Background Musculocontractural Ehlers−Danlos syndrome is caused by biallelic loss-of-function variants in CHST14 (mcEDS-CHST14) or DSE (mcEDS-DSE). Although 48 patients in 33 families with mcEDS-CHST14 have been reported, the spectrum of pathogenic variants, accurate prevalence of various manifestations and detailed natural history have not been systematically investigated.
Methods We collected detailed and comprehensive clinical and molecular information regarding previously reported and newly identified patients with mcEDS-CHST14 through international collaborations.
Results Sixty-six patients in 48 families (33 males/females; 0–59 years), including 18 newly reported patients, were evaluated. Japanese was the predominant ethnicity (27 families), associated with three recurrent variants. No apparent genotype–phenotype correlation was noted. Specific craniofacial (large fontanelle with delayed closure, downslanting palpebral fissures and hypertelorism), skeletal (characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities and recurrent joint dislocation), cutaneous (hyperextensibility, fine/acrogeria-like/wrinkling palmar creases and bruisability) and ocular (refractive errors) features were observed in most patients (>90%). Large subcutaneous haematomas, constipation, cryptorchidism, hypotonia and motor developmental delay were also common (>80%). Median ages at the initial episode of dislocation or large subcutaneous haematoma were both 6 years. Nine patients died; their median age was 12 years. Several features, including joint and skin characteristics (hypermobility/extensibility and fragility), were significantly more frequent in patients with mcEDS-CHST14 than in eight reported patients with mcEDS-DSE.
Conclusion This first international collaborative study of mcEDS-CHST14 demonstrated that the subtype represents a multisystem disorder with unique set of clinical phenotypes consisting of multiple malformations and progressive fragility-related manifestations; these require lifelong, multidisciplinary healthcare approaches.
- musculoskeletal diseases
- human genetics
Data availability statement
Data are available upon reasonable request. All data relevant to this study are included in the article or uploaded as supplementary information. Data are available on reasonable request.
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Contributors MM and TK interpreted the data and drafted the manuscript. TK conceived the work and organized the data collection. AU assisted with data collection. TY, N Matsumoto and N Miyake conducted the molecular study. The others followed up on patients and provided data. All authors participated in revision and approval of the manuscript.
Funding This study was supported by Research on Intractable Diseases (073) (2012–3) (TK) and Research Programme on Policy of Measures for Intractable/Rare Diseases (20FC1046) (2020–2) (TK), Ministry of Health, Labour and Welfare, Japan; Practical Research Project for Rare/Intractable Diseases (105) (2015–7) (TK), Programme for an Integrated Database of Clinical and Genomic Information (16kk0205001h0501, 16kk0205012h1001) (2016–2020) (TK) and (JP19ek0109280, JP19dm0107090, JP19ek0109301, JP19ek0109348, and JP18kk020501) (N Matsumoto) and the Initiative on Rare and Undiagnosed Diseases (IRUD) (19ek0109301h0002) (2018–2020) (TK), Japan Agency for Medical Research and Development (AMED); Grant-in-Aid for Scientific Research (C) (25460405) (2013–5) (TK), Grant-in-Aid for Scientific Research (B) (19H03616) (2019–2021) (TK) and (JP19H03621) (N Miyake), from the Japan Society for the Promotion of Science, Japan; Medical Research Encouragement Prize of the Japan Medical Association (2013) (TK); Japan Foundation for Pediatric Research (2014) (TK); Problem-Solving Oriented Training Programme for Advanced Medical Personnel: NGSD (Next Generation Super Doctor) Project (TK) and the Intramural Research Programme of the National Human Genome Research Institute. Division of Clinical Sequencing, Shinshu University School of Medicine, is an endowment division, supported with an unrestricted grant from BML Inc. and Life Technologies Japan Ltd. Delfien Syx and Fransiska Malfait are research fellows at the Research Foundation Flanders.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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