Interleukin-36 Is Highly Expressed in Skin Biopsies from Two Patients with Netherton Syndrome

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present an interesting study of two cases of Netherton syndrome (NS). They demonstrate that IL-36 is overexpressed in these cases, indicating that NS may be partially driven by Th17 activation, similar to psoriasis. Moreover, they show that LEKTI positivity was maintained in these two cases, despite the presence of the typical SPINK5 mutation. This result challenges the previous assumption that LEKTI expression is consistently absent in all NS cases. It is particularly significant, as it implies that LEKTI staining is not a completely reliable test for NS diagnosis. Nevertheless, given that IL-36 overexpression is also seen in numerous other conditions, its diagnostic utility is also limited. 

Author Response

Comment 1:

The authors present an interesting study of two cases of Netherton syndrome (NS). They demonstrate that IL-36 is overexpressed in these cases, indicating that NS may be partially driven by Th17 activation, similar to psoriasis. Moreover, they show that LEKTI positivity was maintained in these two cases, despite the presence of the typical SPINK5 mutation. This result challenges the previous assumption that LEKTI expression is consistently absent in all NS cases. It is particularly significant, as it implies that LEKTI staining is not a completely reliable test for NS diagnosis. Nevertheless, given that IL-36 overexpression is also seen in numerous other conditions, its diagnostic utility is also limited. 

 

Reply:

Thank you for your feedback. To clarify, only 1 case demonstrated LEKTI positivity. This is clarified in the abstract and discussion.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors submitted a study of lesional IL-36 immunohistochemical expression in formalin-fixed biopsies of SPINK5-confirmed skin lesions in Netherton syndrome. The study is novel, interesting, well-written, thoughtfully discussed, and clinically relevant. Nice work! In the recently published study quality assessment tool for cross-sectional pathology studies (SQAT-Path; PMID 38415867), this study scores 13/27, which is better than some larger series and despite being a n=2 case series in which some criteria (e.g.., statistics) are not applicable.

 

The clinical descriptions suggest both cases may be reasonably classified as NS-ILC, whereas erythroderma and trichorrhexis invaginata were not studied. Can the authors confirm and state that the cases studied were ILC, perhaps even in the title? If not, please comment.

 

For completeness, as mentioned in the Introduction, please comment on the status of dyskeratosis, as well as status of TH2-associated histopathologic features, such as spongiosis (spongiotic vesicles, Langerhans cell collections?) and eosinophils (rare/absent, present, prominent?), in both biopsies. 

 

For completeness, please state the status of LEKTI expression Case #2. E.g. not requested, unavailable.

Author Response

Comment 1:

The authors submitted a study of lesional IL-36 immunohistochemical expression in formalin-fixed biopsies of SPINK5-confirmed skin lesions in Netherton syndrome. The study is novel, interesting, well-written, thoughtfully discussed, and clinically relevant. Nice work! In the recently published study quality assessment tool for cross-sectional pathology studies (SQAT-Path; PMID 38415867), this study scores 13/27, which is better than some larger series and despite being a n=2 case series in which some criteria (e.g.., statistics) are not applicable.

Reply 1:

Thank you for your positive feedback.

 

Comment  2:

The clinical descriptions suggest both cases may be reasonably classified as NS-ILC, whereas erythroderma and trichorrhexis invaginata were not studied. Can the authors confirm and state that the cases studied were ILC, perhaps even in the title? If not, please comment.

Reply 2:

Both cases could be classified as NS-ILC; this is now included in the introduction. Both patients had prior hair mounts confirming trichorrhexis invaginata which is included in the case descriptions.

 

Comment 3:

For completeness, as mentioned in the Introduction, please comment on the status of dyskeratosis, as well as status of TH2-associated histopathologic features, such as spongiosis (spongiotic vesicles, Langerhans cell collections?) and eosinophils (rare/absent, present, prominent?), in both biopsies. 

Reply 3:

In both patients, mild spongiosis with no dyskeratosis was observed. Sparse eosinophils were present.  

Comment 4:

For completeness, please state the status of LEKTI expression Case #2. E.g. not requested, unavailable.

Reply 4:

LEKTI expression is not available for case #2.