Linking the degree of virilization in females with congenital adrenal hyperplasia to genotype

Gurgov, Semyon; Bernabé, Kerlly J.; Stites, John; Cunniff, Christopher M.; Lin‐Su, Karen; Felsen, Diane; New, Maria I.; Poppas, Dix P.

doi:10.1111/nyas.13370

Cited by 17Sexual Differentiation and DisordersAdrenal Hormones and DisordersOvarian function and disorders

Linking the degree of virilization in females with congenital adrenal hyperplasia to genotype

Gurgov, Semyon, Bernabé, Kerlly J., Stites, John, Cunniff, Christopher M., Lin‐Su, Karen, Felsen, Diane, New, Maria I., Poppas, Dix P.·2017·Annals of the New York Academy of Sciences

DOI 10.1111/nyas.13370

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Abstract

Mutations of CYP21A2 variably decrease 21-hydroxylase activity and result in a spectrum of disease expressions in patients with congenital adrenal hyperplasia (CAH). We examined the association between CYP21A2 mutations and virilization (Prader score) in females with CAH. The study population included 187 CAH females with fully characterized CYP21A2 mutations. One hundred fifty-eight patients were sorted into groups by expected enzyme activity (percent of normal activity) of the less severely affected allele: (A) null, 0%; (B) I2G, 1%; (C) I172N, 2%; and (D) V281L, >2%. We observed an inverse relationship between virilization and residual enzyme activity (P < 0.001). Subjects in group A or B had a significantly higher likelihood (unadjusted odds ratio: 16; P < 0.001) of developing severe virilization compared with those in group C. Surprisingly, 24% of group D patients, whose mutation is usually associated with nonclassical (NC) CAH, had severe virilization. Among subjects with the NC P30L mutation, 66% expressed unexpected virilization. Virilization, usually leading to extensive reconstructive surgery, is highly likely in patients with null or I2G mutations; however, NC mutations (P30L/V281L) may also lead to unexpected virilization. These findings have implications for prenatal counseling and highlight the need for additional investigations into other factors that influence virilization in CAH.

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I172N reduces enzymatic activity to <5% of normal and is associated with the SV form of the disorder (mutation Group B).
“( I172N)(154) reduces enzymatic activity to <5% of normal and is associated with the SV form of the disorder (mutation Group B)(107,109,221).”
From Congenital Adrenal Hyperplasia—Current Insights in Pathophysiology, Diagnostics, and Management (2022) · cites this paper as [221]

Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support
Harris, P. A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N., & Conde, J. G. (2009) · Journal of Biomedical Informatics · doi:10.1016/j.jbi.2008.08.010 · Cited by 51,384 · see citing works
Disease expression and molecular genotype in congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Speiser, P. W., Dupont, J., Zhu, D., Serrat, J., Buegeleisen, M., Tusie-Luna, M. T., Lesser, M., New, M. I., & White, P. C. (1992) · Journal of Clinical Investigation · doi:10.1172/jci115897 · Cited by 572 · see citing works
Self-citation
Predicting phenotype in steroid 21-hydroxylase deficiency? Comprehensive genotyping in 155 unrelated, well defined patients from southern Germany
Krone, N., Braun, A., Roscher, A. A., Knorr, D., & Schwarz, H. P. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.3.6441 · Cited by 397 · see citing works
Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: Implications for genetic diagnosis and association with disease manifestation
Wedell, A. (1994) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.78.5.1145 · Cited by 370 · see citing works
Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency
New, M. I., Abraham, M., Gonzalez, B., Dumic, M., Razzaghy-Azar, M., Chitayat, D., Sun, L., Zaidi, M., Wilson, R. C., & Yuen, T. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300057110 · Cited by 365 · see citing works
Self-citation
Noninvasive prenatal diagnosis of congenital adrenal hyperplasia using cell-free fetal DNA in maternal plasma
New, M. I., Tong, Y. K., Yuen, T., Jiang, P., Pina, C., Chan, K. C. A., Khattab, A., Liao, G. J. W., Yau, M., Kim, S.-M., et al. (2014) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2014-1118 · Cited by 319 · see citing works
Self-citation
Testosterone during Pregnancy and Gender Role Behavior of Preschool Children: A Longitudinal, Population Study
Hines, M., Golombok, S. E., Rust, J. N., Johnston, K. J., Golding, J., & Avon Longitudinal Study of Parents and Children Study Team (2002) · Child Development · doi:10.1111/1467-8624.00498 · Cited by 204 · see citing works
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 Deficiency1
Higashi, Y., Hiromasa, T., Tanae, A., Miki, T., Nakura, J., Kondo, T., Ohura, T., Ogawa, E., Nakayama, K., & Fujii-Kuriyama, Y. (1991) · The Journal of Biochemistry · doi:10.1093/oxfordjournals.jbchem.a123433 · Cited by 201 · see citing works
Comprehensive genetic analysis of 182 unrelated families with congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Finkielstain, G. P., Chen, W., Mehta, S. P., Fujimura, F. K., Hanna, R. M., Van Ryzin, C., McDonnell, N. B., & Merke, D. P. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-0319 · Cited by 192 · see citing works
[Genital findings in the female pseudo-hermaphroditism of the congenital adrenogenital syndrome; morphology, frequency, development and heredity of the different genital forms].
Prader, A. (1954) · PubMed · Cited by 151 · see citing works
Steroid 21‐hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype–phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia
Marino, R., Ramirez, P., Galeano, J., Perez Garrido, N., Rocco, C., Ciaccio, M., Warman, D. M., Guercio, G., Chaler, E., Maceiras, M., et al. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04123.x · Cited by 98 · see citing works
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
l'Allemand, D. (2000) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.85.12.4562 · Cited by 90 · see citing works
Biochemical and genetic diagnosis of 21-hydroxylase deficiency
Falhammar, H., Wedell, A., & Nordenström, A. (2015) · Endocrine · doi:10.1007/s12020-015-0731-6 · Cited by 80 · see citing works
Mutational spectrum of the steroid 21-hydroxylase gene in Austria: identification of a novel missense mutation
Baumgartner-Parzer, S. M., Schulze, E., Waldhäusl, W., Pauschenwein, S., Rondot, S., Nowotny, P., Meyer, K., Frisch, H., Waldhauser, F., & Vierhapper, H. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.10.7898 · Cited by 74 · see citing works
Surgical outcomes and complications of reconstructive surgery in the female congenital adrenal hyperplasia patient: What every endocrinologist should know
Wang, L. C., & Poppas, D. P. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.03.021 · Cited by 69 · see citing works
Self-citation
Steroid 21 Hydroxylase Deficiency Congenital Adrenal Hyperplasia
Nimkarn, S., Lin‐Su, K., & New, M. I. (2011) · Pediatric Clinics of North America · doi:10.1016/j.pcl.2011.07.012 · Cited by 62 · see citing works
Self-citation
The degree of external genitalia virilization in girls with 21-hydroxylase deficiency appears to be influenced by the CAG repeats in the androgen receptor gene
Rocha, R. O., Billerbeck, A. E. C., Pinto, E. M., Melo, K. F. S., Lin, C. J., Longui, C. A., Mendonca, B. B., & Bachega, T. A. S. S. (2008) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2007.03023.x · Cited by 43 · see citing works
Substitutions in the CYP21A2 promoter explain the simple‐virilizing form of 21‐hydroxylase deficiency in patients harbouring a P30L mutation
Araujo, R. S., Billerbeck, A. E. C., Madureira, G., Mendonca, B. B., & Bachega, T. A. S. S. (2005) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2005.02184.x · Cited by 42 · see citing works
Mutational spectrum of congenital adrenal hyperplasia in Slovenian patients: a novel Ala15Thr mutation and Pro30Leu within a larger gene conversion associated with a severe form of the disease
Dolžan, V., Stopar-Obreza, M., Žerjav-Tanšek, M., Breskvar, K., Kržišnik, C., & Battelino, T. (2003) · European Journal of Endocrinology · doi:10.1530/eje.0.1490137 · Cited by 41 · see citing works
The classic and nonclassic concenital adrenal hyperplasias
Auchus, R. J. (2015) · Endocrine Practice · doi:10.4158/ep14474.ra · Cited by 35 · see citing works
Analysis of the CYP21A1P pseudogene: Indication of mutational diversity and CYP21A2-like and duplicated CYP21A2 genes
Tsai, L., Cheng, C., Chuang, S.-H., & Lee, H.-H. (2011) · Analytical Biochemistry · doi:10.1016/j.ab.2011.02.016 · Cited by 30 · see citing works
No Correlation between Androgen Receptor CAG and GGN Repeat Length and the Degree of Genital Virilization in Females with 21-Hydroxylase Deficiency
Welzel, M., Schwarz, H., Hedderich, J., Dörr, H. G., Binder, G., Brämswig, J., Krude, H., Richter-Unruh, A., Niedziela, M., Gromoll, J., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-1338 · Cited by 23 · see citing works
The effect of fetal androgen metabolism-related gene variants on external genitalia virilization in congenital adrenal hyperplasia
Kaupert, L., Lemos‐Marini, S., De Mello, M., Moreira, R., Brito, V., Jorge, A., Longui, C., Guerra, G., Mendonca, B., & Bachega, T. (2013) · Clinical Genetics · doi:10.1111/cge.12016 · Cited by 17 · see citing works

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Claahsen - van der Grinten, H. L., Speiser, P. W., Ahmed, S. F., Arlt, W., Auchus, R. J., Falhammar, H., Flück, C. E., Guasti, L., Huebner, A., Kortmann, B. B. M., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab016 · Cited by 556 · see citing works
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Rytting, E., Waltz, J., & Ahmed, M. S. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-818902-3.00007-5 · Cited by 1 · see citing works
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Authors: Gurgov, S., Bernabé, K. J., Stites, J., Cunniff, C. M., Lin‐Su, K., Felsen, D., New, M. I., & Poppas, D. P.
Affiliations: NewYork–Presbyterian Hospital (US)
Icahn School of Medicine at Mount Sinai (US)
Corresponding author: Poppas, Dix P.
ORCID: Bernabé, Kerlly J.
Cunniff, Christopher M.
Lin‐Su, Karen
Felsen, Diane
Venue: Annals of the New York Academy of Sciences
Publisher: Wiley
Published: 2017-06-22
Volume: 1402
Issue: 1
Pages: 56-63
ISSN: 0077-8923 (ISSN-L)
1749-6632
DOI: 10.1111/nyas.13370
OpenAlex: W2649029072
Cited by: 17
References: 23
Citations by year: 2026: 1 · 2025: 1 · 2024: 3 · 2023: 2 · 2021: 5 · 2020: 3 · 2019: 2
FWCI: 0.56
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Annals of the New York Academy of Sciences (publishedVersion)
PubMed (publishedVersion)
Funders: New York Community Trust
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords: congenital adrenal hyperplasia, CYP21A2 mutations, 21-hydroxylase, masculinization, female patients, genotype-phenotype correlation, enzyme activity, prenatal counseling
MeSH terms: Adrenal Hyperplasia, Congenital, Female, Genotype, Humans, Mutation, Phenotype, Virilism

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Linking the degree of virilization in females with congenital adrenal hyperplasia to genotype

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