Digestive complications, including intestinal perforation, are one of the characteristics of EDS. Most perforation cases occur in the sigmoid colon, but the small intestine is occasionally affected [2]. More than 200 cases of spontaneous intestinal perforation in EDS have been reported in the English language [3]. In addition, similar to our case, there are multiple reports of cases of EDS diagnosed after intestinal perforation [6, 7]. However, reports of successfully treated cases requiring multiple operations are rare. Accordingly, this case is noteworthy, because it required four surgical interventions for the repeated intestinal perforations. Moreover, the missense mutation detected in the present case is presumably a pathogenic variation causing vascular EDS.

In 2017, the international EDS Consortium proposed new classification of EDS which divided it to 13 subtypes [8]. Table 1 shows inheritance pattern and clinical features of each subtypes. Vascular EDS, the fourth subtype, is a rare autosomal dominant disorder, with the estimated prevalence of 1/50,000 to 1/20,000 [9]. The characteristic manifestations of vascular EDS include arterial aneurysm, dissection, and rupture, as well as intestinal perforation and rupture of the gravid uterus. EDS results from pathogenic variants of the COL3A1 gene, which encodes the chains of type III procollagen, a major protein in the vascular walls and hollow organs.

Following the guidelines of this proposal of the international EDS Consortium [8], we genetically examined the patient and consequently identified that she had a missense mutation in the COL3A1 gene (c.2095G>T, p.Gly699Cys). Pepin et al. have reported 410 mutations of COL3A1 gene including c.2095G>C, p.Gly699Arg and c.2095G>A, p.Gly699Asp. Given the association of these two mutations with EDS and their similarity with the mutation we detected in the present case, we concluded that the mutation in the present case is likely a pathogenic variation causing EDS.

Byers et al. have reported that 31% of the vascular EDS cases experience repeated colonic perforation. The same authors have also suggested that protracted wound healing and anastomotic failure might occur due to the vulnerability of the connective tissue and vessels caused by the mutation of the COL3A1 gene [9]. The present case necessitated four operations. The first, second, and third operations were required due to the idiopathic perforation of the intestine. The last operation was required due to the dehiscence at the entry hole of the linear stapler, reflecting protracted wound healing (Fig. 2).

Given the report of Byers et al., total colectomy can be used to avoid repeated colonic perforation. Moreover, Germain et al. suggested total colectomy with ileostomy and closure of the rectal stump to cope with recurrent intestinal perforations, because perforations in the small intestine are rare [2, 10]. Nevertheless, we experienced jejunal perforation in the present case, which required a second operation. Since the patient was otherwise a healthy woman in her 50s and her preoperative performance status was good, we did not select total colectomy. Therefore, the treatment strategy per patient should be carefully assessed based on their age, physical status, and opinion.

Appropriate screening and prevention methods for intestinal perforations in patients with vascular EDS are still unclear [3]. Pepin et al. have reported that the median life span of patients with vascular EDS is 48 years (range 6–73 years), mainly due to vascular rupture [11]. The same authors have also reported that the prognosis after treatment is still poor. Prolonged postoperative monitoring via non-invasive imaging techniques, including doppler ultrasound, CT angiography with low radiation alternatives, or magnetic resonance angiography, should be performed. In addition, the patient and family members should be provided with appropriate guidance [7].

An international group of specialists have reached into a consensus of recommendations for vascular EDS patients, including lifestyle modifications to minimize injury, maintaining blood pressure within the normal range [9], and carrying a medical attention bracelet and documents noting the information about the condition [12]. This case required multidisciplinary management including physicians, surgeons, and genetic counselors. Because EDS is an autosomal dominant disorder, the supports for not only the patient but also the family members are important. Centralizing management at centers of experience is also essential. In the present case, we informed the patient of the circumstances and encouraged her to contact us if she experienced a sudden pain. We also carefully continued outpatient follow-up for the treatment of her hypertension. During her follow-up periods of 22 months after the initial surgery, she lives without intestinal perforations.