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Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes
CONTEXT: Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding. OBJECTIVE: We undertook genetic...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530715/ https://www.ncbi.nlm.nih.gov/pubmed/34136918 http://dx.doi.org/10.1210/clinem/dgab437 |
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author | Andrews, Afiya Maharaj, Avinaash Cottrell, Emily Chatterjee, Sumana Shah, Pratik Denvir, Louise Dumic, Katja Bossowski, Artur Mushtaq, Talat Vukovic, Rade Didi, Mohamed Shaw, Nick Metherell, Louise A Savage, Martin O Storr, Helen L |
author_facet | Andrews, Afiya Maharaj, Avinaash Cottrell, Emily Chatterjee, Sumana Shah, Pratik Denvir, Louise Dumic, Katja Bossowski, Artur Mushtaq, Talat Vukovic, Rade Didi, Mohamed Shaw, Nick Metherell, Louise A Savage, Martin O Storr, Helen L |
author_sort | Andrews, Afiya |
collection | PubMed |
description | CONTEXT: Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding. OBJECTIVE: We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH–IGF-I axis defects. METHODS: Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel. RESULTS: Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH–IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver–Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome). CONCLUSION: We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management. |
format | Online Article Text |
id | pubmed-8530715 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-85307152021-10-25 Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes Andrews, Afiya Maharaj, Avinaash Cottrell, Emily Chatterjee, Sumana Shah, Pratik Denvir, Louise Dumic, Katja Bossowski, Artur Mushtaq, Talat Vukovic, Rade Didi, Mohamed Shaw, Nick Metherell, Louise A Savage, Martin O Storr, Helen L J Clin Endocrinol Metab Online Only Articles CONTEXT: Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding. OBJECTIVE: We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH–IGF-I axis defects. METHODS: Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel. RESULTS: Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH–IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver–Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome). CONCLUSION: We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management. Oxford University Press 2021-06-16 /pmc/articles/PMC8530715/ /pubmed/34136918 http://dx.doi.org/10.1210/clinem/dgab437 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Online Only Articles Andrews, Afiya Maharaj, Avinaash Cottrell, Emily Chatterjee, Sumana Shah, Pratik Denvir, Louise Dumic, Katja Bossowski, Artur Mushtaq, Talat Vukovic, Rade Didi, Mohamed Shaw, Nick Metherell, Louise A Savage, Martin O Storr, Helen L Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes |
title | Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes |
title_full | Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes |
title_fullStr | Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes |
title_full_unstemmed | Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes |
title_short | Genetic Characterization of Short Stature Patients With Overlapping Features of Growth Hormone Insensitivity Syndromes |
title_sort | genetic characterization of short stature patients with overlapping features of growth hormone insensitivity syndromes |
topic | Online Only Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530715/ https://www.ncbi.nlm.nih.gov/pubmed/34136918 http://dx.doi.org/10.1210/clinem/dgab437 |
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