Fumarate Hydratase-Deficient Uterine Leiomyomas: Germline Genetic Findings and Clinical Follow-Up in a Single-Center Cohort.

Background

Fumarate hydratase (FH)-deficient uterine leiomyomas are rare tumors that may be associated with germline FH variants and FH tumor predisposition syndrome. This study aimed to evaluate the clinical characteristics, germline genetic findings, and follow-up outcomes of patients with FH-deficient uterine leiomyomas, and to determine the frequency of germline pathogenic/likely pathogenic (P/LP) FH variants.

Methods

This ambispective single-center cohort study included 19 patients diagnosed with FH-deficient uterine leiomyomas at a center between February 2021 and February 2026. Clinical characteristics, surgical data, FH and S-(2-succino) cysteine (2SC) immunohistochemical findings, germline FH analyses, renal imaging, dermatologic evaluation, and follow-up outcomes were reviewed.

Results

Mean age was 44.9 ± 7.2 years, and the median largest leiomyoma diameter was 6.5 cm. Loss of FH expression was observed in 17/19 cases, while diffuse 2SC positivity was present in all cases. Among 17 patients who underwent germline testing, two (11.8%) harbored P/LP FH variants, [c.434C>G, p.(Ser145Ter) and c.1256C>G, p.(Ser419Ter)], and one (5.9%) had a variant of uncertain significance (VUS) [c.1090G>A, p.(Gly364Arg)]. Dermatologic evaluation was completed, with no cutaneous leiomyomas identified; no renal malignancy was detected on imaging in the two P/LP variant carriers. Among nine patients who underwent myomectomy, three developed recurrence; the patient carrying the likely pathogenic variant conceived after myomectomy.

Conclusions

Identification of an FH-deficient uterine leiomyoma on pathologic examination is an important finding that should prompt evaluation for germline FH variants. These patients require integrated genetic, renal, dermatologic, and gynecologic follow-up. Obstetricians and gynecologists have an important role in initiating genetic evaluation and long-term surveillance after surgery.