Colonic perforation is a rare but serious complication of colonoscopy, occurring most commonly in patients with diverticular disease or a strictured, severely diseased segment of colon and particularly affecting the sigmoid . Friable tumors are also more liable to perforate . This case illustrates the increased risk of endoscopic perforation in individuals with fragile tissues secondary to an underlying collagen vascular disease such as EDS-IV.
The exact prevalence of EDS is not known, but is estimated to be between one in 10,000 and one in 25,000 . It comprises a group of hereditary connective tissue disorders which are differentiated into six main types according to the Villefranche classification [6, 7]. The vascular type of Ehlers Danlos syndrome, EDS-IV, is a rare autosomal dominant disorder accounting for 5% to 10% of all cases of EDS . It is caused by heterozygous germline mutations in the COL3A1 gene on chromosome 2q31 , which results in decreased extracellular type III collagen, leading to the loss of tensile strength of connective tissues, vascular structures, and hollow viscera. As a result, the condition is characterized by facial structural abnormalities, easy bruising, translucent skin, and clubfoot, as well as the potentially fatal complications of spontaneous rupture of large vessels and hollow organs, particularly the colon [8–10].
Hyperflexibility of the skin and joints in EDS-IV is less marked than they are in other types of EDS, so colonic perforation or aneurysm rupture may be the first presentation of the disease. As a result, EDS-IV in particular is associated with reduced life expectancy, with a median age of survival of 50 years . Diagnosis of the disorder is made on the basis of clinical signs, as well as the demonstration that cultured dermal fibroblasts synthesize abnormal type III procollagen molecules, or by the identification of a COL3A1 gene mutation . The COL3A1 gene mutation identified in our patient is a new mutation not previously reported in the literature, although similar mutations are well known to be associated with EDS-IV . Specific mutations within the gene are not thought to accurately predict the extent or prognosis of EDS-IV , nor are they associated to the types of complications observed in this condition .
Approximately 80% of patients with EDS-IV have experienced at least one complication by the age of 40 years . Bowel perforations tend to occur between the late teens and early 40s, with the sigmoid colon most often being affected . As in the present case, the histology of colonic specimens in patients with EDS-IV typically shows changes in the caliber of the lamina muscularis and may demonstrate secondary diverticula formation due to reduced resistance of the submucosal soft tissue .
Previous reports have described spontaneous colonic perforations secondary to EDS-IV in the pediatric and adult patient populations [11, 12], although the surgical management and outcomes of these patients have varied . Some cases have been managed with subtotal or total colectomies, although most have been treated with colonic resection and formation of colostomy (Hartmann's procedure) . Attempts at re-anastomosis following resection and diversion have been complicated by recurrent perforations and anastomotic leaks, presumably due to the bowel fragility, and have been compounded by adhesions as found in the present case. Consequently, some commentators have advised against restoration of colonic continuity and have advocated a subtotal colectomy as the first-line management of these patients .
The index case raises several interesting issues. First, many diagnoses of EDS-IV are retrospective and occur following a major complication. Thus, performing more extensive surgery prophylactically in the treatment of a localized colonic perforation may be an unlikely decision in the undiagnosed EDS patient, as in this case. However, if the condition is known or recognized, a total colectomy and ileorectal anastomosis need to be considered. In this case, these procedures would also have helped with regard to the patient's CRC risk.
Second, the present case illustrates the identification of EDS-IV in a patient with an atypical (non-spontaneous), presumably colonoscopy-induced perforation. Whereas large-vessel rupture in a young patient would normally prompt the clinician to consider an underlying connective tissue disorder, this case emphasizes the importance of considering EDS-IV in otherwise healthy young patients presenting with bowel perforation, a less well-known complication of the condition.
Given that there is no particular therapy to prevent further complications from occurring, however, the benefit of a retrospective diagnosis once such events have occurred is debatable. Nonetheless, knowledge of the disease may influence future surgical decisions, such as the extent of surgery in the treatment of further colonic perforations. Also, as in this case, the management of co-existent stable but expansive vascular aneurysms requires consideration of the increased risk of endovascular stenting because of tissue friability and the problems of open surgical intervention, particularly adhesions and suture tearing in the friable artery.
Third, in accordance with guidelines established by the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (ICG-HNPCC) , the index patient would continue to require biannual CRC screening on the basis of his family history. Colonoscopy is the current gold standard for surveillance of HNPCC families [13–15]; however, invasive procedures such as arteriograms and endoscopies are relatively contra-indicated in patients with EDS-IV . Alternatives such as CT colonography, which carries a lower risk of perforation and has similar sensitivities for the detection of CRC , although less so for polyps measuring less than 10 mm, need to be considered for patients requiring ongoing surveillance for CRC. In the present case, however, the patient was later excluded as a carrier for the hMSH2 gene mutation identified in his aunt.
Finally, a diagnosis of this hereditary condition has implications for the patient's family, and genetic testing needs to be offered to living relatives. As the patient has a one in two chance of having an affected child, reproductive counseling as well as predictive, diagnostic, and prenatal testing should be made available.