Uterine Leiomyoma with Fumarate Hydratase Deficiency: A Case Report
Oksana Balanda, MD1, Giulia Lorenzon, MD 2, Bassim Alsadi, MD, Ph.D* 3
*Correspondence to: Bassim Alsadi, Senior Consultant Gynaecologist and Obstetrician, Policlinico San Giorgio – Pordenone. Italy.
© 2026 Bassim Alsadi. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 25 May 2026
Published: 15 June 2026
DOI: https://doi.org/10.5281/zenodo.20729319
Abstract
Background: Uterine leiomyomas are the most common benign neoplasms in women, often with familial predisposition. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare autosomal-dominant syndrome caused by pathogenic variants in the fumarate hydratase (FH) gene, characterized by uterine leiomyomas, cutaneous leiomyomas, and type 2 papillary renal cell carcinoma. Recognition of FH-deficient leiomyomas is critical for timely genetic evaluation and patient management.
Case Presentation: We report a 43-year-old woman presenting with pelvic pain, abdominal heaviness, and bloating. She had a family history of uterine cancer and type 2 diabetes mellitus. Imaging revealed a large anterior wall leiomyoma (72.4 × 64.4 × 75.3 mm). The patient underwent laparoscopic total hysterectomy with bilateral salpingectomy. Histopathology showed a well-circumscribed fusocellular leiomyomatous proliferation with focal cytologic atypia and FH deficiency on immunohistochemistry.
Discussion: FH-deficient leiomyomas may occur sporadically or as part of HLRCC. FH loss disrupts the Krebs cycle, causing fumarate accumulation, pseudohypoxia via HIF-1α stabilization, Warburg metabolism shift, and impaired DNA repair. Early recognition of these leiomyomas prompts genetic counseling, surveillance for renal and cutaneous manifestations, and multidisciplinary monitoring.
Conclusion: FH-deficient uterine leiomyomas are important clinical indicators of possible HLRCC. Early identification enables appropriate follow-up and improves patient management, even in the absence of confirmed germline FH mutation.
Keywords: FH-deficient leiomyoma, uterine fibroids, HLRCC, fumarate hydratase, hereditary leiomyomatosis.
Introduction
Uterine leiomyomas constitute the most prevalent benign neoplasms in women, and their occurrence frequently demonstrates a familial predisposition. Uterine leiomyomas typically manifest during the fourth decade of life; however, syndromic forms may present with a more severe clinical burden. Patients often experience significant symptomatology, including pelvic pain, abnormal uterine bleeding, and dysmenorrhea, which can markedly impair quality of life.
Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an uncommon autosomal-dominant hereditary syndrome resulting from pathogenic variants in the fumarate hydratase (FH) gene. The disease is characterized by a triad of clinical manifestations comprising uterine leiomyomatosis, type 2 papillary renal cell carcinoma, and cutaneous leiomyomas (1). While cutaneous and uterine leiomyomas are benign proliferations, the type 2 papillary renal cell carcinoma associated with HLRCC represents a highly aggressive malignancy, making timely detection crucial for optimizing patient outcomes. Consequently, the precise histopathological identification of FH-deficient leiomyomas is of paramount importance and should prompt comprehensive clinical and genetic evaluation to ensure appropriate management and surveillance (2).
This case report presents the case of a 43-year-old woman with a uterine leiomyoma, which was found to be FH-deficient (FH-negative) upon histological analysis.
Case Presentation
We report the case of a 43-year-old woman who presented to our gynecological outpatient clinic on September 26, 2025, at Casa di Cura San Giorgio in Pordenone, complaining of pelvic pain, a sensation of abdominal heaviness, and bloating. Her family history was notable for uterine cancer in her mother, although no additional details were available, and type 2 diabetes mellitus, also present in her mother. The patient is a non-smoker and does not take any regular medications. Bowel and urinary habits were reported as normal.
Her past medical history included migraine, right-sided lumbosciatica, uterine fibromatosis, and an anxiety-depressive disorder. Obstetric history revealed two term spontaneous deliveries in 2008 and 2009, and one elective termination of pregnancy in 2020, managed with mifepristone and misoprostol according to protocol. Menarche occurred at age 13, and menstrual cycles were regular every 28–30 days, with a normal flow lasting four days. She participates regularly in regional cervical and breast cancer screening programs, all previously reported as negative.
In 2024, the patient underwent hysteroscopic polypectomy, with histology revealing a polyp with atypical features. Serial follow-up hysteroscopies were performed, the latest in March 2025, showing no histological abnormalities. During one of these follow-up hysteroscopies, a levonorgestrel-releasing intrauterine device (LNG-IUD) was inserted, which was subsequently removed at the time of the laparoscopic surgery. A uterine leiomyoma had been detected on ultrasound in 2020 and had been monitored since.
On examination, the abdomen was soft and non-tender in all quadrants. External genitalia and vagina were consistent with multiparity. Gynecological assessment revealed a retroverted, enlarged, hypomobile, and non-tender uterus. Adnexal regions and the pouch of Douglas were unremarkable. Speculum examination showed a macroscopically normal cervix with no abnormal genital discharge.
Transvaginal ultrasound demonstrated a retroverted uterus measuring 94 × 57.9 × 97.1 mm, with irregular morphology due to a leiomyoma measuring 72.4 × 64.4 × 75.3 mm located at the anterior wall. The endometrium measured 5.6 mm in thickness. Both ovaries were normal in position, size, and echotexture, and no pelvic fluid collections were identified.
Given the clinical presentation and imaging findings, the patient underwent laparoscopic total hysterectomy with bilateral salpingectomy and adhesiolysis on October 15, 2025. Intraoperatively, the uterus was enlarged due to adenomyosis, with an intramural infraligamentary leiomyoma of approximately 7 cm on the right. Both adnexa appeared normal. Endometriotic nodules were identified on the left uterosacral ligament. The previously inserted LNG-IUD was removed during the procedure.
The postoperative course was complicated by persistent post-void residuals for approximately seven days, which resolved with conservative management.
Histopathological examination revealed mild chronic cervicitis. The endometrium showed no morphologic evidence of hormonal stimulation. The myometrium contained a well-circumscribed fusocellular leiomyomatous proliferation with focal cytologic atypia, areas of capillary edema, and vessels with a branching pattern. No mitotic activity (0 mitoses per 10 high-power fields) or necrosis was observed. Immunohistochemical analysis for fumarate hydratase (FH) demonstrated loss of expression. Overall, the morphological and immunophenotypic features were consistent with an FH-deficient (FH-negative) uterine leiomyoma.
This case underscores the importance of recognizing FH-deficient leiomyomas in women with symptomatic uterine masses, as their identification may have implications for genetic counseling and surveillance for hereditary leiomyomatosis and renal cell carcinoma (HLRCC).
Discussion
Fumarate hydratase (FH) is an enzyme encoded by the FH gene located on chromosome 1, and it catalyzes the conversion of fumarate to malate, a fundamental step in the Krebs cycle. This highlights the importance of FH in mitochondrial energy production; consequently, mutations in the FH gene reduce enzymatic activity, cause fumarate accumulation, and ultimately lead to dysfunction of the mitochondrial respiratory chain (3).
Germline mutations in FH may be homozygous or heterozygous. Homozygous mutations are extremely rare and result in fumaric aciduria, a severe autosomal recessive disorder in which affected individuals generally do not survive beyond adolescence. Heterozygous germline mutations, on the other hand, lead to loss of enzyme function and predispose to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), which follows an autosomal dominant pattern of inheritance (1-2).
In heterozygous mutations specifically, loss of FH activity leads to excessive intracellular accumulation of fumarate, triggering an oncogenic cascade. This increase induces compensatory metabolic changes, including inhibition of mitochondrial oxidative phosphorylation and a shift toward anaerobic glycolysis. From a metabolic perspective, glucose-6-phosphate is redirected into the pentose phosphate pathway, resulting in reduced overall ATP production. All these alterations reflect the Warburg effect, which is typical of cancer cells and characterized by increased glucose consumption and persistent lactate production despite adequate oxygen availability (3-4).
Fumarate accumulation also stabilizes hypoxia-inducible factor 1α (HIF-1α) by inhibiting the prolyl hydroxylases that normally mediate its degradation. This creates a state of pseudohypoxia that activates genes involved in angiogenesis, epithelial-to-mesenchymal transition, and tumor progression. Increased production of free radicals further exacerbates inhibition of prolyl hydroxylases, amplifying the hypoxic response. In addition, cytosolic FH plays an important role in DNA repair through homologous recombination; therefore, its loss compromises genomic integrity (5).
Turning to FH-deficient uterine leiomyomas, it is important to note that these can occur independently of HLRCC; however, once identified, a thorough clinical and genetic evaluation is warranted to rule out a syndromic origin. Leiomyomas can be managed conservatively or surgically, depending on the patient's symptoms and clinical presentation. A limit of this report is the lack of genetic testing, which prevents confirmation of an underlying FH mutation and assessment of familial risk.
FH-deficient leiomyomas are generally large and symptomatic at a young age, which often necessitates early surgical intervention. In suspected cases of HLRCC, continuous and long-term multidisciplinary monitoring is essential. Dermatologic assessment is important as well, since cutaneous leiomyomas, although usually benign, may be painful and may require surgical excision, cryotherapy, or laser treatment (6,7).
Gynecologic monitoring is also recommended, as leiomyomas of syndromic origin may evolve rapidly. The most significant and concerning manifestation in the HLRCC triad is renal cell carcinoma, owing to its aggressiveness and high metastatic potential. For this reason, annual abdominal imaging is considered essential starting at 10–11 years of age, given that renal tumors have been documented even in pediatric patients. Gadolinium-enhanced magnetic resonance imaging is preferred over CT due to the absence of radiation exposure and its superior diagnostic accuracy. Imaging should be performed with 1–3 mm slice thickness to ensure accurate detection of early renal lesions (8-9).
Conclusion
This case report highlights the clinical and histopathological characteristics of an FH-deficient uterine leiomyoma in a symptomatic patient. Recognition of FH deficiency is crucial, as it may represent an early indicator of hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Although genetic confirmation and follow-up data were not available, awareness of this entity can guide clinicians and pathologists to implement appropriate monitoring and multidisciplinary evaluation. Early identification of FH-deficient leiomyomas may improve patient management and facilitate surveillance for associated renal and cutaneous manifestations.
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