Congenital Adrenal Hyperplasia: Diagnostic Pitfalls in Prolonged Neonatal Jaundice

Reviewer’s Comments

Authors’ Responses

Overall

This is interesting report

Thank you for your kind comment.

Comment 1:

Ultrasound pictures, especially gallbladder

Thank you for your comments.

The ultrasound pictures, especially gallbladder has been provided.

The pictures can be seen on page 4, line 151.

Comment 2:

Please show the blood test result as table.

Thank you for the recommendation.

The blood test results as table has been provided.

The table can be seen on page 4, line 149.

Comment 3:

No pigmentation or dehydration? Please add patient picture.

Thank you for the suggestion.

There was hyperpigmentation after birth generally, no dehydration.

The picture can be seen on page 5, line 155.

Reviewer’s Comments

Authors’ Responses

Overall

The authors presented an interesting case report but the way of presentation is full of flaws.

There are some suggestions for improvement.

Thank you for your kind suggestions.

Comment 1:

Pathogenesis of cholestasis in congenital adrenal hyperplasia reflects the cortisol deficiency.

Thank you for your comments.

The authors have provided the pathogenesis of cholestasis in congenital adrenal hyperplasia reflects the cortisol deficiency.

It can be seen on page 7, line 185-189

Comment 2:

Propose to change the title into: Diagnostic pitfalls in cholestasis.

Thank you for your opinion.

The revised title is “Congenital Adrenal Hyperplasia: Diagnostic pitfalls in cholestasis”.

Comment 3:

The manuscript needs shortening.

Thank you for the suggestion.

The authors have revised the manuscript as suggested.

Comment 4:

Line 70: Provide the biochemical diagnosis of cholestasis

Thank you for the recommendation.

The authors have provided the biochemical diagnosis of cholestasis on page 2, line 71-75

Comment 5

Line 90: Define the serum total and direct bilirubin concentration.

Thank you for your comments.

The serum total and direct bilirubin concentration has been mentioned on page 2, line 96-97

Comment 6

Line 103: The Authors have to provide results of direct bilirubin concentration, not only serum total bilirubin. Cholestasis is defined as serum direct bilirubin is above 1mg/dL

Thank you for your comments.

We understand that some literatures defined cholestasis as serum direct bilirubin above 1mg/dL, but a recent study by Davis et al stated that in the first 14 days after birth, the cut-off for elevated conjugated bilirubin may be greater than 0.5mg/dL.

The results of direct bilirubin concentration have been provided on page 4, line 149

Reviewer’s Comments

Authors’ Responses

Overall

This case report is very interesting, presenting the third case of Congenital Adrenal Hyperplasia in neonates, reported internationally, and the first in Malaysia

Thank you for your kind comment.

Comment 1:

Try to reorganize a little bit the “Case Report” Section, to be easier to follow. Maybe you can add some data to a table.

Thank you for your comments.

A table has been included and can be seen on page 4, line 149.

Comment 2:

The manuscript needs proofreading to correct the typographical and grammatical errors because there are some punctuation and grammatical mistakes present throughout the manuscript.

Thank you for noticing the typographical and grammatical errors.

The manuscript has undergone proofreading.

Reviewer’s Comments

Authors’ Responses

Comment 1:

The current definition of cholestasis is very simple: an abnormal
direct/conjugated bilirubin is defined as a serum value >1.0 mg/dL (17mmol/L)''.

See, Fawaz et al. Guideline for the Evaluation of Cholestatic Jaundice in Infants: Joint Recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. JPGN 2017.

Thank you for your comments.

We understand that most literatures mentioned cholestasis as direct bilirubin of >1.0 mg/dL (17mmol/L). However, several other literatures reported that, the levels for suspicion of cholestasis for direct or conjugated bilirubin within the first 5 days of life could be as low as 5μmol/l (0.3–0.4mg/dl), with another literature defined as defect in either formation or excretion of bile, with a resulting increase in the serum or retained biliary components

The explanations can be seen on page 2, line 71-78.

Further explanation of the conjugated bilirubin cut off point reflected in this case was in the discussion section on page 7, line 209-214.

Comment 2:

In the presented manuscript - see Table 1 - the highest level of serum direct bilirubin was 12.1 17mmol/L. There is no information about serum biliary acids concentration.

What's more, in Table 1 there is also no more data about serum direct bilirubin concentration.

Reflecting this point, the Authors could not state about the presence of cholestasis in the reported patient.

Thank you for your comments.

We understand the limited information on value of direct bilirubin as it was not measured frequently.

The available results of direct bilirubin are given in Table 1 (page 4, line 151).

Reviewer’s Comments

Authors’ Responses

Comment 1:

I appreciate the Authors' efforts made to this manuscript.

In fact, the presented case report is not about cholestasis - there was no conjugated hyperbilirubinemia according to the current guidelines of biochemical cholestasis recognition. There is also no information about serum biliary acids, serum GGTP activity.

Thus, I propose to the change the title into:

CAH: Diagnostic difficulties/pitfalls in prolonged neonatal jaundice''. The proposed title better reflects the aim of the manuscript.

The Authors should change their discussion into the point of view from prolonged neonatal jaundice (not cholestasis, because this case report is not a case of cholestatic infant, per se).

The manuscript is worth publishing after these changes.

Thank you for your insightful comments.

We already changed the title and discussion as advised by the reviewer.

The changes have been made as per advice and are highlighted in yellow.

Discussion on neonatal cholestasis has been reduced further.

We have also just received the genetic confirmation result for the patient and have added this result in the case report section to further improve the manuscript.