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

Hosomi, Silvério S.; Salles, Igor C.; Bachega, Tânia A. S. S.

doi:10.20945/2359-3997000000593

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Review • Arch. Endocrinol. Metab. 67 (3) • May-Jun 2023 • https://doi.org/10.20945/2359-3997000000593 copy

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

Authorship SCIMAGO INSTITUTIONS RANKINGS

ABSTRACT

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.

Keywords
Congenital adrenal hyperplasia; CYP21A2 gene; Brazilian patients; molecular diagnosis; classical forms; 21-hydroxylase deficiency

Author	Region	Number of patients	Large gene rearrangement	Point-mutation
De Carvalho D²⁸28 Kopacek C, Prado M, da Silva C, de Castro S, Beltrão L, Vargas P, et al. Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation. J Pediatr. 2019;95(3):282-90.	Southeast	158 SW/116 SV/206 NC	Southern-Blot, MLPA	Sequencing, AS-PCR
Paulino L²⁷27 Araújo V. Estudo dos genes CYP21A2 e HSD3B2 em indivíduos portadores de hiperplasia adrenal congênita residentes do Distrito Federal [master's thesis]. Brasília: Universidade de Brasília; 2013.	Southeast	27 SW/14 SV	Southern-Blot	AS-PCR
Coeli-Lacchini F²⁹29 Paulino L, Araujo M, Guerra G, Marini S, Mello M. Mutation distribution and CYP21/C4 locus variability in Brazilian families with the classical form of the 21-hydroxylase deficiency. Acta Paediatr. 2007;88(3):275-83.	Southeast	32 SW/29 SV/29 NC	MLPA	Sequencing, AS-PCR
Castro P³⁰30 de Carvalho D, Miranda M, Gomes L, Madureira G, Marcondes J, Billerbeck A, et al. Molecular CYP21A2 diagnosis in 480 Brazilian patients with congenital adrenal hyperplasia before newborn screening introduction. Eur J Endocrinol. 2016;175(2):107-16.	Southeast	0 SW/0 SV/10 NC	MLPA	AS-PCR
Kopacek C²⁶26 Toralles M. Deficiência de 21-hidroxilase (forma clássica) em indivíduos miscigenados da Bahia – Estudo clínico, familial e molecular [unpublished dissertation]. Salvador: Universidade Federal da Bahia; 1999.	South	12 SW/3 SV/7 NC	MLPA	SNaPshot assay
Araújo V²⁵25 Campos V, Pereira R, Torres N, Castro M, Aguiar-Oliveira M. High frequency of p.Q318X mutation in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency in northeast Brazil. Arq Bras Endocrinol Metabol. 2009;53(1):40-6.	Center-West	15 SW/14 SV	MLPA	Sequencing, AS-PCR
Carvalho T²²22 Sarkar S, Chang C. The Simes Method for Multiple Hypothesis Testing with Positively Dependent Test Statistics. J Am Stat Assoc. 1997;92(440):1601-8.	North	15 SW/19 SV/12 NC	-	Sequencing
Toralles M²⁴24 Carvalho T, Souza I, Yoshioka F, Caldato M, Torres N, Garcia L, et al. CYP21 gene mutations in Brazilian patients with 21-hydroxylase deficiency from the Amazon region. Genet Mol Biol. 2008;31(3):626-31.	Northeast	10 SW/20 SV	-	AS-PCR
Campos V²³23 R Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, Austria; 2016. Available from: https://www.R-project.org/ https://www.R-project.org/...	Northeast	7 SW/9 SV/5 NC	-	AS-PCR

Mutations	Center-West			Northeast			North			Southeast			South
	SW	SV	NC	SW	SV	NC	SW	SV	NC	SW	SV	NC	SW	SV	NC
IVS2-13A/C>G	10	12	0	7.2	8. 4	2.4	21.7	14.1	3.2	12.4	5.8	3.8	17.5	5	2.5
p.Q318X	14	2	0	10.8	6	0	3.2	4.3	5.4	4.5	2	0.4	2.5	0	5
p.I172N	2	2	0	1.2	10.8	0	0	1.1	1.1	0.6	9.9	0.8	2.5	7.5	0
p.V281L	4	4	0	1.2	1. 2	4.8	3.2	5.4	4.3	0.4	0.2	25.7	0	0	20
p.R356W	0	0	0	2.4	4. 8	1.2	0	1.1	0	3.9	1.8	1	2.5	0	5
p.L307Ffs	4	0	0	3.6	0	0	0	1.1	1,1	1.5	0.2	0.4	2.5	2.5	0
CL6	0	0	0	0	0	0	3.2	3.2	1.1	0.6	0.4	0.2	2.5	0	0
p.G110Vfs	0	0	0	0	0	1.2	0	2.1	1.1	1.3	0.2	0.4	0	0	0
p.P30L	2	2	0	0	0	1.2	0	6.5	1.1	0	0.4	0.9	0	0	0
p.P453S	0	2	0	0	2. 4	0	0	0	0	0	0	1	0	0	5

Section and Topic	Item #	Checklist item	Location where item is reported
TITLE
Title	1	Identify the report as a systematic review.	1
ABSTRACT
Abstract	2	See the PRISMA 2020 for Abstracts checklist.	2
INTRODUCTION
Rationale	3	Describe the rationale for the review in the context of existing knowledge.	3
Objectives	4	Provide an explicit statement of the objective(s) or question(s) the review addresses.	4
METHODS
Eligibility criteria	5	Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.	4
Information sources	6	Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies. Specify the date when each source was last searched or consulted.	4
Search strategy	7	Present the full search strategies for all databases, registers and websites, including any filters and limits used.	4
Selection process	8	Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.	4
Data collection process	9	Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.	4
Data items	10a	List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.	4-5
	10b	List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.	5
Study risk of bias assessment	11	Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.	5
Effect measures	12	Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.	5
Synthesis methods	13a	Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).	5
	13b	Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.	NA
	13c	Describe any methods used to tabulate or visually display results of individual studies and syntheses.	NA
	13d	Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.	NA
	13e	Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).	NA
	13f	Describe any sensitivity analyses conducted to assess robustness of the synthesized results.	NA
Reporting bias assessment	14	Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).	NA
Certainty assessment	15	Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome.	NA
RESULTS
Study selection	16a	Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.	5
	16b	Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.	5
Study characteristics	17	Cite each included study and present its characteristics.	05-Jun
Risk of bias in studies	18	Present assessments of risk of bias for each included study.	05-Jun
Results of individual studies	19	For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.	06-Jul
Results of syntheses	20a	For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies.	6
	20b	Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.	NA
	20c	Present results of all investigations of possible causes of heterogeneity among study results.	NA
Reporting biases	21	Present assessments of risk of bias due to missing results (arising from reporting biases) for each synthesis assessed.	NA
Certainty of evidence	22	Present assessments of certainty (or confidence) in the body of evidence for each outcome assessed.	NA
DISCUSSION
Discussion	23a	Provide a general interpretation of the results in the context of other evidence.	08-Nov
	23b	Discuss any limitations of the evidence included in the review.	10-Nov
	23c	Discuss any limitations of the review processes used.	11
	23d	Discuss implications of the results for practice, policy, and future research.	11
OTHER INFORMATION
Registration and protocol	24a	Provide registration information for the review, including register name and registration number, or state that the review was not registered.	4
	24b	Indicate where the review protocol can be accessed, or state that a protocol was not prepared.	4
	24c	Describe and explain any amendments to information provided at registration or in the protocol.	NA
Support	25	Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.	1
Competing interests	26	Declare any competing interests of review authors.	1
Availability of data, code and other materials	27	Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.	NA

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[1] Correspondence to: Tânia A. S. S. Bachega, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, Disciplina de Endocrinologia e Metabologia Av. Dr. Enéas de Carvalho Aguiar, 155, 2º andar, bloco 6 05403-900 – São Paulo, SP, Brasil. tbachega@usp.br