Phenotypic Carney-Stratakis syndrome with DIS3L2 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 SDHB, SDHC, and SDHD 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 cKIT exon 11 mutation, and germline testing showed a variant of uncertain significance in the DIS3L2 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 DIS3L2 variant. Further reports and studies are needed to establish a definitive association between this gene and CSS.