21-Hydroxylase deficiency in Brazil

Bachega, Tânia A.S.S.; Billerbeck, Ana Elisa C.; Madureira, Guiomar; Marcondes, José Antônio Miguel; Longui, Carlos Alberto; Leite, Maria Laís dos Santos; Arnhold, Ivo J.P.; Mendonça, Berenice Bilharinho

doi:10.1590/s0100-879x2000001000011

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…O estudo dos grandes rearranjos e das mutações de ponto derivadas do pseudogene identificou mutações em 76 a 93% dos alelos na população brasileira com as formas clássica e não clássica da deficiência da 21 hidroxilase (18)(19)(20)(21)(22), indicando que os demais alelos devem conter mutações novas.…”

Section: Freqüência Das Mutações Na Populaçãounclassified

Estudo multicêntrico de pacientes brasileiros com deficiência da 21-hidroxilase: correlação do genótipo com o fenótipo

Bachega

Billerbeck

Parente

et al. 2004

Arq Bras Endocrinol Metab

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We analyzed the clinical and molecular data of 205 patients with the three different clinical forms of 21-hydroxylase deficiency, in whom the clinical and molecular diagnosis were already defined. The most frequent mutations were I2 splice in the salt wasting form, I172N in the simple virilizing and V281L in the nonclassical form, presenting similar frequencies as those observed in other populations. We found a lower frequency of 21-hydroxylase gene deletion, similar to that previously identified in Argentinean and Mexican populations. Five new mutations were described in our population: G424S, H28+C, Ins 1003 1004 A, R408C and IVS2-2A>G. The genotype was classified in three groups according to the impairment of enzymatic activity observed in vitro, Group A: 0-2%, Group B: 3-7% and Group C: >20%. Group A mutations correlated with the salt wasting form, the Group B with simple virilizing form and Group C with the non classical form. The severity of genotype showed a positive correlation with higher 17OH-progesterone and testosterone levels. The I2 splice mutation in homo or hemizygosis confers classical form phenotype with both salt wasting and simple virilizing forms, precluding the prediction of the clinical form through genotype in pre and neonatal diagnosis. The good genotype-phenotype correlation in patients with 21-hydroxylase deficiency shows the usefulness of genotype to predict the clinical form for genetic counseling, prenatal diagnosis and to confirm neonatal screening diagnosis, except in cases with I2 splice mutation.

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Section: Freqüência Das Mutações Na Populaçãounclassified

Estudo multicêntrico de pacientes brasileiros com deficiência da 21-hidroxilase: correlação do genótipo com o fenótipo

Bachega

Billerbeck

Parente

et al. 2004

Arq Bras Endocrinol Metab

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“…The incidence of CYP21A2 mutations might vary among ethnic groups; previous studies observed a lower frequency of CYP21A2 deletions in the Brazilian population than in Caucasian subjects ( 17 ). Interestingly, a higher frequency of mutations in the founder effect gene, not derived from the pseudogene, was identified in the former individuals ( 18 , 19 ).…”

Section: Introductionmentioning

confidence: 95%

“…This genotype-phenotype correlation is useful in clinical practice to predict clinical form, especially for prenatal diagnosis and neonatal screening (12)(13)(14)(15). Still, a French study indicates that neonatal screening using serum 17-OHP levels has a low positive predictive value in special situations, such as in premature infants. That is, a significant false positives rate is observed, causing increased workload for health care systems and concern among parents (16).…”

Section: Introductionmentioning

confidence: 99%

Mutation distributions among patients with congenital adrenal hyperplasia from five regions of Brazil: a systematic review

Hosomi¹,

Salles²,

Bachega³

2023

Archives of Endocrinology and Metabolism

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Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is an autosomal recessive disorder caused by CYP21A2 gene mutations, and its molecular diagnosis is widely used in clinical practice to confirm the hormonal diagnosis. Hence, considering the miscegenation of the Brazilian population, it is important to determine a mutations panel to optimise the molecular diagnosis. The objective was to review the CYP21A2 mutations' distribution among Brazilian regions. Two reviewers screened Brazilian papers up to February 2020 in five databases. The pair-wise comparison test and Holm method were used in the statistical analysis. Nine studies were selected, comprising 769 patients from all regions. Low proportion of males and salt-wasters was identified in the North and Northeast regions, although without significant difference. Large gene rearrangements also had a low frequency, except in the Center-West and South regions (p < 0.05). The most frequent mutations were p.I172N, IVS2-13A/C>G, p.V281L and p.Q318X, and significant differences in their distributions were found: p.V281L was more frequent in the Southeast and p.Q318X in the Center-West and Northeast regions (p < 0.05). Thirteen new mutations were identified in 3.8%-15.2% of alleles, being more prevalent in the North region, and six mutations presented a founder effect gene. Genotype-phenotype correlation varied from 75.9%-97.3% among regions. The low prevalence of the salt-wasting form, affected males and severe mutations in some regions indicated pitfalls in the clinical diagnosis. The good genotype-phenotype correlation confirms the usefulness of molecular diagnosis; however, the Brazilian population also presents significant prevalence of novel mutations, which should be considered for a molecular panel.

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“…Estudos de seqüenciamento complementando as técnicas anteriores identificaram mutações em 100% dos alelos da forma clássica, enquanto que a forma não clássica, em nossa amostra, permanece ainda com fre- qüência alta (23%) de alelos sem mutações identificadas (29). Nenhum paciente portador de forma não clássica e com valor da 17OHP pós-ACTH <17ng/mL teve seu genótipo definido.…”

Section: Genética Molecularunclassified

Bases Moleculares da Hiperplasia Adrenal Congênita

Mello

Bachega

Costa-Santos

et al. 2002

Arq Bras Endocrinol Metab

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RESUMOHiperplasia 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 11β-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 3β-HSD é causada por mutações no gene HSD3B2, que codifica a enzima 3β-HSD tipo II e estas mutações têm sido associadas tanto com a forma clássica como com a forma não clássica da deficiência da 3β-HSD. Congenital adrenal hiperplasia (CAH) is a recessive autossomic disease caused by inherited defects in cortisol biosynthesis. The manifestations are caused both by the deficient synthesis of cortisol, and sometimes of aldosterone, and by accumulation of the precursor steroids. The objective of this review is to present the molecular mechanisms of the main enzymatic defects involved in the etiopathogenesis of CAH. Deficiency of 21-hydroxylase (21OH) accounts for more than 95% of all cases of CAH. The human genome contains two CYP genes: one active, CYP21, and a pseudogene, CYP21P. Both are highly homologous (98%), facilitating recombination events during meiosis, leading to duplication and/or deletion or conversion of these genes. Additionally, point mutations have also been described. Deficiency of 11β-hydroxylase (11βOH) is caused by mutations in the CYP11B1 gene, and accounts for 5% of all cases. Some mutations are recurrent, and mainly located on exons 6-8, which is considered a hot-spot area in CYP11B1 gene. Deficiency of 17α-hydroxylase (17OH) is caused by mutations in the CYP17 gene, producing a truncated or impaired protein. These mutations have been described in patients with combined defi-

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21-Hydroxylase deficiency in Brazil

Cited by 7 publications

References 22 publications

Estudo multicêntrico de pacientes brasileiros com deficiência da 21-hidroxilase: correlação do genótipo com o fenótipo

Estudo multicêntrico de pacientes brasileiros com deficiência da 21-hidroxilase: correlação do genótipo com o fenótipo

Mutation distributions among patients with congenital adrenal hyperplasia from five regions of Brazil: a systematic review

Bases Moleculares da Hiperplasia Adrenal Congênita

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