CHST14/D4ST1 deficiency: New form of Ehlers–Danlos syndrome
Abstract
Carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase-1 (CHST14/D4ST1) deficiency represents a specific form of Ehlers-Danlos syndrome (EDS) caused by recessive loss-of-function mutations in CHST14. The disorder has been independently termed "adducted thumb-clubfoot syndrome", "EDS, Kosho type", and "EDS, musculocontractural type". To date, 31 affected patients from 21 families have been described. Clinically, CHST14/D4ST1 deficiency is characterized by multiple congenital malformations (craniofacial features including large fontanelle, hypertelorism, short and downslanting palpebral fissures, blue sclerae, short nose with hypoplastic columella, low-set and rotated ears, high palate, long philtrum, thin upper lip vermilion, small mouth, and micro-retrognathia; multiple congenital contractures including adduction-flexion contractures and talipes equinovarus as well as other visceral or ophthalmological malformations) and progressive multisystem fragility-related complications (skin hyperextensibility, bruisability, and fragility with atrophic scars; recurrent dislocations; progressive talipes or spinal deformities; pneumothorax or pneumohemothorax; large subcutaneous hematomas; and diverticular perforation). Etiologically, multisystem fragility is presumably caused by impaired assembly of collagen fibrils resulting from loss of dermatan sulfate (DS) in the decorin glycosaminoglycan side chain that promotes electrostatic binding between collagen fibrils. This is the first reported human disorder that specifically affects biosynthesis of DS. Its clinical characteristics indicate that CHST14/D4ST1 and, more fundamentally, DS, play a critical role in fetal development and maintenance of connective tissues in multiple organs. Considering that patients with CHST14/D4ST1 deficiency develop progressive multisystem fragility-related manifestations, establishment of a comprehensive and detailed natural history and health-care guidelines as well as further elucidation of the pathophysiology in view of future etiology-based therapy are crucial.
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Skin fragility in patients with EDS caused by D4ST1 deficiency is postulated to result from impaired assembly of collagen fibrils caused by replacement of a DS with a CS chain of decorin through alterations in electrostatic binding of decorin to collagen fibrils followed by a difference in the spatial relationship between collagen fibrils and decorin.
“In view of these findings, skin fragility in patients with EDS caused by D4ST1 deficiency is postulated to result from impaired assembly of collagen fibrils caused by the replacement of a DS with a CS chain of decorin through alterations in the electrostatic binding of decorin to collagen fibrils followed by difference in the spatial relationship between collagen fibrils and decorin”
From The Ehlers–Danlos syndromes, rare types (2017) · cites this paper as Kosho, 2016
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Loss-of-function mutations of CHST14 in a new type of Ehlers-Danlos syndrome
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Diagnosis, natural history, and management in vascular Ehlers-Danlos syndrome
Byers, P. H., Belmont, J., Black, J., De Backer, J., Frank, M., Jeunemaitre, X., Johnson, D., Pepin, M., Robert, L., Sanders, L., et al. (2017) · American Journal of Medical Genetics Part C: Seminars in Medical Genetics · doi:10.1002/ajmg.c.31553 · Cited by 381 · see citing works
The Ehlers–Danlos syndromes, rare types
Brady, A. F., Demirdas, S., Fournel‐Gigleux, S., Ghali, N., Giunta, C., Kapferer‐Seebacher, I., Kosho, T., Mendoza‐Londono, R., Pope, M. F., Rohrbach, M., et al. (2017) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.31550 · Cited by 249 · see citing works
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- Authors
- Kosho, T.
- Affiliations
- Shinshu University (JP)
- Corresponding author
- Kosho, Tomoki
- ORCID
- Kosho, Tomoki
- Venue
- Pediatrics International
- Publisher
- Wiley
- Published
- 2016-02
- Volume
- 58
- Issue
- 2
- Pages
- 88-99
- ISSN
- 1328-8067 (ISSN-L)
- 1442-200X
- OpenAlex
- W2189967343
- Cited by
- 53
- References
- 9
- Citations by year
- 2026: 3 · 2025: 3 · 2023: 5 · 2022: 3 · 2021: 8 · 2020: 8 · 2019: 5 · 2018: 7 · 2017: 8 · 2016: 3
- FWCI
- 0.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pediatrics International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (25460405)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Dermatological and Skeletal Disorders
- Keywords
- Ehlers-Danlos syndrome, dermatan sulfate, congenital contractures, clubfoot, adducted thumbs, connective tissue fragility, collagen fibril assembly, decorin, glycosaminoglycan synthesis, craniofacial anomalies, natural history (disease), health care guidelines
- MeSH terms
- Adolescent, Animals, Child, Child, Preschool, Dermatan Sulfate, Ehlers-Danlos Syndrome, Female, Humans, Infant, Male, Mutation, Sulfotransferases, Young Adult
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