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Clinical and molecular features of 66 patients with musculocontractural Ehlers−Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14)
  1. Mari Minatogawa1,2,
  2. Ai Unzaki1,2,3,
  3. Hiroko Morisaki4,5,
  4. Delfien Syx6,7,
  5. Tohru Sonoda8,
  6. Andreas R Janecke9,10,
  7. Anne Slavotinek11,
  8. Nicol C Voermans12,
  9. Yves Lacassie13,14,
  10. Roberto Mendoza-Londono15,
  11. Klaas J Wierenga16,
  12. Parul Jayakar17,
  13. William A Gahl18,19,
  14. Cynthia J Tifft18,19,
  15. Luis E Figuera20,
  16. Yvonne Hilhorst-Hofstee21,
  17. Alessandra Maugeri22,
  18. Ken Ishikawa23,
  19. Tomoko Kobayashi24,25,26,
  20. Yoko Aoki27,
  21. Toshihiro Ohura28,
  22. Hiroshi Kawame29,30,31,
  23. Michihiro Kono32,33,
  24. Kosuke Mochida34,
  25. Chiho Tokorodani35,
  26. Kiyoshi Kikkawa35,
  27. Takayuki Morisaki5,36,37,
  28. Tetsuyuki Kobayashi38,
  29. Takaya Nakane39,
  30. Akiharu Kubo40,
  31. Judith D Ranells41,
  32. Ohsuke Migita42,
  33. Glenda Sobey43,
  34. Anupriya Kaur44,
  35. Masumi Ishikawa1,2,
  36. Tomomi Yamaguchi1,2,45,
  37. Naomichi Matsumoto46,
  38. Fransiska Malfait6,7,
  39. Noriko Miyake46,
  40. Tomoki Kosho1,2,45,47
  1. 1Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan
  2. 2Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
  3. 3Problem-Solving Oriented Training Program for Advanced Medical Personnel: NGSD (Next Generation Super Doctor) Project, Matsumoto, Japan
  4. 4Department of Medical Genetics, Sakakibara Heart Institute, Tokyo, Japan
  5. 5Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center, Suita, Japan
  6. 6Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium
  7. 7Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
  8. 8Department of Occupational Therapy, School of Health and Science, Kyushu University of Health and Welfare, Nobeoka, Japan
  9. 9Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria
  10. 10Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
  11. 11Division of Genetics, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA
  12. 12Department of Neurology, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands
  13. 13Department of Pediatrics, Louisiana State University Health Science Center, New Orleans, LA, USA
  14. 14Division of Clinical Genetics and Department of Genetics, Children’s Hospital of New Orleans, New Orleans, LA, USA
  15. 15Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
  16. 16Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA
  17. 17Division of Genetics and Metabolism, Nicklaus Children’s Hospital, Miami, FL, USA
  18. 18Undiagnosed Diseases Program, Office of the NIH Director, National Institutes of Health, Bethesda, MD, USA
  19. 19Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
  20. 20División de Genética, Centro de Investigación Biomédica de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Mexico
  21. 21Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  22. 22Department of Clinical Genetics, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands
  23. 23Department of Pediatrics, Iwate Medical University, Morioka, Japan
  24. 24Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan
  25. 25Department of Preventive Medicine and Epidemiology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
  26. 26Graduate School of Medicine, Tohoku University, Senda, Japan
  27. 27Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
  28. 28Division of Clinical Laboratory, Sendai City Hospital, Sendai, Japan
  29. 29Division of Genomic Medicine Support and Genetic Counseling, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
  30. 30Miyagi Children’s Hospital, Sendai, Japan
  31. 31Division of Clinical Genetics, Jikei University Hospital, Tokyo, Japan
  32. 32Department of Dermatology, Nagoya University Graduate School of Medicine Faculty of Medicine, Nagoya, Japan
  33. 33Department of Dermatology and Plastic Surgery, Akita University Graduate School of Medicine School of Medicine, Akita, Akita, Japan
  34. 34Department of Dermatology, University of Miyazaki Faculty of Medicine, Miyazaki, Japan
  35. 35Department of Pediatrics, Kochi Health Sciences Center, Kochi, Japan
  36. 36Division of Molecular Pathology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
  37. 37Department of Internal Medicine, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
  38. 38Department of Internal Medicine, Nagano Chuo Hospital, Nagano, Japan
  39. 39Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, Japan
  40. 40Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
  41. 41Department of Pediatrics, University of South Florida, College of Medicine, Tampa, FL, USA
  42. 42Department of Clinical Genetics, St. Marianna University, School of Medicine, Kawasaki, Japan
  43. 43EDS National Diagnostic Service, Sheffield Children’s Hospital, Sheffield, UK
  44. 44Department of Pediatrics (Genetics Division), Advanced Pediatric Cente, Post Graduate Institute of Medical Education and Research, Chandigarh, Chandigarh, India
  45. 45Division of Clinical Sequencing, Shinshu University School of Medicine, Matsumoto, Japan
  46. 46Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  47. 47Research Center for Supports to Advanced Science, Shinshu University, Matsumoto, Japan
  1. Correspondence to Professor Tomoki Kosho, Department of Medical Genetics, Shinshu University Graduate School of Medicine School of Medicine, Matsumoto 390-8621, Japan; ktomoki{at}shinshu-u.ac.jp

Abstract

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.

http://dx.doi.org/10.1136/jmedgenet-2020-107623

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    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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    Footnotes

    • 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.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.