Intestinal Failure in Pediatric Vascular Ehlers–Danlos Syndrome: A Case Series and Literature Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Two interesting cases, although manuscript in my opinion could be improved significantly.

Aim of paper: The paper aims to describe cases of intestinal failure in vEDS. Intestinal failure could be seen as a clinical management failure? Would it perhaps be of greater interest to look at severe pediatric intestinal complications to vEDS also including cases that were wellmanaged and thus did not result in intestinal failure? In the discussion it is stated that the authors look for best practice, then it may be prudent to include more cases.

Introduction: Maybe omit "extreme" and "dramatic".

Table 1 does not add to the paper aim, would be appropriate in a thesis perhaps, but not here.

Paragraph regarding genetic counseling is quite basic - omit at least "each child of an affected individual has a 50% chance inheriting the mutation". This must be assumed to be something the reader of a scientific journal knows?

Intestinal complications, when arising, may be a significant challenge. However they are rare- please rephrase around that.

Perhaps a mention of eccogenic bowel - is this seen in vEDS? (also representing bowl perferation)

results: no genetic testing performed on patient 1? this is a significant limitation. 

What was the variant found in patient 2? Was it de novo?

Discussion. Bowel perforation is not hte first sign in 87% of vEDS patients. It may be that vEDS is present in 87% of spontaneous perforations in the young?

Patient selection: Should "subsequently" be ommited? I suppose children with IF later found to have vEDS would also have been of interest? Patient 1 for instance.

Litterature search: no mesh terms used, no search on gene name? No mention of how litterature was evaluated, did two people read through abstracts?

Good point with catheters and vascular fragility, but repeated could be better phrased.

paragrapf of optimizing lif quality of life is not scientifically needed.

Comments on the Quality of English Language

Very elaborate - slight concern that AI has corrected it?

Author Response

Comments 1: Two interesting cases, although manuscript in my opinion could be improved significantly.

Response 1: Thank you for your thorough review and constructive feedback. 

Comments 2: Aim of paper: The paper aims to describe cases of intestinal failure in vEDS. Intestinal failure could be seen as a clinical management failure? Would it perhaps be of greater interest to look at severe pediatric intestinal complications to vEDS also including cases that were well managed and thus did not result in intestinal failure? In the discussion it is stated that the authors look for best practice, then it may be prudent to include more cases.

Response 2: We acknowledge the potential value of including a broader range of cases. However, vEDS is characterized by sporadic and often spontaneous complications, making it challenging to definitively categorize cases as "well-managed" or "poorly managed." These complications can occur independently of medical or surgical intervention. Furthermore, while extensive literature exists on intestinal complications in vEDS, reports specifically focusing on intestinal failure are limited. Therefore, our focus on intestinal failure cases aims to address this gap in the current literature.

Comments 3: Introduction: Maybe omit "extreme" and "dramatic".

Response 3: Changes have been made. “This deficiency in properly formed type III collagen compromises the structural integrity and resilience of connective tissues throughout the body, resulting in the hallmark characteristic of significant tissue fragility. This fragility manifests most severely in the increased vulnerability of blood vessels to aneurysm formation, dissection, and rupture, as well as the increased risk of organ rupture, including the intestines, uterus, and spleen” [5–9].

Comments 4: Table 1 does not add to the paper aim, would be appropriate in a thesis perhaps, but not here.

Response 4: Table 1 has been deleted.

Comments 5: Paragraph regarding genetic counseling is quite basic - omit at least "each child of an affected individual has a 50% chance inheriting the mutation". This must be assumed to be something the reader of a scientific journal knows?

Response 5: “Each child of an affected individual has a 50% chance of inheriting the mutation” has been deleted.

Comments 6: results: no genetic testing performed on patient 1? this is a significant limitation. 

Response 6: Thank you for pointing out this limitation. We acknowledge that genetic testing would have provided definitive confirmation. However, the patient's distinct facial features along with the patients medical history provided a very strong clinical diagnosis. Furthermore, genetic testing was not performed due to resource limitations. While we recognize that this limits definitive confirmation, the clinical presentation was compelling. We added to the text: “Although genetic testing was precluded by resource constraints, the patient's distinctive facial features and extensive medical history strongly supported a clinical diagnosis of Ehlers-Danlos syndrome.”

Comments 7: What was the variant found in patient 2? Was it de novo?

Response 7: Patient 2 has a c.1662+1G>A variant. It was added to the manuscript: “Clinical suspicion for vEDS arose during the postoperative course due to the unusual pattern of multiple bowel perforations. Subsequent genetic testing confirmed a mutation in the COL3A1 gene (c.1662+1G>A variant), confirming the molecular diagnosis of vEDS.”

Comments 8: Discussion. Bowel perforation is not the first sign in 87% of vEDS patients. It may be that vEDS is present in 87% of spontaneous perforations in the young?

Response 8: Thank you for highlighting this discrepancy. We sincerely apologize for the error. The original statement was incorrect. The correct percentage, as derived from the cited literature, is 21% (reported in 87 patients in a 419 patients study. We corrected that number in the text.

Comments 9: Patient selection: Should "subsequently" be omitted? I suppose children with IF later found to have vEDS would also have been of interest? Patient 1 for instance.

Response 9: We agree and have omitted the word "subsequently" from the patient selection criteria.

Comments 10: Literature search: no mesh terms used, no search on gene name? No mention of how literature was evaluated, did two people read through abstracts?

Response 10: The terms used were MeSH terms so we added the concept to the paragraph. The term COL3A1 is not a MeSH term so it was not used. To address the concern about literature evaluation, we have added a description of our review process. Two independent reviewers screened titles and abstracts for relevance based on predefined inclusion and exclusion criteria. That was added to the paragraph.

Comments 11: Good point with catheters and vascular fragility, but repeated could be better phrased.

Response 11: Thank you. We changed the sentence to: “Given that these patients are already at increased risk for vascular events, the added stress of catheterizations and the potential for catheter-related complications further underscores the importance of careful monitoring and proactive management.”, omitting “repeated”.

Comments 12: paragrapf of optimizing lif quality of life is not scientifically needed.

Response 12: While we acknowledge that a detailed discussion of quality of life optimization may not be strictly scientifically necessary in the context of intestinal failure in vEDS, we believe it is highly clinically relevant for a comprehensive review article.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Dr. Percul C et al. work is aimed at a significant topic of intestinal failure in pediatric vascular EDS. This is an important topic that would help doctors around the world to provide the necessary care for a neglected group of patients with vEDS. The manuscript is well written. Nonetheless, there are some concerns that require attention.

1. I would strongly urge the authors to divide this manuscript into two separate submissions. The clinical case manuscript and the review article are fundamentally different in their presentation. In this work, the authors are calling it a review, but it is a Discussion section of the clinical case presentation. Every Discussion also requires a literature search that we don't write about in methods. A review article is written in a different way and should have a CONSORT figure, illustrations, and a different structure. This manuscript has a structure of a research paper, not a review article.
2. Why did authors include only 6 types of EDS in their table and not all 13?
3. Last paragraph of the introduction. Intestinal failure is a rare or underreported complication? Perforation is one of the criteria, so it should be quite often in this group of patients.
4. Was this study approved by the Ethical Committee? 
5. What are the major and minor clinical criteria of vascular EDS type? Which of them did the patients have? 
6. It is an autosomal-dominant disorder and family history is one of the criteria. Please provide a family history of each of the patients. 
7. In the method section when describing patients' data collection, what did the authors mean by long-term outcomes? Outcomes of what?
8. Were there bleeding complications after the surgical interventions?
9. Was the early postoperative period in any way different from people without vascular EDS or with other EDS types?
10. Page 5 bottom line. It looks like there is a part of a sentence missing.

Author Response

Comments 1: I would strongly urge the authors to divide this manuscript into two separate submissions. The clinical case manuscript and the review article are fundamentally different in their presentation. In this work, the authors are calling it a review, but it is a Discussion section of the clinical case presentation. Every Discussion also requires a literature search that we don't write about in methods. A review article is written in a different way and should have a CONSORT figure, illustrations, and a different structure. This manuscript has a structure of a research paper, not a review article.

Response 1: Thank you for your feedback regarding the manuscript's structure. We understand and acknowledge your point that clinical case reports and review articles are different and recognize that our current manuscript structure may reflect a research paper. However, we were encouraged by the journal to submit it as a review article, incorporating our clinical case series.  While we understand that the manuscript may not fully adhere to the traditional review article format, we have made efforts to comply with the journal's instructions and to provide a comprehensive analysis of the literature within the constraints given. Also, we added the requested information to the methods section about how we did the literature review. 

Comments 2: Why did authors include only 6 types of EDS in their table and not all 13?

Response 2: Table 1 was deleted due to the suggestion of another reviewer.

Comments 3: Last paragraph of the introduction. Intestinal failure a rare or underreported complication? Perforation is one of the criteria, so it should be quite often in this group of patients.

Response 3: We understand the concern about the frequency of intestinal perforation versus intestinal failure in vEDS. We acknowledge that while intestinal perforation is a recognized complication in vEDS, the progression to intestinal failure, which involves severe and prolonged intestinal dysfunction requiring parenteral nutrition, is far less common and sparsely reported in the literature. It is precisely this scarcity of reports on intestinal failure in pediatric vEDS that motivates our article. 

Comments 4: Was this study approved by the Ethical Committee? 

Response 4: Due to the retrospective nature of the study proposed for publication, no IRB approval was needed according to our institution’s regulations. Both patients whose cases are being reported have granted authorization for their cases to be published.

Comments 5: What are the major and minor clinical criteria of vascular EDS type? Which of them did the patients have? 

Response 5:

Major Clinical Criteria: arterial rupture or dissection, spontaneous intestinal rupture (present in both patients), uterine rupture, family history of vEDS: A confirmed diagnosis in a first-degree relative

Minor Clinical Criteria: Thin and translucent skin (both patients), easy bruising  (both patients), characteristic facial features (thin lips, narrow nose, large eyes, small chin)  (both patients), hypermobility of small joints (patient 1), tendon or muscle rupture (patient 1), spontaneous pneumothorax, acrogeria, congenital hip dislocation. 

Comments 6: It is an autosomal-dominant disorder and family history is one of the criteria. Please provide a family history of each of the patients.

Response 2: In both patients there was no known family history of vEDS or related connective tissue disorders.  This information was added in the last paragraph of results.

Comments 7: In the method section when describing patients' data collection, what did the authors mean by long-term outcomes? Outcomes of what?

Response 7: Thank you for requesting clarification on the definition of "long-term outcomes." We understand that this term requires more specific detail. We added it to the paragraph: “surgical history, and long-term outcomes, including clinical evolution (surgical and medical complications and the possibility of intestinal transit reconstruction), nutritional status (intestinal sufficiency or parenteral nutrition dependency), time of parenteral nutrition usage.”

Comments 8: Were there bleeding complications after the surgical interventions?

Response 8: There were no bleeding complications in either patient. “No bleeding complications were observed.” was added to the text for both patients.

Comments 9: Was the early postoperative period in any way different from people without vascular EDS or with other EDS types?

Response 9: The early postoperative period in our vEDS patients was indeed significantly different from what is typically observed in patients without vEDS or with other EDS types, particularly in terms of the frequency and severity of complications. In both patients the early postoperative period following the initial appendectomy was marked by severe complications, including spontaneous perforations, anastomotic leakage, multiple perforations, and the development of multiple enterocutaneous fistulae. None of these complications is frequent in pediatric patients with acute abdomen.

Comments 10: Page 5 bottom line. It looks like there is a part of a sentence missing.

Response 10: Thank you for pointing out the issue with the final sentence. We agree that the sentence was unclear and have been revised, to improve clarity. The sentence now reads: "Eleven years after the initial diagnosis, the patient remains on home PN with a stable clinical course over the past three years. He has type 1 short bowel syndrome with a high-output proximal jejunostomy and a low-output second remaining enterocutaneous fistula."

Author Response File: Author Response.docx

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The reviewer thanks the authors for their replies. One concern remains, requiring their attention.

Please include the major and minor criteria of the vEDS in the manuscript (maybe as a Table?) to help clinicians recognize it and include in the manuscript patients’ major and minor criteria in their descriptions.

Author Response

Comments 1: The reviewer thanks the authors for their replies. One concern remains, requiring their attention. Please include the major and minor criteria of the vEDS in the manuscript (maybe as a Table?) to help clinicians recognize it and include in the manuscript patients’ major and minor criteria in their descriptions.

Response 1: Thank you for your valuable comment. We have now included the major and minor diagnostic criteria for vascular Ehlers-Danlos syndrome (vEDS) in the manuscript as Table 1, adapted from the 2017 International Classification of the Ehlers-Danlos Syndromes (Malfait et al., Am J Med Genet C, 2017). (Cited as number [10].)

Additionally, we have specified the major and minor criteria met by each patient in the case descriptions:

For patient 1: “This patient fulfilled one major criterion (spontaneous intestinal perforation) and five minor criteria for vEDS, including thin and translucent skin, easy bruising, characteristic facial features, hypermobility of small joints, and tendon/muscle rupture (evident during postoperative recovery).”

For patient 2: This patient met one major criterion (spontaneous intestinal perforation) and four minor criteria, including thin and translucent skin, easy bruising, characteristic facial features, and hypermobility of small joints.