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Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report

BACKGROUND: Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN ge...

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Autores principales: Mohammadian Khonsari, Nami, Mohammad Poor Nami, Sahar, Hakak-Zargar, Benyamin, Voth, Tessa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492327/
https://www.ncbi.nlm.nih.gov/pubmed/32935225
http://dx.doi.org/10.1186/s40348-020-00104-6
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author Mohammadian Khonsari, Nami
Mohammad Poor Nami, Sahar
Hakak-Zargar, Benyamin
Voth, Tessa
author_facet Mohammadian Khonsari, Nami
Mohammad Poor Nami, Sahar
Hakak-Zargar, Benyamin
Voth, Tessa
author_sort Mohammadian Khonsari, Nami
collection PubMed
description BACKGROUND: Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature. CASE PRESENTATION: We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient’s phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient’s father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature. CONCLUSION: We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.
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spelling pubmed-74923272020-09-28 Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report Mohammadian Khonsari, Nami Mohammad Poor Nami, Sahar Hakak-Zargar, Benyamin Voth, Tessa Mol Cell Pediatr Case Study BACKGROUND: Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature. CASE PRESENTATION: We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient’s phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient’s father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature. CONCLUSION: We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case. Springer Berlin Heidelberg 2020-09-16 /pmc/articles/PMC7492327/ /pubmed/32935225 http://dx.doi.org/10.1186/s40348-020-00104-6 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Case Study
Mohammadian Khonsari, Nami
Mohammad Poor Nami, Sahar
Hakak-Zargar, Benyamin
Voth, Tessa
Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report
title Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report
title_full Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report
title_fullStr Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report
title_full_unstemmed Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report
title_short Mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report
title_sort mutations of uncertain significance in heterozygous variants as a possible cause of severe short stature: a case report
topic Case Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492327/
https://www.ncbi.nlm.nih.gov/pubmed/32935225
http://dx.doi.org/10.1186/s40348-020-00104-6
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