Novel Variant in CLDN16: A Further Step in the Diagnosis of Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis—A Case Report

Round 1

Reviewer 1 Report

Thanks to the Authors for the appreciable paper.

Starting for this case report You  clearly described the clinical, surgical and diagnostical workout performed from an interesting clinical presentation. 

Appropriate description and review of what is known about the genetical landscape of this condition and its clinical effects. 

Could you add some details:

Has the patient any other metabolic or ormonal alteration in his history?

Did you find any alteration on parathormonal status ?

A better description of endourological manouvres can be added: PCNL (mini-micro?) and ureteroscopy and stents duration (did you report any problem with stent ecrustation in this case?) .

Finally, What kind of radiological follow up have you scheduled for Him and what dietary prescriptions you proposed (if any)?

Author Response

We thank the reviewer for their comments. 

We have addressed each of their comments within the text. Specifically we have added commentary on the patients history of metabolic/hormonal abnormalities,  PTH level and work up, details regarding his PCNL and ureteroscopy and details regarding his surveillance imaging. 

Reviewer 2 Report

A well written report of a genetically determined case of renal stone disease and nephrocalcinosis.

Clinical and genetic study is exaustive.

Author Response

We thank the reviewer for their comments. 

Reviewer 3 Report

In this article the AA described the interesting case of a patient affected by familial hypomagnesemia with hypercalciuria and nephrocalcinosis, showing a pathogenic variant of claudin-16 and a further variant of uncertain significance, never described before.

If the topic is of interest, additional information may improve the quality of this case report:

• Although the patient has no family history for nephrolithiasis and based on genetic analyses results, did the AA consider to include urinary parameters of his family members?
• In the case report section, the AA described the urinary solute excretion anomalies of the patient, including elevated urine pH and hypocitraturia. Since incomplete distal RTA have been associated to this condition, it would be interesting to know if an ammonium chloride loading test was performed and to include additional information on plasma bicarbonate and TCO2.
• Since the patient was affected by severe hypocitraturia, multiple stone recurrence despite supportive therapy and was treated with thiazide diuretics, known to worsen hypocitraturia; did the AA considered to add also citrate supplementation and to discuss further?

Author Response

We appreciate the reviews comments and suggestions. Below we address each suggestion.  

• Although the patient has no family history for nephrolithiasis and based on genetic analyses results, did the AA consider to include urinary parameters of his family members?
  • We did consider providing further analysis of the patients family members urinary parameters; however, they are not patients of our institution. The patients mother was contacted for genetic counseling but no further urinary tests were performed on her or the patients other family members. Therefore, this information is unavailable. 
• Since incomplete distal RTA have been associated to this condition, it would be interesting to know if an ammonium chloride loading test was performed and to include additional information on plasma bicarbonate and TCO2.
  • The patient did not have an ammonium chloride loading test. The consideration of an incomplete distal RTA is astute. Plasma HCO3 levels would be helpful in understanding the patients clinical picture and have been included where appropriate. 
• Since the patient was affected by severe hypocitraturia, multiple stone recurrence despite supportive therapy and was treated with thiazide diuretics, known to worsen hypocitraturia; did the AA considered to add also citrate supplementation and to discuss further
  • The patient makes calcium phosphate stones and despite his profound hypocitraturia has a urinary pH that is alkali. Citrate management would help with improving his hypocitraturia, but may also exacerbate his alkali pH and result in worse calcium phosphate stone precipitation. The reviewer brings up a key point regarding these patients - that competing interests are at hand when treating them medically with supplementation. A short discussion to this point has been added. 

 

Reviewer 4 Report

The authors in this well written case report (familial hypomagnesemia with hypercalciuria and nephrocalcinosis, FHHNC) included a comprehensive introduction and discussion of a rare cause of nephrocalcinosis and recurrent urolithiasis. 

Author Response

We thank the reviewer for their comments. 

Round 2

Reviewer 3 Report

The AA responded to almost all suggestions. Although some information are still lacking, the AA included plasma bicarbonate and discussed more about hypocitraturia.

Author Response

We thank the reviewer for their comments.