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J Clin Invest. 1992 August; 90(2): 584–595.
PMCID: PMC443137

Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Abstract

Genotyping for 10 mutations in the CYP21 gene was performed in 88 families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Southern blot analysis was used to detect CYP21 deletions or large gene conversions, and allele-specific hybridizations were performed with DNA amplified by the polymerase chain reaction to detect smaller mutations. Mutations were detected on 95% of chromosomes examined. The most common mutations were an A----G change in the second intron affecting pre-mRNA splicing (26%), large deletions (21%), Ile-172----Asn (16%), and Val-281----Leu (11%). Patients were classified into three mutation groups based on degree of predicted enzymatic compromise. Mutation groups were correlated with clinical diagnosis and specific measures of in vivo 21-hydroxylase activity, such as 17-hydroxyprogesterone, aldosterone, and sodium balance. Mutation group A (no enzymatic activity) consisted principally of salt-wasting (severely affected) patients, group B (2% activity) of simple virilizing patients, and group C (10-20% activity) of nonclassic (mildly affected) patients, but each group contained patients with phenotypes either more or less severe than predicted. These data suggest that most but not all of the phenotypic variability in 21-hydroxylase deficiency results from allelic variation in CYP21. Accurate prenatal diagnosis should be possible in most cases using the described strategy.

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Selected References

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  • White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes. Proc Natl Acad Sci U S A. 1986 Jul;83(14):5111–5115. [PubMed]
  • 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 May;83(9):2841–2845. [PubMed]
  • Dupont B, Oberfield SE, Smithwick EM, Lee TD, Levine LS. Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency). Lancet. 1977 Dec 24;2(8052-8053):1309–1312. [PubMed]
  • Levine LS, Zachmann M, New MI, Prader A, Pollack MS, O'Neill GJ, Yang SY, Oberfield SE, Dupont B. Genetic mapping of the 21-hydroxylase-deficiency gene within the HLA linkage group. N Engl J Med. 1978 Oct 26;299(17):911–915. [PubMed]
  • White PC, Vitek A, Dupont B, New MI. Characterization of frequent deletions causing steroid 21-hydroxylase deficiency. Proc Natl Acad Sci U S A. 1988 Jun;85(12):4436–4440. [PubMed]
  • 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 Mar;85(5):1600–1604. [PubMed]
  • Globerman H, Amor M, Parker KL, New MI, White PC. Nonsense mutation causing steroid 21-hydroxylase deficiency. J Clin Invest. 1988 Jul;82(1):139–144. [PMC free article] [PubMed]
  • White PC. Analysis of mutations causing steroid 21-hydroxylase deficiency. Endocr Res. 1989;15(1-2):239–256. [PubMed]
  • Strachan T. Molecular pathology of congenital adrenal hyperplasia. Clin Endocrinol (Oxf) 1990 Mar;32(3):373–393. [PubMed]
  • Kuhnle U, Chow D, Rapaport R, Pang S, Levine LS, New MI. The 21-hydroxylase activity in the glomerulosa and fasciculata of the adrenal cortex in congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1981 Mar;52(3):534–544. [PubMed]
  • Kohn B, Levine LS, Pollack MS, Pang S, Lorenzen F, Levy D, Lerner AJ, Rondanini GF, Dupont B, New MI. Late-onset steroid 21-hydroxylase deficiency: a variant of classical congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1982 Nov;55(5):817–827. [PubMed]
  • Collier S, Sinnott PJ, Dyer PA, Price DA, Harris R, Strachan T. Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase and complement C4 gene repeats in 21-hydroxylase deficiency haplotypes. EMBO J. 1989 May;8(5):1393–1402. [PubMed]
  • Partanen J, Koskimies S, Sipilä I, Lipsanen V. Major-histocompatibility-complex gene markers and restriction-fragment analysis of steroid 21-hydroxylase (CYP21) and complement C4 genes in classical congenital adrenal hyperplasia patients in a single population. Am J Hum Genet. 1989 May;44(5):660–670. [PubMed]
  • White PC, New MI, Dupont B. HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7505–7509. [PubMed]
  • Morel Y, André J, Uring-Lambert B, Hauptmann G, Bétuel H, Tossi M, Forest MG, David M, Bertrand J, Miller WL. Rearrangements and point mutations of P450c21 genes are distinguished by five restriction endonuclease haplotypes identified by a new probing strategy in 57 families with congenital adrenal hyperplasia. J Clin Invest. 1989 Feb;83(2):527–536. [PMC free article] [PubMed]
  • Speiser PW, New MI, White PC. Molecular genetic analysis of nonclassic steroid 21-hydroxylase deficiency associated with HLA-B14,DR1. N Engl J Med. 1988 Jul 7;319(1):19–23. [PubMed]
  • Higashi Y, Tanae A, Inoue H, Hiromasa T, Fujii-Kuriyama Y. Aberrant splicing and missense mutations cause steroid 21-hydroxylase [P-450(C21)] deficiency in humans: possible gene conversion products. Proc Natl Acad Sci U S A. 1988 Oct;85(20):7486–7490. [PubMed]
  • Owerbach D, Crawford YM, Draznin MB. Direct analysis of CYP21B genes in 21-hydroxylase deficiency using polymerase chain reaction amplification. Mol Endocrinol. 1990 Jan;4(1):125–131. [PubMed]
  • Mornet E, Crété P, Kuttenn F, Raux-Demay MC, Boué J, White PC, Boué A. Distribution of deletions and seven point mutations on CYP21B genes in three clinical forms of steroid 21-hydroxylase deficiency. Am J Hum Genet. 1991 Jan;48(1):79–88. [PubMed]
  • Pang S, Hotchkiss J, Drash AL, Levine LS, New MI. Microfilter paper method for 17 alpha-hydroxyprogesterone radioimmunoassay: its application for rapid screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1977 Nov;45(5):1003–1008. [PubMed]
  • Korth-Schutz S, Virdis R, Saenger P, Chow DM, Levine LS, New MI. Serum androgens as a continuing index of adequacy of treatment of congenital adrenal hyperplasia. J Clin Endocrinol Metab. 1978 Mar;46(3):452–458. [PubMed]
  • Rauh W, Levine LS, Gottesdiener K, New MI. Mineralocorticoids, salt balance and blood pressure after prolonged ACTH administration in juvenile hypertension. Klin Wochenschr. 1978;56 (Suppl 1):161–167. [PubMed]
  • New MI, Lorenzen F, Lerner AJ, Kohn B, Oberfield SE, Pollack MS, Dupont B, Stoner E, Levy DJ, Pang S, et al. Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J Clin Endocrinol Metab. 1983 Aug;57(2):320–326. [PubMed]
  • LUETSCHER JA, DOWDY AJ, CALLAGHAN AM, COHN AP. Studies of secretion and metabolism of aldosterone and cortisol. Trans Assoc Am Physicians. 1962;75:293–300. [PubMed]
  • New MI, Miller B, Peterson RE. Aldosterone excretion in normal children and in children with adrenal hyperplasia. J Clin Invest. 1966 Mar;45(3):412–428. [PMC free article] [PubMed]
  • PRADER A. Vollkommen männliche äussere Genitalentwicklung und Salzverlustsyndrom bei Madchen mit kongenitalem adrenogenitalem Syndrom. Helv Paediatr Acta. 1958 Feb;13(1):5–14. [PubMed]
  • Wyman AR, White R. A highly polymorphic locus in human DNA. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6754–6758. [PubMed]
  • Johns MB, Jr, Paulus-Thomas JE. Purification of human genomic DNA from whole blood using sodium perchlorate in place of phenol. Anal Biochem. 1989 Aug 1;180(2):276–278. [PubMed]
  • 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 May;5(5):685–692. [PubMed]
  • Pang SY, Wallace MA, Hofman L, Thuline HC, Dorche C, Lyon IC, Dobbins RH, Kling S, Fujieda K, Suwa S. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics. 1988 Jun;81(6):866–874. [PubMed]
  • Stoner E, Dimartino-Nardi J, Kuhnle U, Levine LS, Oberfield SE, New MI. Is salt-wasting in congenital adrenal hyperplasia due to the same gene as the fasciculata defect? Clin Endocrinol (Oxf) 1986 Jan;24(1):9–20. [PubMed]
  • Tusie-Luna MT, Traktman P, White PC. Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus. J Biol Chem. 1990 Dec 5;265(34):20916–20922. [PubMed]
  • Higashi Y, Hiromasa T, Tanae A, Miki T, Nakura J, Kondo T, Ohura T, Ogawa E, Nakayama K, Fujii-Kuriyama Y. 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 Apr;109(4):638–644. [PubMed]
  • 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 Jan 17;324(3):145–149. [PubMed]
  • Loukopoulos D. Thalassemia: genotypes and phenotypes. Ann Hematol. 1991 Apr;62(4):85–94. [PubMed]
  • Treisman R, Orkin SH, Maniatis T. Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes. Nature. 1983 Apr 14;302(5909):591–596. [PubMed]
  • Wong C, Antonarakis SE, Goff SC, Orkin SH, Forget BG, Nathan DG, Giardina PJ, Kazazian HH., Jr Beta-thalassemia due to two novel nucleotide substitutions in consensus acceptor splice sequences of the beta-globin gene. Blood. 1989 Mar;73(4):914–918. [PubMed]
  • Hall JG. How imprinting is relevant to human disease. Dev Suppl. 1990:141–148. [PubMed]
  • Okano Y, Eisensmith RC, Güttler F, Lichter-Konecki U, Konecki DS, Trefz FK, Dasovich M, Wang T, Henriksen K, Lou H, et al. Molecular basis of phenotypic heterogeneity in phenylketonuria. N Engl J Med. 1991 May 2;324(18):1232–1238. [PubMed]

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