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

Area of Science:

• Genetics
• Endocrinology
• Nephrology

Background:

• Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disorder linked to MEN1 gene mutations.
• MEN1 is primarily known for endocrine tumors, but renal manifestations are often overlooked.

Observation:

• A three-generation family with a pathogenic MEN1 mutation and a Claudin 16 (CLDN16) variant was studied.
• Patients presented with primary hyperparathyroidism, hypercalcemia, hypercalciuria, early nephrocalcinosis, and renal hypomagnesemia.
• The CLDN16 variant co-segregated with hypomagnesemia and renal issues, suggesting a modifying role.

Findings:

• Genetic testing, including MLPA and whole-exome sequencing (WES), identified a pathogenic MEN1 mutation (c.1351-3_1359del) and a CLDN16 variant (c.324+13C>G).
• Bioinformatics analysis confirmed variant pathogenicity.
• The co-occurrence of MEN1 mutation and CLDN16 variant was associated with significant renal phenotypes.

Implications:

• Comprehensive genetic screening is crucial for MEN1 patients presenting with atypical renal symptoms.
• Concomitant genetic variations can significantly influence the clinical presentation of MEN1.
• This study highlights the importance of considering modifier genes in rare genetic disorders.