Clinical and pathophysiological delineation of musculocontractural Ehlers—Danlos syndrome caused by dermatan sulfate epimerase deficiency (mcEDS‐ DSE ): A detailed and comprehensive glycobiological and pathological investigation in a novel patient

Abstract

Musculocontractural Ehlers-Danlos syndrome caused by dermatan sulfate epimerase deficiency (mcEDS-DSE) is a rare connective tissue disorder. This is the first report describing the detailed and comprehensive clinical and pathophysiological features of mcEDS-DSE. The patient, with a novel homozygous nonsense variant (NM_013352.4:c.2601C>A:p.(Tyr867*)), exhibited mild skin hyperextensibility without fragility and small joint hypermobility, but developed recurrent large subcutaneous hematomas. Dermatan sulfate (DS) moieties on chondroitin sulfate/DS proteoglycans were significantly decreased, but remained present, in skin fibroblasts. Electron microscopy examination of skin specimens, including cupromeronic blue-staining to visualize glycosaminoglycan (GAG) chains, revealed coexistence of normally assembled collagen fibrils with attached curved GAG chains and dispersed collagen fibrils with linear GAG chains from attached collagen fibrils across interfibrillar spaces to adjacent fibrils. Residual activity of DS-epi1, encoded by DSE, and/or compensation by DS-epi2, a minor homolog of DS-epi1, may contribute to the mild skin involvement through this "mosaic" pattern of collagen fibril assembly.

Pathophysiological Investigation of Skeletal Deformities of Musculocontractural Ehlers–Danlos Syndrome Using Induced Pluripotent Stem Cells

“…Musculocontractural EDS is a recently identified subtype caused by biallelic pathogenic variants in the genes encoding carbohydrate sulfotransferase 14 (mcEDS- CHST14 : MIM#601776) or dermatan sulfate epimerase (mcEDS- DSE : MIM#615539) [ 3 ]. To date, 66 patients (48 families) with mcEDS- CHST14 and 14 patients (eight families) with mcEDS- DSE have been described [ 4 , 5 ]. Patients with mcEDS- CHST14 have distinct craniofacial characteristics, multiple congenital contractures, and progressive multisystem fragility-related manifestations in the cutaneous, skeletal, and ocular systems [ 4 ], while those with mcEDS- DSE are less common and have fewer characteristics, including joint manifestations and skin features [ 5 ].…”

“…To date, 66 patients (48 families) with mcEDS- CHST14 and 14 patients (eight families) with mcEDS- DSE have been described [ 4 , 5 ]. Patients with mcEDS- CHST14 have distinct craniofacial characteristics, multiple congenital contractures, and progressive multisystem fragility-related manifestations in the cutaneous, skeletal, and ocular systems [ 4 ], while those with mcEDS- DSE are less common and have fewer characteristics, including joint manifestations and skin features [ 5 ].…”

Detailed Courses and Pathological Findings of Colonic Perforation without Diverticula in Sisters with Musculocontractural Ehlers–Danlos Syndrome Caused by Pathogenic Variant in CHST14 (mcEDS-CHST14)

“…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].…”

Clinical Presentation and Characteristics of the Upper Extremity in Patients with Musculocontractural Ehlers–Danlos Syndrome

“…The subtype is further classified into mcEDS- CHST14 , which is caused by dermatan 4- O -sulfotransferase 1 deficiency based on CHST14 gene mutation, and mcEDS- DSE , which is caused by dermatan sulfate epimerase deficiency. Both subtypes result in the systemic depletion of dermatan sulfate [ 2 , 3 , 4 , 5 ]. Clinical features of mcEDS- CHST14 include distinct craniofacial features, multiple joint contractures, progressive connective tissue weakness (i.e., skin laxity and giant subcutaneous hematoma), repetitive joint dislocations and deformities due to joint laxity, and severe damage to the locomotor system of the whole body [ 3 ].…”

“…Clinical features of mcEDS- CHST14 include distinct craniofacial features, multiple joint contractures, progressive connective tissue weakness (i.e., skin laxity and giant subcutaneous hematoma), repetitive joint dislocations and deformities due to joint laxity, and severe damage to the locomotor system of the whole body [ 3 ]. Although the clinical presentation of mcEDS- DSE is similar to that of mcEDS- CHST14 , joint-related symptoms (dislocation and hypermobility), cutaneous features (hyperextensibility and frailty), hypotonia, and gross motor developmental delays are less common than in mcEDS- CHST14 [ 5 ].…”