Bases Moleculares da Hiperplasia Adrenal Congênita
Open accessAbstract
Hiperplasia adrenal congênita (HAC) é uma doença autossômica recessiva decorrente da alteração de enzimas que participam da síntese do cortisol. As manifestações podem ser causadas pela deficiência do cortisol e, em alguns casos, aldosterona e pelo acúmulo de precursores. O objetivo desta revisão é apresentar os mecanismos moleculares dos principais defeitos enzimáticos envolvidos na etiopatogênese da HAC. A deficiência da 21-hidroxilase (21OH) ocorre em 95% dos casos de HAC. Existem dois genes que codificam o P450c21: um ativo, CYP21, e um pseudogene CYP21P. Ambos são altamente homólogos (98%), o que favorece o emparelhamento desigual dos cromossomos homólogos durante a meiose, levando a duplicações e/ou deleções ou conversões desses genes. Adicionalmente, foram também descritas mutações de ponto, muitas delas presentes no pseudogene sugerindo microconversões. Mutações no gene CYP11B1 causam HAC por deficiência da 11beta-hidroxilase, forma esta que corresponde a 5% dos casos. Algumas mutações são recorrentes, situando-se principalmente entre os exons 6-8 que representaria uma área hot-spot no gene CYP11B1. A deficiência de 17-hidroxilase é causada por mutações no gene CYP17, que codificam uma proteína alterada, levando a deficiência total ou parcial de 17-hidroxilação e 17,20-liase ou deficiência isolada de 17,20-liase. Finalmente, deficiência de 3beta-HSD é causada por mutações no gene HSD3B2, que codifica a enzima 3beta-HSD tipo II e estas mutações têm sido associadas tanto com a forma clássica como com a forma não clássica da deficiência da 3beta-HSD.
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The remaining 20-25% of pathogenic CYP21A2 variants are attributable to unequal meiotic crossovers, giving rise to large deletions, duplications, and chimeric CYP21A1P/CYP21A2 genes.
“The remaining 20–25% are attributable to unequal meiotic crossovers, giving rise to extensive genomic rearrangements, including large deletions, duplications, and the formation of chimeric CYP21A1P/CYP21A2 genes.”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [20]
Microconversion events, in which one or more deleterious pseudogene-derived variants are transferred into CYP21A2 during meiosis, represent 70-75% of all cases.
“Among these, microconversion events, in which one or more deleterious pseudogene-derived variants are transferred into CYP21A2 during meiosis, represent 70–75% of all cases (5, 16, 19, 20).”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [20]
Only 5-10% of small pathogenic variants in CYP21A2 occur independently of gene conversion events, and some of these have founder effects.
“In contrast, only 5-10% of small pathogenic variants in CYP21A2 occur independently of gene conversion events; some of these have founder effects, providing valuable insights into population history and migration patterns (5, 16, 19–22).”
From Evolution of molecular diagnostic strategies for 21-hydroxylase deficiency: from classical methods to advanced genomic techniques (2026) · cites this paper as [20]
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Miranda, M. C. D., Oliveira, A. C. M. D., Soares, G. J., Batatinha, J. A. P., Latronico, A. C., Mendonca, B. B., & Bachega, T. A. S. S. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1770274 · Cited by 2 · see citing works
Self-citation
- Authors
- Mello, M. P. D., Bachega, T. A. S. S., Costa-Santos, M. D., Mermejo, L. M., & Castro, M. D.
- Affiliations
- UNICAMP; FMUSP; Universidade Federal de São Paulo; USP
- Universidade de São Paulo (BR)
- Venue
- Arquivos Brasileiros de Endocrinologia & Metabologia
- Publisher
- FapUNIFESP (SciELO)
- Published
- 2002-08
- Volume
- 46
- Issue
- 4
- Pages
- 457-477
- ISSN
- 0004-2730 (ISSN-L)
- OpenAlex
- W2043183294
- Cited by
- 11
- References
- 22
- Citations by year
- 2026: 1 · 2024: 2 · 2019: 2 · 2016: 1 · 2014: 1
- FWCI
- 0.35
- Type
- journal article
- Language
- pt
- Open access
- diamond
- doi.org
- Licence
- cc-by-nc
- Locations
- Arquivos Brasileiros de Endocrinologia & Metabologia (publishedVersion, cc-by-nc)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Americanae (AECID Library) (submittedVersion, cc-by-nc)
- The Scientific Electronic Library Online (Fundação de Amparo à Pesquisa do Estado de São Paulo) (submittedVersion, other-oa)
- 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 › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- congenital adrenal hyperplasia, 21-hydroxylase deficiency, CYP21, CYP11B1, 11beta-hydroxylase deficiency, CYP17, 17-hydroxylase deficiency, HSD3B2, 3β-hydroxysteroid dehydrogenase deficiency, autosomal recessive inheritance, gene conversion, point mutations, cortisol production, aldosterone deficiency
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