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 Tajima, T. Articles by Cutler, G. B. Search for Related Content PubMed PubMed Citation Articles by Tajima, T. Articles by Cutler, G. B., Jr.

Molecular Basis of Nonclassical Steroid 21-Hydroxylase Deficiency Detected by Neonatal Mass Screening in Japan

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health (T.Ta., G.B.C.), Bethesda, Maryland 20892; and the Department of Pediatrics, Hokkaido University School of Medicine (T.Ta., K.F., J.N.), Hokkaido; the Department of Pediatrics, Tokyo Medical and Dental University (T.To., K.S.), Tokyo; the Department of Neonatology, Osaka Medical Center (S.K.), Osaka; the Department of Endocrinology and Metabolism, Hyogo Children’s Hospital (K.G.), Hyogo; and the Department of Pediatrics, Kushiro Red Cross Hospital (T.N.), Kushiro, Japan

Address all correspondence and requests for reprints to: Toshihiro Tajima, M.D., Ph.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862.

Since 1989, neonatal mass screening for congenital adrenal hyperplasia (CAH) has been performed in Japan, and the frequency of the classical form of 21-hydroxylase deficiency was found to be nearly identical to that in other countries. However, it has not yet been determined whether our mass screening program can detect the nonclassical (NC) form.

From 1991 to 1994, about 4,500,000 infants underwent CAH mass screening in Japan. During this period, we identified by screening 2 siblings and 2 unrelated patients who had mild elevation of serum 17-hydroxyprogesterone levels at 5 days of age, but who revealed no symptoms of CAH. They were diagnosed as having probable NC steroid 21-hydroxylase deficiency. To clarify the molecular basis of NC CAH detectable by neonatal screening in Japan, the steroid 21-hydroxylase (CYP21) genes from these cases were analyzed. The 2 siblings (patients 1 and 2) had I172N and R356W mutations in 1 allele and in the other allele had local gene conversion, including the P30L mutation in exon 1. Patient 3, who was unrelated, had gene conversion encoding the same P30L mutation in 1 allele and in the other allele had an intron 2 mutation (668–12 AG), causing aberrant ribonucleic acid splicing, and the R356W mutation. Patient 4, also a compound heterozygote, had the R356W and 707del8 mutations.

The estimated rate of detection of the NC form by mass screening (1:1,100,000) seemed low compare to the established detection rate for the classical form (1:18,000). As all of our 4 patients were compound heterozygotes with at least 1 allele bearing 1 or more mutations associated with classic CAH, it may be difficult to detect NC cases carrying only NC-associated alleles using our current neonatal mass screening methods.

This article has been cited by other articles:

				P. W. Speiser and P. C. White Congenital Adrenal Hyperplasia N. Engl. J. Med., August 21, 2003; 349(8): 776 - 788. [Full Text] [PDF]

				S. Koyama, T. Toyoura, S. Saisho, K. Shimozawa, and J. Yata Genetic Analysis of Japanese Patients with 21-Hydroxylase Deficiency: Identification of a Patient with a New Mutation of a Homozygous Deletion of Adenine at Codon 246 and Patients without Demonstrable Mutations within the Structural Gene for CYP21 J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2668 - 2673. [Abstract] [Full Text] [PDF]

				D. l’Allemand, V. Tardy, A. Grüters, D. Schnabel, H. Krude, and Y. Morel 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., December 1, 2000; 85(12): 4562 - 4567. [Abstract] [Full Text]

				P. C. White and P. W. Speiser Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency Endocr. Rev., June 1, 2000; 21(3): 245 - 291. [Abstract] [Full Text]

				H.-H. Lee, J.-G. Chang, C.-H. Tsai, F.-J. Tsai, H.-T. Chao, and B.-c. Chung Analysis of the Chimeric CYP21P/CYP21 Gene in Steroid 21-Hydroxylase Deficiency Clin. Chem., May 1, 2000; 46(5): 606 - 611. [Abstract] [Full Text] [PDF]