Central Precocious Puberty in Boys and Girls: Similarities and Differences

Round 1

Reviewer 1 Report

Cristina Mucaria and colleagues are presenting an interesting and complete review regarding gender similarities and differences concerning Central Precocious Puberty.  The review is of clinical interest since gender differences on the topic are reported in the literature and a  female cohort preponderance in the papers, to which clinical decisions are frequently extrapolated to males, is clearly evident.

However Authors should consider the following Minor concerns in order to improve the quality of the review.

Minor concerns:

• Pag 2, line 63 (Epidemiology): you should cite recent data regarding the reported increase of CPP in girls during COVID-19 pandemic, such as: “Recent data of an Italian cohort during COVID-19 Pandemic has reported an increase in incidence of CPP in females along with an increase of rapidly progressing forms, possibly due to triggering environmental factors” [ref: Stagi, S., De Masi, S., Bencini, E. et al.Increased incidence of precocious and accelerated puberty in females during and after the Italian lockdown for the coronavirus 2019 (COVID-19) pandemic. Ital J Pediatr 46, 165 (2020). https://doi.org/10.1186/s13052-020-00931-3]. You should also state that to date, similar data are not yet reported in males.
• Pag 4 line 122 (Etiology). When explaining MKRN3 gene, you should mention that familiar causes of genetic variants of the gene are frequently under recognized due to the imprinting pattern of inheritance of the gene, that can be carried from an asymptomatic father. At the end of the chapter (after line 125) you should also strengthen the idea that although implications of genetic variants on the clinical phenotype are still unknown, genetic analysis should be routinely included in CPP diagnosis [ref. Ana Claudia Latronico, Vinicius Nahime Brito, Jean-Claude Carel, Causes, diagnosis, and treatment of central precocious puberty, Lancet 2018].
• Table 4: It is not clear why reference Brito et al (ref. 40 in you paper) has two LH peak cut-offs rows in the table for both genders: please modify or specify accordingly in the text.
• Table 4: Moreover, in the text lines 164-167 you state that Resende et al (ref. 41 in your paper) found higher cut-offs in girls, while contrary results with another assay which I assume you are mentioning in the table… I personally found the sentence confusing when comparing it to Table 4; please modify/specify.
• Table 4: Also, you should specify in the caption of Table 4 the symbols used in order to let the reader better understand gender differences in LH measures: F = females; M = males; no symbol = data referred for both sexes?

• Pag 6, line 215 (Therapy). You should also mention that a new formulation of long acting leuproreline given twice yearly has been recently approved for both sexes for CPP treatment from the FDA [ref: Karen O. Klein, Analia Freire, Mirta Graciela Gryngarten, Gad B. Kletter, Matthew Benson, Bradley S. Miller, Tala S. Dajani, Erica A. Eugster and Nelly Mauras. Phase 3 Trial of a Small-volume Subcutaneous 6-Month Duration Leuprolide Acetate Treatment for Central Precocious Puberty.; J Clin Endocrinol Metab, October 2020, 105(10):1–12]. You should add also a row citing this treatment in Table 6.
• Table 8: you should specify in the caption of Table 8, similarly to Table 7, that data of “FH-TH” is expressed as SDS.

Author Response

We thank a lot the reviewer for the positive comments.

The following modification have been made:

Pag 2, line 63: the comment on the Italian cohort has been added.

Pag 4 line 122: : the comment on the routine genetic analysis has been added.

Table 4 has been completely re-written clearly showing cut-off values for boys and girls. In the same table some inaccuracies have been corrected. Thanks for your remark.

Pag 6, line 215 the data on very long acting leuprolide depot (45 mg) has been added with the related reference.

Table 7 and 8: all data are in cm (as stated in the tables) except for those of Vuralli et al. (as shown in the legend).

Reviewer 2 Report

This is a very interesting review assessing similarities and differences among Central Precocious Puberty (CPP) between boys and girls. The topic is of great interesting and well presented by the authors. One major comment is that authors should try to follow their title and present difference among sexes rather in several chapter rather than an overall presentation of what is already known about CPP.   Moreover, there are some minor points that should be addressed:

Epidemiology, lines 57-63: The differences among the reported incidence are so vast, with three studies reported very small incidence rates (0.1-2.7 per 10.000 children in girls) and two presenting very large (8.0 and 27.0 per 10.000 children). Authors should try to explain more thoroughly these differences.

Etiology, lines 98-125: There are no reporting about any genetic similarities or differences between boys and girls. Authors should report If not and should try to focus more on discrepancies among sexes.

Therapy, table 8, footnote: the footnote is not corresponding to the table content. Please correct it.

Author Response

We thank a lot the reviewer for the positive comments.

Modifications:

Etiology, lines 98-125: some tentative of expalations are provided in the tex also considering the new observation of Stagi et al. regading a Italian cohort (see last lines of the paragraph)

Etiology, lines 98-125: A tentative short sentence on  genetic similarities or differences between boys and girls has been added.

Therapy, table 8: the mistakes in the footnotes have been corrected