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Ehlers-Danlos syndrome (EDS) is a genetically and clinically heterogeneous group of connective tissue disorders that typically present with skin hyperextensibility, joint hypermobility, and tissue fragility. The major cause of EDS appears to be impaired biosynthesis and enzymatic modification of collagen. In this chapter, we discuss two types of EDS that are associated with proteoglycan abnormalities: spondylodysplastic EDS and musculocontractural EDS. Spondylodysplastic EDS is caused by pathogenic variants in B4GALT7 or B3GALT6, both of which encode key enzymes that initiate glycosaminoglycan synthesis. Musculocontractural EDS is caused by mutations in CHST14 or DSE, both of which encode enzymes responsible for the post-translational biosynthesis of dermatan sulfate. The clinical and molecular characteristics of both types of EDS are described in this chapter., (© 2021. Springer Nature Switzerland AG.)

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is an autosomal recessive condition characterized by distinct craniofacial features, multisystem congenital malformations and progressive fragility of connective tissues. It is caused by pathogenic variants in CHST14 and DSE genes. There are three reports of pathogenic variants in DSE in four mcEDS patients. In this study we provide clinical and molecular presentation of two new patients with DSE related mcEDS. Analysing clinical exome data, a homozygous pathogenic DSE variant, c.1150_1157del p.(Pro384Trpfs*9), was identified in a 32 year old man with bilateral congenital talipes equinovarus, characteristic facial features, myopia, hyperextensible skin at the elbows, significant palmar wrinkling, bilateral inguinal hernias and chronic leg, back and joint pain. Electron microscopical examination of skin biopsy showed changes consistent with mild compensatory elastic fibre hypertrophy and mildly loose collagen bundles. The variant is predicted to result in a frameshift and introduction of a premature termination codon in the final exon of the DSE gene, anticipated to lead to the loss of approximately 60% of the normal reading frame. The second patient has a phenotype consistent with previously reported cases of DSE associated musculocontractural EDS. A novel homozygous missense DSE variant of uncertain clinical significance was detected. This case study further delineates the DSE associated mcEDS phenotype and illustrates absence of major cutaneous, cardiovascular, renal and respiratory features, which supports previous suggestions that patients with DSE associated mcEDS present with a milder phenotype compared to those with CHST14 mutations., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Musculocontractural Ehlers-Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4- O -sulfotransferase 1 ( CHST14 / D4ST1 , mcEDS- CHST14 ), or in the gene for dermatan sulfate epimerase ( DSE , mcEDS- DSE ). Thus far, 41 patients from 28 families with mcEDS- CHST14 and five patients from four families with mcEDS- DSE have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous ( Chst14 -/- ) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS- DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies.

Musculocontractural Ehlers-Danlos syndrome (mcEDS) due to CHST14/D4ST1 deficiency (mcEDS-CHST14) is a recently delineated type of EDS caused by biallelic loss-of-function mutations in CHST14, which results in the depletion of dermatan sulfate (DS). Clinical characteristics of mcEDS-CHST14 consist of multiple malformations and progressive fragility-related manifestations, including skin hyperextensibility and fragility. Skin fragility is suspected to result from the impaired assembly of collagen fibrils caused by alteration of the glycosaminoglycan (GAG) chain of decorin-proteoglycan (PG) from DS to chondroitin sulfate (CS). This systematic investigation of the skin pathology of patients with mcEDS-CHST14 comprised both immunostaining of decorin and transmission electron microscopy-based cupromeronic blue staining to visualize GAG chains. Collagen fibrils were dispersed in the affected papillary to reticular dermis; in contrast, they were regularly and tightly assembled in controls. Moreover, the fibrils exhibited a perpendicular arrangement to the affected epidermis, whereas fibrils were parallel to control epidermis. Affected GAG chains were linear, stretching from the outer surface of collagen fibrils to adjacent fibrils; in contrast, those of controls were curved, maintaining close contact with attached collagen fibrils. This is the first observation of compositional alteration, from DS to CS, of GAG side chains, which caused structural alteration of GAG side chains and resulted in spatial disorganization of collagen networks; this presumably disrupted the ring-mesh structure of GAG side chains surrounding collagen fibrils. McEDS-CHST14 provides a critical example of the importance of DS in GAG side chains of decorin-PG during assembly of collagen fibrils in maintenance of connective tissues., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Bi-allelic variants in CHST14, encoding dermatan 4-O-sulfotransferase-1 (D4ST1), cause musculocontractural Ehlers-Danlos syndrome (MC-EDS), a recessive disorder characterized by connective tissue fragility, craniofacial abnormalities, congenital contractures, and developmental anomalies. Recently, the identification of bi-allelic variants in DSE, encoding dermatan sulfate epimerase-1 (DS-epi1), in a child with MC-EDS features, suggested locus heterogeneity for this condition. DS-epi1 and D4ST1 are crucial for biosynthesis of dermatan sulfate (DS) moieties in the hybrid chondroitin sulfate (CS)/DS glycosaminoglycans (GAGs). Here, we report four novel families with severe MC-EDS caused by unique homozygous CHST14 variants and the second family with a homozygous DSE missense variant, presenting a somewhat milder MC-EDS phenotype. The glycanation of the dermal DS proteoglycan decorin is impaired in fibroblasts from D4ST1- as well as DS-epi1-deficient patients. However, in D4ST1-deficiency, the decorin GAG is completely replaced by CS, whereas in DS-epi1-deficiency, still some DS moieties are present. The multisystemic abnormalities observed in our patients support a tight spatiotemporal control of the balance between CS and DS, which is crucial for multiple processes including cell differentiation, organ development, cell migration, coagulation, and connective tissue integrity., (© 2015 WILEY PERIODICALS, INC.)

Ehlers Danlos syndrome musculocontractural type (mcEDS) is a rare hereditary connective tissue disorder caused by biallelic pathogenic variants in the CHST14 or dermatan sulfate (DS) epimerase genes resulting in defective DS biosynthesis. It is characterized by congenital malformations and contractures, distinctive facial features and multisystemic fragility-related complications. To date, less than 100 patients with mcEDS have been reported. Vascular complications remain the major morbidity and may lead to mortality in the affected individuals. In this clinical report, we report on a currently 12-year-old boy with a novel homozygous CHST14 variant who presented with typical mcEDS symptoms and subsequently developed a life-threatening subcutaneous skull hematoma following a minor trauma, which required intensive care unit admission and surgical drainage along with several blood transfusions. This case expands the clinical and genetic spectrum of CHST14-related mcEDS which is essential for providing accurate prognosis, management and genetic counseling. [ABSTRACT FROM AUTHOR]

A 36-year-old male with congenital equinovarus deformity was admitted to the hospital due to worsen deformity. He was known to have ear perforation in childhood. After hospitalization, he received equinovarus correction surgery, fourth toe osteotomy, and external fixation for right foot during the procedure. During his hospital stay, the patient has been treated with multiple gastrointestinal perorations, accompanied with multiple organ dysfunction and fragile soft tissues. During his in-hospital stay, multiple organ dysfunctions were observed, including the heart, kidney, liver, and intestines. In order to identify the mutation site, whole-exome sequencing (WES) was performed, and further verified with Sanger sequencing analysis in this patient. One-site mutation located at CHST14 [c.883_884del, p (Phe295Cysfs*5)] was identified in this patient, whereas this mutation was not observed in other 100 healthy controls. Also, this variant has not been reported in public databases (ExAC and gnomAD). Our report showed that unanticipated multiple tissue deformation observed the musculocontractural EDS patient was caused by mutation located at CHST14 [c.883_884del, p (Phe295Cysfs*5)] induced truncated CHST14 protein. [ABSTRACT FROM AUTHOR]

Background: Musculocontractural Ehlers–Danlos syndrome (mcEDS) is a rare heritable connective tissue disease with various symptoms. The diagnosis of mcEDS is difficult because of the large overlap of clinical symptoms between different EDS subtypes. Methods: We performed karyotype analysis, gene copy number variation detection, whole-exome sequencing, and Sanger sequencing to reveal the underlying genetic etiology of a fetus with structural abnormalities in feet and kidneys. Results: A likely pathogenic mutation [NM_130468.3 c.958C>T (p.Arg320*)] and an uncertain significance mutation [NM_130468.3 c.896A>G (p.Tyr299Cys)] were identified in the carbohydrate sulfotransferase 14 (CHST14) gene by whole-exome sequencing and validated by Sanger sequencing. Conclusion: The two identified mutations appear highly likely to be the genetic causes of the fetal structural abnormalities. [ABSTRACT FROM AUTHOR]

Background: Musculocontractural Ehlers–Danlos syndrome (mcEDS) is a rare heritable connective tissue disease with various symptoms. The diagnosis of mcEDS is difficult because of the large overlap of clinical symptoms between different EDS subtypes.Methods: We performed karyotype analysis, gene copy number variation detection, whole-exome sequencing, and Sanger sequencing to reveal the underlying genetic etiology of a fetus with structural abnormalities in feet and kidneys.Results: A likely pathogenic mutation [NM_130468.3 c.958C>T (p.Arg320*)] and an uncertain significance mutation [NM_130468.3 c.896A>G (p.Tyr299Cys)] were identified in the carbohydrate sulfotransferase 14 (CHST14) gene by whole-exome sequencing and validated by Sanger sequencing.Conclusion: The two identified mutations appear highly likely to be the genetic causes of the fetal structural abnormalities.

We report on a consanguineous, Afghani family with two sisters affected with characteristic facial features, multiple contractures, progressive joint and skin laxity, hemorrhagic diathesis following minor trauma and multisystem fragility-related manifestations suggestive of a diagnosis of musculocontractural Ehlers-Danlos syndrome (EDS). This novel form of connective tissue disorder was recently reported in patients of Japanese, Turkish, and Indian descent who were formerly classified as having EDS type VIB and has now been recognized to be a part of spectrum including patients previously classified as having adducted thumb-clubfoot syndrome. We identified a previously unreported mutation in the CHST14 gene, which codes for the enzyme dermatan 4- O-sulfotransferase. We discuss the prenatal presentation, detailed clinical manifestations, and neurological findings in two sisters with this newly described musculocontractural EDS-CHST14 type. We demonstrate that fibroblasts from one of our patients produce more chondroitin sulfate than normal and show lower than normal deposition of collagens I and II and fibrillin 1-containing microfibrills. These findings suggest that the imbalance in the glycosaminoglycan content in developing tissues might interfere with normal deposition of other extracellular matrix components and ultimately contribute to the development of the phenotype observed in these patients. Furthermore, we ruled out the contribution of intrinsic platelet factors to the bleeding diathesis observed in some affected individuals. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Musculocontractural Ehlers–Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1 (CHST14/D4ST1, mcEDS-CHST14), or in the gene for dermatan sulfate epimerase (DSE, mcEDS-DSE). Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous (Chst14−/−) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies. [ABSTRACT FROM AUTHOR]