Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare autosomal recessive connective tissue disorder characterized by fragility of skin, vasculature and musculoskeletal structures. We report a case of a young male with CHST14(Carbohydrate sulfotransferase 14)-related mcEDS who developed a massive subcutaneous hematoma following minor trauma, necessitating surgical evacuation. This case highlights the potential for life-threatening bleeding complications in mcEDS and underscores the importance of early recognition and multidisciplinary management. Musculocontractural Ehlers-Danlos syndrome (mcEDS) is characterized by multiple congenital contractures, progressive foot and ankle deformities, hypermobility of the small joints, recurrent dislocations, spinal deformities, characteristic craniofacial features (large anterior fontanel with delayed closure, short and downslanted palpebral fissures, hypertelorism, blue sclera, low-set posteriorly rotated ears, short nose with hypoplastic columella, long philtrum, thin vermilion of the upper lip, small mouth, high palate, micrognathia), skin features (hyperextensibility, bruisability, delayed wound healing, and fragility with atrophic scars), large subcutaneous hematoma, and ocular abnormalities (strabismus, refractive errors, and glaucoma). Additional organ systems can be involved including genitourinary, cardiovascular, neurologic, and gastrointestinal. The diagnosis of mcEDS is established in a proband with suggestive findings and biallelic pathogenic variants in CHST14 or DSE identified by molecular genetic testing. Treatment of manifestations: Braces for joint and spine deformities with surgical correction as needed per orthopedist; standard treatment for osteoporosis and constipation; surgical sutures as needed for skin lacerations; hygiene and topical or oral antibiotics as needed for skin fistula; corrective lenses for refractive errors and strabismus; surgical correction as needed for strabismus; treatment of glaucoma and retinal detachment per ocular specialist; surgical fixation of cryptorchidism; prophylactic antibiotics for recurrent urinary tract infection and surgical correction of urologic abnormalities if necessary; treatment of nephrolithiasis and urolithiasis per nephrologist and/or urologist; compression, icing, surgical drainage, and administration of desmopressin if necessary for large subcutaneous hematomas; treatment of cardiac valve abnormalities and congenital heart defects per cardiologist and cardiac surgeon; physical therapy for hypotonia and motor delay; surgical treatment as needed for hernia; treatment of diverticula per gastroenterologist; hearing aids as needed; treatment of pneumothorax per intensivists and thoracic surgeon; dental correction as needed; surgical closure for cleft palate and speech therapy as needed; psychosocial counseling. Surveillance: Orthopedic evaluation of foot deformities every three months in infancy, every six months in childhood, and annually in adolescence and adulthood; orthopedic evaluations of spine deformities and digit contractures every six to 12 months beginning in infancy; bone density scan annually beginning in adulthood; orthodontic evaluation annually beginning in childhood; ophthalmologic evaluation, urologic evaluation including ultrasound, cardiac evaluation, and otologic evaluation annually beginning in infancy; assessment of gross motor skills every three months beginning in infancy and every six months throughout childhood. Agents/circumstances to avoid: Contact or competitive sports; upper arm sphygmomanometer and use of a tight tourniquet during blood collection in individuals with hyperalgesia to pressure. Pregnancy management: Pregnancy and delivery in women with mcEDS should be managed in a perinatal center; planned cesarean section would be a reasonable approach due to risk of premature rupture of membranes, birth canal laceration, and excessive bleeding with vaginal delivery. Musculocontractural EDS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CHST14 or DSE pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the mcEDS-related pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Dermatan sulfate (DS) is a type of glycosaminoglycan present in the extracellular matrix, and which is related to tissue strength, structure, and healing. Dermatan 4-O-sulfotransferase 1 (D4ST1) is an enzyme that catalyzes the transfer of a sulfate group to the N-acetylgalactosamine residue of dermatan, resulting in mature DS. Biallelic loss-of-function variants in the carbohydrate sulfotransferase 14 (CHST14) gene encoding D4ST1, induce defective DS biosynthesis. DS deficiency causes severe connective tissue fragility and deformities in humans (musculocontractural Ehlers-Danlos Syndrome [mcEDS]) and mice (Chst14 gene knockout [Chst14-/-] mice). Many patients with mcEDS experience gastrointestinal symptoms such as constipation, diverticula, diverticulitis, and perforation. However, pathogenesis of these symptoms has not been systematically investigated. Therefore, we sought to determine the effects of DS deficiency on the colon using Chst14-/- mice. We found that collagen fibrils were abnormally arranged in the submucosa of the colon. The mice also exhibited accelerated colonic contraction. Unexpectedly, no significant aggravation of dextran sulfate sodium-induced colitis was observed in Chst14-/- mice compared with wild-type mice. These findings suggest a physiological role of DS in the colon and may shed light on the potential mechanisms underlying the gastrointestinal symptoms of mcEDS.

Collagen fibrils in the dermis are bundled by glycosaminoglycan (GAG) chains of decorin, which contribute to its strength. The three-dimensional structure of collagen fibrils and GAG chains has been discussed on the basis of observations and experiments. This study uses scanning transmission electron microscope (STEM) tomography with high Z-axis resolution to analyze the three-dimensional structure of GAG chains in the dermis from a healthy individual and a patient with musculocontractural Ehlers-Danlos syndrome caused by pathogenic variants in CHST14 (mcEDS-CHST14). This observation revealed that the dermis from a healthy individual featured multiple GAG chains that wrapped around collagen fibrils and formed incomplete ring structures. However, in the dermis from a patient with mcEDS-CHST14, GAG chains were linear and did not form rings. Based on the relationship between collagen fibrils and GAG chains, we suggest the three-dimensional structure of normal GAG chains in a new model named the 'segmented ring-mesh model'. The interactions between collagen fibrils and GAG chains in this model also apply to the dermis of mcEDS-CHST14 patients, in which the GAG chain composition changes to become CS-rich and more linear. This change leads to an increased inter-fibrillar space, which inhibits the dense packing of collagen fibrils. These findings suggest that this phenomenon contributes to the skin fragility observed in mcEDS-CHST14 patients. Our study suggests the 'segmented ring-mesh model' of GAG chains is essential for the dense packing of collagen fibrils in normal dermis. STEM tomography is highly effective in analyzing the three-dimensional structure of collagen fibrils and GAG chains.

Musculocontractural Ehlers-Danlos syndrome (mcEDS) is a rare autosomal recessive connective tissue disorder caused by systemic depletion of dermatan sulfate. Symptoms characteristic of mcEDS include multiple contractures, fragile skin with subcutaneous bleeding, and hypermobile joints, which suggest difficulty in perioperative management. However, safe surgical techniques and perioperative management of this disorder remain unknown because of its rarity. We report a patient with mcEDS who developed endometrial cancer and underwent surgery, with emphasis on perioperative management. A female patient, who had been genetically diagnosed with mcEDS-CHST14 at the age of 25, presented with symptoms characteristic of mcEDS, including: congenital contractures of fingers and clubfeet, recurrent joint dislocation, progressive foot and spinal deformities, and large subcutaneous hematomas. At age 33, she had been diagnosed with atypical endometrial hyperplasia, and scheduled to undergo total abdominal hysterectomy. To address the risk of massive hemorrhage during the surgery due to mcEDS-related tissue fragility, plasma-derived factor VIII concentrate was prophylactically administered before surgery. During the surgery, neither fragility, hyperextensibility, nor hemorrhagic tendency of the uterus or adnexa observed was observed. The surgery was uneventful, with blood loss of 180 mL and operative time of 2 h and 54 min. However, on the sixth postoperative day, a 2.5-cm dissection was noted at the site of skin incision. Subcutaneous fluid accumulation developed under the skin incision and it persisted for 1.5 months. The postoperative pathological diagnosis was endometrioid carcinoma grade 1, stage IA. The present case suggested that the prophylactic use of factor VIII was effective for the prevention of hemorrhage during surgery. However, delayed wound healing of the skin and subcutaneous tissues was considered a subject for future improvement.

The patient was a six-year-old boy with a history of musculocontractural Ehlers-Danlos syndrome (mcEDS). He presented to the emergency department after falling on the road the day before admission, which led to an increase in subcutaneous hematoma in his left lower leg and brief syncope. Initial blood tests revealed a decreased hemoglobin level of 8.1 g/dL (normal range: 14 g/dL). Contrast-enhanced CT showed a massive subcutaneous and intermuscular hematoma in the left thigh. He was diagnosed with hemorrhagic shock due to this extensive hemorrhage and was admitted to the ICU. The affected area was elevated, and hemostasis was achieved through compression. The swelling gradually improved, and he was discharged from the hospital on day 13 after admission. EDS is a systemic condition caused by genetic mutations affecting collagen and collagen-modifying enzymes. mcEDS is an extremely rare variant with a recently identified causative gene, characterized by abnormal connective tissue development and progressive fragility. Giant subcutaneous hematomas resulting from tissue fragility are serious complications of this disease, often occurring with minor trauma and sometimes leading to gradual hemorrhagic shock. Desmopressin nasal drops can be effective in preventing such hematomas. It is crucial to consider the risk of hemorrhagic shock from subcutaneous hemorrhage in patients with mcEDS, especially when repeated subcutaneous hematomas of unknown origin are observed.