Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect

Autores
Marino, Roxana Marcela; Garrido, Natalia Perez; Costanzo, Mariana; Guercio, Gabriela Viviana; Juanes, Matías Hernan; Rocco, Carlos Alberto; Ramirez, Pablo; Warman, Diana M.; Ciaccio, Marta; Pena, Gladys; Feyling, José García; Miras, Mirta Beatriz; Rivarola, Marco Aurelio; Belgorosky, Alicia; Saraco, Nora Isabel
Año de publicación
2015
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Context: Aromatase is the key enzyme for estrogen biosynthesis and is encoded by the CYP19A1 gene. Since 1991, several molecular CYP19A1 gene alterations associated with aromatase deficiency have been described in both sexes. Objective: The objective of the study was to detect CYP19A1 mutations in five aromatasedeficient 46, XX patients, to describe the clinical follow-up from birth to puberty and to perform haplotype analysis associated with the high-frequency c.628G>A splice mutation in Argentinean patients. Design: The design of the study was the sequencing of the coding and flanking intronic regions of the CYP19A1 gene in all patients and parents. Haplotype analysis of patients carrying the c.628G>A mutation was also performed. Patients: Clinical and biochemical findings in five new cases and one previously reported female aromatase-deficient patient (46, XX) are described. All patients presented with ambiguous genitalia at birth. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency as well as other steroidogenic defects were ruled out. Results: Phenotypic variability among the affected patients was found during follow-up. Direct sequencing of the CYP19A1 gene from genomic DNA revealed one novel mutation (c.574C>T) in two patients. In silico analysis predicted the c.574C>T mutation to be probably damaging. Four of six nonrelated patients presented with the c.628G>A splice mutation. Haplotype analysis showed that the c.628G>A splice mutation is associated with the same haplotype in our population. Conclusions: Increased knowledge on phenotypical variability found in female aromatase-deficient patients is useful to improve the detection rate in this disorder. In our population, a genetic founder defect has probably contributed to an increase in the incidence of the c.628G>A splice mutation.
Fil: Marino, Roxana Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Garrido, Natalia Perez. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Costanzo, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Guercio, Gabriela Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Juanes, Matías Hernan. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rocco, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ramirez, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Warman, Diana M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Ciaccio, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Pena, Gladys. Hospital Infantil Municipal de Cordoba; Argentina
Fil: Feyling, José García. Hospital Regional de Concepcion; Argentina
Fil: Miras, Mirta Beatriz. Hospital de Ninos de la Santisima Trinidad; Argentina
Fil: Rivarola, Marco Aurelio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Saraco, Nora Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Materia
Aromatase
Aromatase Deficiency
Founder Effect
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/37138
Acceder
id CONICETDig_622dd60af02c6d42dde75a6a107b8728
oai_identifier_str oai:ri.conicet.gov.ar:11336/37138
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effectMarino, Roxana MarcelaGarrido, Natalia PerezCostanzo, MarianaGuercio, Gabriela VivianaJuanes, Matías HernanRocco, Carlos AlbertoRamirez, PabloWarman, Diana M.Ciaccio, MartaPena, GladysFeyling, José GarcíaMiras, Mirta BeatrizRivarola, Marco AurelioBelgorosky, AliciaSaraco, Nora IsabelAromataseAromatase DeficiencyFounder Effecthttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Context: Aromatase is the key enzyme for estrogen biosynthesis and is encoded by the CYP19A1 gene. Since 1991, several molecular CYP19A1 gene alterations associated with aromatase deficiency have been described in both sexes. Objective: The objective of the study was to detect CYP19A1 mutations in five aromatasedeficient 46, XX patients, to describe the clinical follow-up from birth to puberty and to perform haplotype analysis associated with the high-frequency c.628G>A splice mutation in Argentinean patients. Design: The design of the study was the sequencing of the coding and flanking intronic regions of the CYP19A1 gene in all patients and parents. Haplotype analysis of patients carrying the c.628G>A mutation was also performed. Patients: Clinical and biochemical findings in five new cases and one previously reported female aromatase-deficient patient (46, XX) are described. All patients presented with ambiguous genitalia at birth. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency as well as other steroidogenic defects were ruled out. Results: Phenotypic variability among the affected patients was found during follow-up. Direct sequencing of the CYP19A1 gene from genomic DNA revealed one novel mutation (c.574C>T) in two patients. In silico analysis predicted the c.574C>T mutation to be probably damaging. Four of six nonrelated patients presented with the c.628G>A splice mutation. Haplotype analysis showed that the c.628G>A splice mutation is associated with the same haplotype in our population. Conclusions: Increased knowledge on phenotypical variability found in female aromatase-deficient patients is useful to improve the detection rate in this disorder. In our population, a genetic founder defect has probably contributed to an increase in the incidence of the c.628G>A splice mutation.Fil: Marino, Roxana Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Garrido, Natalia Perez. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Costanzo, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Guercio, Gabriela Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Juanes, Matías Hernan. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rocco, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ramirez, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Warman, Diana M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Ciaccio, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Pena, Gladys. Hospital Infantil Municipal de Cordoba; ArgentinaFil: Feyling, José García. Hospital Regional de Concepcion; ArgentinaFil: Miras, Mirta Beatriz. Hospital de Ninos de la Santisima Trinidad; ArgentinaFil: Rivarola, Marco Aurelio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Saraco, Nora Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaEndocrine Society2015-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/37138Marino, Roxana Marcela; Garrido, Natalia Perez; Costanzo, Mariana; Guercio, Gabriela Viviana; Juanes, Matías Hernan; et al.; Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 100; 2; 2-2015; E301-E3070021-972XCONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1210/jc.2014-2967info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jcem/article/100/2/E301/2814966info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:06:16Zoai:ri.conicet.gov.ar:11336/37138instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 12:06:16.678CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect
title Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect
spellingShingle Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect
Marino, Roxana Marcela
Aromatase
Aromatase Deficiency
Founder Effect
title_short Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect
title_full Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect
title_fullStr Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect
title_full_unstemmed Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect
title_sort Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect
dc.creator.none.fl_str_mv Marino, Roxana Marcela
Garrido, Natalia Perez
Costanzo, Mariana
Guercio, Gabriela Viviana
Juanes, Matías Hernan
Rocco, Carlos Alberto
Ramirez, Pablo
Warman, Diana M.
Ciaccio, Marta
Pena, Gladys
Feyling, José García
Miras, Mirta Beatriz
Rivarola, Marco Aurelio
Belgorosky, Alicia
Saraco, Nora Isabel
author Marino, Roxana Marcela
author_facet Marino, Roxana Marcela
Garrido, Natalia Perez
Costanzo, Mariana
Guercio, Gabriela Viviana
Juanes, Matías Hernan
Rocco, Carlos Alberto
Ramirez, Pablo
Warman, Diana M.
Ciaccio, Marta
Pena, Gladys
Feyling, José García
Miras, Mirta Beatriz
Rivarola, Marco Aurelio
Belgorosky, Alicia
Saraco, Nora Isabel
author_role author
author2 Garrido, Natalia Perez
Costanzo, Mariana
Guercio, Gabriela Viviana
Juanes, Matías Hernan
Rocco, Carlos Alberto
Ramirez, Pablo
Warman, Diana M.
Ciaccio, Marta
Pena, Gladys
Feyling, José García
Miras, Mirta Beatriz
Rivarola, Marco Aurelio
Belgorosky, Alicia
Saraco, Nora Isabel
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Aromatase
Aromatase Deficiency
Founder Effect
topic Aromatase
Aromatase Deficiency
Founder Effect
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Context: Aromatase is the key enzyme for estrogen biosynthesis and is encoded by the CYP19A1 gene. Since 1991, several molecular CYP19A1 gene alterations associated with aromatase deficiency have been described in both sexes. Objective: The objective of the study was to detect CYP19A1 mutations in five aromatasedeficient 46, XX patients, to describe the clinical follow-up from birth to puberty and to perform haplotype analysis associated with the high-frequency c.628G>A splice mutation in Argentinean patients. Design: The design of the study was the sequencing of the coding and flanking intronic regions of the CYP19A1 gene in all patients and parents. Haplotype analysis of patients carrying the c.628G>A mutation was also performed. Patients: Clinical and biochemical findings in five new cases and one previously reported female aromatase-deficient patient (46, XX) are described. All patients presented with ambiguous genitalia at birth. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency as well as other steroidogenic defects were ruled out. Results: Phenotypic variability among the affected patients was found during follow-up. Direct sequencing of the CYP19A1 gene from genomic DNA revealed one novel mutation (c.574C>T) in two patients. In silico analysis predicted the c.574C>T mutation to be probably damaging. Four of six nonrelated patients presented with the c.628G>A splice mutation. Haplotype analysis showed that the c.628G>A splice mutation is associated with the same haplotype in our population. Conclusions: Increased knowledge on phenotypical variability found in female aromatase-deficient patients is useful to improve the detection rate in this disorder. In our population, a genetic founder defect has probably contributed to an increase in the incidence of the c.628G>A splice mutation.
Fil: Marino, Roxana Marcela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Garrido, Natalia Perez. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Costanzo, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Guercio, Gabriela Viviana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Juanes, Matías Hernan. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Rocco, Carlos Alberto. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Ramirez, Pablo. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Warman, Diana M.. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Ciaccio, Marta. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Pena, Gladys. Hospital Infantil Municipal de Cordoba; Argentina
Fil: Feyling, José García. Hospital Regional de Concepcion; Argentina
Fil: Miras, Mirta Beatriz. Hospital de Ninos de la Santisima Trinidad; Argentina
Fil: Rivarola, Marco Aurelio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Belgorosky, Alicia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Saraco, Nora Isabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
description Context: Aromatase is the key enzyme for estrogen biosynthesis and is encoded by the CYP19A1 gene. Since 1991, several molecular CYP19A1 gene alterations associated with aromatase deficiency have been described in both sexes. Objective: The objective of the study was to detect CYP19A1 mutations in five aromatasedeficient 46, XX patients, to describe the clinical follow-up from birth to puberty and to perform haplotype analysis associated with the high-frequency c.628G>A splice mutation in Argentinean patients. Design: The design of the study was the sequencing of the coding and flanking intronic regions of the CYP19A1 gene in all patients and parents. Haplotype analysis of patients carrying the c.628G>A mutation was also performed. Patients: Clinical and biochemical findings in five new cases and one previously reported female aromatase-deficient patient (46, XX) are described. All patients presented with ambiguous genitalia at birth. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency as well as other steroidogenic defects were ruled out. Results: Phenotypic variability among the affected patients was found during follow-up. Direct sequencing of the CYP19A1 gene from genomic DNA revealed one novel mutation (c.574C>T) in two patients. In silico analysis predicted the c.574C>T mutation to be probably damaging. Four of six nonrelated patients presented with the c.628G>A splice mutation. Haplotype analysis showed that the c.628G>A splice mutation is associated with the same haplotype in our population. Conclusions: Increased knowledge on phenotypical variability found in female aromatase-deficient patients is useful to improve the detection rate in this disorder. In our population, a genetic founder defect has probably contributed to an increase in the incidence of the c.628G>A splice mutation.
publishDate 2015
dc.date.none.fl_str_mv 2015-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/37138
Marino, Roxana Marcela; Garrido, Natalia Perez; Costanzo, Mariana; Guercio, Gabriela Viviana; Juanes, Matías Hernan; et al.; Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 100; 2; 2-2015; E301-E307
0021-972X
CONICET Digital
CONICET
url http://hdl.handle.net/11336/37138
identifier_str_mv Marino, Roxana Marcela; Garrido, Natalia Perez; Costanzo, Mariana; Guercio, Gabriela Viviana; Juanes, Matías Hernan; et al.; Five new cases of 46, XX aromatase deficiency: Clinical follow-up from birth to puberty, a novel mutation, and a founder effect; Endocrine Society; Journal of Clinical Endocrinology and Metabolism; 100; 2; 2-2015; E301-E307
0021-972X
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1210/jc.2014-2967
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/jcem/article/100/2/E301/2814966
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Endocrine Society
publisher.none.fl_str_mv Endocrine Society
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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