Phenotypic Carney-Stratakis syndrome with <i>DIS3L2</i> variant: a case challenging the current genetic paradigm

Carney-Stratakis syndrome (CSS) is a rare hereditary disorder involving gastrointestinal stromal tumors (GISTs) and paraganglioma/pheochromocytoma, typically linked to mutations in the <i>SDHB</i>, <i>SDHC</i>, and <i>SDHD</i> genes. The unique mechanism of tumorigenesis, including pseudohypoxia and hypermethylation caused by succinate dehydrogenase deficiency, renders target therapy with tyrosine kinase inhibitors ineffective; therefore, complete surgical resection is the optimal treatment in the absence of tumor metastases. Herein, we report the case of a 74-year-old woman with gastric GIST and urinary bladder paraganglioma. Molecular testing on the gastric GIST revealed a <i>cKIT</i> exon 11 mutation, and germline testing showed a variant of uncertain significance in the <i>DIS3L2</i> gene. The patient has been on imatinib since July 2023 with controlled disease. To the best of our knowledge, this is the first reported case of CSS with a <i>DIS3L2</i> variant. Further reports and studies are needed to establish a definitive association between this gene and CSS.