Identifying underlying medical causes of pediatric obesity: Results of a systematic diagnostic approach in a pediatric obesity center

Lotte Kleinendorst; Ozair Abawi; Bibian van der Voorn; Mieke H. T. M. Jongejan; Annelies E. Brandsma; Jenny A. Visser; Elisabeth F. C. van Rossum; Bert van der Zwaag; Mariëlle Alders; Elles M. J. Boon; Mieke M. van Haelst; Erica L. T. van den Akker

doi:10.1371/journal.pone.0232990

Peer Review History

Original SubmissionFebruary 25, 2020
19 Mar 2020 Decision Letter - David A. Buchner, Editor Transfer Alert This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present. PONE-D-20-05457 Identifying underlying medical causes of pediatric obesity: results of a systematic diagnostic approach in a pediatric obesity center PLOS ONE Dear Dr. van den Akker, 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. ============================== Your manuscript has now been reviewed by two independent reviewers. As you can see from the positive reviews, both thought that this was a strong manuscript that would be of great interest to the readers of PLOS ONE. Both reviewers did have minor suggestions for the manuscript which we hope you will take into consideration, including adding additional discussion of how you treat and manage your patients. We look forward to receiving a revised manuscript with these minor changes for publication in PLOS ONE. ============================== We would appreciate receiving your revised manuscript by May 03 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: a nicely written straightforward audit of clinical practice of a clinical problem that will continue to require specialist input. this wil be of interest to clinical groups doing similar work and will be of great benefit to those thinking of setting up such a service . the finding look to commensurate with what one might expect from what we know to date about causes of and give it a helpful real world feel which is to it credit being as this group look to be doing such good work,i wonder if they might like to share a little more on how they treat and manage their patients with a know diagnosis-they mention it briefly around line 415 but their reflections on say leptin replacemenr or glp1 based therapies etc would be helpful to the target audience Reviewer #2: This is a very important study that utilized an extensive systematic diagnostic approach in a specialized obesity center to identify underlying causes of obesity among pediatric patients. This adds significantly to our knowledge base of the etiology of pediatric obesity and demonstrates that patients being referred to specialty clinics may have a higher prevalence of genetic obesity, medication induced obesity, and obesity due to cerebral injury. Major comments: More exploration as to why the investigators believe that BMI SDA was not significantly higher in patients with genetic obesity disorder when compared to patients without underlying medical causes. How does the obesogenic environment and socioeconomic factors in which we live play a role? This needs more emphasis in the discussion. More information regarding how to specifically treat the different types of obesity would be beneficial in the discussion (Though I recognize it must be brief given word constraints). Minor comments: There are a couple of times throughout the manuscript that the authors write, “significantly more often”. This is awkward to read and should be revised for clarity. The manuscript would benefit from editing by a native English speaker. ****** 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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0232990.r001
Revision 1
7 Apr 2020 Author Response Review Comments to the Author Reviewer #1: a nicely written straightforward audit of clinical practice of a clinical problem that will continue to require specialist input. this will be of interest to clinical groups doing similar work and will be of great benefit to those thinking of setting up such a service . the finding look to commensurate with what one might expect from what we know to date about causes of and give it a helpful real world feel which is to it credit being as this group look to be doing such good work, i wonder if they might like to share a little more on how they treat and manage their patients with a known diagnosis-they mention it briefly around line 415 but their reflections on say leptin replacement or glp1 based therapies etc would be helpful to the target audience Authors’ response: We would like to thank the reviewer for their thoughtful comments. Based on his/her comment, as well as the comment from reviewer #2, we have added additional information about the different treatment and management options in the manuscript discussion: “Treatment of multifactorial disorders such as obesity is complex. In our approach, all patients received a multidisciplinary treatment advice tailored to their personal needs, including personalized dietary and physical activity advice (Fig 2). Furthermore, a monitoring and follow-up plan was developed for every patient. Local health care providers, including child health clinic physicians, general practitioners, general pediatricians, and psychologists, were contacted for local implementation of the care plan. In cases with severe hyperphagia, parental support by an educational therapist was offered to cope with the child’s behavior. Rehabilitation physicians were consulted when obesity interfered with performance of daily activities such as walking.[10] Establishing a main underlying cause of obesity can improve personalized treatment.[34] In all our 54 patients with an underlying medical cause, counseling about the diagnosis was given. This included advice pertaining to bariatric surgery, which has unclear long-term success rates for patients with underlying medical causes.[43, 48] Patients with genetic obesity were counseled by a clinical geneticist regarding inheritance, associated medical problems and reproductive decisions. Hormonal supplementation was started in case of hormonal deficiencies associated with specific genetic obesity disorders (such as growth hormone treatment in cases with leptin receptor deficiency).[49] In cases of syndromic obesity, the patients were evaluated for associated organ abnormalities or referred for disease-specific surveillance.[13, 25-32] In patients with cerebral/hypothalamic injury as cause of obesity and hyperphagia, dexamphetamine treatment was considered.[50] In patients with medication-induced obesity, evaluation of necessity and alternatives for the weight-inducing medication took place in collaboration with the prescribing physician. Follow-up studies are necessary to evaluate the different individual responses to these treatment options. Interesting novel developments are clinical trials with MC4R-agonists in patients with leptin-melanocortin pathway deficiencies, e.g. POMC and LEPR deficiency,[44] and glucagon-like peptide 1 (GLP-1) agonists for adolescents with obesity.[51] These GLP-1 agonists might also be a future treatment option for patients with genetic obesity disorders, as they have been shown to be equally as effective in adults with heterozygous MC4R mutations compared to adults without.[52] Recently, it was suggested that a subgroup of patients with severe early-onset obesity might have relative leptin deficiency and therefore might benefit from recombinant leptin administration.[53] However, the (long-term) effects of these new potential treatment options remain to be investigated.” Reviewer #2: This is a very important study that utilized an extensive systematic diagnostic approach in a specialized obesity center to identify underlying causes of obesity among pediatric patients. This adds significantly to our knowledge base of the etiology of pediatric obesity and demonstrates that patients being referred to specialty clinics may have a higher prevalence of genetic obesity, medication induced obesity, and obesity due to cerebral injury. Major comments: 1. More exploration as to why the investigators believe that BMI SDS was not significantly higher in patients with genetic obesity disorder when compared to patients without underlying medical causes. How does the obesogenic environment and socioeconomic factors in which we live play a role? This needs more emphasis in the discussion. Authors’ response: We would like to thank the reviewer for their recognition of our manuscript. We added more information on the potential explanations of the comparable BMI SDS in the two mentioned patient groups in the discussion section: “A possible explanation is that severity of obesity increases the probability of being referred to a pediatric obesity center regardless of whether genetic obesity is diagnosed. Important factors that were more frequently present in the patients without underlying medical causes were psychosocial problems (DSM-5 diagnosis or involvement of authorities such as child protective services). These psychosocial problems might contribute to developing a higher BMI SDS.[47] On group level, we did not find evidence for significant differences in socio-economic status scores between patients with genetic obesity and patients without underlying medical causes, but individual differences in socio-economic factors and obesogenic environments might also play a role.” 2. More information regarding how to specifically treat the different types of obesity would be beneficial in the discussion (Though I recognize it must be brief given word constraints). Authors’ response: Based on this comment and the comment from reviewer #1, we have added additional information about the different treatment and management options in the manuscript discussion: “Treatment of multifactorial disorders such as obesity is complex. In our approach, all patients received a multidisciplinary treatment advice tailored to their personal needs, including personalized dietary and physical activity advice (Fig 2). Furthermore, a monitoring and follow-up plan was developed for every patient. Local health care providers, including child health clinic physicians, general practitioners, general pediatricians, and psychologists, were contacted for local implementation of the care plan. In cases with severe hyperphagia, parental support by an educational therapist was offered to cope with the child’s behavior. Rehabilitation physicians were consulted when obesity interfered with performance of daily activities such as walking.[10] Establishing a main underlying cause of obesity can improve personalized treatment.[34] In all our 54 patients with an underlying medical cause, counseling about the diagnosis was given. This included advice pertaining to bariatric surgery, which has unclear long-term success rates for patients with underlying medical causes.[43, 48] Patients with genetic obesity were counseled by a clinical geneticist regarding inheritance, associated medical problems and reproductive decisions. Hormonal supplementation was started in case of hormonal deficiencies associated with specific genetic obesity disorders (such as growth hormone treatment in cases with leptin receptor deficiency).[49] In cases of syndromic obesity, the patients were evaluated for associated organ abnormalities or referred for disease-specific surveillance.[13, 25-32] In patients with cerebral/hypothalamic injury as cause of obesity and hyperphagia, dexamphetamine treatment was considered.[50] In patients with medication-induced obesity, evaluation of necessity and alternatives for the weight-inducing medication took place in collaboration with the prescribing physician. Follow-up studies are necessary to evaluate the different individual responses to these treatment options. Interesting novel developments are clinical trials with MC4R-agonists in patients with leptin-melanocortin pathway deficiencies, e.g. POMC and LEPR deficiency,[44] and glucagon-like peptide 1 (GLP-1) agonists for adolescents with obesity.[51] These GLP-1 agonists might also be a future treatment option for patients with genetic obesity disorders, as they have been shown to be equally as effective in adults with heterozygous MC4R mutations compared to adults without.[52] Recently, it was suggested that a subgroup of patients with severe early-onset obesity might have relative leptin deficiency and therefore might benefit from recombinant leptin administration.[53] However, the (long-term) effects of these new potential treatment options remain to be investigated.” Minor comments: 1. There are a couple of times throughout the manuscript that the authors write, “significantly more often”. This is awkward to read and should be revised for clarity. Authors’ response: We thank the reviewer for the suggestion and have revised this phrasing throughout the manuscript. 2. The manuscript would benefit from editing by a native English speaker. Authors’ response: We thank the reviewer for this suggestion and asked a native (American) English speaker to edit our manuscript. Please see the track changes version of our manuscript for further details. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0232990.r002
27 Apr 2020 Decision Letter - David A. Buchner, Editor Identifying underlying medical causes of pediatric obesity: results of a systematic diagnostic approach in a pediatric obesity center PONE-D-20-05457R1 Dear Dr. van den Akker, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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. With kind regards, David A. Buchner, PhD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0232990.r003
Formally Accepted
29 Apr 2020 Acceptance Letter - David A. Buchner, Editor PONE-D-20-05457R1 Identifying underlying medical causes of pediatric obesity: results of a systematic diagnostic approach in a pediatric obesity center Dear Dr. van den Akker: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. David A. Buchner Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0232990.r004

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