[Clinicopathological and molecular genetic analysis of 126 cases of fumarate hydratase-deficient uterine leiomyomas].

Objective: To investigate the clinicopathological features of fumarate hydratase (FH)-deficient uterine leiomyomas associated with germline mutations of FH gene, and to provide a basis for efficient screening of high-risk individuals with FH gene germline mutations. Methods: The clinical data of 126 patients with FH-deficient uterine leiomyoma diagnosed in Women's Hospital, Zhejiang University School of Medicine from January 2023 to November 2025 were collected and retrospectively analyzed. The diagnosis of FH-deficient uterine leiomyoma in all patients was confirmed by FH or 2-succinate-cysteine (2SC) immunohistochemistry. Peripheral blood or normal tissue samples of all patients were collected for FH gene germline mutation detection by high-throughput next-generation sequencing technology. Results: A total of 15.9% (20/126) of the patients with FH-deficient uterine leiomyoma carried pathogenic or likely pathogenic germline mutations of FH gene. Univariate analysis showed that younger age, previous myomectomy history, no history of childbearing, presence of multiple leiomyomas, especially, patients with multiple FH-deficient leiomyomas (≥2 FH-deficient leiomyomas) and multifocal FH-deficient leiomyomas (FH-deficient leiomyomas distributed in different parts of the uterus, cervix, broad ligament, etc.) were more likely to carry FH gene germline mutations (all P<0.001). The prediction model based on "age≤45 years" and "multiple FH-deficient leiomyomas" had good predictive efficacy (area under the curve was 0.869, sensitivity was 90.0%, and specificity was 86.8%). Conclusion: Integration of clinicopathological features including patient age, multiple and multifocal distribution of FH-deficient leiomyomas could effectively improve the identification of high-risk individuals for FH gene germline mutation, so as to provide a basis for the development of accurate genetic screening.