# Familial MEN1 Syndrome with Atypical Renal Features and a Coexisting CLDN16 Variant: A Case Series

## TL;DR

This study reports a family with MEN1 syndrome and unusual kidney symptoms linked to a previously benign CLDN16 variant, suggesting genetic interactions affect disease presentation.

## Contribution

Identifies a CLDN16 variant as a potential modifier of renal features in MEN1 syndrome through a three-generation case series.

## Key findings

- All three patients showed primary hyperparathyroidism, hypercalcemia, and early nephrocalcinosis.
- The CLDN16 variant co-segregated with hypomagnesemia and renal involvement, indicating a modifying role.
- Comprehensive genetic screening is recommended for atypical renal presentations in MEN1 patients.

## Abstract

Background and Clinical Significance: Multiple Endocrine Neoplasia type 1 (MEN1) is a rare autosomal dominant disorder caused by mutations in the MEN1 gene. Although primarily characterized by endocrine tumors, renal manifestations remain underreported. Case Presentation: We report a three-generation family carrying a pathogenic MEN1 mutation (c.1351-3_1359del) with a co-occurring Claudin 16 (CLDN16) variant (c.324+13C>G). Genetic testing included MLPA and whole-exome sequencing (WES), with bioinformatics analysis validating variant pathogenicity. All three patients exhibited primary hyperparathyroidism, hypercalcemia, hypercalciuria, early nephrocalcinosis, and renal hypomagnesemia. The CLDN16 variant, previously considered benign, co-segregated with hypomagnesemia and renal involvement, suggesting a potential modifying role. Conclusions: These findings support the need for comprehensive genetic screening in MEN1 patients with atypical renal presentations. Concomitant genetic variations can alter the principal phenotype.