Fumarate Hydratase-deficient Uterine Leiomyoma in a 25-Year-Old Woman

Abstract

Fumarate hydratase (FH) is an essential enzyme in the citric acid (Krebs) cycle. Genetic mutations in the FH gene can contribute to tumor development. FH-deficient uterine leiomyoma is a rare subtype of uterine leiomyoma, accounting for approximately 0.4–1.6% of all uterine leiomyomas. It can occur in both syndromic and sporadic settings. Germline mutations in FH are associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome, which presents with cutaneous and uterine leiomyomas and an aggressive form of renal cell carcinoma (RCC). Identifying FH-deficient uterine leiomyomas may facilitate early detection of patients at risk for RCC. Here, we present a case of a 25-year-old woman, gravida 0, had pelvic pain, dyspareunia, and heavy menstrual bleeding, significantly affecting her daily activities. Pelvic MRI revealed a 3.5 cm intramural fibroid in the posterior uterine wall. The patient opted for myomectomy. The surgical specimen consists of multiple tan, nodular, rubbery tissue fragments, including one large 4 cm nodule and several smaller nodules (0.4–1.3 cm). Sectioning shows whorled cut surface without hemorrhage or necrosis.  Microscopically, the tumor exhibited spindle and epithelioid cell proliferation, alveolar edema, and staghorn/hemangiopericytoma-like vessels. Tumor cells also displayed ovoid nuclei with eosinophilic nucleoli and bizarre nuclei. Rhabdoid /eosinophilic cytoplasmic inclusions are present. Immunohistochemical analysis showed positivity for smooth muscle actin and desmin, confirming smooth muscle differentiation. The tumor was negative for FH and positive for S-(2-succino) cysteine (2SC). The diagnosis of FH-deficient leiomyoma was rendered based on these histological findings and confirmed by loss of FH expression on immunostaining. The negative FH and positive 2SC indicate biallelic FH inactivation. Genetic counseling was recommended to rule out germline FH mutations and HLRCC syndrome. Through this case report, we want to raise awareness that an early-onset large leiomyoma with bizarre nuclei needs to consider the possibility of FH-deficient uterine leiomyomas to facilitate early detection of patients at risk for RCC. [N A J Med Sci. 2025;18(1):028-031.   DOI:  10.7156/najms.2025.1801028]

Key Words: fumarate hydratase-deficient, leiomyoma, hereditary

leiomyomatosis and renal cell carcinoma (HLRCC) syndrome