This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krone, N. Articles by Schwarz, H. P. Search for Related Content PubMed PubMed Citation Articles by Krone, N. Articles by Schwarz, H. P.

Predicting Phenotype in Steroid 21-Hydroxylase Deficiency? Comprehensive Genotyping in 155 Unrelated, Well Defined Patients from Southern Germany

University Children’s Hospital, Ludwig Maximilians University, D-80337 Munich, Germany

Address all correspondence and requests for reprints to: Dr. Hans Peter Schwarz, University Children’s Hospital, Ludwig Maximilians University, Lindwurmstrasse 4, D-80337 Munich, Germany. E-mail: hp.schwarz{at}kk-i.med.uni-muenchen.de

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders. CAH is most often caused by deficiency of steroid 21-hydroxylase. The frequency of CYP21-inactivating mutations and the genotype-phenotype relationship were characterized in 155 well defined unrelated CAH patients. We were able to elucidate 306 of 310 disease-causing alleles (diagnostic sensitivity, 98.7%). The most frequent mutation was the intron 2 splice site mutation (30.3%), followed by gene deletions (20.3%), the I172N mutation (19.7%) and large gene conversions (7.1%). Five point mutations were detected that have not been described in other CAH cohorts. Genotypes were categorized in 4 mutation groups (null, A, B, and C) according to their predicted functional consequences and compared to the clinical phenotype. The positive predictive value for null mutations (ppv_null) was 100%, as all patients with these mutations had a salt-wasting phenotype. In mutation group A (intron 2 splice site mutation in homozygous or heterozygous form with a null mutation), the ppv_A to manifest with salt-wasting CAH was 90%. In group B predicted to result in simple virilizing CAH (I172N in homozygous or compound heterozygous form with a more severe mutation), ppv_B was 74%. In group C (P30L, V281L, P453S in homozygous or compound heterozygous form with a more severe mutation), ppv_C was 64.7% to exhibit the nonclassical form of CAH, but 90% when excluding the P30L mutation. Thus, in general, a good genotype-phenotype relationship is shown in patients with either the severest or the mildest mutations. A considerable degree of divergence is observed within mutation groups of intermediate severity. As yet undefined factors modifying 21-hydroxylase gene expression and steroid hormone action are likely to account for these differences in phenotypic expression.

This article has been cited by other articles:

				L. G. Gomes, N. Huang, V. Agrawal, B. B. Mendonca, T. A. S. S. Bachega, and W. L. Miller The Common P450 Oxidoreductase Variant A503V Is Not a Modifier Gene for 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2913 - 2916. [Abstract] [Full Text] [PDF]

				F. G. Riepe, O. Hiort, J. Grotzinger, W. G. Sippell, N. Krone, and P.-M. Holterhus Functional and Structural Consequences of a Novel Point Mutation in the CYP21A2 Gene Causing Congenital Adrenal Hyperplasia: Potential Relevance of Helix C for P450 Oxidoreductase-21-Hydroxylase Interaction J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2891 - 2895. [Abstract] [Full Text] [PDF]

				F. C. Soardi, M. Barbaro, I. F. Lau, S. H. V. Lemos-Marini, M. T. M. Baptista, G. Guerra-Junior, A. Wedell, S. Lajic, and M. P. de Mello Inhibition of CYP21A2 Enzyme Activity Caused by Novel Missense Mutations Identified in Brazilian and Scandinavian Patients J. Clin. Endocrinol. Metab., June 1, 2008; 93(6): 2416 - 2420. [Abstract] [Full Text] [PDF]

				R. Menassa, V. Tardy, F. Despert, C. Bouvattier-Morel, J. P. Brossier, M. Cartigny, and Y. Morel p.H62L, a Rare Mutation of the CYP21 Gene Identified in Two Forms of 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., May 1, 2008; 93(5): 1901 - 1908. [Abstract] [Full Text] [PDF]

				M. Welzel, N. Wustemann, G. Simic-Schleicher, H. G. Dorr, E. Schulze, G. Shaikh, P. Clayton, J. Grotzinger, P.-M. Holterhus, and F. G. Riepe Carboxyl-Terminal Mutations in 3{beta}-Hydroxysteroid Dehydrogenase Type II Cause Severe Salt-Wasting Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., April 1, 2008; 93(4): 1418 - 1425. [Abstract] [Full Text] [PDF]

				D. P. Merke Approach to the Adult with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., March 1, 2008; 93(3): 653 - 660. [Abstract] [Full Text] [PDF]

				W. Bonfig, S. Bechtold, H. Schmidt, D. Knorr, and H. P. Schwarz Reduced Final Height Outcome in Congenital Adrenal Hyperplasia under Prednisone Treatment: Deceleration of Growth Velocity during Puberty J. Clin. Endocrinol. Metab., May 1, 2007; 92(5): 1635 - 1639. [Abstract] [Full Text] [PDF]

				Y. Grischuk, P. Rubtsov, F. G. Riepe, J. Grotzinger, S. Beljelarskaia, V. Prassolov, N. Kalintchenko, T. Semitcheva, V. Peterkova, A. Tiulpakov, et al. 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., December 1, 2006; 91(12): 4976 - 4980. [Abstract] [Full Text] [PDF]

				T. Robins, J. Carlsson, M. Sunnerhagen, A. Wedell, and B. Persson Molecular Model of Human CYP21 Based on Mammalian CYP2C5: Structural Features Correlate with Clinical Severity of Mutations Causing Congenital Adrenal Hyperplasia Mol. Endocrinol., November 1, 2006; 20(11): 2946 - 2964. [Abstract] [Full Text] [PDF]

				M. Janner, A. V Pandey, P. E Mullis, and C. E Fluck Clinical and biochemical description of a novel CYP21A2 gene mutation 962_963insA using a new 3D model for the P450c21 protein. Eur. J. Endocrinol., July 1, 2006; 155(1): 143 - 151. [Abstract] [Full Text] [PDF]

				A Luczay, D Torok, A Ferenczi, J Majnik, J Solyom, and G. Fekete Potential advantage of N363S glucocorticoid receptor polymorphism in 21-hydroxylase deficiency. Eur. J. Endocrinol., June 1, 2006; 154(6): 859 - 864. [Abstract] [Full Text] [PDF]

				A. Grigorescu Sido, M. M. Weber, P. Grigorescu Sido, S. Clausmeyer, U. Heinrich, and E. Schulze 21-Hydroxylase and 11{beta}-Hydroxylase Mutations in Romanian Patients with Classic Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5769 - 5773. [Abstract] [Full Text] [PDF]

				V Dolz;an, J Solyom, G Fekete, J Kovacs, V Rakosnikova, F Votava, J Lebl, Z Pribilincova, S. Baumgartner-Parzer, S Riedl, et al. Mutational spectrum of steroid 21-hydroxylase and the genotype-phenotype association in Middle European patients with congenital adrenal hyperplasia Eur. J. Endocrinol., July 1, 2005; 153(1): 99 - 106. [Abstract] [Full Text] [PDF]

				F. G. Riepe, S. Tatzel, W. G. Sippell, J. Pleiss, and N. Krone Congenital Adrenal Hyperplasia: The Molecular Basis of 21-Hydroxylase Deficiency in H-2aw18 Mice Endocrinology, June 1, 2005; 146(6): 2563 - 2574. [Abstract] [Full Text] [PDF]

				T. Robins, M. Barbaro, S. Lajic, and A. Wedell Not All Amino Acid Substitutions of the Common Cluster E6 Mutation in CYP21 Cause Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2148 - 2153. [Abstract] [Full Text] [PDF]

				S. Kosel, S. Burggraf, R. Fingerhut, H. G. Dorr, A. A. Roscher, and B. Olgemoller Rapid Second-Tier Molecular Genetic Analysis for Congenital Adrenal Hyperplasia Attributable to Steroid 21-Hydroxylase Deficiency Clin. Chem., February 1, 2005; 51(2): 298 - 304. [Abstract] [Full Text] [PDF]

				N. Krone, F. G. Riepe, J. Grotzinger, C.-J. Partsch, and W. G. Sippell 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., January 1, 2005; 90(1): 445 - 454. [Abstract] [Full Text] [PDF]

				M. Kharrat, V. Tardy, R. M'Rad, F. Maazoul, L. B. Jemaa, M. Refai, Y. Morel, and H. Chaabouni 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., January 1, 2004; 89(1): 368 - 374. [Abstract] [Full Text] [PDF]

				B. Olgemoller, A. A. Roscher, B. Liebl, and R. Fingerhut Screening for Congenital Adrenal Hyperplasia: Adjustment of 17-Hydroxyprogesterone Cut-Off Values to Both Age and Birth Weight Markedly Improves the Predictive Value J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5790 - 5794. [Abstract] [Full Text] [PDF]

				N. M. M. L. Stikkelbroeck, L. H. Hoefsloot, I. J. de Wijs, B. J. Otten, A. R. M. M. Hermus, and E. A. Sistermans 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., August 1, 2003; 88(8): 3852 - 3859. [Abstract] [Full Text] [PDF]

				G. Pinto, V. Tardy, C. Trivin, C. Thalassinos, S. Lortat-Jacob, C. Nihoul-Fekete, Y. Morel, and R. Brauner Follow-Up of 68 Children with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Relevance of Genotype for Management J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2624 - 2633. [Abstract] [Full Text] [PDF]

				S. M. Baumgartner-Parzer, P. Nowotny, W. Waldhausl, and H. Vierhapper A Rare Duplicated 21-Hydroxylase Haplotype and a de Novo Mutation: A Family Analysis J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2794 - 2796. [Abstract] [Full Text] [PDF]

				P F J Koppens, H J M Smeets, I J de Wijs, and H J Degenhart Mapping of a de novo unequal crossover causing a deletion of the steroid 21-hydroxylase (CYP21A2) gene and a non-functional hybrid tenascin-X (TNXB) gene J. Med. Genet., May 1, 2003; 40(5): e53 - 53. [Full Text] [PDF]

				P. W. Speiser Adrenomedullary Function May Predict Phenotype and Genotype in Classic 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3029 - 3030. [Full Text] [PDF]

				E. Charmandari, G. Eisenhofer, S. L. Mehlinger, A. Carlson, R. Wesley, M. F. Keil, G. P. Chrousos, M. I. New, and D. P. Merke Adrenomedullary Function May Predict Phenotype and Genotype in Classic 21-Hydroxylase Deficiency J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3031 - 3037. [Abstract] [Full Text] [PDF]

				Y. L. Giwercman, A. Nordenskjold, E. M. Ritzen, K. O. Nilsson, S.-A. Ivarsson, U. Grandell, and A. Wedell An Androgen Receptor Gene Mutation (E653K) in a Family with Congenital Adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency as well as in Partial Androgen Insensitivity J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2623 - 2628. [Abstract] [Full Text] [PDF]

				N. Krone, A. Braun, S. Weinert, M. Peter, A. A. Roscher, C.-J. Partsch, and W. G. Sippell Multiplex Minisequencing of the 21-Hydroxylase Gene as a Rapid Strategy to Confirm Congenital Adrenal Hyperplasia Clin. Chem., June 1, 2002; 48(6): 818 - 825. [Abstract] [Full Text] [PDF]

				R. C. Olney, E. B. Mougey, J. Wang, D. I. Shulman, and J. E. Sylvester Using Real-Time, Quantitative PCR for Rapid Genotyping of the Steroid 21-Hydroxylase Gene in a North Florida Population J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 735 - 741. [Abstract] [Full Text] [PDF]

				M. I. New, A. Carlson, J. Obeid, I. Marshall, M. S. Cabrera, A. Goseco, K. Lin-Su, A. S. Putnam, J. Q. Wei, and R. C. Wilson EXTENSIVE PERSONAL EXPERIENCE: Prenatal Diagnosis for Congenital Adrenal Hyperplasia in 532 Pregnancies J. Clin. Endocrinol. Metab., December 1, 2001; 86(12): 5651 - 5657. [Abstract] [Full Text] [PDF]

				S. M. Baumgartner-Parzer, E. Schulze, W. Waldhausl, S. Pauschenwein, S. Rondot, P. Nowotny, K. Meyer, H. Frisch, F. Waldhauser, and H. Vierhapper Mutational Spectrum of the Steroid 21-Hydroxylase Gene in Austria: Identification of a Novel Missense Mutation J. Clin. Endocrinol. Metab., October 1, 2001; 86(10): 4771 - 4775. [Abstract] [Full Text] [PDF]

				M. Dracopoulou-Vabouli, M. Maniati-Christidi, and C. Dacou-Voutetakis The Spectrum of Molecular Defects of the CYP21 Gene in the Hellenic Population: Variable Concordance between Genotype and Phenotype in the Different Forms of Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., June 1, 2001; 86(6): 2845 - 2848. [Abstract] [Full Text] [PDF]

				P. F. Collett-Solberg Congenital Adrenal Hyperplasia: From Genetics and Biochemistry to Clinical Practice, Part 1 Clinical Pediatrics, January 1, 2001; 40(1): 1 - 16. [Abstract] [PDF]