Orthopedic manifestations of congenital muscular dystrophy subtypes in children: Emerging signatures need consolidation: a scoping review

Identifying research questions

This scoping review was carried out in accordance with the guidelines of the PRISMA extension for scoping reviews.^[32,33]

The goal of this scoping review was broken down into three research subquestions, namely;

1. How often are orthopedic manifestations reported in publications on CMD children and adolescents?

2. How precise is the reporting of the orthopedic manifestations, for example, completeness and accuracy?

3. How appropriate is it in informing clinical practice and research?

The above specifics of reporting orthopedic manifestations were weighed against the standard components of orthopedic examination whenever applicable. That is history-taking and orthopedic couch examination with special emphasis on deformity/contracture characteristics. Gait analysis and motor development were not directly targeted. For clarity, the terms orthopedic manifestations and orthopedic deformities/contractures will often be used synonymously across the manuscript.

Search strategy

We searched the publications in MEDLINE through PubMed advanced search builder https://pubmed.ncbi.nlm.nih.gov/advanced/#. We performed the initial search in November 2021, and an additional search was performed on April 23, 2022 before manuscript submission to ensure the identified literature was up to date. The age filter was set to child: Birth-18 years and species set to humans. We did not include additional search filters. Our search strategy comprised phrases, index words, and Medical Subject Headings pertinent to pathology, that is, CMD subtypes. We used the following words to indicate the three main CMD subtypes: CMD, Walker-Warburg syndrome, LAMA2, merosin, Bethlem, and Ullrich. We used other words in separate searches to indicate the miscellaneous and less common CMD subtypes, namely, rigid spine syndrome, SEPN1-related myopathy, LMNA-related CMD, and laminopathies. The search objective was mainly focused on recall. We screened the titles and abstracts of the initially identified articles. After making necessary omissions, we assessed the remaining articles for potential inclusion.

Moreover, we obtained the full text of the final included articles [Supplementary File S1]. A flowchart of the literature extraction process is shown [Figure 1]. We checked the reference lists of the relevant articles and reviews for additional eligible articles. We manually checked similar articles and cited by functions regarding these relevant articles.

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Figure 1:

Flowchart of the literature extraction process. An updated search was performed before manuscript submission to ensure the identified literature was current. Detailed description of excluded articles with reasons can be found in Supplementary File S1.

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Eligibility criteria

Articles were included if they represented original/primary research and addressed orthopedic manifestations in any subtype of CMD in a descriptive or intervention (surgical or non-surgical) setting. To be included, the article needed to focus clearly on reporting the clinical orthopedic examination/manifestations as one of the study objectives. This can occur solely or among other clinical manifestations. Simple/broad or binary referral to the presence or absence of orthopedic manifestations was not included in the analysis. This scoping review was primarily exploratory and descriptive regarding the evidence for reporting orthopedic manifestations. Thus, we considered all study designs, for example, (longitudinal vs. cross-sectional/prospective vs. retrospective) and all research types (case reports vs. case series) eligible for inclusion. Articles were also included if they investigated CMD exclusively or as a constituent of a larger cohort of genetic muscle diseases. We excluded non-peer-reviewed material, experimental or preclinical articles, and those reporting exclusively on genetic muscle diseases other than CMD as congenital myopathies.

Data extraction and synthesis of results

We extracted elementary data elements, namely, study designs and research types, patient populations (CMD subtype), and authors’ disciplines of included articles. In this regard, we were particularly interested in identifying authors or coauthors in the discipline of musculoskeletal/orthopedics, namely, rehabilitation physicians, physiotherapists, orthotists, and orthopedic surgeons. In addition, we extracted data pertaining to the research questions, namely, (1) frequency and nature of reporting, which included qualitative or categorical reporting or quantitative as goniometric joint measurements, etc., (2) precision, which included completeness and accuracy of reporting of orthopedic manifestations, and (3) appropriateness in informing clinical practice and research. The authors performed a pilot test on screening the titles and abstracts of the initially identified articles and another on data extraction/charting of the included full-text articles. Disagreements between authors were settled by joint meetings. The final review and charting of the above data items were performed by author TAE, whereas the rest of the authors verified the data extraction/charting. We did not critically appraise the sources of evidence – articles – included in this scoping review.

Characteristics of sources of evidence

The 100 final articles included peer-reviewed descriptive observational research, namely, case reports of one or two patients, 47 (47%) articles or case series of affected families or unrelated patients, and 53 (53%) articles. The diagnosis was verified with the aid of genetic analysis and/or muscle biopsy immunostaining supplemented by clinical presentation and brain MRI or neuromuscular electrophysiological investigations.

Results of individual sources of evidence

The initial search for the three main CMD subtypes and the two additional searches for LMNA -related CMD, a subtype of laminopathies and SEPN1 -related myopathies/CMD or rigid spine syndrome identified 830 articles, and the titles and abstracts of which were screened for any irrelevant articles. Following the exclusion of 501 irrelevant articles, 329 remaining ones were assessed for eligibility criteria. Additional articles were excluded with reasons (n = 255) either due to the clinical content, and consequently, the orthopedic was absent or near absent as a study objective, for example, focused on genetic analysis, muscle biopsy/immunostaining, or muscle/brain MRI features and so forth or because the articles were primarily focused on a specific non-orthopedic clinical parameter, for example, cardiac, anesthetic complications or because the article’s clinical orthopedic content was not reported as per eligibility criteria, either solely or as one of the constituents of clinical manifestations, among other reasons [Supplementary File S1 and S2]. These latter exclusions necessitated retrieval and investigation of the full-text articles, six of which were irretrievable. Among the latter exclusions were five articles that reported negative/absent orthopedic manifestations. Although this was deemed adequate reporting, they did not technically allow for evaluation of the precision of reporting. Fifteen more articles were added through manual search, as they fit the inclusion criteria. Thus, the final number of included articles in the current review was 100.^{[14,23,28,34-130]} Of the 100 articles, two^[95,96] were captured through an additional search performed on April 23, 2022, before manuscript submission to ensure the identified literature was up to date [Supplementary File S1]. Another nine articles^[122-130] were captured through another pre-submission-focused search performed on May 19, 2022 [Supplementary File S1]. The latter complementary search was intended specifically to enhance the recall of articles on Walker-Warburg syndrome (alpha DG -related CMD). The total number of patients enrolled in these articles was 1078, distributed as follows: LAMA2-related CMD 399 (37%) patients, collagen VI-related CMD 132 (12%), alpha DG -related CMD 75 (7%), LMNA-related rigid spine CMD/syndrome 196 (18%), and LMNA -related CMD 276 (26%). A flowchart of the literature extraction process is shown in Figure 1. Of the final included articles, 94 (94%) addressed clinical – non-surgical – orthopedic aspects of CMD, and 6 (6%) addressed orthopedic surgical interventions.^{[35-37,73,84,110]} Only 26 (26%) of articles included authors affiliated to musculoskeletal disciplines, medicine or surgery; orthopedic surgery 18 articles,^{[28,35-37,39,40,42,48,53,73,84,87,104,105,110,117,119,125]} rehabilitation medicine/therapy 7,^{[44,83,91,94,97,103,112]} and kinetic therapy 1.^[43]

Synthesis of results

Data items and extraction (charting) of included articles are shown in [Supplementary Tables S1-3] per CMD subtype. Overall, there seems to be a fairly consistent pattern of orthopedic manifestations for most of the CMD subtypes [Figure 2]. Most of the 329 articles retrieved for eligibility assessment were excluded 255 (77.5%) despite being pertinent to clinical research on CMD. The full text of the final included articles was searched for precision in reporting orthopedic manifestations (deformities or contractures) in CMD regarding anatomic localization of deformities, severity grading, symmetry, range of motion features, age at onset and course of deformity, and additional relevant information. The majority of included case series articles did not report orthopedic contractures in a correlative manner, namely, correlations between orthopedic contractures on the one side and patient’s genotype, distribution and onset of muscle weakness/wasting, general motor function, and so forth on the other side. There were notable exceptions.^[14,87,94] Although many of the included articles reported the overall disease progression and anatomic distribution of muscle weakness, few reported the progression and distribution of orthopedic contractures particularly. There were notable exceptions.^[23,94] The overall orthopedic indicators of CMD subtypes are shown in Figure 2. A proposed flowchart for comprehensive eporting of orthopedic deformities in CMD children is presented in Figure 3. We successfully contacted the authors of the included articles^[111] to retrieve relevant supplementary files, which were inaccessible in the PDF versions. We unsuccessfully contacted the authors of an eligible yet excluded article^[131] to retrieve supplementary files, which contained the clinical spectrum of alpha DG -related CMD in a large cohort of Chinese patients.

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Figure 2:

Graphical abstract image: General orthopedic indicators of congenital muscular dystrophy (CMD) subtypes. Indicators are based on the best available evidence and are not necessarily all-inclusive or pathognomonic. Collagen VI-related CMD indicators are most applicable to the Ullrich subtype.

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Figure 3:

Proposed flowchart for comprehensive reporting of orthopedic deformities in congenital muscular dystrophy children.

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Orthopedic manifestations of neuromuscular diseases

The motor and orthopedic manifestations of genetic neuromuscular diseases are valuable clinical tools allowing for refinement of differential diagnosis,^[132,133] identification of age- and disease-specific orthopedic and rehabilitation treatment endpoints,^[29,134-137] informed surgical decision-making,^[138] and assessment of efficacy of experimental therapeutics and improvement of clinical trial designs.^[139] For example, emerging evidence suggests that familiarity with orthopedic manifestations can help in the differential diagnosis of Charcot-Marie-Tooth subtypes and related genetic polyneuropathies^[132] and fascioscapulohumeral muscular dystrophy^[133] and guide their orthopedic and rehabilitation management plans. Additional studies underscored the importance of orthopedic manifestations to the surgical decision-making in myotonic dystrophy^[140] and to the monitoring of enzyme replacement therapy in early-onset Pompe disease.^[137,141] The accurate description of the orthopedic manifestations of CMD subtypes^[28,38-40] is particularly important to low-resource countries where diagnosis and subsequent referral to specialized centers depend highly on the physician’s clinical judgment.^[142]

Although experimental research on CMD subtypes is promising,^[143-147] early diagnosis can facilitate supportive and system-specific management per recommended disease standards of care.^[12,148] Relatedly, neglected spine deformities can accentuate cardiac^[21,149-151] and pulmonary^[20,152] complications.

Strengths and limitations

The strength of our study is that it mapped an underreported yet central feature in CMD children, namely, orthopedic manifestations.^{[148,149,153-156]} Accurate and systematic reporting can provide valuable insights into the mechanisms of disease causation of the wide mutation/variant spectrum CMD subtypes. It can also establish correlative relationships between gene variants and the diverse phenotype presentations of CMD subtypes and similar genetic muscle diseases with result improvement in the genetic/molecular diagnostic yield.^{[22,30,31,157]} The elucidation of the orthopedic manifestations in future reports can expand the phenotype/clinical profile of CMD subtypes, which can help clinicians diagnose CMD subtypes with more precision. Our study has limitations. We searched only one database. Given the ultra-specialized nature of CMD, we assumed that most research on it would be published in reputable PubMed-indexed journals. Consequently, we believe that our search should have captured at least the main bulk of relevant articles.

Further, the recall and precision of a search strategy depend on multiple variables such as the operational specifics and degree of indexing inaccuracies or delays of the electronic database and the contribution of a health information librarian to the search design among others. However, we believe that the ample amount of literature recall regarding the included number of articles and patients in this analysis has provided fairly representative material to justify meaningful conclusions, at least as far as a scoping review is concerned.

What does this paper add?

• Orthopedic manifestations of congenital muscular dystrophy (CMD) in children/adolescents are generally underreported and insufficiently detailed.

• There is reliable evidence that accurate reporting of orthopedic manifestations can be a valuable clinical supplement to differential diagnosis in patients with collagen VI-related, LAMA2-related, LMNA-related, and SEPN1-related CMD (SELENON).

• For alpha dystroglycan-related CMD, there is insufficient information to delineate a subtype-specific pattern.

• There is emerging evidence that reporting spine surgery outcomes may assist in orthopedic decision-making.

• The greatest clinical/research utility was provided by articles with longitudinal, comprehensive, and correlative reporting of larger cohorts.

• Comprehensive reporting of orthopedic manifestations is recommended in future research.