PPP2R5D-Related Neurodevelopmental Disorder and Multiple Haemangiomas: A Novel Phenotypic Trait?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a very nice case report with sufficient details about the patient and genetic analysis. I recommend adding more discussion on genomic analysis and the complexity of genomics to the paper. This paper (PMID: 37759745) is a good example of a comprehensive description of the genomics of Mendelian diseases.

Author Response

Thank you for your feedback on our case report. Your recommendation to expand the discussion on genomic analysis and the complexity of genomics is greatly appreciated and will significantly improve the clarity of our work. Page 4, lines 118-125; page 5, lines 178-186.

Reviewer 2 Report

Comments and Suggestions for Authors

This report by Comisi et al reports on a male infant with PPP2R5D-related disorder, ascribed to a novel heterozygous mutation in the PPP2R5D gene. This case had multiple skin hemangiomas in the face, chest and abdomen. The chest abdomen underwent surgical resection. Authors suggested that hemangiomas may be a novel phenotype of PPP2R5D-related disorder.

This case report is well written, succinct and informative. However, authors are advised to answer the following questions:

1. What was the in silico predicted pathogenicity of the novel PPP2R5D mutation?

2. Description on the morphologic features of hemangiomas are not precise enough. What were their sizes: small (legend to Figure 1, line 78) or different (text, line 76)? What was the pathological diagnosis of the chest angioma resected surgically?

3. In Case Presentation, many somatic anomalies are described. Have all of them been reported in previous cases of PPP2R5D-related disorder?

4. This patient underwent a strict, periodic follow-up until a12 months of age. Did this infant show any signs of psychomotor delay and/or abnormal behavior (other than stereotypes)? 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

To the AA

The Authors report a clinical case of an 1-yr-old boy with PPP2R5D (Protein Phosphatase 2 Regulatory Subunit B' Delta)-related disorder, also known as Houge-Janssens syndrome 1 (OMIM #616355), carrying a novel heterozygous missense pathogenetic variant c.592G>A (p. 94 Glu198Lys) in the PPP2R5D gene (NM_006245.4) and multiple progressive hemangiomas. The Authors suggest a new phenotypic association for the syndrome, based on a literature review and  prior research suggesting a key role of the B56 subunit encoded by the PPP2R5D 106 gene, in several functions, including the negative regulation of the  PI3K/AKT growth regulatory pathway, and therefore the crucial role of PI3K/AKT on the regulation of vasculature and angiogenesis.

The suggested causal relationship needs more validation. I would like to suggest the Authors to address the following weakness points points to try to improve the case description and clinical interpretation:  

1.       Iconography of the lesions should be substantially improved

2.      An ultrasound study of the lesions is missing. Please clarify and/or justify

3.      There is no information on the possible inner involvement of multiple hemangiomas. Please clarify and/or justify

 

4.      No information on the family history for hemangiomas is reported. Please provide the corresponding information

5.      There is no information on prenatal diagnosis, and perinatal period. Please provide the corresponding information

6.     No information on the early developmental trajectory of the patients is present. Please provide age at acquisition of main neurodevelopmental stage in the described patient

7.      The transient hypoglycemia shown by the index case should be better characterized (i.e., glucose/insulin ratio etc).

8.      The follow-up period is far too short. Please clarify and/or justify

9.     The Ms title is suggesting a Literature Review. This should be either reinforced by a corresponding table with key features reported in the literature related to the presented case or it is better to omit it from the title.

10.  Although the language is not preventing the understanding of the Ms content, a thorough english grammar and style revision should be carried out, and repetitions (i.e., Abstract, lines 24-25 […] disorder case from Sardinia cases).

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

To the Authors

 

Review of the revised Ms pediatrrep-3216159 entitled “PPP2R5D-Related Neurodevelopmental Disorder and Multiple Haemangiomas: A Novel Phenotypic Trait? Special caution should be taken when proposing new pathological entities, as well as new features and/or new phenotypic traits in already described diseases or syndromes. The Authors, in my own opinion, have made significant efforts in addressing all my raised points of constructive criticism. Despite some limitations that would remain, the Ms is certainly improved.