Systematic Literature Review of Colonic Perforations in Vascular Ehlers-Danlos Syndrome

Abstract

Introduction

Vascular Ehlers-Danlos Syndrome (VEDS) is a rare disorder caused by pathogenic variants in COL3A1 that cause a type III collagen abnormality or deficiency. Intestinal perforation is a known complication in this syndrome.

Objective

The purpose of this meta-analysis is to quantify the risk of VEDS-associated intestinal perforation.

Materials and Methods

A literature search was performed in August 2023 by PubMed, CINAHL, Cochrane, MEDLINE, and EMBASE identifying VEDS-related intestinal perforation publications. The search produced 615 articles with 530 articles screened. Two independent reviewers and a third reviewer for conflict resolution performed data extraction. Included studies discussed patients with VEDS and intestinal perforation. Reviews, case reports/series, expert opinions, consensus guidelines and abstracts only were excluded. Certainty of evidence was assessed by the Grading Recommendations, Assessment, Development and Evaluations framework. All data were reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Statistical R© software was used to calculate rates of colonic perforation and re-perforation.

Results

Four non-randomized studies were selected for the meta-analysis, which consisted of 721 patients with VEDS. The pooled colonic perforation rate was 15% (n = 111), and reperforation rate 33% (n = 29). Bowel perforation preceded the diagnosis of VEDS in 72% of patients. Considering the rarity of VEDS, limitations include lack of available data for patients. Given the small sample size, a large heterogeneity index was reported.

Conclusions

While patients with VEDS have high colonic perforation and subsequent reperforation risks, many VEDS diagnoses are not made until after the inciting event. No consensus guidelines exist for the surgical management of VEDS-related bowel perforations.

 

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Keywords

ehlers-danlos syndrome - type IV - intestinal perforation - colonic diseases

Introduction

The Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders characterized by tissue fragility, joint hypermobility, and skin hyper-elasticity. To date, there are 13 recognized subtypes of which 12 have a genetic etiology.[1] One of the subtypes is vascular EDS (VEDS), previously called EDS type IV, which accounts for 5% of EDS cases.[2] VEDS arises from autosomal dominant pathogenic variants in COL3A1, which encodes type III procollagen. These genetic alterations result in defective or insufficient type III collagen production, an essential component of the arterial and intestinal walls' connective tissues. In addition to early-onset aortic and arterial complications, individuals with VEDS are prone to spontaneous intestinal perforation.[3]

Spontaneous intestinal perforation presents as the first major complication in 25% of patients with VEDS, mainly affecting the sigmoid colon.[4] Per prior reviews, upwards of 55% of patients experience a second spontaneous perforation.[5] [6] Colonic histology in these cases shows thinning of the submucosa, muscularis mucosa, and muscularis propria layers.[7] Additionally, secondary diverticulae are observed, attributed to weakened submucosal resistance. These findings suggest that the fragility of the intestinal wall is related to defective type III collagen but can also be related to arterial rupture in the intestinal wall, leading to intramural hematoma, focal necrosis, and subsequent perforation.[8] [9]

Surgical decision making in this population is especially challenging. The choice of index repair includes subtotal colectomy with rectal stump closure and the creation of an end colostomy or ileostomy, and to a lesser extent primary end-to-end anastomosis. Perioperative complications include intraoperative hemorrhage, anastomosis and incisional healing and dehiscence, enterocutaneous fistulae formation, and incisional hernia.[4] [5] Patients with an end colostomy or ileostomy face two distinct surgical options due to the high risk of a second intestinal perforation: elective ostomy reversal, which carries a recurrence risk, or total abdominal colectomy with ileorectal anastomosis to prevent future perforations.[4] [5]

Given the lack of consensus guidelines to guide surgical decision making in this population, we performed a systematic literature review on this topic to synthesize the existing literature and guide in surgical decision making.

 

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Materials and Methods

This Study was IRB Exempt

The literature search was conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) search strategy and screening protocol.[10] Five major databases were queried: PubMed, CINAHL, MEDLINE, Cochrane, and EMBASE using the search strategy (vascular Ehlers-Danlos Syndrome or Ehlers-Danlos Syndrome type IV) and (intraoperative complications or perioperative care or perioperative period or postoperative complications) and (digestive system surgical procedures or drainage or elective surgical procedures, surgical or laparotomy or minimally invasive surgical procedures or minor surgical procedures or monitoring, intraoperative or ostomy or prophylactic surgical procedures or second-look surgery or wound closure techniques or anesthesia) and perforate. The search on PubMed was conducted on 8/16/23, and the search on the latter 4 databases was conducted on 8/24/2023.

We utilized Covidence systematic review software, a web-based collaboration platform, to streamline our screening process. Studies were included if they were retrospective or prospective studies including VEDS patients with intestinal perforation. Expert opinion, reviews, abstracts without a full text component, letters to the editor, book chapters, case reports and case series were excluded. Articles that did not pertain to intestinal perforation were excluded. An additional article was excluded due to use of the same French patient population as one of the other included papers. Only English articles or articles with an available English translation were included. All abstracts and full texts were screened by two independent reviewers. A third independent reviewer performed conflict resolution for inclusion or exclusion of articles.

When available, we retrieved data relating to patient demographics (age, gender), VEDS diagnosis (modality of diagnosis, COL3A1 variant, timing of diagnosis in relation to the index intestinal perforation), location of perforation, surgical management, and perioperative complications ([Table 1] and [2]). A second perforation is defined as a new perforation in a different segment of bowel and is distinct from anastomotic dehiscence or leak.

Table 1 Patient demographic information obtained from each paper

Author	Number of included patients with vEDS	Gender (patients with vEDS)	Age at diagnosis	Modality of diagnosis	Gender (perforated patients)	Age at first perforation	Diagnosis of vEDS post perforation or complication
Adham et al	148	39% male	median: 26 years old (IQR 22–36.5)	genetic testing	50% male for initial perforation, reperforations mostly males	median: 22 years old (IQR 18.2–26)	87% after GI event
Pepin et al	220 index patients +199 family members= 419	51% male	mean: 28.7 years old	biochemically confirmed and cultured fibroblasts	49% male	mean: 20.6 +/− 11.0	70% after any major complication (arterial, organ rupture or GI)
Shalhub et al	86	47.7% male	median: 41 years (IQR 31–49.6 years)	genetic analysis- molecular testing	—	—	—
Wang et al	68	41% male	mean: 38.1 +/− 16.6 years	genetic testing &/or medical genetics consult	—	—	—

Given the variabiltity in reporting statistics, the median with interquartile range (IQR) or mean with standard deviation (SD) is provided in the form of median (IQR) or mean +/− SD, respectively.

Table 2 Summary of the perforation data in the four studies included in this systematic review

Author	Year Published	Number of included patients with vEDS	Study Design	Number of institutions	Years of study inclusion	Rates of intestinal perforation	Rate of reperforation	Rate of surgical complications
Adham et al	2019	148	Retrospective review	Single tertiary referral center	2000–2016	20.20%	9.40%	33% for first surgery 36% for the reperforation operation 41% with Hartman procedure failure
Pepin et al	2000	220 index patients +199 family members= total 419	Retrospective review	Two- University of Washington & zurich	1976–1988	16%	21.70%	—
Shalhub et al	2019	86	Cross sectional retrospective review	Multi-institutional- 11	2000–2015	16%	—	—
Wang et al	2021	68	Retrospective review	Single- Mayo clinic	1994–2018	7.50%	—	—

To perform a meta-analysis on calculating the pooled estimates of the effect sizes, a random-effects model was constructed using the Paule-Mandel estimator to calculate the heterogeneity variance between individual studies. Knapp-Hartung adjustments were used to calculate the confidence interval for the pooled effect, and the prediction interval for the treatment effect was generated. An I² statistic was used to assess the magnitude of the between-study heterogeneity, with values greater than 50% regarded as being indicative of moderate-to-high heterogeneity. The Cochran Q test was utilized to assess heterogeneity between studies, with p values <0.05 as statistically significant. A further sub-analysis was used to assess the risk of intestinal reperforation in VEDS patients. All statistical analyses were performed using ‘meta’ package in R© 4.2.2 software (R Foundation).

Certainty of evidence and bias evaluation was assessed utilizing the Grading Recommendations, Assessment, Development and Evaluations (GRADE) framework. Two independent reviewers utilized the information from statistics to identify the certainty for each outcome.

 

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Results

In all, 4 retrospective cohort studies of patients with genetically confirmed VEDS met inclusion criteria ([Fig. 1]).[8] [11] [12] [13] [14] Overall, studies included between 68–419 patients each and a cumulative 721 patients. [Table 1] includes the demographic information and diagnosis information extracted from each included study, and [Table 2] includes details about each paper including the percentage of intestinal perforation, second perforation and management.

Fig. 1 PRISMA flow diagram of the methods of study selection for the review. The initial searched yielded 615 articles with 530 articles screened after the removal of duplicates. The initial screen consisted of article titles and abstracts. The second screen included full text reviews. A total of 8 articles were included in the full text review after the removal of studies based on the inclusion and exclusion criteria. After full text review, 4 articles were selected for the systematic review.

Rates of Spontaneous Colonic Perforation

All studies detailed rates of spontaneous colonic perforation, as it was the most frequently reported gastrointestinal complication. There were 111 reported cases of colonic perforation. The adjusted random-effects weight was assigned to each study using estimated between-study variance and the variances of each effect size. The colonic perforation rate range was 7–20% ([Fig. 2]). The pooled colonic perforation rate was 0.15 [CI 0.09–0.26]. The heterogeneity index of I² was 50%, indicating moderate heterogeneity between studies, and the heterogeneity between studies was not statistically significant (p = 0.11).

Fig. 2 Pooled estimates of the proportion of colonic perforations.

Two papers noted the temporal relationship between intestinal perforation and VEDS diagnosis showing that intestinal perforation preceded the diagnosis of VEDS in 72% of the cases. The Adham, et al., paper noted that 87% of their patients had their first GI event within a median of 31 months before diagnosis. Often genetic testing was performed after a patient has an aortic or GI tract complication.

 

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Rates of Spontaneous Reperforation

Two of the papers included their data on reperforations. There were a reported 29 events of reperforation ([Fig. 3]).[8] [14] The pooled spontaneous reperforation rate was 0.33. The heterogeneity index of I² was 83%, indicating substantial heterogeneity and it was statistically significant (p = 0.01)

Fig. 3 Pooled estimates of the risk of bowel re-perforation from each of the studies that reported this information.

 

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Surgical Management

Adham et al and Pepin et al provide the most detail regarding the surgical management and outcomes of intestinal perforations in VEDS (n = 30 and n = 69 respectively) and comprise most of the published data on this topic outside of case reports ([Table 3]).

Table 3 Summary table of the Adham et al and Pepin et al papers <

	Location of Perforations	Average Age of First Colonic Perforation	Surgical Management of 1<sup>st</sup> Perforation	Perioperative Complications	Reperforations	Surgical Recommendations
Adham	R colon: 2 (4%) L colon: 2 (4%) Sigmoid colon: 33 (72%) “colonic perforation”: 9 (20%)	26.0 years, IQR 22.0-36.5, range 14.0-61.0 years	Subtotal colectomy: 1 (3.3%) Partial colectomy with anastomosis: 2 (6.7%) Primary repair: 3 (30%) Hartmann procedure: 23 (76.7%)	Perioperative complications occurred in 10 (33%) patients after the first operation: hemorrhage (n = 1), incisional hernia (n =1), septic shock (n = 2), wound abscess (n = 2), anastomotic leakage (n = 1), and reperforation (n = 16)	16 patients suffered reperforations (47%)	May benefit from subtotal colectomy with ileorectal anastomosis
Pepin	Sigmoid colon: 29 (71.2%) Small bowel: 7 (11.2%)	20.6±11.0 (n=41)	Partial colectomy:42 (60.9%) -with colostomy: 26 - with anastomosis: 8 - unknown: 8	Included wound dehiscence, evisceration, hemorrhage, fistulas, reperforation, and adhesions	15 (21.7%) patients suffered reperforation - occurred between 2 weeks and 26 years of initial perforation	Colostomy over a primary anastomosis due to higher initial failure

The Adham, et al., retrospective study includes a 16-year longitudinal follow up of 148 patients with VEDS at a French tertiary referral center. The most common location for a colonic perforation was in the sigmoid colon (72% of perforations). The patients who presented with a perforation were at an average age of 26 years. The most reported by Adham et al was the Hartmann procedure. Given the risk of anastomotic leaks or reperforation the authors recommended considering a subtotal colectomy with ileorectal anastomosis electively.

The study by Pepin, et al. is a cross sectional, retrospective review of 220 index patients and 199 of their affected family members. The average age for a colonic perforation was 20.6 years old. Forty-six patients underwent a partial colectomy with 26 of these patients undergoing a colostomy creation. They recommended creation of colostomy over a primary anastomosis due to a higher anastomotic leak or dehiscence rate. They reported 22 (84%) of the patients with a colostomy subsequently underwent colostomy reversal within 1 month to 1 year of their initial perforation. Seven out of the 22 (32%) patients who had a subsequent primary anastomosis had a second bowel perforation. They also reported that a primary end to end anastomosis was created in the index operation for 8 patients with a second bowel perforation reported in 5 of these patients. Ultimately, Pepin et al, noted the increased rate of complications with primary anastomosis and suggest that removal of the sigmoid colon may decrease the risk of recurrence.

 

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Post-operative Complications

Given the presence of tissue fragility, VEDS patients are at increased risk of postoperative complications. The Adham et al and Pepin et al papers discussed complications present in their cohort of VEDs patients.

The Adham et al paper mentions specifics about their complication rate. The authors note the difference in complication rate with the index operation (10/30 patients) then a subsequent operation (7/14 patients). The most reported complications included perioperative bleeding, incisional hernia, fistula, abscesses and recurrent perforations ([Table 4]). The surgical mortality for VEDs patients who had a colonic perforation was reported as 2/30 (7%) patients.

Table 4 Description of post-operative complications in VEDS patients noted in the Adham et al and Pepin et al papers

Paper	Complication rate	Complications reported index operation	Complications reported in subsequent operations	Surgical mortality
Adham et al	index operation: 10/30 (33%) subsequent operations: 7/14 (50%)	-perioperative bleeding: 1 (10%) -incisional hernia: 1 (10%) -septic shock: 2 (20%) -wound abscess: 2 (20%) -postoperative recurrent perforation: 4 (40%)	-perioperative bleeding: 2 (28.6%) -fistula: 2 (28.6%) -recurrent perforation: 2 (28.6%) -incisional hernia: 1 (14.2%)	2/30 (7%)
Pepin et al		-dehiscence of wound -evisceration -hemorrhage -fistulas -adhesions -recurrent bowel perforations

The Pepin et al paper did note the observed complications in their patient population but did not provide the specifics in terms of the numbers of patients affected. They reported similar complications as those in the Adham et al paper, including hemorrhage, fistulas, recurrent perforations, dehiscence of wound and evisceration ([Table 4]).

 

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GRADE Criteria

Given the relatively small sample size, minimal information, and heterogeneity seen in our statistical analysis the outcome of colonic perforation was given a GRADE score of low certainty and a reperforation GRADE score of very low certainty meaning the confidence in the effect estimate is limited ([Table 5]).

Table 5 The GRADE criteria for each outcome analyzed in the review including colonic perforation and re-perforation

Proportion of Bowel Perforation in patients with Vascular Ehlers Danlos
Patient population: Vascular Ehlers Danlos
Outcomes	N° of participants (studies)	Total number of patients	Certainty of the evidence (GRADE)	Proportion of perforations
Proportion of colonic perforations	111 (4 non-randomized studies)	721	⨁⨁◯◯ Low	mean 0.15 [CI 0.09 to 0.26]
Proportion of bowel re-perforations	29 (2 non-randomized studies)	99	⨁◯◯ ◯ Very Low	Mean 0.33 [CI 0.00–1.00]

Abbreviation: CI, confidence interval.

GRADE Working Group grades of evidence.

High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.

Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

 

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Discussion

The recommended operation for a spontaneous colonic perforation in a patient with VEDS remains to be determined. This review delineates the rates of perforation and how they have been managed in the population. Given the small patient population, the statistical analysis performed included a high heterogeneity index. Given heterogeneity indices of over 75% for the reperforation analysis there is a limited ability to estimate the real proportion based on two papers reporting outcomes, so our proportions may not be reflective of the true population proportions. Given the relatively small sample size and heterogeneity seen in our statistical analysis, the GRADE criteria assigned to each outcome was considered low or very low. Again, this is consistent with a limited ability to state if the proportions calculated would be similar to the true patient population.

We identified another three systematic reviews of patients with VEDS. The systematic review by El Masri et al included 27 case reports and 4 retrospective studies.[15] Their study differed from ours as their inclusion criteria consisted of case reports and studies written in French. They excluded perforations that were due to invasive procedures. Soborg et al conducted a review regarding gastrointestinal surgery in all subtypes of EDS.[4] Out of 538 patients with VEDS, there was a GI perforation rate of 12.4–25% and a GI surgery rate of 20.7–33.3%. The average age of perforation was 24 years old in this study.

Speake et al included 43 case reports.[16] Their main outcome measure was reperforation following colonic surgery in patients with VEDS. Within the case reports they identified 48 patients who underwent 102 operations, including 58 procedural reinterventions. The researchers found a significant difference in the reperforation rate between those whose ostomies were reversed and those who had restoration of colonic continuity. Their analysis also demonstrated a statistically significant decreased risk of reperforation for patients who underwent a total abdominal colectomy with ileorectal anastomosis compared with colo-colonic anastomosis.[17] They concluded that the risk of reperforation is higher after partial colon resection with anastomosis or with primary repair when compared with total colectomy. While they may have determined statistical significance using data from case reports, which are inherently biased, these results do not necessarily reflect outcomes of all patients with VEDS. Elective total abdominal colectomy with ileorectal anastomosis also puts the patient at risk of perioperative complications, including anastomotic leak.

Most of what is known about colonic perforation in VEDS comes from case reports that have been published on the topic. Many of the case reports detail patients who suffer multiple perforations, undergo several operations, and experience morbid complications. The complications most commonly encountered included development of EC fistula, anastomotic complications (leak, dehiscence, stenosis), and subsequent perforations.[15] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] Given the quality of the tissue in VEDS patients they are also at risk of intraoperative enterotomy.[19] [27] [28] [29] Case reports will naturally skew toward more severe case presentations but can provide valuable information about the management and outcomes of these patients.

One common issue is that a VEDS diagnosis has not yet been made when patients present with spontaneous intestinal perforation. A diagnosis of VEDS should be suspected in younger patients presenting with a spontaneous intestinal perforation, especially if they meet any of the other major or minor criteria of VEDS. Other signs of VEDS may be friable tissue or excessive bleeding intraoperatively.[30] [31] Pathology results of resected colon may be inconsistent with other causes of colonic perforation (ie: diverticulitis, Crohn's disease), and instead showed areas of irregular, thin, and tearing muscularis and/or submucosa.[32] [33] These intraoperative and pathological findings should prompt surgeons to consider an underlying cause.

Given this is not a commonly encountered disease process there remains disagreement in the best surgical management of intestinal perforation in the VEDS population. Overall, there appears to be consensus that primary anastomosis should be avoided for patients with a known VEDS diagnosis. In a similar vein, there appears to be a considerable risk of reperforation after reversing a colostomy.[14] Some authors suggest a total colectomy with end ileostomy or ileorectal anastomosis (with or without diverting loop ileostomy) should be done as a definitive procedure in patients with VEDS who have a history of a spontaneous colonic perforation, but there remains no consensus.[6] [8] [20] [34] The argument is that risk of colonic reperforation is too high (up to 37%), in our study; so resection will prevent recurrence. However, rates of complications are high in patients with VEDS. The available published data are not sufficient to adequately characterize the risk of reperforation with different operative strategies nor the risk of serious complications with each operation. Identifying predictive factors of severity of intestinal perforations in vEDS could lead to further risk stratification, preventing unnecessary operations and/or morbid reperforation events. For all these reasons that indicate a lack of knowledge in this arena, more research in EDS and bowel perforation should be performed.

Due to fragility of tissue in VEDS, it is important to emphasize careful tissue handling, gentle retraction, and close inspection prior to closing the abdomen. Patients should be observed for a longer post-operative period than the average patient. A bowel regimen should be established as soon as appropriate post-operatively, and the patient should be counseled to continue once discharged. There should be a low threshold to work up abdominal complaints for possible perforation events or hypotensive episodes such as arterial rupture.

The main limitation of this review is that there is not enough high-quality data to draw evidence-based conclusions on the ideal management of intestinal perforation with VEDS. The rarity of VEDS prevents feasibility of prospective randomized clinical trials, and thus there are none to summarize within this review. Given this review by design is retrospective in nature with retrospective reviews there is also a component of selection bias. The heterogeneity amongst the studies demonstrated by a high I² value further limits the accuracy amongst the data. Within these four studies, the cumulative 721patients with VEDS reflects all patients outside case reports whose data has been published regarding colonic perforations. This low sample size reflects the need for multi-institutional and international databases with subsequent analyses to further delineate the nature of disease, best practices, risk profiles, and genetic influence on severity of disease. These studies do provide a preliminary estimate of the prevalence and severity of colonic perforation in VEDS and its management; however, we are unable to definitively determine surgical outcomes between different surgical options or provide patients with accurate statistics regarding their risk.

 

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Conclusion

VEDS is a rare disease with serious complications, which makes recognition and treatment of intestinal perforations in these patients a challenge. This paper serves to compile the data from published studies of patients with VEDS who have suffered intestinal perforation. Future randomized trials and collaborative multi-institutional database studies may help to determine guidelines for surgical management in VEDS patients.

 

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Conflicts of Interest

Dr Shalhub is a member of the Ehlers-Danlos Society Advisory Board and principal investigator of the VEDS Collaborative Natural History Study. Otherwise, there are no conflicts of interest for any of the authors listed.

Acknowledgments

The authors would like to thank Andrew S. Hamilton from the library of the Oregon Health & Science University for his help with the literature search strategy of this systematic review.

Presentations

The abstract was submitted to ASCRS 2025 for a poster/oral presentation and was accepted as an eposter (Abstract ID: 1956614). The project was presented by Cynthia Araradian at the 7^th GASTROENTEROLOGY & HEPATOLOGY Webinar-2024 (virtual, European) from October 21–22, 2024. A version of this project including case reports was presented at Northwest Colorectal Society by Maura Walsh on July 25, 2024.

Authors' Contributions

MW: Conceptualization, data curation, investigation, methodology, project administration, visualization, writing, reviewing, and editing; CAA: Data curation, formal analysis, investigation, methodology, project administration, validation, visualization, writing, reviewing, and editing; SC: Formal analysis; MMA: Data curation, investigation, writing, reviewing, and editing; TL: Writing, reviewing, and editing; SS: Conceptualization, methodology, project administration, supervision, writing, reviewing, and editing; SHF: Conceptualization, methodology, project administration, supervision, writing, reviewing, and editing.

^* Maura Walsh and Cynthia Araradian contributed equally to this paper.

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Publication History

Received: 18 May 2025

Accepted: 16 July 2025

Article published online:
27 August 2025