP21, linked chromosome 6p markers, and a sex-specific gene in neonatal screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab 84:960-966
5. Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI 1985 High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet 37:650-667
6. Saxena K, Kitzmiller KJ, Wu YL, Zhou B, Esack N, Hiremath L, Chung EK, Yang Y, Yu CY 2009 Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: a comparison of Asian-Indian and European American populations. Mol Immunol 46:1289-1303
7. Parajes S, Quinteiro C, Domínguez F, Loidi L 2008 High frequency of copy number variations and sequence variants at CYP21A2 locus: implication for the genetic diagnosis of 21-hydroxylase deficiency. PLoS ONE 3:e2138
8. Koppens PF, Hoogenboezem T, Degenhart HJ 2002 Duplication of the CYP21A2 gene complicates mutation analysis of steroid 21- hydroxylase deficiency: characteristics of three unusual haplotypes. Hum Genet 111:405-410
9. Wedell A, Stengler B, Luthman H 1994 Characterization of mutations on the rare duplicated C4/CYP21 haplotype in steroid 21- hydroxylase deficiency. Hum Genet 94:50-54
10. Blanchong CA, Zhou B, Rupert KL, Chung EK, Jones KN, Sotos JF, Zipf WB, Rennebohm RM, Yung Yu C 2000 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 191:2183-2196
11. Koppens PF, Hoogenboezem T, Degenhart HJ 2002 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 11:2581-2590
12. White PC, Vitek A, Dupont B, New MI 1988 Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 85:4436-4440
13. Krone N, Braun A, Roscher AA, Knorr D, Schwarz HP 2000 Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany. J Clin Endocrinol Metab 85:1059-1065
14. Stikkelbroeck NM, Hoefsloot LH, de Wijs IJ, Otten BJ, Hermus AR, Sistermans EA 2003 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 88:3852-3859
15. Jääskelainen J, Levo A, Voutilainen R, Partanen J 1997 Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population. J Clin Endocrinol Metab 82:3293-3297
16. Speiser PW, Dupont J, Zhu D, Serrat J, Buegeleisen M, Tusie-Luna MT, Lesser M, New MI, White PC 1992 Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Clin Invest 90:584-595
17. Krone N, Braun A, Weinert S, Peter M, Roscher AA, Partsch CJ, Sippell WG 2002 Multiplex minisequencing of the 21-hydroxylase gene as a rapid strategy to confirm congenital adrenal hyperplasia. Clin Chem 48:818-825
18. Day DJ, Speiser PW, White PC, Barany F 1995 Detection of steroid 21-hydroxylase alleles using gene-specific PCR and a multiplexed ligation detection reaction. Genomics 29:152-162
19. Chung EK, Wu YL, Yang Y, Zhou B, Yu CY 2005 Human complement components C4A and C4B genetic diversities: complex genotypes and phenotypes. Curr Protoc Immunol Chap 13:Unit 13.8
20. Lee HH, Lee YJ, Lin CY 2004 PCR-based detection of the CYP21 deletion and TNXA/TNXB hybrid in the RCCX module. Genomics 83:944-950
21. Parajes S, Quinterio C, Domínguez F, Loidi L 2007 A simple and robust quantitative PCR assay to determine CYP21A2 gene dose in the diagnosis of 21-hydroxylase deficiency. Clin Chem 53:1577-1584
22. Wu YL, Savelli SL, Yang Y, Zhou B, Rovin BH, Birmingham DJ, Nagaraja HN, Hebert LA, Yu CY 2007 Sensitive and specific realtime polymerase chain reaction assays to accurately determine copy number variations (CNVs) of human complement C4A, C4B, C4-long, C4-short, and RCCX modules: elucidation of C4 CNVs in 50 consanguineous subjects with defined HLA genotypes. J Immunol 179:3012-3025
23. Wedell A, Thilén A, Ritzén EM, Stengler B, Luthman H 1994 Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J Clin Endocrinol Metab 78:1145-1152
24. Higashi Y, Hiromasa T, Tanae A, Miki T, Nakura J, Kondo T, Ohura T, Ogawa E, Nakayama K, Fujii-Kuriyama Y 1991 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 109:638-644
25. Krone N, Riepe FG, Grötzinger J, Partsch CJ, Sippell WG 2005 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 90:445-454 (Pubitemid 40116693)
26. Speiser PW, New MI 1987 Genotype and hormonal phenotype in nonclassical 21-hydroxylase deficiency. J Clin Endocrinol Metab 64:86-91
27. Armengaud JB, Charkaluk ML, Trivin C, Tardy V, Bréart G, Brauner R, Chalumeau M 2009 Precocious pubarche: distinguishing late-onset congenital adrenal hyperplasia from premature adrenarche. J Clin Endocrinol Metab 94:2835-2840
28. Zeng X, Witchel SF, Dobrowolski SF, Moulder PV, Jarvik JW, Telmer CA 2004 Detection and assignment of CYP21 mutations using peptide mass signature genotyping. Mol Genet Metab 82:38-47
29. Wedell A, Luthman H 1993 Steroid 21-hydroxylase deficiency: two additional mutations in salt-wasting disease and rapid screening of disease-causing mutations. Hum Mol Genet 2:499-504
30. Wedell A, Ritzén EM, Haglund-Stengler B, Luthman H 1992 Steroid 21-hydroxylase deficiency: three additional mutated alleles and establishment of phenotype-genotype relationships of common mutations. Proc Natl Acad Sci USA 89:7232-7236
31. Barbaro M, Lajic S, Baldazzi L, Balsamo A, Pirazzoli P, Cicognani A, Wedell A, Cacciari E 2004 Functional analysis of two recurrent amino acid substitutions in the CYP21 gene from Italian patients with congenital adrenal hyperplasia. J Clin Endocrinol Metab 89:2402-2407
32. Krone N, Riepe FG, Partsch CJ, Vorhoff W, Brämswig J, Sippell WG 2006 Three novel point mutations of the CYP21 gene detected in classical forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Exp Clin Endocrinol Diabetes 114:111-117
33. Loidi L, Quinteiro C, Parajes S, Barreiro J, Leston DG, Cabezas-Agricola JM, Sueiro AM, Araujo-Vilar D, Catro-Feijoo L, Costas J, Pombo M, Dominguez F 2006 High variability in CYP21A2 mutated alleles in Spanish 21-hydroxylase deficiency patients, six novel mutations and a founder effect. Clin Endocrinol (Oxf) 64:330-336
34. Grischuk Y, Rubtsov P, Riepe FG, Grötzinger J, Beljelarskaia S, Prassolov V, Kalintchenko N, Semitcheva T, Peterkova V, Tiulpakov A, Sippell WG, Krone N 2006 Four novel missense mutations in the CYP21A2 gene detected in Russian patients suffering from the classical form of congenital adrenal hyperplasia: identification, functional characterization, and structural analysis. J Clin Endocrinol Metab 91:4976-4980
35. Wedell A, Luthman H 1993 Steroid 21-hydroxylase (P450c21): a new allele and spread of mutations through the pseudogene. Hum Genet 91:236-240
36. Nikoshkov A, Lajic S, Vlamis-Gardikas A, Tranebjaerg L, Holst M, Wedell A, Luthman H 1998 Naturally occurring mutants of human steroid 21-hydroxylase (P450c21) pinpoint residues important for enzyme activity and stability. J Biol Chem 273:6163-6165
37. Kleinle S, Lang R, Fischer GF, Vierhapper H, Waldhauser F, Födinger M, Baumgartner-Parzer SM 2009 Duplications of the functional CYP21A2 gene are primarily restricted to Q318X alleles: evidence for a founder effect. J Clin Endocrinol Metab 94:3954-3958
38. Parker EA, Hovanes K, Germak J, Porter F, Merke DP 2006 Maternal 21-hydroxylase deficiency and uniparental isodisomy of chromosome 6 and X results in a child with 21-hydroxylase deficiency and Klinefelter syndrome. Am J Med Genet A 140:2236-2240
39. Gomes LG, Huang N, Agrawal V, Mendonça BB, Bachega TA, Miller WL 2009 Extraadrenal 21-hydroxylation by CYP2C19 and CYP3A4: effect on 21-hydroxylase deficiency. J Clin Endocrinol Metab 94:89-95
40. Wilson RC, Mercado AB, Cheng KC, New MI 1995 Steroid 21- hydroxylase deficiency: genotype may not predict phenotype. J Clin Endocrinol Metab 80:2322-2329
41. L'Allemand D, Tardy V, Grüters A, Schnabel D, Krude H, Morel Y 2000 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 85:4562-4567
42. Araújo RS, Mendonca BB, Barbosa AS, Lin CJ, Marcondes JA, Billerbeck AE, Bachega TA 2007 Microconversion between CYP21A2 and CYP21A1P promoter regions causes the nonclassical form of 21-hydroxylase deficiency. J Clin Endocrinol Metab 92: 4028-4034
43. Bobba A, Marra E, Lattanzio P, Iolascon A, Giannattasio S 2000 Characterization of the CYP21 gene 5′ flanking region in patients affected by 21-OH deficiency. Hum Mutat 15:481
44. Dogan RI, Getoor L, Wilbur WJ, Mount SM 2007 SplicePort - an interactive splice-site analysis tool. Nucleic Acids Res 35:W285-W291
45. Robins T, Carlsson J, Sunnerhagen M, Wedell A, Persson B 2006 Molecular model of human CYP21 based on mammalian CYP2C5: structural features correlate with clinical severity of mutations causing congenital adrenal hyperplasia. Mol Endocrinol 20:2946-2964
46. Billerbeck AE, Mendonca BB, Pinto EM, Madureira G, Arnhold IJ, Bachega TA 2002 Three novel mutations in CYP21 gene in Brazilian patients with the classical form of 21-hydroxylase deficiency due to a founder effect. J Clin Endocrinol Metab 87:4314-4317
47. Soardi FC, Barbaro M, Lau IF, Lemos-Marini SH, Baptista MT, Guerra-Junior G, Wedell A, Lajic S, de Mello MP 2008 Inhibition of CYP21 A2 enzyme activity caused by novel missense mutations identified in Brazilian and Scandinavian patients. J Clin Endocrinol Metab 93:2416-2420
48. Baumgartner-Parzer SM, Schulze E, Waldhäusl W, Pauschenwein S, Rondot S, Nowotny P, Meyer K, Frisch H, Waldhauser F, Vierhapper H 2001 Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation. J Clin Endocrinol Metab 86:4771-4775
49. Barbaro M, Baldazzi L, Balsamo A, Lajic S, Robins T, Barp L, Pirazzoli P, Cacciari E, Cicognani A, Wedell A 2006 Functional studies of two novel and two rare mutations in the 21-hydroxylase gene. J Mol Med 84:521-528 (Pubitemid 43801331)
50. Speiser PW, White PC 2003 Congenital adrenal hyperplasia. N Engl J Med 349:776-788
51. Sinnott P, Collier S, Costigan C, Dyer PA, Harris R, Strachan T 1990 Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency. Proc Natl Acad Sci USA 87:2107-2111
52. Baumgartner-Parzer SM, Fischer G, Vierhapper H 2007 Predisposition for de novo gene aberrations in the offspring of mothers with a duplicated CYP21A2 gene. J Clin Endocrinol Metab 92:1164-1167
53. Concolino P, Mello E, Toscano V, Ameglio F, Zuppi C, Capoluongo E 2009 Multiplex ligation-dependent probe amplification (MLPA) assay for the detection of CYP21A2 gene deletions/duplications in congenital adrenal hyperplasia: first technical report. Clin Chim Acta 402:164-170
54. Chen W, Kim MS, Shanbhag S, Arai A, VanRyzin C, McDonnell NB, Merke DP 2009 The phenotypic spectrum of contiguous deletion of CYP21A2 and tenascin XB: quadricuspid aortic valve and other midline defects. Am J Med Genet A 149A:2803-2808