Genotype-Phenotype Correlation Study in 529 Patients with Multiple Hereditary Exostoses: Identification of “Protective” and “Risk” Factors

Pedrini, Elena; Jennes, Ivy; Tremosini, Morena; Milanesi, Annamaria; Mordenti, Marina; Parra, Alessandro; Sgariglia, Federica; Zuntini, Monia; Campanacci, Laura; Fabbri, Nicola; Pignotti, Elettra; Wuyts, Wim; Sangiorgi, Luca

doi:10.2106/jbjs.j.00949

Cited by 111 publications

(132 citation statements)

References 25 publications

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“…As such, part of our study aim was to record the number of surgeries patients with multiple hereditary exostoses have undergone as an approximation of their disease burden. There is large variation among patients in the number and location of lesions, and the degree of orthopaedic deformities and how functional impairments manifest [11].…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have shown a wide range in the numbers of patients with multiple hereditary exostoses who have had malignant change to chondrosarcoma, and these studies [3,7,8,[12][13][14] cite proportions derived from smaller population clusters in seemingly isolated geographic areas. Historically, reported proportions of transformation have ranged from less than 1% to approximately 25% [3,4,[7][8][9][11][12][13][14]. Some of the larger studies we are aware of include rates of 4.9% in 529 patients [11], 0.38% in 526 patients [8], and 7% in 184 patients [4].…”

Section: Introductionmentioning

confidence: 99%

“…Historically, reported proportions of transformation have ranged from less than 1% to approximately 25% [3,4,[7][8][9][11][12][13][14]. Some of the larger studies we are aware of include rates of 4.9% in 529 patients [11], 0.38% in 526 patients [8], and 7% in 184 patients [4]. Pedrini et al [11] presented the largest cohort to date in their genotype-phenotype correlation study of 529 patients with multiple hereditary exostoses.…”

Section: Introductionmentioning

confidence: 99%

“…Some of the larger studies we are aware of include rates of 4.9% in 529 patients [11], 0.38% in 526 patients [8], and 7% in 184 patients [4]. Pedrini et al [11] presented the largest cohort to date in their genotype-phenotype correlation study of 529 patients with multiple hereditary exostoses. They primarily sought to identify ''protective'' and ''risk'' factors associated with the disease.…”

Section: Introductionmentioning

confidence: 99%

“…They primarily sought to identify ''protective'' and ''risk'' factors associated with the disease. Their comprehensive analytic study secondarily identified a malignant progression rate of 4.9% (26 cases of chondrosarcoma in 529 patients with multiple hereditary exostoses) [11]. Therefore, we sought to determine a more accurate proportion of patients with multiple hereditary exostoses who have had malignant degeneration.…”

Section: Introductionmentioning

confidence: 99%

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What is the Proportion of Patients With Multiple Hereditary Exostoses Who Undergo Malignant Degeneration?

Czajka

DiCaprio

2015

Clinical Orthopaedics &Amp; Related Research

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Background Multiple hereditary exostoses is an autosomal-dominant skeletal disorder that has a wide-ranging reported risk of malignant degeneration to chondrosarcoma. Questions/purposes The aims of our study were to use a large, web-based survey approach to characterize (1) the demographic distribution of patients with multiple hereditary exostoses, (2) the number of surgeries performed related to one's diagnosis of multiple hereditary exostoses, and (3) the proportion of survey respondents who described experiencing malignant degeneration in a large international, heterogeneous cohort of patients with multiple hereditary exostoses. Methods An anonymous web-based survey was distributed to several online support groups and social media networks designed to support and educate patients with multiple hereditary exostoses and their families. The survey collected demographic and epidemiologic data on 779 respondents. Data were recorded to assess respondents' disease burden and the rate of malignant degeneration.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

What is the Proportion of Patients With Multiple Hereditary Exostoses Who Undergo Malignant Degeneration?

Czajka

DiCaprio

2015

Clinical Orthopaedics &Amp; Related Research

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Molecular Genetics of Multiple Osteochondromas

Andrea

Hogendoorn

Bovée

2016

Encyclopedia of Life Sciences

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Multiple osteochondromas (MOs) is an autosomal dominant disease characterised by MOs (previously named exostoses). Their formation requires bi‐allelic inactivation of EXT1 or EXT2 genes in growth plate cartilage. They encode glycosyltransferases that catalyse the chain elongation step in heparan sulfate biosynthesis and when mutated cause a variety of growth factor signalling defects, impaired cell–matrix interactions and loss of polarity. Osteochondromas are not clonal neoplasms, but a mixed population of cells harbouring homozygous loss of either EXT genes or cells retaining the EXT wild‐type allele. About 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary chondrosarcoma. Cells harbouring the wild‐type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation, possibly by inactivation of the CDKN2A locus. This locus encodes INK4a (p16), which regulates RB1, and p19ARF, which regulates P53. Inactivation of CDKN2A by mutation or deletion is a common pathway for oncogenesis. Key Concepts Patients with MO are characterised genetically by germline mutations in EXT1 and EXT2 genes and phenotypically by the development of at least two osteochondromas. Osteochondroma is a benign cartilage‐capped bony projection arising on the external surface of bone containing a marrow cavity that is continuous with that of the underlying bone. Osteochondromas are the most frequent cartilaginous lesions, most often found on the femur (21%), humerus (17%) and tibia (11%). Somatic inactivation of both EXT alleles results in significantly shorter heparan sulfate chains. Defective heparan sulfate biosynthesis results in abnormal diffusion and signalling of IHH and FGFR3 causing increased proliferation and delayed differentiation. Approximately 1–5% of patients with MO at the age of 30–60 years will eventually develop a secondary peripheral chondrosarcoma. An osteochondroma cap exceeding 1.5–2 cm in adults is suggestive of malignancy. The most common location for malignant transformation of an osteochondroma is the pelvis, where large lesions can be difficult to excise completely. Cells harbouring the wild‐type alleles of EXT1 and EXT2 genes are thought to preferentially undergo malignant transformation. Secondary peripheral chondrosarcoma typically shows chromosome instability with gains and losses and genomic diversity that increases with increasing grade of malignancy. Loss of heterozygosity for the chromosomal bands bearing the RB1 and CDKN2A ( p16INK4a ) tumour suppressor genes is often found.

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Associations Between Safety of Certolizumab Pegol, Disease Activity, and Patient Characteristics, Including Corticosteroid Use and Body Mass Index

Bykerk

Blauvelt

Curtis

et al. 2021

ACR Open Rheumatology

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Objective To investigate the impact of baseline and time‐varying factors on the risk of serious adverse events (SAEs) in patients during long‐term certolizumab pegol (CZP) treatment. Methods Safety data were pooled across 34 CZP clinical trials in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and plaque psoriasis (PSO). Cox proportional hazards modeling was used to investigate the association of baseline patient characteristics with risk of serious infectious events (SIEs), malignancies, and major adverse cardiac events (MACEs). Cox modeling for recurrent events assessed the impact of time‐varying body mass index (BMI), systemic corticosteroid (CS) use, and disease activity on SIE risk in RA and SAE risk in PSO. Results Data were pooled from 8747 CZP‐treated patients across indications. Cox models reported a 44% increase in SIE risk associated with a baseline BMI of 35 kg/m2 or more versus a baseline BMI of 18.5 kg/m2 to less than 25 kg/m2. Baseline systemic CS use, age of 65 years or more, and disease duration of 10 years or longer also increased SIE risk. Older age was the only identified risk factor for malignancies. The risk of MACEs increased 107% for BMI of 35 kg/m2 or more versus BMI of 18.5 kg/m2 to less than 25 kg/m2 and increased 51% for men versus women. Higher disease activity, older age, systemic CS use, BMI of 35 kg/m2 or more, and baseline comorbidities were SIE risk factors in RA. Age and systemic CS use were risk factors for SAEs in PSO. Conclusion Age, BMI, systemic CS use, and disease activity were identified as SIE risk factors in CZP‐treated patients. Risk of malignancies was greater in older patients, whereas obesity and male sex were MACE risk factors.

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Genotype-Phenotype Correlation Study in 529 Patients with Multiple Hereditary Exostoses: Identification of “Protective” and “Risk” Factors

Cited by 111 publications

References 25 publications

What is the Proportion of Patients With Multiple Hereditary Exostoses Who Undergo Malignant Degeneration?

What is the Proportion of Patients With Multiple Hereditary Exostoses Who Undergo Malignant Degeneration?

Molecular Genetics of Multiple Osteochondromas

Associations Between Safety of Certolizumab Pegol, Disease Activity, and Patient Characteristics, Including Corticosteroid Use and Body Mass Index

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