Muscle Connective Tissue in Limb Development and Disease

Study Overview
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Brief Summary
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The objective of this work is to understand how the disruption of the muscle connective tissue contributes to the limb soft-tissue defects in radial dysplasia. In parallel, the researchers will investigate the role of muscle connective tissue in normal limb development.

Detailed Description
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The objective of this work is to understand the origins of the soft tissue defects in a disabling, disfiguring limb anomaly called radial dysplasia, and what mechanisms of normal limb development have been disrupted in these patients to produce their phenotype. The investigators aim to use this knowledge to improve their treatment. Currently, despite sophisticated surgical treatment, the limb malformation the child is born with typically recurs as they grow: it is thus an 'unsolved problem'. The investigators have previously shown, in an experimental mouse model of radial dysplasia, the underlying soft tissue problem is a change in the muscle connective tissue and its derivatives, causing abnormal soft-tissue patterning. The investigators wish to expand this work into the investigators' patient population by comparing samples of post-natal muscle connective tissue derivatives from radial dysplasia patients with control samples. The investigators will ask patients undergoing corrective hand surgery to let the investigators take small tissue samples during their planned operations. The investigators will also ask patients having other forms of hand surgery, such as surgery for hand injuries, to let the investigators take similar samples for comparison. In either case, their scar and peri-operative treatment will be unchanged. The investigators will examine the tissue samples in the investigators' laboratory to look for changes in tissue architecture, cellular composition, cell signalling, and how they behave when grown in culture. The investigators will also make attempts to derive cell lines from biopsy samples to use in further studies, exploring cellular phenotype and functional capacity. Simultaneously, the investigators will look at the long-term surgical outcomes and the range of genetic changes in the investigators' patient population. Eligible patients will be referred for consideration in the (separate) 100,000 genome project; this should further expand the investigators' knowledge of the genetic changes underlying limb anomalies. The ability to combine data on genotype, long-term phenotype and soft tissue changes will give a comprehensive overview of the condition. The investigators expect this to lead to a better understanding of patient subgroups, and to provide a rational basis for improved treatment approaches.

Official Title
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Muscle Connective Tissue in Limb Development and Disease

Conditions
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Radial Dysplasia

Intervention / Treatment
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* Procedure: Tissue biopsy


Participation Criteria
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Eligibility Criteria
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Cases Inclusion Criteria: Patients with a clinical diagnosis of radial dysplasia, requiring reconstructive surgery Either sex Informed (parental) consent to participate Exclusion Criteria: Patients with a clinical diagnosis of radial dysplasia, but not requiring reconstructive surgery Patients with a diagnosis other than radial dysplasia Patients with extensive previous scarring to their forearm and hand. Patients with a significant pathological skin or soft tissue lesion at the donor site. Controls Inclusion Criteria: Patients with an injury requiring reconstructive surgery Either sex Informed (parental) consent to participate Exclusion Criteria: Patients with extensive previous scarring to their forearm and hand. Patients with a significant pathological skin or soft tissue lesion at the donor site.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Radial dysplasia patients<br>Recruited participants will have 2-3 small tissue biopsy samples taken during 1-2 of their planned reconstructive surgical procedures for radial dysplasia, whilst under general anaesthesia in the operating theatre. Samples will be taken by scalpel or scissors, by the operating surgeon, from within the surgical site in the forearm and hand. The skin incision and deep dissection will have to be made as part of the normal course of reconstructive surgery, regardless of participation in this study. | Procedure: Tissue biopsy<br>* Sampling of tissue as described.<br>|
| Control patients<br>Recruited participants will have 2-3 small tissue biopsy samples taken during their planned reconstructive surgery for hand trauma, whilst under general anaesthesia in the operating theatre. Samples will be taken by scalpel or scissors, by the operating surgeon, from within the surgical site in the forearm and hand. The skin incision and deep dissection will have to be made as part of the normal course of reconstructive surgery, regardless of participation in this study. | Procedure: Tissue biopsy<br>* Sampling of tissue as described.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterisation of muscle connective tissue derivatives - structure | The characterization of any structural difference in tissue organisation within muscle connective tissue derivatives, comparing normal control patients to patients with radial dysplasia. | 3 years | 
| Characterisation of muscle connective tissue derivatives - function | The characterization of any functional difference in gene expression within muscle connective tissue derivatives, comparing normal control patients to patients with radial dysplasia. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identification of biomarker(s). | The identification of a novel biomarker (or biomarkers) for human muscle connective tissue derivatives, which may potentially serve as a diagnostic or prognostic tool | 3 years | 
| Identification of muscle connective tissue progenitor-cell pool. | The potential identification of a stem-cell-like or progenitor-cell pool for muscle connective tissue derivatives in mature soft tissue. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Muscle connective tissue, Small leucine-rich proteoglycans, Limb development