scholarly journals Hereditary Multiple Exostoses—A Review of the Molecular Background, Diagnostics, and Potential Therapeutic Strategies

2021 ◽  
Vol 12 ◽  
Author(s):  
Ewelina Bukowska-Olech ◽  
Wiktoria Trzebiatowska ◽  
Wiktor Czech ◽  
Olga Drzymała ◽  
Piotr Frąk ◽  
...  
Keyword(s):  
Treatment Options ◽  
Cord Compression ◽  
Diagnostic Methods ◽  
Molecular Diagnostic ◽  
Loss Of Function ◽  
Systematic Analysis ◽  
Hereditary Multiple Exostoses ◽  
Pathogenic Variants ◽  
Multiple Osteochondromas ◽  
Multiple Exostoses

Hereditary multiple exostoses (HMEs) syndrome, also known as multiple osteochondromas, represents a rare and severe human skeletal disorder. The disease is characterized by multiple benign cartilage-capped bony outgrowths, termed exostoses or osteochondromas, that locate most commonly in the juxta-epiphyseal portions of long bones. Affected individuals usually complain of persistent pain caused by the pressure on neighboring tissues, disturbance of blood circulation, or rarely by spinal cord compression. However, the most severe complication of this condition is malignant transformation into chondrosarcoma, occurring in up to 3.9% of HMEs patients. The disease results mainly from heterozygous loss-of-function alterations in the EXT1 or EXT2 genes, encoding Golgi-associated glycosyltransferases, responsible for heparan sulfate biosynthesis. Some of the patients with HMEs do not carry pathogenic variants in those genes, hence the presence of somatic mutations, deep intronic variants, or another genes/loci is suggested. This review presents the systematic analysis of current cellular and molecular concepts of HMEs along with clinical characteristics, clinical and molecular diagnostic methods, differential diagnosis, and potential treatment options.

scholarly journals Identification of a Novel EXT Mutation in A Kindred With Hereditary Multiple Exostoses Using Whole-Exome Sequencing and Overview of Mutation Spectrum

2021 ◽  
Author(s):  
yanhan deng ◽  
yujian liu ◽  
wei tu ◽  
liu yang
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Mutation Spectrum ◽  
Loss Of Function ◽  
Site Mutation ◽  
Hereditary Multiple Exostoses ◽  
Multiple Osteochondromas ◽  
Online Databases ◽  
Whole Exome ◽  
Multiple Exostoses

Abstract Background: Hereditary Multiple Osteochondromas(HMO) is a rare genetic musculoskeletal disorder characterized by multiple osteochondromas that form near to the growth plates of many bones. Loss-of-function mutations in EXT1 or EXT2 that encode glycosyltrasferases are the causal mutations for most HMO patients.Methods: After collecting the family history and clinical information, we used Whole-Exome Sequencing to find the pathogenic mutations in one Chinese Hereditary Multiple Exostoses pedigree. Sanger sequencing and relevant online databases were used to validate the screened variants. Lollipop plots were drew to map the reported mutations from online databases (Multiple Osteochondroma Mutation Database and clinvar)on a linear protein domains by MutationMapper.Results: A novel heterozygous splicing-site mutation in gene EXT1 (NM_000127:exon5:c.1417+1G>C，chr8:118834703) was found in this pedigree and mutation spectrum of genes EXT1 and EXT2 were demonstrated.Conclusions: Our results help this pedigree to identify the pathogenic variant and guide the prenatal diagnosis, also expand the mutation spectrum in Hereditary Multiple Osteochondromas.

Assessment of a highly curated somatic oncology mutation database to facilitate identification of clinically important variants in NGS results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18086-e18086
Author(s):  
Xiaoju Max Ma ◽  
Stephanie J. Yaung ◽  
Liu Xi ◽  
Christine Ju ◽  
John F. Palma ◽  
...  
Keyword(s):  
Clinical Evidence ◽  
Kinase Inhibitor ◽  
Treatment Options ◽  
Standard Of Care ◽  
Diagnostic Methods ◽  
Initial Assessment ◽  
Treatment Regimens ◽  
Pathogenic Variants ◽  
Mutation Database ◽  
Egfr Tki

e18086 Background: The increasing adoption of Next Generation Sequencing (NGS) in molecular profiling of cancer presents a growing need for streamlined interpretation of NGS results in clinical labs. This can be achieved through bioinformatics tools equipped with a highly-curated database on clinically important variants. Methods: We performed an initial assessment of an NGS result interpretation tool called NAVIFY Mutation Profiler (NMP), which enabled us to process a Variant Call Format (VCF) file and generate a report with consensus recommendations of NCCN, ASCO, CAP and ACMG. This annotation tool identifies pathogenic variants and variants of unknown clinical significance (VUS), and groups variants by AMP Tiers. At the time of this assessment, NMP contained curation for ~4,000 variants. In this study, we used NGS results from 38 anonymized clinical cases with known treatment regimens to retrospectively assess NMP as the variant interpretation tool. Our cohort contained lung cancer subjects treated with EGFR tyrosine kinase inhibitor (TKI) (5 cases), as well as subjects relapsed against EGFR TKI (1 case) or ALK TKI crizotinib (22 cases). We also included 10 control cases where standard of care chemo was used because initial diagnostic methods did not reveal any actionable targets. Results: NMP annotated NGS VCF data and generated a report within 10 minutes per case although some cases contained > 100 variants. NMP correctly associated EGFR TKI therapies options with the corresponding 5 cases. As expected, NMP did not recommend targeted therapies for the 10 chemo-treated control cases. For the subject relapsed against EGFR TKI, NMP correctly interpreted the complex EGFR mutation profile containing both activating (L858R) and drug-resistance (T790M) variants. In addition, out of 22 cases relapsed against ALK TKI crizotinib, NMP correctly marked 14 with crizotinib resistance when a known ALK variant conferring crizotinib resistance was detected. There was limited or no published clinical evidence to interpret the remaining 8 cases of ALK TKI resistance. Conclusions: NMP correctly interpreted cases containing EGFR and ALK variants in this study. With a highly-curated knowledge base, this tool simplifies NGS clinical reporting by identifying clinically actionable mutations and associating treatment options qualified by supporting clinical evidence.

Hereditary multiple exostoses: an unusual cause of spinal cord compression

2015 ◽  
Vol 116 (3) ◽  
pp. 357-358 ◽  
Author(s):  
Antonija Krstačić ◽  
Ivana Župetić ◽  
Goran Krstačić ◽  
Ljubica Luetić Čavor ◽  
Silva Butković Soldo
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Compression ◽  
Cord Compression ◽  
Hereditary Multiple Exostoses ◽  
Multiple Exostoses

Acute spinal cord compression in hereditary multiple exostoses

2005 ◽  
Vol 148 (2) ◽  
pp. 195-198 ◽  
Author(s):  
S. Aldea ◽  
F. Bonneville ◽  
J. Poirier ◽  
J. Chiras ◽  
B. George ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Compression ◽  
Cord Compression ◽  
Hereditary Multiple Exostoses ◽  
Multiple Exostoses

Hereditary Multiple Exostoses and Cervical Cord Compression

1989 ◽  
Vol 13 (2) ◽  
pp. 330-333 ◽  
Author(s):  
Richard J. Tully ◽  
James Pickens ◽  
John Oro ◽  
Clive Levine
Keyword(s):  
Cord Compression ◽  
Cervical Cord ◽  
Hereditary Multiple Exostoses ◽  
Cervical Cord Compression ◽  
Multiple Exostoses

scholarly journals A Young Boy with Multiple Bony Overgrowths

2019 ◽  
Vol 9 (1) ◽  
pp. 60-63
Author(s):  
MA Hannan ◽  
Md Rakibul Hasan ◽  
Sharmin Jahan ◽  
Md Shahed Morshed
Keyword(s):  
Autosomal Dominant ◽  
Bone Development ◽  
Loss Of Function ◽  
Hereditary Multiple Exostoses ◽  
Multiple Exostoses ◽  
Careful Screening ◽  
Timely Referral ◽  
Definite Treatment

Hereditary multiple exostoses is a rare autosomal dominant pediatric disorder with an incidence of about 1:50000 characterized by multiple cartilage-capped bony protuberances, called osteochondromas or exostoses, projecting from the metaphyses of long bones. It is caused by loss of function mutations in exostosin-1 and exostosin-2 genes that encode glycosyltransferase enzymes involved in the synthesis of heparan sulfate which has fundamental role in extracellular matrix formation during bone development. It commonly presents with compressive symptoms due to bony overgrowth involving all bones except calvarium and rarely transformed into malignancy. No definite treatment is available, but careful screening of these exostoses with timely referral to respective surgeon prevents long term complications and improves quality of life. J Enam Med Col 2019; 9(1): 60-63

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