Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation
Open accessAbstract
To describe the results obtained in a neonatal screening program after its implementation and to assess the clinical and molecular profiles of confirmed and suspicious congenital adrenal hyperplasia cases. A cross-sectional study was conducted. Newborns with suspected disease due to high 17-hydroxyprogesterone levels and adjusted for birth weight were selected. Classical congenital adrenal hyperplasia (salt-wasting and simple virilizing forms) was diagnosed by an increase in 17-hydroxyprogesterone levels as confirmed in the retest, clinical evaluation, and genotype determined by SNaPshot and multiplex ligation-dependent probe amplification. After 24 months, 15 classic congenital adrenal hyperplasia cases were diagnosed in a total of 217,965 newborns, with an estimated incidence of 1:14,531. From 132 patients, seven non-classical and 14 heterozygous patients were screened for CYP21A2 mutations, and 96 patients presented false positives with wild type CYP21A2. On retest, increased 17-hydroxyprogesterone levels were found in classical congenital adrenal hyperplasia patients and showed significant correlation with genotype-related classical genital adrenal hyperplasia. The most frequent mutations were IVS2-13A/C>G followed by gene deletion or rearrangement events in the classical form. In non-classical and heterozygous diseases, p.Val282Leu was the most common mutation. The results underscore the effectiveness of congenital adrenal hyperplasia neonatal screening in the public health system and indicate that the adopted strategy was appropriate. The second sample collection along with genotyping of suspected cases helped to properly diagnose both severe and milder cases and delineate them from false positive patients. Descrever os resultados obtidos em um programa de triagem neonatal após sua implantação e avaliar os perfis clínicos e moleculares de casos confirmados e suspeitos de hiperplasia adrenal congênita. Foi feito um estudo transversal. Recém-nascidos com suspeita da doença devido aos altos níveis de 17-alfa-hidroxiprogesterona e ajustados pelo peso ao nascer foram selecionados. A hiperplasia adrenal congênita clássica (forma perdedora de sal e forma virilizante simples) foi diagnosticada por um aumento nos níveis de 17-alfa-hidroxiprogesterona confirmado no reteste, avaliação clínica e genótipo determinado com o uso do ensaio SNaPshot e amplificação multiplex de sondas dependente de ligação. Após 24 meses, 15 casos clássicos de hiperplasia adrenal congênita foram diagnosticados em 217.965 recém-nascidos, com uma incidência estimada de 1: 14.531. De 132 pacientes, sete não-clássicos e 14 heterozigotos foram submetidos à triagem para mutações no gene CYP21A2 e 96 pacientes apresentaram resultados falso-positivos com CYP21A2 do tipo selvagem. No reteste, níveis aumentados de 17-alfa-hidroxiprogesterona foram encontrados em pacientes com hiperplasia adrenal congênita clássica e mostraram correlação significativa com HAC clássica relacionada ao genótipo. As mutações mais frequentes foram IVS2-13A/C>G, seguidas de deleção gênica ou eventos de rearranjo na forma clássica. Em casos doenças não clássicas e heterozigose, a mutação p.Val282Leu foi a mais comum. Os resultados ressaltam a eficácia da triagem neonatal para a hiperplasia adrenal congênita no sistema público de saúde e indicam que a estratégia adotada foi adequada. A segunda coleta de amostras, juntamente com a genotipagem dos casos suspeitos, ajudou a diagnosticar adequadamente os casos graves e mais leves e diferenciá-los de pacientes com resultado falso-positivo.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CAH screening is generally successful in identifying affected patients with classic CAH, especially if combined with a second-tier follow-up.
“Although often plagued by ambiguous results and false calls, the CAH screening is generally successful in identifying affected patients with classic CAH, especially if combined with a secondtier follow-up. 3,27”
From High-Throughput Screening for CYP21A1P-TNXA/TNXB Chimeric Genes Responsible for Ehlers Danlos Syndrome in Patients with Congenital Adrenal Hyperplasia. (2019) · cites this paper as [27]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The Molecular Biology, Biochemistry, and Physiology of Human Steroidogenesis and Its Disorders
Miller, W. L., & Auchus, R. J. (2011) · Endocrine Reviews · doi:10.1210/er.2010-0013 · Cited by 2,458 · see citing works
Speiser, P. W., Azziz, R., Baskin, L. S., Ghizzoni, L., Hensle, T. W., Merke, D. P., Meyer-Bahlburg, H. F. L., Miller, W. L., Montori, V. M., Oberfield, S. E., et al. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2631 · Cited by 1,484 · see citing works
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency*
White, P. C., & Speiser, P. W. (2000) · Endocrine Reviews · doi:10.1210/edrv.21.3.0398 · Cited by 1,432 · see citing works
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
Genetics of congenital adrenal hyperplasia
Krone, N., & Arlt, W. (2009) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2008.10.014 · Cited by 312 · see citing works
Pang, S., Clark, A. C., Neto, E. C., Giugliani, R., Dean, H., Winter, J., Dhondt, J., Farriaux, J. P., Graters, A., CACCIARI, E., et al. (1993) · Screening · doi:10.1016/0925-6164(93)90024-d · Cited by 160 · see citing works
Olgemöller, B., Roscher, A. A., Liebl, B., & Fingerhut, R. (2003) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2002-021732 · Cited by 124 · see citing works
Bachega, T. A. S. S., Billerbeck, A. E. C., Madureira, G., Marcondes, J. A. M., Longui, C. A., Leite, M. V., Arnhold, I. J. P., & Mendonca, B. B. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.12.5350 · Cited by 108 · see citing works
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
Bachega, T. A. S. S. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.83.12.4416 · Cited by 81 · 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
de Carvalho, D. F., Miranda, M. C., Gomes, L. G., Madureira, G., Marcondes, J. A. M., Billerbeck, A. E. C., Rodrigues, A. S., Presti, P. F., Kuperman, H., Damiani, D., et al. (2016) · European Journal of Endocrinology · doi:10.1530/eje-16-0171 · Cited by 75 · see citing works
Soardi, F. C., Barbaro, M., Lau, I. F., de Lemos‐Marini, S. H. V., Baptista, M. T. M., Guerra‐Júnior, G., Wedell, A., Lajić, S., & de Mello, M. P. (2008) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-2594 · Cited by 65 · see citing works
Krone, N. P., Braun, A. D., Weinert, S., Peter, M., Roscher, A. A., Partsch, C., & Sippell, W. G. (2002) · Clinical Chemistry · doi:10.1093/clinchem/48.6.818 · Cited by 64 · see citing works
Gatelais, F., Berthelot, J., Beringue, F., Descamps, P., Bonneau, D., Limal, J.-M., & Coutant, R. (2004) · Pediatric Research · doi:10.1203/01.pdr.0000142733.50918.6e · Cited by 60 · see citing works
Impact of Molecular Genetics on Congenital Adrenal Hyperplasia Management
Balsamo, A., Baldazzi, L., Menabò, S., & Cicognani, A. (2010) · Sexual Development · doi:10.1159/000315959 · Cited by 54 · see citing works
Silveira, E. L., Santos, Ε. Ρ., Bachega, T. A. S. S., Nader, I., Gross, J. L., & Elnecave, R. H. (2008) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2008.21.5.455 · Cited by 37 · see citing works
Kopacek, C., de Castro, S. M., Prado, M. J., da Silva, C. M. D., Beltrão, L. A., & Spritzer, P. M. (2017) · BMC Pediatrics · doi:10.1186/s12887-016-0772-x · Cited by 36 · see citing works
Self-citationHayashi, G. Y., Faure, C., Brondi, M. F., Vallejos, C., Soares, D., Oliveira, É., Brito, V. N., Mendonca, B. B., & Bachega, T. A. S. S. (2011) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302011000800019 · Cited by 35 · see citing works
Silveira, E., Elnecave, R., Dos Santos, E., Moura, V, Pinto, E., Van Der Linden Nader, I., Mendonca, B., & Bachega, T. (2009) · Clinical Genetics · doi:10.1111/j.1399-0004.2009.01274.x · Cited by 31 · see citing works
Salt wasting in simple virilizing congenital adrenal hyperplasia
Frisch, H., Battelino, Τ., Schober, Ε., Baumgartner-Parzer, S., Nowotny, P., & Vierhapper, Η. (2001) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem.2001.14.9.1649 · Cited by 29 · see citing works
Ten-year evaluation of a Neonatal Screening Program for Congenital Adrenal Hyperplasia
Nascimento, M. L., Cristiano, A. N. B., de Campos, T., Ohira, M., Cechinel, E., Simoni, G., Lee, J. V. D. S., Linhares, R. M. M., & da Silva, P. C. A. (2014) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/0004-2730000003310 · Cited by 26 · see citing works
Bachega, T. A. S. S., Billerbeck, A. E. C., Parente, É. B., Lemos-Marini, S. H. V., Baptista, M. T. M., Mello, M. P., Guerra Jr., G., Kuperman, H., Setian, N., Damiani, D., et al. (2004) · Arquivos Brasileiros de Endocrinologia & Metabologia · doi:10.1590/s0004-27302004000500016 · Cited by 25 · see citing works
Vakili, R., Baradaran-Heravi, A., Barid-Fatehi, B., Gholamin, M., Ghaemi, N., & Abbaszadegan, M. R. (2005) · Hormone Research in Paediatrics · doi:10.1159/000084570 · Cited by 21 · see citing works
Development of CYP21A2 Genotyping Assay for the Diagnosis of Congenital Adrenal Hyperplasia
Prado, M. J., de Castro, S. M., Kopacek, C., de Mello, M. P., Rispoli, T., Grandi, T., da Silva, C. M. D., & Rossetti, M. L. R. (2017) · Molecular Diagnosis & Therapy · doi:10.1007/s40291-017-0296-6 · Cited by 17 · see citing works
Self-citationNeocleous, V., Shammas, C., Phedonos, A., Karaoli, E., Kyriakou, A., Toumba, M., Phylactou, L. A., & Skordis, N. (2012) · PubMed · Cited by 11 · see citing works
López, I. D., Estévez, A. R., Molina, E. G., Ayúcar, M. M., Pérez, B. R., & Zubicaray, B. E. (2009) · Anales de Pediatría · doi:10.1016/j.anpedi.2009.08.006 · Cited by 3 · see citing works
Nordenström, A., Thilén, A., Hagenfeldt, L., Larsson, A., & Wedell, A. (1999) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.84.5.5651 · Cited by 2 · see citing works
Flagged first, then by citations
5 of the 33 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- Prader A. Der Genitalbefund beim Pseudohermaphroditismus Femininus des kongenitalen Adrenogenitalen Syndromes. Helv Paediatr Acta. 1954;3:231---48.
Cited by
Sorted by citations
Newborn Screening for Congenital Adrenal Hyperplasia: Review of Factors Affecting Screening Accuracy
Held, P. K., Bird, I. M., & Heather, N. L. (2020) · International Journal of Neonatal Screening · doi:10.3390/ijns6030067 · Cited by 68 · see citing works
Navarro-Zambrana, A. N., & Sheets, L. (2022) · Hormone Research in Paediatrics · doi:10.1159/000526401 · Cited by 30 · see citing works
Lao, Q., Brookner, B., & Merke, D. P. (2019) · The Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2019.06.001 · Cited by 29 · see citing works
Bialk, E. R., Lasarev, M. R., & Held, P. K. (2019) · International Journal of Neonatal Screening · doi:10.3390/ijns5030033 · Cited by 25 · see citing works
Newborn screening for congenital adrenal hyperplasia: beyond 17-hydroxyprogesterone concentrations
Witchel, S. F. (2018) · Jornal de Pediatria · doi:10.1016/j.jped.2018.06.003 · Cited by 11 · see citing works
Castro, P. S., Rassi, T. D. O., Araújo, R. F., Pezzuti, I. L., Rodrigues, A. S., Bachega, T. A. S. S., & Silva, I. N. (2019) · Journal of Pediatric Endocrinology and Metabolism · doi:10.1515/jpem-2018-0398 · Cited by 10 · see citing works
Impact of Newborn Screening on Clinical Presentation of Congenital Adrenal Hyperplasia
Navardauskaitė, R., Banevičiūtė, K., Songailienė, J., Grigalionienė, K., Čereškevičius, D., Šukys, M., Mockevičienė, G., Smirnova, M., Utkus, A., & Verkauskienė, R. (2021) · Medicina · doi:10.3390/medicina57101035 · Cited by 8 · see citing works
de Castro, S. M., Wiest, P., Spritzer, P. M., & Kopacek, C. (2023) · Endocrine Connections · doi:10.1530/ec-23-0162 · Cited by 7 · see citing works
Self-citationProdução de conhecimento sobre as doenças rastreadas pela triagem neonatal no Brasil de 2008 a 2018
Baggio, F. L., Ansbach, N., Kapusta, B. B., & Luz, G. D. S. (2020) · Revista Eletrônica Acervo Saúde · doi:10.25248/reas.e2596.2020 · Cited by 4 · see citing works
Xia, Y., Yu, F., Bai, Y., Jiang, L., Shi, P., Jiang, Z., & Kong, X. (2024) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-024-03414-4 · Cited by 2 · see citing works
Hosomi, S. S., Salles, I. C., & Bachega, T. A. S. S. (2023) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000593 · Cited by 2 · see citing works
Moderate congenital adrenal hyperplasia in two girls diagnosed by newborn screening
Banaszak-Ziemska, M., Małecka, E., Łacna, K., Ginalska-Malinowska, M., & Niedziela, M. (2021) · Pediatric Endocrinology Diabetes and Metabolism · doi:10.5114/pedm.2021.109123 · Cited by 2 · see citing works
de Miranda, M. C. (2020) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/t.5.2020.tde-29102020-162042
Newborn screening for congenital adrenal hyperplasia: beyond 17‐hydroxyprogesterone concentrations
Witchel, S. F. (2019) · Jornal de Pediatria (Versão em Português) · doi:10.1016/j.jpedp.2018.08.001
PARREIRA, P. H., Ruppert, E. P., Carvalho, M. F. A., Rodrigues, M. C. F. R., & Dutra, P. R. (2023) · Revista Foco · doi:10.54751/revistafoco.v16n9-035
Grosse, S. D. (2025) · Jornal de Pediatria · doi:10.1016/j.jped.2025.02.001
- Authors
- Kopacek, C., Prado, M. J., da Silva, C. M. D., de Castro, S. M., Beltrão, L. A., Vargas, P. R., Grandi, T., Rossetti, M. L. R., & Spritzer, P. M.
- Affiliations
- Universidade Federal do Rio Grande do Sul (BR)
- Universidade Federal de Ciências da Saúde de Porto Alegre (BR)
- Governo do Estado do Rio Grande do Sul (BR)
- Corresponding author
- Kopacek, Cristiane
- ORCID
- Venue
- Jornal de Pediatria
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 95
- Issue
- 3
- Pages
- 282-290
- ISSN
- 0021-7557 (ISSN-L)
- OpenAlex
- W2801151983
- Cited by
- 17
- References
- 33
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 1
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Jornal de Pediatria (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-nd)
- Americanae (AECID Library) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Redalyc (Universidad Autónoma del Estado de México) (submittedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (INCT 573747/2008–3, 573747/2008‐3, CNPq INCT 573747/2008‐3)
- Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- congenital adrenal hyperplasia, newborn screening, 17-hydroxyprogesterone, CYP21A2 mutations, salt-wasting form, non-classical congenital adrenal hyperplasia, heterozygous carriers, false positives, genotype-phenotype correlation, incidence
- MeSH terms
- Adrenal Hyperplasia, Congenital, Brazil, Cross-Sectional Studies, Female, Genotype, Humans, Infant, Newborn, Male, Mutation, Phenotype, Steroid 21-Hydroxylase, Biomarkers, Incidence, Neonatal Screening, 17-alpha-Hydroxyprogesterone
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
