Exome sequencing in 16 patients with pituitary stalk interruption syndrome: A monocentric study

Raja Brauner; Joelle Bignon-Topalovic; Anu Bashamboo; Ken McElreavey

doi:10.1371/journal.pone.0292664

Peer Review History

Original SubmissionJuly 31, 2023
16 Aug 2023 Decision Letter - Nejat Mahdieh, Editor PONE-D-23-22676Exome sequencing in 16 patients with pituitary stalk interruption syndrome: a monocentric studyPLOS ONE Dear Dr. Brauner, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Sep 30 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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We will update your Data Availability statement to reflect the information you provide in your cover letter. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: Yes ****** 3. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes Reviewer #2: Yes ****** 4. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 5. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors conducted exome sequencing on 16 unpublished PSIS cases, most of which were idiopathic, out of the 68 cases they followed up at their facility. As a result, they found that many of the identified variants were VUS, highlighting the challenges of genetic diagnosis in idiopathic PSIS. This study conducted exome sequencing on rare diseases, and given the rarity of the disease, the small sample size of 16 is considered inevitable. However, the conclusion that "genetic diagnosis of idiopathic PSIS is challenging" might be too weak. Considering that the low diagnostic yield in idiopathic PSIS has been previously reported [Jullien N et al, Clin Endocrinol 94(2):277–289, 2020] as the authors cited, it might be difficult to define the scientific significance of the study. Is it possible to draw a conclusion that more strongly emphasizes the scientific significance of the study? Minor comments are noted below. What were the criteria used to diagnose PSIS? From Table 1 alone, the reviewer did not understand how the diagnosis of PSIS was made. The description about abbreviations in the footnote of Table 1 seems to be truncated. Also, it is unclear whether a pituitary height of 4 is small or not. Reviewer #2: Authors performed exome sequencing in 16 patients with isolated PSIS and described variants they found. It is an interesting report, but I have some comments. On what basis do the authors define the ACTH deficiency? Serum cortisol varies so much in individuals that it would be difficult to define it without a functional test. Also, hypoglycemia does not necessarily occur in ACTH deficiency. Since ACTH deficiency may be over or underestimated, a limitation should be stated. How to evaluate the function of the VUS found and how the pathogenic mutation found is involved in the structural abnormality of the stalk should be mentioned in the discussion. Table 1: Abbreviation section was interrupted. What does “E” and “I” mean? What is the unit of “pituitary height”? When the stalk is normal, how did authors diagnose PSIS? Table 2: Abbreviation section was missing. What does “MAF and population” mean? I assume that authors noted “minor allele frequency” and its given population. So, the SNP was not detected in other populations? For the case 1, FANCD2, information of MAF and population were inversed. What does “MI” mean? If it is “AD”, does it mean the SNP can induce the phenotype as autosomal dominant? I am wondering how those SNPs were recognized as dominant, as most of SNPs were “VUS”. If these “MI” means the genetic form of “MIM”, it is difficult for readers to understand. Line 142:” No candidate gene was identified in cases 6,8 and 15.” Does it mean that “no mutation/SNP of the candidate gene”? ****** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0292664.r001
Revision 1
24 Aug 2023 Author Response To Reviewer 1 Dear Reviewer, Thank you for reviewing our manuscript. As you suggested, the conclusions that “genetic diagnosis of idiopathic PSIS is challenging” of the Abstract and of the Introduction have been completed. The criteria used to diagnose PSIS are now at the onset of “Patients”. The anterior pituitary gland height, mainly 4 mm, has been indicated. We added to the introduction of the Abstract that “The triad of PSIS can be incomplete”. The abbreviations of Table 1 have been completed. To Reviewer 2 Dear Reviewer, Thank you for reviewing our manuscript. Concerning the definition of the ACTH deficiency, the values indicated in “Methods” have been completed by the individual values of the 3 patients with ACTH deficiency (below Table 1). Table 1: Abbreviation section has been completed and the unit of pituitary height added. As suggested by the other Reviewer, we completed the diagnosis criteria of the PSIS and detailed the pituitary height at the onset of “Patients”. We added to the introduction of the Abstract that “The triad of PSIS can be incomplete”. Q: What does “MAF and population” mean? I assume that authors noted “minor allele frequency” and its given population. So, the SNP was not detected in other populations? A: MAF is the minor allelic frequency and it cited population is the population with the highest known frequency of the variant in GnomAD. The variant may well be present in other populations but at lower allelic frequencies. Q: For the case 1, FANCD2, information of MAF and population were inversed. A: This has been corrected. Q: What does “MI” mean? A: MI is the known mode of inheritance of the disorder associated with the gene. It does not reflect the mode of inheritance in the particular case. Q: Line 142:” No candidate gene was identified in cases 6,8 and 15.” Does it mean that “no mutation/SNP of the candidate gene”? A: For clarity this sentence has been modified to “Genetic variants associated with the phenotype could not be identified in candidate genes in the cases 6,8 and 15” Attachments Attachment Submitted filename: Reviewers.docx https://doi.org/10.1371/journal.pone.0292664.r002
7 Sep 2023 Decision Letter - Nejat Mahdieh, Editor PONE-D-23-22676R1Exome sequencing in 16 patients with pituitary stalk interruption syndrome: a monocentric studyPLOS ONE Dear Dr. Brauner, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Oct 22 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Nejat Mahdieh Academic Editor PLOS ONE Journal Requirements: Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: (No Response) Reviewer #2: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A Reviewer #2: Yes ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: No Reviewer #2: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: Given that PLOS ONE’s publication criteria do not include novelty, impact, or interest, the reviewer finds the study's conclusions to be well-founded. However, the reviewer identifies the following issues that need to be addressed. Comment 1: The diagnostic criteria for PSIS remain unclear. While the authors state that they have provided the diagnostic criteria for PSIS in the opening of the “Patient” section, they presented a clinical description of the patients rather than clear criteria. A clearer presentation of the diagnostic criteria might look like: “A diagnosis of PSIS was made if the patient met at least ?two? of the following criteria: (1) an absent or ectopic posterior pituitary, (2) an interrupted, malformed, or thin pituitary stalk, and (3) a small anterior pituitary gland.” Based on Table 1 in the original version of the manuscript (which seems to be absent in the revised file), the patient 7 seems to have normal posterior pituitary gland, an interrupted pituitary stalk, and an anterior pituitary with a height of 4 mm. Is her anterior pituitary considered small? Please clarify the reference range for the height of the anterior pituitary gland. Comment 2: The reviewer was unable to locate the tables in the revised PDF version of the manuscript. Reviewer #2: (No Response) ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ******** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.] While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0292664.r003
Revision 2
22 Sep 2023 Author Response To Reviewer 1 Dear Reviewer, Thank you for reviewing our manuscript. Please find joined the answers to your questions. 4. Have the authors made all data underlying the findings in their manuscript fully available? Reviewer #1: No Reviewer #2: Yes Answer: All relevant data are within the manuscript and all novel variants are deposited with ClinVar. 6. Review Comments to the Author Reviewer #1: Given that PLOS ONE’s publication criteria do not include novelty, impact, or interest, the reviewer finds the study's conclusions to be well-founded. However, the reviewer identifies the following issues that need to be addressed. Comment 1: The diagnostic criteria for PSIS remain unclear. While the authors state that they have provided the diagnostic criteria for PSIS in the opening of the “Patient” section, they presented a clinical description of the patients rather than clear criteria. A clearer presentation of the diagnostic criteria might look like: “A diagnosis of PSIS was made if the patient met at least ?two? of the following criteria: (1) an absent or ectopic posterior pituitary, (2) an interrupted, malformed, or thin pituitary stalk, and (3) a small anterior pituitary gland.” Based on Table 1 in the original version of the manuscript (which seems to be absent in the revised file), the patient 7 seems to have normal posterior pituitary gland, an interrupted pituitary stalk, and an anterior pituitary with a height of 4 mm. Is her anterior pituitary considered small? Please clarify the reference range for the height of the anterior pituitary gland. Answer: The diagnostic criteria of PSIS have been clarified as you suggested. A pituitary height of 4 mm is normal, as measured in 5 patients and this is indicated in the text as well as the reference with the normal range of the anterior pituitary height. Comment 2: The reviewer was unable to locate the tables in the revised PDF version of the manuscript. Answer: The two Tables are now included in the text. To Reviewer 2 Dear Reviewer, Thank you for reviewing our manuscript. Comment 2: The reviewer was unable to locate the tables in the revised PDF version of the manuscript. Answer: The two Tables are now included in the text. Attachments Attachment Submitted filename: To Reviewers.docx https://doi.org/10.1371/journal.pone.0292664.r004
27 Sep 2023 Decision Letter - Nejat Mahdieh, Editor Exome sequencing in 16 patients with pituitary stalk interruption syndrome: a monocentric study PONE-D-23-22676R2 Dear Dr. Brauner, We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Nejat Mahdieh Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #1: All comments have been addressed ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: N/A ****** 4. Have the authors made all data underlying the findings in their manuscript fully available? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified. Reviewer #1: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The authors addressed all the comments, with the clear description of the diagnostic criteria and the inclusion of the missing tables in the main text. One minor comment: The authors might consider revising the definition of "N" in Table 1 from "normal puberty" to just "normal" because N is referred to as "N puberty" in the 6th column and also used in the "PP" and "Stalk" columns. ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No ******** https://doi.org/10.1371/journal.pone.0292664.r005
Formally Accepted
5 Dec 2023 Acceptance Letter - Nejat Mahdieh, Editor PONE-D-23-22676R2 Exome sequencing in 16 patients with pituitary stalk interruption syndrome: a monocentric study Dear Dr. Brauner: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Nejat Mahdieh Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0292664.r006

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