This manuscript describes a family suffering from PLACK syndrome, a rare genodermatosis mainly characterized by peeling skin syndrome and other skin features due to breakage of intercellular connections in upper epidermal layers.
The paper has several originalities, including the detection and characterization of a previously unrecognized splicing mutation and description of a therapeutic treatment that led to significant improvements of the clinical symptoms in the affected patient.
I have some major comments:
- there is no direct link between the therapeutic treatment and the pathophysiology of PLACK syndrome. To this regard, what did you hypothesize in regard to calpastatin/calpain axis? Is there a direct link between lipid and vitamin supply and downstream effectors of calpastatin activity? May the activity of modifier genes (inherited at the homozygous status because of the endogamy) be involved in the modulation of the clinical manifestations? I would like to read a comment about this.
- How leaky is the splicing mutation? Did you find a unique transcript with the ATAG insertion or a normal transcript could be also detected? There are no (supplemental) figures related to the molecular analysis.
- Mutation is located in intron 21, while exon 22 is erroneously reported at page 7, line 42. In my opinion the mutation designation at protein level should be:
p.(Lys474insIle)Asp475Glyfs2 (detailed option) or, more simply, p.Asp475Glyfs2. Please, check.
- Several imperfections in English grammar are present. For example, in the abstract, a comma instead of a full stop should be used to link the phrases as follows: “PLACK syndrome, which is an untreatable…etc” at lines 13-14.
- Was the affected younger sister treated with lipid and vitamin A infusion as the proband?
- Please, make uniform in Table 2 the designation of mutations at protein level (use “asterisk” for stop codon and not a single letter code for amino acids).
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Minor points
Please, report the entire designation for the acronym PLACK when it is cited for the first time in Introduction.

Results of the molecular analysis have been improved. In general, figures and tables can be ameliorated. For example, histological images should contain arrows/asterisks indicating the findings described in the corresponding legend (for example "superficial intraepidermal blister": where is the blister?). Last column on the right in Table 2, which reports on other clinical manifestations, should be co-aligned with the text of the other columns.