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  • Edoardo Staderini1,2,3,
  • Gioele Gioco1 and
  • Federica Guglielmi1,2,3,*
  • et al.

Reviewer 1: Sorin Mihali Reviewer 2: Luka Šimunović Reviewer 3: Anonymous Reviewer 4: Anonymous Reviewer 5: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is well-structured, written clearly, and adheres to CARE guidelines. The integration of genetic, clinical, and radiographic data strengthens the case’s validity. The ethical and interdisciplinary considerations are particularly commendable. That said, several points could be refined to enhance the manuscript’s scientific depth, clarity, and utility for clinicians:

1. Provide incidence figures for Infantile Refsum Disease specifically (if available) or cite the most recent reviews to contextualize its rarity in introduction section.

2. The discussion of peroxisomal dysfunction and its link to odontogenesis is insightful but superficial. Please elaborate on the specific molecular mechanisms affecting ameloblast and odontoblast activity. A deeper connection between peroxisomal metabolism and dental tissue differentiation would strengthen the biological rationale.

3. The OPG image (Figure 3, page 4) is valuable. However, higher-resolution labeling or annotations (e.g., indicating impacted teeth positions or malformations) would improve interpretability for readers unfamiliar with such cases.

4. The manuscript describes treatment planning but does not detail whether any prosthetic rehabilitation was completed or if long-term follow-up occurred. Including even short-term outcomes (comfort, adaptation, oral function) would provide practical clinical guidance.

5. The discussion could be enriched by contrasting the current case with prior reports focusing on pediatric IRD dental findings. A table summarizing previously reported oral manifestations versus the present case would make the novelty clearer.

6. Terms such as “edentulism” and “tooth agenesis” appear interchangeably. Please clarify the distinction between failure of eruption and absence of tooth buds, as this has diagnostic implications.

The paper provides a valuable contribution to the understanding of dental manifestations in peroxisomal biogenesis disorders. Addressing the above comments especially elaborating on molecular mechanisms, adding radiographic clarity, and ensuring reference accuracy would enhance its scientific rigor and clinical impact.

Comments on the Quality of English Language

The manuscript is written in clear and comprehensible English. Minor linguistic revisions are recommended to enhance readability and correct minor typographical inconsistencies. A professional English language edit or proofreading pass before final submission is advisable.

Author Response

Reviewer 1

We thank the Reviewer for the insightful and constructive comments, which have significantly improved the quality and clarity of our manuscript. Below, we provide a detailed, point-by-point response. All corresponding modifications have been incorporated into the revised manuscript and highlighted in green. 

 

  1. Provide incidence figures for Infantile Refsum Disease specifically (if available) or cite the most recent reviews to contextualize its rarity in introduction section.

R: Thanks for the comment. Accordingly, we have added epidemiological information from the most recent reviews addressing leukodystrophies and Zellweger spectrum disorders, which contextualize the rarity of IRD (birth prevalence for the entire PBD-ZSD spectrum is estimated to be approximately 1 in 50,000 live births).

We have cited a recent study concerning the IRB prevalence “Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016 Mar;117(3):313-21. doi: 10.1016/j.ymgme.2015.12.009. Epub 2015 Dec 23. PMID: 26750748; PMCID: PMC5214431]”. Please see page 2, lines 46-56.

 

  1. The discussion of peroxisomal dysfunction and its link to odontogenesis is insightful but superficial. Please elaborate on the specific molecular mechanisms affecting ameloblast and odontoblast activity. A deeper connection between peroxisomal metabolism and dental tissue differentiation would strengthen the biological rationale.

R: Thanks for highlighting this interesting aspect. We have expanded the section “Interpretation of the Results” with the molecular pathways through which peroxisomal dysfunction may disrupt ameloblast and odontoblast activity. Specific mechanisms- such as impaired expression of amelogenin, altered vimentin organization, increased oxidative stress, and defective differentiation processes- have been clarified and referenced. This addition strengthens the biological rationale linking IRD to enamel defects and eruption disturbances. Please see pages 8-9, lines 240-271.

  1. The OPG image (Figure 3, page 4) is valuable. However, higher-resolution labeling or annotations (e.g., indicating impacted teeth positions or malformations) would improve interpretability for readers unfamiliar with such cases.

R: Thanks for the kind suggestion. Figure 3 has been replaced with a higher-resolution version. Additionally, we have included clear annotations indicating impacted teeth and morphological abnormalities to aid interpretation for readers. The revised OPG now clearly indicates the specific locations and dental numbering of the multiple impacted permanent teeth, highlights areas exhibiting abnormal morphology (e.g., incomplete root development), and provides better visualization of the severe maxillary hypoplasia, thereby significantly enhancing its clinical interpretability. Please see pages 7-8, lines 212-213.

 

  1. The manuscript describes treatment planning but does not detail whether any prosthetic rehabilitation was completed or if long-term follow-up occurred. Including even short-term outcomes (comfort, adaptation, oral function) would provide practical clinical guidance.

R: Thanks for the kind suggestion. We appreciate the request for practical clinical outcomes. We confirm that no prosthetic rehabilitation was initiated, and consequently, no short-term or long-term follow-up data (comfort, adaptation, oral function) is available. However, we have significantly expanded Section 2.6 (Treatment Progress) and Section 4.4 (Clinical Implication) to fully detail the rationale and outcome of the clinical decision-making process.

We explicitly state the following:

  1. The intervention was deferred pending a comprehensive systemic assessment (liver function) due to the patient’s IRD and associated life expectancy concerns.
  2. The patient declined the conservative removable prosthetic solution due to personal preferences (discomfort, functional limitations) and economic reasons.

The focus of our revised discussion is now centered on the complex ethical and strategic balance required when managing dental rehabilitation in patients with rare, progressive multi-systemic disorders.

This clarified management strategy itself constitutes a valuable clinical guide for similar complex cases where prognosis is limited. Please see pages 6-7, lines 163-198.

 

  1. The discussion could be enriched by contrasting the current case with prior reports focusing on pediatric IRD dental findings. A table summarizing previously reported oral manifestations versus the present case would make the novelty clearer.

R: Thanks for the kind suggestion. We have revised the discussion to include a clearer comparison between our adult case-report and previously published pediatric IRD reports. Moreover, we have added a new table (Table 1) summarizing the oral findings reported in the literature versus those observed in our patient, highlighting the novelty and severity of the present case. Please see page 10.

 

  1. Terms such as “edentulism” and “tooth agenesis” appear interchangeably. Please clarify the distinction between failure of eruption and absence of tooth buds, as this has diagnostic implications.

R: We have revised the terminology throughout the manuscript to ensure accuracy and consistency, recognizing the important diagnostic distinction between these concepts.

 

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript presents a rare and valuable case of Infantile Refsum Disease (IRD) associated with multiple impacted teeth and near-complete edentulism in an adult patient. The topic is original and clinically significant, offering an important addition to the limited literature connecting peroxisomal biogenesis disorders with oral and dental manifestations. The paper aligns with the CARE guidelines and is overall well structured, but several aspects require refinement to reach publication quality.

The introduction provides a clear background on IRD and its systemic features, contextualizing the rarity of the presented case. However, it could benefit from a more focused discussion of existing dental findings in similar metabolic disorders to strengthen the rationale and highlight the novelty more explicitly. A brief mention of previously reported oral anomalies in peroxisomal diseases would improve the framing.

The research design—being a single case report—is appropriate for the objective. Ethical approval and informed consent are clearly stated, which reinforces methodological soundness. Nevertheless, the methods section could be expanded with more detail regarding diagnostic imaging parameters, specific radiographic protocols, and the rationale behind treatment planning decisions, particularly the ethical deliberations influencing the prosthetic choice. Inclusion of a more structured timeline of clinical events would also enhance clarity and compliance with CARE checklist standards.

The results are described adequately, but they would benefit from more comprehensive clinical and radiographic documentation—such as figure captions that interpret rather than merely describe images. The current figures are useful but should be integrated more effectively into the text to support diagnostic reasoning and findings.

The discussion is the strongest section, successfully linking biochemical dysfunctions of peroxisomal disorders to odontogenic anomalies. The mechanistic interpretation is scientifically grounded and well referenced. Nonetheless, minor redundancies could be reduced, and the logical flow between the biological mechanisms and the specific patient findings could be made more explicit. It would also be valuable to contrast this case more directly with the few existing reports of IRD-related dental anomalies, to better contextualize its contribution.

The conclusion appropriately summarizes the clinical implications, emphasizing the importance of multidisciplinary management and early dental involvement in systemic rare diseases. However, it should avoid overly general statements and more clearly delineate what new understanding this case brings.

Overall, the figures and tables are clear but could be improved in resolution and accompanied by concise, informative legends. The English language is satisfactory but would benefit from minor grammatical and stylistic revisions to enhance precision and readability—particularly in sections where sentence structures are long or repetitive.

Author Response

We sincerely thank the Reviewer for the thoughtful, thorough, and constructive evaluation of our manuscript. We appreciate the recognition of the originality and clinical relevance of this rare case and are grateful for the detailed suggestions, which have substantially improved the clarity and rigor of the paper. Below, we provide a point-by-point response to each comment.

 

  1. The introduction provides a clear background on IRD and its systemic features, contextualizing the rarity of the presented case. However, it could benefit from a more focused discussion of existing dental findings in similar metabolic disorders to strengthen the rationale and highlight the novelty more explicitly. A brief mention of previously reported oral anomalies in peroxisomal diseases would improve the framing.

R: We agree with the Reviewer’s opinion. The introduction has been expanded to include a more focused discussion of dental anomalies previously reported in peroxisomal biogenesis disorders, including enamel hypoplasia, delayed eruption, and morphological defects. Please see page 2, lines 68-84.

 

  1. The research design—being a single case report—is appropriate for the objective. Ethical approval and informed consent are clearly stated, which reinforces methodological soundness. Nevertheless, the methods section could be expanded with more detail regarding diagnostic imaging parameters, specific radiographic protocols, and the rationale behind treatment planning decisions, particularly the ethical deliberations influencing the prosthetic choice. Inclusion of a more structured timeline of clinical events would also enhance clarity and compliance with CARE checklist standards.

R: Thanks for the kind suggestion. We have revised the Methods section to provide additional details regarding the diagnostic imaging procedures (including OPG and CBCT acquisition parameters) and the radiographic evaluation protocol used.
Furthermore, we elaborated on the clinical and ethical considerations that informed the treatment planning, particularly the balance between invasiveness, patient preference, systemic prognosis, and long-term feasibility. Please see page 4, lines 138-146.

 

  1. The results are described adequately, but they would benefit from more comprehensive clinical and radiographic documentation—such as figure captions that interpret rather than merely describe images. The current figures are useful but should be integrated more effectively into the text to support diagnostic reasoning and findings.

R: We appreciate this recommendation and have revised the figure captions to provide interpretive information rather than simple descriptions. Visual resolution and annotation of the OPG image have also been enhanced, as suggested. Please see page 7, lines 205-210.

 

  1. The discussion is the strongest section, successfully linking biochemical dysfunctions of peroxisomal disorders to odontogenic anomalies. The mechanistic interpretation is scientifically grounded and well referenced. Nonetheless, minor redundancies could be reduced, and the logical flow between the biological mechanisms and the specific patient findings could be made more explicit. It would also be valuable to contrast this case more directly with the few existing reports of IRD-related dental anomalies, to better contextualize its contribution.

R: Thanks for the kind suggestion. We have refined the Discussion by removing redundancies and improving the logical flow between the biological mechanisms of peroxisomal dysfunction and the specific dental phenotype presented by the patient. Additionally, a clearer comparison between our adult case and previously published pediatric IRD reports has been incorporated, and a new table summarizing previously documented oral findings versus those observed here has been added to contextualize the case’s uniqueness and scientific contribution. Please see page 10.

  1. The conclusion appropriately summarizes the clinical implications, emphasizing the importance of multidisciplinary management and early dental involvement in systemic rare diseases. However, it should avoid overly general statements and more clearly delineate what new understanding this case brings.

Thanks for the kind suggestion. The Conclusion has been revised to avoid overly general statements and instead highlight the specific contributions of this report-namely, the documentation of severe eruption failure and near-complete edentulism in an adult IRD patient, expanding the known oral phenotype of the disorder and underscoring the need for early dental involvement in the management of peroxisomal diseases. Please see page 11-12, lines 338-345.

  1. Overall, the figures and tables are clear but could be improved in resolution and accompanied by concise, informative legends. The English language is satisfactory but would benefit from minor grammatical and stylistic revisions to enhance precision and readability—particularly in sections where sentence structures are long or repetitive.

R: Thanks for the kind suggestion. We have improved the quality of the images and added clearer, more concise legends. We have thoroughly revised the manuscript to improve grammar, sentence structure, and overall readability. Particular attention was given to sections with long or repetitive phrasing, ensuring clearer and more precise scientific communication. Please see pages 7, 10.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear authors, 

Congratulations on your manuscript!

The case report you are presenting is valuable and provides meaningful clinical insight.

However, I consider that for clarity and adherence to case report structure, the clinical findings -and imaging results described in lines 128-141 would be better placed in the Results section rather than in Materials and Methods.

Another section that needs revision is the References. These are not written in MDPI style.

I look forward to this article being published!

Author Response

We sincerely thank the reviewer for their thoughtful comments and valuable suggestions.

  1. The case report you are presenting is valuable and provides meaningful clinical insight. However, I consider that for clarity and adherence to case report structure, the clinical findings -and imaging results described in lines 128-141 would be better placed in the Results section rather than in Materials and Methods.

R: We agree with the reviewer’s observation. We have revised the manuscript so that the clinical findings and imaging results previously described in lines 128–141 are now appropriately placed in the Results section. This change improves the clarity and logical flow of the manuscript in accordance with standard case report structure. Please see page 7, lines 200-210.

  1. Another section that needs revision is the References. These are not written in MDPI style.

R: We appreciate the reviewer pointing out the formatting issue. All references have now been revised and formatted according to MDPI style. Please see page 12-13, lines 365-403.

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for submitting your work to the prestigious journal Oral.

I hope that my suggestions and remarks will be useful in order to improve the quality of the paper.

General Aspects:

The abstract presents a rare and clinically relevant case report describing severe dental anomalies—specifically multiple impacted teeth and near-complete edentulism—in a 24-year-old patient with genetically confirmed Infantile Refsum disease (IRD). The topic is novel, as dental findings of this severity have not been previously associated with IRD. The abstract is concise, well-structured, and highlights the interdisciplinary nature of this condition. Overall, the study is scientifically sound and aligns with the objectives of MDPI journals focused on rare diseases, dentistry, or interdisciplinary clinical sciences.

Strong Aspects/Points of the paper:

  1. Originality and novelty:
    The report presents what appears to be a previously undocumented manifestation of IRD—a significant contribution to the literature on peroxisomal disorders and their orofacial implications;
  2. Clinical relevance:
    The description of near-complete impaction of permanent teeth in the context of a rare metabolic disease highlights an important diagnostic clue for dental practitioners and medical specialists;
  3. Interdisciplinary importance:
    The paper emphasizes the need for collaboration among dentists, geneticists, neurologists, and dermatologists, which aligns with MDPI’s emphasis on integrative clinical perspectives;

Improvements of the paper:

  1. Lines 18-30 are not necessary because they do not fit the format of the journal;
  2. Several typographical and spacing/typing errors need correction for publication-level clarity;
  3. Professional e-mail are preferred;
  4. The size of Figures 2 should be increased;
  5. Please use an exported panorex instead of a picture of a panorex in Fig.3
  6. Lines 159-164 – Please extend the Results section as it is unsufficient right now.
  7. Lines 248-251 – The text should be rephrased as you didn’t your any cohort and it’s just a a case report.
  8. Please emphasise the impact of your case report in improving clinical practice of other colleagues.
  9. A table of abbreviations will be useful.

Best of luck with your future work!

Author Response

1: Lines 18-30 are not necessary because they do not fit the format of the journal.
R: Thanks for the kind suggestion. We have removed lines 18–30 as suggested, in order to better align the manuscript with the journal’s format.

2: Several typographical and spacing/typing errors need correction for publication-level clarity.
R: Thanks for the kind suggestion. All typographical, spacing, and formatting errors have been carefully reviewed and corrected throughout the manuscript to ensure publication-level clarity.

3: Professional e-mail are preferred.
R: We appreciate this recommendation. The corresponding author’s email has been updated to a professional institutional email address. Please see page 1, lines 6-15.

4: The size of Figures 2 should be increased.
R: Thanks for the kind suggestion. Figure 2 has been resized to improve clarity and visibility in the manuscript. Please see page 5.

5: Please use an exported panorex instead of a picture of a panorex in Fig.3.
R: Thanks for the kind suggestion. Figure 3 has been replaced with a high-quality exported panorex image to enhance accuracy and visual clarity. Please see page 5.

6: Lines 159-164 – Please extend the Results section as it is insufficient right now.
R: Thanks for the kind suggestion. The Results section has been expanded to provide more detailed observations. Please see page 7, lines 200-210.

7: Lines 248-251 – The text should be rephrased as you didn’t study any cohort and it’s just a case report.
R: Thanks for highlighting this interesting aspect. The text has been rephrased to accurately reflect that this is a single case report rather than a cohort study.

8: Please emphasise the impact of your case report in improving clinical practice of other colleagues.
R: Thanks for the kind suggestion. We have added a paragraph in the Discussion emphasizing how this case report can inform clinical decision-making, and potentially improve management strategies for similar cases in other clinical settings. Please see page 10, lines 289-292 and page 11, lines 317-321.

Comment 9: A table of abbreviations will be useful.
R: Thanks for the kind suggestion. A table of abbreviations has been added to the manuscript for reader convenience and to improve clarity. Please see page 10.

Reviewer 5 Report

Comments and Suggestions for Authors

Any new description of the clinical condition of the unknown developmental impairment is crucial for understanding the aethiology, diagnosing and treatment options of the condition. Infantile Refsum Disease (IDS) is a complex condition affecting several organs. Case report is well documented, describing never described condition and as such worth publication. It would be interesting to add few sentences on possibility to improve diagnosing process with the dental findings.

Author Response

Reviewer 5.

  1. Any new description of the clinical condition of the unknown developmental impairment is crucial for understanding the aethiology, diagnosing and treatment options of the condition. Infantile Refsum Disease (IDS) is a complex condition affecting several organs. Case report is well documented, describing never described condition and as such worth publication. It would be interesting to add few sentences on possibility to improve diagnosing process with the dental findings.

We thank the reviewer for the insightful comment. Following your suggestion, we have added a brief discussion highlighting how specific dental findings observed in this case may support the diagnostic process of Infantile Refsum Disease. These findings could provide additional clinical clues, potentially allowing earlier recognition and a more comprehensive assessment of this rare and complex condition.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

This is a well-prepared, scientifically valuable, and clearly written manuscript that documents an unprecedented dental manifestation in a long-surviving IRD patient. It contributes significantly to the literature on peroxisomal biogenesis disorders and their oral phenotypes. I`ll recomand minor suggestions:

  • in Figure 5, consider clarifying in the legend that dental numbering follows the FDI system, to aid international readers.
  • verify the uniform formatting of all reference DOIs and journal titles according to the journal’s citation style.
  • if required by the journal, provide a brief Graphical Abstract summarizing the case visually (the CBCT image could serve as the basis).

Author Response

 

We thank the Reviewer for the insightful and constructive comments, which have significantly improved the quality and clarity of our manuscript. Below, we provide a detailed, point-by-point response. All corresponding modifications have been incorporated into the revised manuscript and highlighted in green. 

 

  1. In Figure 5, consider clarifying in the legend that dental numbering follows the FDI system, to aid international readers.

 

R: Thanks for the comment. Accordingly, we have clarified we followed the FDI system. Please see page 8 lines 209-210

 

  1. Verify the uniform formatting of all reference DOIs and journal titles according to the journal’s citation style.

 

R: We appreciate the reviewer pointing out the formatting issue. All references have now been revised and formatted according to MDPI style. Please see page 12-13, lines 366-419.

  1. If required by the journal, provide a brief Graphical Abstract summarizing the case visually (the CBCT image could serve as the basis).

 

Thank you for the suggestion. We have created and provided a Graphical Abstract summarizing the key clinical and radiographic findings of the case, utilizing the CBCT images as a basis as requested.

Author Response File: Author Response.docx