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The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency

The deficiency of 21-hydroxylase due to CYP21A2 pathogenic variants is a rather frequent disease with serious consequences, going from a real mortality risk to infertility and to milder symptoms, nevertheless important for affecting the patients' self-esteem. In the most severe cases life-threa...

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Autores principales: Pignatelli, Duarte, Carvalho, Berta L., Palmeiro, Aida, Barros, Alberto, Guerreiro, Susana G., Macut, Djuro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620563/
https://www.ncbi.nlm.nih.gov/pubmed/31333583
http://dx.doi.org/10.3389/fendo.2019.00432
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author Pignatelli, Duarte
Carvalho, Berta L.
Palmeiro, Aida
Barros, Alberto
Guerreiro, Susana G.
Macut, Djuro
author_facet Pignatelli, Duarte
Carvalho, Berta L.
Palmeiro, Aida
Barros, Alberto
Guerreiro, Susana G.
Macut, Djuro
author_sort Pignatelli, Duarte
collection PubMed
description The deficiency of 21-hydroxylase due to CYP21A2 pathogenic variants is a rather frequent disease with serious consequences, going from a real mortality risk to infertility and to milder symptoms, nevertheless important for affecting the patients' self-esteem. In the most severe cases life-threatening adrenal salt wasting crises may occur. Significant morbidity including the possibility of mistaken gender determination, precocious puberty, infertility and growth arrest with consequent short stature may also affect these patients. In the less severe cases milder symptoms like hirsutism will likely affect the image of the self with strong psychological consequences. Its diagnosis is confirmed by 17OH-progesterone dosages exceeding the cut-off value of 10/15 ng/ml but genotyping is progressively assuming an essential role in the study of these patients particularly in confirming difficult cases, determining some aspects of the prognosis and allowing a correct genetic counseling. Genotyping is a difficult process due to the occurrence of both a gene and a highly homologous pseudo gene. However, new tools are opening new possibilities to this analysis and improving the chances of a correct diagnosis and better understanding of the underlying mechanisms of the disease. Beyond the 10 classic pathogenic variants usually searched for in most laboratories, a correct analysis of 21OH-deficiency cases implies completely sequencing of the entire gene and the determination of gene duplications. These are now recognized to occur frequently and can be responsible for some false positive cases. And finally, because gene conversions can include several pathogenic variants one cannot be certain of identifying that both alleles are affected without studying parental DNA samples. A complete genotype characterization should be considered essential in the preparation for pregnancy, even in the case of parents with milder forms of the disease, or even just carriers, since it has been reported that giving birth to progeny with the severe classic forms occurs with a much higher frequency than expected.
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spelling pubmed-66205632019-07-22 The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency Pignatelli, Duarte Carvalho, Berta L. Palmeiro, Aida Barros, Alberto Guerreiro, Susana G. Macut, Djuro Front Endocrinol (Lausanne) Endocrinology The deficiency of 21-hydroxylase due to CYP21A2 pathogenic variants is a rather frequent disease with serious consequences, going from a real mortality risk to infertility and to milder symptoms, nevertheless important for affecting the patients' self-esteem. In the most severe cases life-threatening adrenal salt wasting crises may occur. Significant morbidity including the possibility of mistaken gender determination, precocious puberty, infertility and growth arrest with consequent short stature may also affect these patients. In the less severe cases milder symptoms like hirsutism will likely affect the image of the self with strong psychological consequences. Its diagnosis is confirmed by 17OH-progesterone dosages exceeding the cut-off value of 10/15 ng/ml but genotyping is progressively assuming an essential role in the study of these patients particularly in confirming difficult cases, determining some aspects of the prognosis and allowing a correct genetic counseling. Genotyping is a difficult process due to the occurrence of both a gene and a highly homologous pseudo gene. However, new tools are opening new possibilities to this analysis and improving the chances of a correct diagnosis and better understanding of the underlying mechanisms of the disease. Beyond the 10 classic pathogenic variants usually searched for in most laboratories, a correct analysis of 21OH-deficiency cases implies completely sequencing of the entire gene and the determination of gene duplications. These are now recognized to occur frequently and can be responsible for some false positive cases. And finally, because gene conversions can include several pathogenic variants one cannot be certain of identifying that both alleles are affected without studying parental DNA samples. A complete genotype characterization should be considered essential in the preparation for pregnancy, even in the case of parents with milder forms of the disease, or even just carriers, since it has been reported that giving birth to progeny with the severe classic forms occurs with a much higher frequency than expected. Frontiers Media S.A. 2019-07-04 /pmc/articles/PMC6620563/ /pubmed/31333583 http://dx.doi.org/10.3389/fendo.2019.00432 Text en Copyright © 2019 Pignatelli, Carvalho, Palmeiro, Barros, Guerreiro and Macut. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Pignatelli, Duarte
Carvalho, Berta L.
Palmeiro, Aida
Barros, Alberto
Guerreiro, Susana G.
Macut, Djuro
The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency
title The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency
title_full The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency
title_fullStr The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency
title_full_unstemmed The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency
title_short The Complexities in Genotyping of Congenital Adrenal Hyperplasia: 21-Hydroxylase Deficiency
title_sort complexities in genotyping of congenital adrenal hyperplasia: 21-hydroxylase deficiency
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620563/
https://www.ncbi.nlm.nih.gov/pubmed/31333583
http://dx.doi.org/10.3389/fendo.2019.00432
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