Case report: Multiple gastrointestinal perforations in a rare musculocontractural Ehlers–Danlos syndrome with multiple organ dysfunction

Abstract

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.

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)

“…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]. Recovery from subsequent septic shock was achieved through anti-infective therapy, nutritional support, blood transfusion, and mechanical ventilation.…”

“…Ten days after the perforation, he developed a perforation of the gastric antrum, followed by septic shock. Eight days after the gastric perforation, he developed another possible intestinal perforation, complicated by a third septic shock, resulting in multiple organ failure and death [5]. Diverticula were not mentioned, and pathological study showed the infiltration of a large number of inflammatory cells and abscess formation on the first colonic perforation site and inflammatory cell infiltration with fibroblast proliferation in the fibrous connective tissue at the gastric perforation site [5].…”

“…Eight days after the gastric perforation, he developed another possible intestinal perforation, complicated by a third septic shock, resulting in multiple organ failure and death [5]. Diverticula were not mentioned, and pathological study showed the infiltration of a large number of inflammatory cells and abscess formation on the first colonic perforation site and inflammatory cell infiltration with fibroblast proliferation in the fibrous connective tissue at the gastric perforation site [5]. It was speculated that his colonic perforation had been caused by tissue and muscle fragility, and worsened by weakened gastrointestinal peristalsis and secondary intestinal obstruction caused by long-term bed rest after orthopedic surgery [5].…”

“…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].…”

Histories of Dermatan Sulfate Epimerase and Dermatan 4-O-Sulfotransferase from Discovery of Their Enzymes and Genes to Musculocontractural Ehlers-Danlos Syndrome

“…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].…”