Primary Hyperparathyroidism in the Pediatric Population: Surgical Considerations and Outcomes: A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive and well-structured review of pediatric primary hyperparathyroidism (PHPT), covering its diagnostic challenges, etiological spectrum, and management strategies. The authors effectively synthesize current evidence and highlight key considerations specific to pediatric populations. The review is clinically relevant and fills an important gap in the literature. While the overall quality is high, minor revisions could further strengthen the paper before publication.

1. Could you clarify whether differences in symptom severity between neonates and older children (e.g., musculoskeletal vs. renal manifestations) correlate with specific genetic subtypes or biochemical profiles (e.g., PTH/Ca²⁺ levels)?

2. The stepwise imaging approach favors ultrasound as the first-line modality. For recurrent/persistent PHPT, what specific criteria should guide the progression to advanced imaging techniques (e.g., ¹⁸F-FCH PET/CT vs. 4D-CT), particularly considering radiation exposure risks in pediatric patients?

3. You mention stricter intraoperative PTH decline criteria for children compared to adults (e.g., requiring >50% decline). Are these thresholds based on empirical pediatric data or extrapolated from adult studies?

4. How do you recommend integrating genetic testing (e.g., MEN1, CASR) into the initial diagnostic workup for seemingly sporadic PHPT cases without a family history, given its potential impact on surgical planning?

5. For patients with genetic PHPT who are poor surgical candidates, what evidence supports the long-term use of calcimimetics (e.g., durability of effect, age-specific dosing)? Are there pediatric-specific adverse effects that clinicians should monitor for?

Author Response

Revi1: This manuscript provides a comprehensive and well-structured review of pediatric primary hyperparathyroidism (PHPT), covering its diagnostic challenges, etiological spectrum, and management strategies. The authors effectively synthesize current evidence and highlight key considerations specific to pediatric populations. The review is clinically relevant and fills an important gap in the literature. While the overall quality is high, minor revisions could further strengthen the paper before publication.

Response: We thank the reviewer for the positive and constructive assessment. The manuscript has been revised accordingly, and all suggested minor revisions have been carefully addressed to further strengthen the paper.

1. Could you clarify whether differences in symptom severity between neonates and older children (e.g., musculoskeletal vs. renal manifestations) correlate with specific genetic subtypes or biochemical profiles (e.g., PTH/Ca²⁺ levels)? Response: The association between clinical severity, genetic background, and biochemical profiles across different pediatric age groups has been clarified in the revised manuscript.
2. The stepwise imaging approach favors ultrasound as the first-line modality. For recurrent/persistent PHPT, what specific criteria should guide the progression to advanced imaging techniques (e.g., ¹⁸F-FCH PET/CT vs. 4D-CT), particularly considering radiation exposure risks in pediatric patients?- Response: The criteria guiding escalation from ultrasound to advanced imaging modalities and the selection between ¹⁸F-fluorocholine PET/CT and 4D-CT have been clarified in the revised manuscript.
3. You mention stricter intraoperative PTH decline criteria for children compared to adults (e.g., requiring >50% decline). Are these thresholds based on empirical pediatric data or extrapolated from adult studies? Response: We have clarified that ioPTH decline thresholds in children are largely extrapolated from adult criteria and supported by limited pediatric series, highlighting the need for further studies to establish pediatric-specific standards.
4. How do you recommend integrating genetic testing (e.g., MEN1, CASR) into the initial diagnostic workup for seemingly sporadic PHPT cases without a family history, given its potential impact on surgical planning?Response:  We clarified the role of early genetic testing in pediatric PHPT, including apparently sporadic cases, and its implications for surgical decision-making.
5. For patients with genetic PHPT who are poor surgical candidates, what evidence supports the long-term use of calcimimetics (e.g., durability of effect, age-specific dosing)? Are there pediatric-specific adverse effects that clinicians should monitor for?-Response: The Medical therapy section has been expanded to address the evidence supporting long-term use of calcimimetics in pediatric patients with genetically determined PHPT. The revised text clarifies that available data are limited and largely extrapolated from adult studies, discusses the durability of calcium-lowering effects, the lack of standardized pediatric dosing, and highlights adverse effects requiring close monitoring.

Reviewer 2 Report

Comments and Suggestions for Authors

This is an interesting and comprehensive review dealing with an unusual pediatric disease. Treatment of primary Hyperparathyroidism in children is  challenging with  controversial criteria to achieve a surgical success. 

I have the following comments:

Currently the intraoperative parathyroid hormone (ioPTH) dosage should be systematically used in order to perform a more conservative and sparing surgery avoiding unnecessary neck exploration.  If possible, at least in patients with sporadic PHPT, an unilaleral thyroidal compartment should be preserved to reduce surgical morbidity above all in case of high risk of reoperation. 

A decrease of ioPTH of at least 50% should be considered not sufficient to obtain a surgical success because of the high percentage of persistent/recurrent disease observed. 

Familiar Hypocalciuric Hypercalcemia (FHH): this condition has to be carefully considered in the diagnostic algorithm of HP in order to avoid unnecessary surgery.

 

 

Author Response

Rev2: This is an interesting and comprehensive review dealing with an unusual pediatric disease. Treatment of primary Hyperparathyroidism in children is  challenging with  controversial criteria to achieve a surgical success. -Response:  We thank the reviewer for this thoughtful and positive assessment. We agree that the management of pediatric primary hyperparathyroidism is challenging, particularly with regard to defining reliable criteria for surgical success, and these aspects have been carefully addressed and clarified in the revised manuscript.

I have the following comments:

Currently the intraoperative parathyroid hormone (ioPTH) dosage should be systematically used in order to perform a more conservative and sparing surgery avoiding unnecessary neck exploration.  If possible, at least in patients with sporadic PHPT, an unilaleral thyroidal compartment should be preserved to reduce surgical morbidity above all in case of high risk of reoperation. - Response: We agree with the reviewer and have revised the manuscript to further emphasize the role of systematic intraoperative PTH monitoring in enabling focused, tissue-sparing surgery and preserving uninvolved thyroidal compartments, particularly in sporadic PHPT.

A decrease of ioPTH of at least 50% should be considered not sufficient to obtain a surgical success because of the high percentage of persistent/recurrent disease observed. -Response:  We agree and have clarified that a ≥50% ioPTH decline alone may be insufficient to predict surgical cure in pediatric patients and should be interpreted within the broader clinical context.

Familiar Hypocalciuric Hypercalcemia (FHH): this condition has to be carefully considered in the diagnostic algorithm of HP in order to avoid unnecessary surgery.-Response:  Although FHH was already discussed in the manuscript, its role in the diagnostic algorithm has now been further highlighted to emphasize its implications for surgical decision-making.

 

Reviewer 3 Report

Comments and Suggestions for Authors

This review aims to synthesize current knowledge on pediatric primary hyperparathyroidism, with a focus on its etiology, diagnostic challenges, imaging strategies, and management approaches in children and adolescents.

It seeks to clarify how PHPT in pediatric populations differs from adult-onset disease, in terms of clinical presentation, genetic underpinnings, and therapeutic considerations.

this manuscript attempts to provide an updated and structured overview that integrates recent genetic insights, evolving imaging modalities, and refined surgical guidelines. 

Here are my comments :

• Specify type of review in title
• Intro is too short and does not specify the orginality of the research
• References spelling is atypical : (1.) ?
• Avoid some objective words to describe the work : ' Critical step ? ' ...
• Include a Methods section detailing search strategy, inclusion/exclusion criteria, and study selection process.
• Several abbreviations are reused and redefined many times , especially PHPT
• Text should be reworked , as many repetitions and redundance are found 
• AI generated , and high ratio of plagiarism detected.
• Table 2 must be rewritten as age groups are not well separated
• Figure 1 absent
• Conclusion works as a discussion here , and is way too long 
• Figure 2 not contributive and must be well explained
• References spelling not homogeneous

 

 

Author Response

Rev3: This review aims to synthesize current knowledge on pediatric primary hyperparathyroidism, with a focus on its etiology, diagnostic challenges, imaging strategies, and management approaches in children and adolescents.

It seeks to clarify how PHPT in pediatric populations differs from adult-onset disease, in terms of clinical presentation, genetic underpinnings, and therapeutic considerations.

this manuscript attempts to provide an updated and structured overview that integrates recent genetic insights, evolving imaging modalities, and refined surgical guidelines. 

Here are my comments :

• Specify type of review in title-Response: The title has been revised to specify that this manuscript is a narrative review.
• Intro is too short and does not specify the orginality of the research-Response: The Introduction has been expanded, and the originality of the manuscript has been explicitly clarified by highlighting its pediatric-specific and integrative approach.
• References spelling is atypical : (1.) ?-Response: The reference formatting has been revised, and atypical citation styles have been corrected throughout the manuscript.
• Avoid some objective words to describe the work : ' Critical step ? ' ...-Response: Subjective wording, including expressions such as “critical step,” has been revised, and similar phrases have been moderated throughout the manuscript to maintain a neutral academic tone.
• Include a Methods section detailing search strategy, inclusion/exclusion criteria, and study selection process.-Response: A Methods section has been added to describe the literature search strategy, inclusion and exclusion criteria, and the study selection process applied in this narrative review.
• Several abbreviations are reused and redefined many times , especially PHPT-Response: Abbreviations have been standardized, defined at first mention, and used consistently throughout the manuscript.
• Text should be reworked , as many repetitions and redundance are found -Response: The manuscript has undergone a thorough revision to minimize repetition and redundancy. Several sections were restructured and condensed to improve narrative flow and overall readability.
• AI generated , and high ratio of plagiarism detected.-Response: The manuscript has been carefully revised to reduce redundancy, improve narrative flow, and strengthen the authorial voice, with particular attention to sentence structure and clarity. All sections have been reviewed to ensure originality of expression and appropriate citation of the relevant literature.
• Table 2 must be rewritten as age groups are not well separated-Response: Table 2 has been revised to improve clarity. Age groups are now more clearly distinguished by adjusting the table structure and column headings dealing with only serum calcium level.
• Figure 1 absent-Response: Figure 1 has been included in the revised manuscript.
• Conclusion works as a discussion here , and is way too long-Response: The manuscript structure has been revised to clearly separate the Discussion and Conclusions sections. Content previously included in the Conclusions has been moved to a dedicated Discussion section, and the Conclusions have been shortened to provide a concise summary of key messages.
• Figure 2 not contributive and must be well explained-Response: Figure 2 has been revised by expanding the figure legend to provide a clear explanation of each step in the proposed diagnostic and management pathway, thereby improving its contribution to the manuscript.
• References spelling not homogeneous-Response: The reference formatting and spelling have been reviewed and standardized throughout the manuscript to ensure consistency.

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The authors made a lot of revisions and answered all the reviewers' comments.

The manuscript could be accepted for publication.