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Characteristic craniofacial aspects of MC-EDS. Note hypertelorism, down-slanting palpebral fissures, microcorneae, prominent nasolabial folds, a thin upper lip vermillion, prominent and often low-set and posteriorly-rotated ears. The face appears myopathic. These aspects are present at different age. y, years; m, months.
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The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14...
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... main clinical findings of the four index patients and the three affected sibs together with those MC-EDS patients published previously are listed in Table I. There were common characteristic craniofacial features ( Fig. 1), as well as common features of the hands and feet (Fig. 2). The parents of all patients were ...
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... ( Figs. 1 and 2), a Hispanic boy, was born at term to first cousins once removed, with birth weight 2.9 kg, and length 45.7 cm. Three older sibs were healthy. ...
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... ( Figs. 1 and 2), the index patient, was a girl born by emergency Cesarean section at 42 weeks gestation to healthy Hispanic parents, who denied consanguinity. The infant emerged with poor respiratory effort and Apgar scores of 1 at 1 min and 8 at 5 min. ...
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Citations
... Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare subtype of EDS, caused by biallelic pathogenic variants in the carbohydrate sulfotransferase 14 gene (CHST14) encoding dermatan 4-O-sulfotransferase 1 (mcEDS-CHST14; MIM#601776) or in the dermatan sulfate epimerase gene (DSE) (mcEDS-DSE; MIM#615539) [1][2][3]. To date, 67 patients (49 families) with mcEDS-CHST14 and 14 patients (eight families) with mcEDS-DSE have been reported [4][5][6][7][8]. Patients with mcEDS typically present with multiple congenital malformations (e.g., craniofacial characteristics, congenital multiple contractures, and congenital visceral/ocular abnormalities) and progressive multisystem-fragilityrelated manifestations (e.g., skin hyperextensibility/fragility/bruisability, joint hypermo-2 of 7 bility/dislocation, spinal/foot deformities, and large subcutaneous hematomas) [1][2][3]. ...
... Previously reported patients with mcEDS-CHST14 who developed colonic perforation were complicated by diverticula [4], suggesting that diverticula confer susceptibility to perforation, although no clear pathological evidence of this has been identified [4,7,8]. A recently described patient, a 36-year-old male with mcEDS-CHST14, developed colonic perforation at the splenic flexure 11 days after corrective surgery for talipes equinovarus, ...
... Previously reported patients with mcEDS-CHST14 who developed colonic perforation were complicated by diverticula [4], suggesting that diverticula confer susceptibility to perforation, although no clear pathological evidence of this has been identified [4,7,8]. A recently described patient, a 36-year-old male with mcEDS-CHST14, developed colonic perforation at the splenic flexure 11 days after corrective surgery for talipes equinovarus, and underwent an emergency laparotomy plus partial colectomy with proximal fistulotomy [5]. ...
Musculocontractural Ehlers–Danlos syndrome (mcEDS) is a heritable connective tissue disorder characterized by multiple congenital malformations and progressive connective-tissue-fragility-related manifestations in the cutaneous, skeletal, cardiovascular, visceral, ocular, and gastrointestinal systems. It is caused by pathogenic variants in the carbohydrate sulfotransferase 14 gene (mcEDS-CHST14) or in the dermatan sulfate epimerase gene (mcEDS-DSE). As gastrointestinal complications of mcEDS-CHST14, diverticula in the colon, small intestine, or stomach have been reported, which may lead to gastrointestinal perforation, here, we describe sisters with mcEDS-CHST14, who developed colonic perforation with no evidence of diverticula and were successfully treated through surgery (a resection of perforation site and colostomy) and careful postoperative care. A pathological investigation did not show specific abnormalities of the colon at the perforation site. Patients with mcEDS-CHST14 aged from the teens to the 30s should undergo not only abdominal X-ray photography but also abdominal computed tomography when they experience abdominal pain.
... These abnormalities are risk factors for retinal detachments [7]. Previous studies have reported cases of EDS with RD (Table 1) [8][9][10][11][12][13][14]. Minatogawa and associates [15] reviewed 66 patients with mcEDS-CHST14, including 48 patients who had been reported earlier. ...
... The ophthalmologic complications were refractive errors including myopia, astigmatism, hyperopia, and amblyopia. As opposed to eyes with mcEDS-DSE, RD was present in six patients whose median age was 15.5 years with a range of 9 to 20 years [10][11][12]15] (Table 1). Retinal angioid streaks were present in two patients [15]. ...
Musculocontractural Ehlers–Danlos syndrome, caused by biallelic loss-of-function variants for dermatan sulfate epimerase (mcEDS-DSE), is a rare connective tissue disorder. Eight patients with mcEDS-DSE have been described with ocular complications, including blue sclera, strabismus, high refractive errors, and elevated intraocular pressure. However, a case with rhegmatogenous retinal detachment (RRD) has not been reported. We report our findings in a 24-year-old woman who was diagnosed with mcEDS-DSE in childhood and presented to our clinic with an RRD in the left eye. The RRD extended to the macula and was associated with an atrophic hole. The patient underwent scleral buckling surgery and cryopexy with drainage of subretinal fluid through a sclerotomy under local anesthesia. The sclera did not appear blue but was very thin at the sclerotomy site. The patient developed frequent bradycardia during the surgery. Subretinal or choroidal hemorrhages were not observed intraoperatively; however, a peripapillary hemorrhage was observed one day after operation. The retina was reattached postoperatively, and the peripapillary hemorrhage was absorbed after one month. The peripapillary retinal hemorrhages, thin sclera, and bradycardia were most likely due to the fragility of the eye. The genetic diagnosis of mcEDS-DSE played an important role before and during the surgery by alerting the surgeons to possible surgical complications due to the thin sclera.
... They proposed to unify the D4ST1-related syndromes, the novel EDS and the adducted thumb-clubfoot syndrome, as ''musculocontractural EDS'' [143], which was adopted in the International Classification of Ehlers-Danlos Syndromes in 2017 as EDS musculocontractural type 1 [144,145]. In addition to these mutations in CHST14, many probands with EDS musculocontractural type 1 have been reported to date [146][147][148][149][150][151][152][153][154][155][156][157][158][159]. ...
Dermatan sulfate (DS) and its proteoglycans are essential for the assembly of the extracellular matrix and cell signaling. Various transporters and biosynthetic enzymes for nucleotide sugars, glycosyltransferases, epimerase, and sulfotransferases, are involved in the biosynthesis of DS. Among these enzymes, dermatan sulfate epimerase (DSE) and dermatan 4-O-sulfotranserase (D4ST) are rate-limiting factors of DS biosynthesis. Pathogenic variants in human genes encoding DSE and D4ST cause the musculocontractural type of Ehlers-Danlos syndrome, characterized by tissue fragility, joint hypermobility, and skin hyperextensibility. DS-deficient mice exhibit perinatal lethality, myopathy-related phenotypes, thoracic kyphosis, vascular abnormalities, and skin fragility. These findings indicate that DS is essential for tissue development as well as homeostasis. This review focuses on the histories of DSE as well as D4ST, and their knockout mice as well as human congenital disorders.
... These proteoglycans connect collagen fibrils via GAG chains and influence the structure and functions of the extracellular matrix [27,29]. DS was not detected in the urine or skin fibroblast of patients with mcEDS-CHST14 [30,31]. DS was absent or significantly decreased in skin fibroblasts and urine derived from patients with mcEDS-DSE [7,13,32]. ...
Musculocontractural Ehlers–Danlos syndrome (mcEDS) is a subtype of EDS caused by mutations in the gene for carbohydrate sulfotransferase 14 (CHST14) (mcEDS-CHST14) or dermatan sulfate epimerase (DSE) (mcEDS-DSE). These mutations induce loss of enzymatic activity in D4ST1 or DSE and disrupt dermatan sulfate (DS) biosynthesis. The depletion of DS causes the symptoms of mcEDS, such as multiple congenital malformations (e.g., adducted thumbs, clubfeet, and craniofacial characteristics) and progressive connective tissue fragility-related manifestations (e.g., recurrent dislocations, progressive talipes or spinal deformities, pneumothorax or pneumohemothorax, large subcutaneous hematomas, and/or diverticular perforation). Careful observations of patients and model animals are important to investigate pathophysiological mechanisms and therapies for the disorder. Some independent groups have investigated Chst14 gene-deleted (Chst14-/-) and Dse-/- mice as models of mcEDS-CHST14 and mcEDS-DSE, respectively. These mouse models exhibit similar phenotypes to patients with mcEDS, such as suppressed growth and skin fragility with deformation of the collagen fibrils. Mouse models of mcEDS-CHST14 also show thoracic kyphosis, hypotonia, and myopathy, which are typical complications of mcEDS. These findings suggest that the mouse models can be useful for research uncovering the pathophysiology of mcEDS and developing etiology-based therapy. In this review, we organize and compare the data of patients and model mice.
... Both genes encode enzymes involved in the biosynthesis of DS, a linear polysaccharide which forms DS-proteoglycans by attaching to core proteins and plays a role in cell surfaces and extracellular matrices. DS is an essential component of connective tissue and it is found mainly in skin, blood vessels, cartilage and tendons (4)(5)(6). Vascular complications which may sometimes be life threatening may be seen in these patients (7). In this clinical report, we described a mcEDS patient with a novel ...
... Large subcutaneous hematomas were previously reported in 46 out of 58 (79%) mcEDS patients (3). No major coagulation abnormality is observed in mcEDS patients as was the case in our patient (5). Tendency to massive bleeding in mcEDS is generally explained by vascular abnormalities leading to vascular fragility which is thought to be caused mainly by a lack of DS (6,7). ...
... It connects collagen fibrils, plays a role in the cell surface and plays role in matrix assembly and cell differentiation (9,10). It was observed that in the skin fibroblast samples of mcEDS patients, DS disaccharides on decorin was absent, while chondroitin sulfate (CS) was abundant (2,5,10). This imbalance between CS and DS is thought to be responsible for multi-systemic findings affecting various organ systems in early development (5,9,10). ...
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.
... DSPG is universally expressed in vascular wall, cornea, skin, tendons, cartilage, bone, and undifferentiated mesenchymal tissues. It participated in different pathophysiological processes such as cardiovascular disease, tumorigenesis, inflammation, injury repair, and fibrosis (Malfait et al., 2010;Janecke et al., 2016;Mizumoto et al., 2017). CHST14 mutation decreases DSPG levels, affecting the collagen formation and fibers structure. ...
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.
... D4ST encoded by carbohydrate sulfotransferase 14 (CHST14) catalyzes the transfer of a sulfate group from 3 -phosphoadenosine 5 -phosphosulfate to the C-4 hydroxy group of GalNAc residues in DS chains ( Figure 2) [26,27]. EDS musculocontractural type 1 is caused by a variety of pathogenic variants in CHST14 [22][23][24]81,[87][88][89][90][91][92][93][94][95][96] (Table 2). The characteristic manifestations of the EDS musculocontractural type 1 were craniofacial features including large fontanelle with delayed closure, downslanting palpebral fissures, and hypertelorism; skeletal features including characteristic finger morphologies, joint hypermobility, multiple congenital contractures, progressive talipes deformities, and recurrent joint dislocation; cutaneous features including hyperextensibility, fine/acrogeria-like/wrinkling palmar creases, and bruisability; refractive errors of vision, large subcutaneous hematomas, constipation, cryptorchidism, hypotonia, and motor developmental delay [96]. ...
The crucial roles of dermatan sulfate (DS) have been demonstrated in tissue development of the cutis, blood vessels, and bone through construction of the extracellular matrix and cell signaling. Although DS classically exerts physiological functions via interaction with collagens, growth factors, and heparin cofactor-II, new functions have been revealed through analyses of human genetic disorders as well as of knockout mice with loss of DS-synthesizing enzymes. Mutations in human genes encoding the epimerase and sulfotransferase responsible for the biosynthesis of DS chains cause connective tissue disorders including spondylodysplastic type Ehlers–Danlos syndrome, characterized by skin hyperextensibility, joint hypermobility, and tissue fragility. DS-deficient mice show perinatal lethality, skin fragility, vascular abnormalities, thoracic kyphosis, myopathy-related phenotypes, acceleration of nerve regeneration, and impairments in self-renewal and proliferation of neural stem cells. These findings suggest that DS is essential for tissue development in addition to the assembly of collagen fibrils in the skin, and that DS-deficient knockout mice can be utilized as models of human genetic disorders that involve impairment of DS biosynthesis. This review highlights a novel role of DS in tissue development studies from the past decade.
... Hypotonia can also be present in cEDS, aEDS, kEDS, mcEDS and spEDS and is variably associated with delayed gross motor development, myopathy with variability in fiber diameter on muscle biopsy, signs of axonal polyneuropathy on electromyography and elevated creatine kinase [12,21,22]. ...
The Ehlers–Danlos syndromes are a group of multisystemic heritable connective tissue disorders with clinical presentations that range from multiple congenital malformations, over adolescent-onset debilitating or even life-threatening complications of connective tissue fragility, to mild conditions that remain undiagnosed in adulthood. To date, thirteen different EDS types have been recognized, stemming from genetic defects in 20 different genes. While initial biochemical and molecular analyses mainly discovered defects in genes coding for the fibrillar collagens type I, III and V or their modifying enzymes, recent discoveries have linked EDS to defects in non-collagenous matrix glycoproteins, in proteoglycan biosynthesis and in the complement pathway. This genetic heterogeneity explains the important clinical heterogeneity among and within the different EDS types. Generalized joint hypermobility and skin hyperextensibility with cutaneous fragility, atrophic scarring and easy bruising are defining manifestations of EDS; however, other signs and symptoms of connective tissue fragility, such as complications of vascular and internal organ fragility, orocraniofacial abnormalities, neuromuscular involvement and ophthalmological complications are variably present in the different types of EDS. These features may help to differentiate between the different EDS types but also evoke a wide differential diagnosis, including different inborn errors of metabolism. In this narrative review, we will discuss the clinical presentation of EDS within the context of inborn errors of metabolism, give a brief overview of their underlying genetic defects and pathophysiological mechanisms and provide a guide for the diagnostic approach.
... Light microscopic investigation of skin specimens from the patients showed that fine collagen fibers were predominant in the reticular to papillary dermis and the number of thick collagen bundles was markedly reduced (Miyake et al. 2010;Mochida et al. 2016;Kono et al. 2016). Electron microscopic examination of the specimens showed that collagen fibrils were dispersed throughout the reticular dermis, whereas they were regularly and tightly assembled in control tissue (Miyake et al. 2010;Mochida et al. 2016;Kono et al. 2016;Janecke et al. 2016). Surprisingly, each collagen fibril was smooth and round, with little variation in size or shape, similar to the fibril in the control tissue ( Fig. 10.4d, f) (Miyake et al. 2010). ...
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.
... These bridging molecules, which are heterodimeric transmembrane receptors, connect ECM to cytoskeleton by interacting via their extracellular domain with collagens and other matrix molecules, thus mediating cell adhesion and motility (Campbell and Humphries 2011). Some integrins, the α5β1 and α2β1 are involved in ECM organization of fibronectin and fibrillar collagens, respectively and their expression results de-regulated in various types of EDS, reasonably as secondary effects of the primary collagen defect (Zoppi et al. 2004;Janecke et al. 2016). Among vertebrates, there are 28 distinct collagen glycoproteins that are encoded by at least 45 genes. ...
Ehlers-Danlos syndrome is an umbrella term for a clinically and genetically heterogeneous group of hereditary soft connective tissue disorders mainly featuring abnormal cutaneous texture (doughy/velvety, soft, thin, and/or variably hyperextensible skin), easy bruising, and joint hypermobility. Currently, musculoskeletal manifestations related to joint hypermobility are perceived as the most prevalent determinants of the quality of life of affected individuals. The 2017 International Classification of Ehlers-Danlos syndromes and related disorders identifies 13 clinical types due to deleterious variants in 19 different genes. Recent publications point out the possibility of a wider spectrum of conditions that may be considered members of the Ehlers-Danlos syndrome community. Most Ehlers-Danlos syndromes are due to inherited abnormalities affecting the biogenesis of fibrillar collagens and other components of the extracellular matrix. The introduction of next-generation sequencing technologies in the diagnostic setting fastened patients’ classification and improved our knowledge on the phenotypic variability of many Ehlers-Danlos syndromes. This is impacting significantly patients’ management and family counseling. At the same time, most individuals presenting with joint hypermobility and associated musculoskeletal manifestations still remain without a firm diagnosis, due to a too vague clinical presentation and/or the lack of an identifiable molecular biomarker. These individuals are currently defined with the term “hypermobility spectrum disorders”. Hence, in parallel with a continuous update of the International Classification of Ehlers-Danlos syndromes, the scientific community is investing efforts in offering a more efficient framework for classifying and, hopefully, managing individuals with joint hypermobility.
