Fumarate Hydratase Gene Research Articles

A Missense Mutation c.1132G > A in Fumarate Hydratase (FH) Leads to Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) Syndrome and Insights into Clinical Management in Uterine Leiomyomata

HLRCC syndrome is a hereditary cancer predisposition syndrome caused by heterozygous germline pathogenic variant of the fumarate hydratase (FH) gene and characterized by cutaneous leiomyomas (CL), uterine leiomyomas (UL), and renal cell carcinoma (RCC). Loss of function variant of FH gene inactivates the Kreb's cycle enzyme activity and predisposes individuals with such variant to the development of HLRCC. Next-generation sequencing (NGS) and Sanger confirmation were given to family members accessible. Following that, a functional study in vitro was performed to further confirm the pathogenicity of the variant. FH-Wild type (FH-WT) and FH-mutant (FH-MUT) (E378K) plasmid were constructed and transfected into 293T and uterine leiomyoma cell lines, respectively. Proliferation assessment was executed to show how this mutation affects the growth of uterine leiomyoma. qPCR and Western blotting were performed to investigate the change of transcription and translation of FH with mutation (E378K), and FH enzyme assay activity were tested in 293T cells with mutation and wild-type plasmids. Here, we presented two families with the same missense variant (c.1132G > A) that has not been reported as a germline mutation in hereditary uterine leiomyomas before and classified as VUS in gene databases. Our in vitro experiments supported the pathogenicity of this missense variant, especially in uterine leiomyomata. According to the American College of Medical Genetics (ACMG) guideline, the E378K variant was classified as likely pathogenic (with evidence PS4_support, PS3_support, PM2_support, PP1, PP3 and PP4 evidence). Further insights into clinical management in uterine leiomyomata were discussed and should be practiced in gynecological clinical settings.

Variants of Fumarate Hydratase Gene in Uterine Disorders: A Clinical Trial

Objective: The dysregulation of metabolism is a hallmark of cancer. Enzymes of tricarboxylic acid (TCA) cycle have a key role in pathogenesis of carcinogenesis as oncometabolits. The variants in fumarate hydratase (FH) gene have been linked to sporadic tumors and familial tumor propensity. To asses the prevalence of variants in the FH gene in endometrial carcinoma (EC) and uterine leiomyomas (UL). Material and Methods: This prospective study included 58 patients with EC and 44 with UL. The FH gene variants were analyzed in the DNA samples collected from peripheral circulation. All exons of the FH gene were replicated by polymerase chain reaction utilizing specific primers including intron-exon boundaries and than was sequenced with Sanger method. Results: Only two variants were detected in two different patients. The c.927G>A (p.Pro309Pro) and c.63C>T (p.Ala21Ala) variants were observed in patients with UL, EC respectively. c.927G>A (p.Pro309=) and c.63C>T (p.Ala21=) are rare variants inside the overall population with allele frequency ranges of 0.02428, 0.000014 respectively. Conclusion: The contribution of variants in genes encoding the TCA cycle enzymes in tumor cells has provided understanding fundamental role on metabolic alterations in carcinogenesis. Further studies are needed to discover the novel tumor mutations and identify appropriate treatment.

Wild soybean salt tolerance metabolic model: Assessment of storage protein mobilization in cotyledons and C/N balance in the hypocotyl/root axis.

Salt stress has become one of the main factors limiting crop yield in recent years. The post-germinative growth is most sensitive to salt stress in soybean. In this study, cultivated and wild soybeans were used for an integrated metabonomics and transcriptomics analysis to determine whether wild soybean can resist salt stress by maintaining the mobilization of stored substances in cotyledons and the balance of carbon and nitrogen in the hypocotyl/root axis (HRA). Compared with wild soybean, the growth of cultivated soybean was significantly inhibited during the post-germinative growth period under salt stress. Integrating analysis found that the breakdown products of proteins, such as glutamate, glutamic acid, aspartic acid, and asparagine, increased significantly in wild soybean cotyledons. Asparagine synthase and fumarate hydratase genes and genes encoding HSP20 family proteins were specifically upregulated. In wild soybean HRA, levels of glutamic acid, aspartic acid, asparagine, citric acid, and succinic acid increased significantly, and the glutamate decarboxylase gene and the gene encoding carbonic anhydrase in nitrogen metabolism were significantly upregulated. The metabolic model indicated that wild soybean enhanced the decomposition of stored proteins and the transport of amino acids to the HRA in cotyledons and the GABA shunt to maintain carbon and nitrogen balance in the HRA to resist salt stress. This study provided a theoretical basis for cultivating salt-tolerant soybean varieties and opened opportunities for the development of sustainable agricultural practices.

The Exiguous Imetus-Fumarate Hydratase Deficient Renal Cell Carcinoma

Fumarate hydratase deficient renal cell carcinoma is an exceptionally discerned neoplasm which arises on account of germline mutations within fumarate hydratase (FH) gene. Commonly, clinical manifestations as non-renal leiomyomatosis may concur. Neoplasm is associated with autosomal dominant mode of disease transmission. Neoplasm may configure as a high grade, infiltrative lesion comprised of papillary articulations or solid sheets of neoplastic cells. Characteristically, tumour cells nuclei are pervaded with inclusion-like nucleoli and demonstrate peri-nucleolar clearing. Neoplasm arises on account of oncogenesis triggered due to metabolic inconsistencies emerging as a consequence of defective fumarate hydratase enzyme. The high grade, infiltrative neoplasm articulating papillary structures or solid sheets is comprised of tumour cells incorporated with prominent cytomegalovirus (CMV)-like nucleolar inclusions and foci of peri-nucleolar clearing. Neoplastic cells manifest overexpression and immunoreactivity to modified cysteine (2SC) along with decimation of fumarate hydratase enzyme.

Uterine Leiomyoma with Bizarre Nuclear Morphology: Report of a Rare Case

Abstract Introduction/Objective Sporadic fumarate hydratase (FH)-deficient leiomyoma occurs as a result of somatic inactivation of the FH gene and has been found to represent 1% of uterine leiomyomas. Germline inactivation of the FH gene is associated with a rare autosomal dominant syndrome known as hereditary leiomyomatosis and renal cell carcinoma (HLRCC). Women with HLRCC develop cutaneous and uterine leiomyomas and an aggressive renal cell carcinoma, with 57% reported to undergo hysterectomy at 30 years of age or younger. All FH-deficient leiomyomas display a distinct histology characterized by scattered bizarre nuclei, eosinophilic cytoplasmic inclusions, conspicuous eosinophilic nucleoli, and perinuclear clearing. Immunohistochemically, the neoplastic cells do not express FH while they are positive for S-(2-succino)-cysteine (2SC), a metabolite that accumulates when FH is inactivated. Methods/Case Report We present a 48-year-old woman who underwent supracervical hysterectomy for a symptomatic uterine leiomyoma. She was status post left salpingo-oophorectomy for left adnexal endometriosis. Grossly, the hysterectomy specimen was significant for one 8.0 cm intramural uterine corpus tumor with a tan-white whorled cut surface. Histology showed a smooth muscle neoplasm in the myometrium composed of spindled cells with abundant eosinophilic cytoplasm, occasional enlarged prominent nucleoli with perinuclear halos, intracytoplasmic eosinophilic globules, focal bizarre nuclear atypia and thin-walled staghorn vessels with widespread hyaline necrosis with no mitotic activity. Immunohistochemical studies demonstrated that the neoplastic cells expressed desmin, SMA, SMMH, and 2SC and were negative for FH; consistent with a FH-deficient leiomyoma. Results (if a Case Study enter NA) NA Conclusion Although rarely seen, pathologists should be cognizant of FH-deficient neoplasms. Genetic counseling and close follow up of the individuals harboring germline inactivating mutations of the FH gene could lead to early detection of the RCC in these patients and their family members.

FUMARASE DEFICIENCY CARRIERS AND ITS EFFECT ON INFERTILITY

Fumarase deficiency (FD) is an autosomal recessive condition characterized by severe neurologic abnormalities due to homozygous pathogenic variants in the fumarate hydratase (FH) gene. Heterozygous carriers of FH mutations have an increased risk of developing uterine leiomyomas. There is limited data regarding the infertility diagnoses and treatment outcomes of patients with FH mutations. Therefore, the objective of our study was to characterize the incidence, infertility diagnoses, treatments, and outcomes of women presenting to our fertility center who were found to be carriers of FH mutations.

Reed’s syndrome: a combination of a renal cyst with leiomyoma of the skin and uterus (clinical observation)

Multiple cutaneous and uterine leiomyomatosis (MCUL), also known as Reeds syndrome, is a rare genodermatosis, with an autosomal dominant pattern of inheritance. It results from a germline heterozygous mutation of fumarate hydratase gene, that is classified as a tumor suppressor gene. Hereditary leiomyomatosis and renal cell cancer is characterized by the association of multiple cutaneous and uterine leiomyomatosis with renal cell carcinoma. The diagnosis of multiple leiomyomas is based on the identification of morphological characteristic rashes (small, oval, red-brown or flesh-colored nodules located around the hair follicles, often painful) and is confirmed by the method of pathomorphological examination. Treatment of leiomyomas depends on their number, size, area of skin lesion and severity of subjective symptoms. With single rashes, surgical excision of the largest and most painful elements is possible, with severe pain syndrome ― calcium channel blockers, alpha-blockers and gabapentin. Cryotherapy, diathermocoagulation, and laser ablation with a carbon dioxide laser are used to destroy the nodes.
 The presence of cutaneous leiomyomas in patients dictates the need for careful collection of anamnesis, including family and obstetric-gynecological, conducting a full-fledged clinical, laboratory and instrumental examination and consulting by related specialists. Annual screening for early detection and therapy of renal cell carcinoma is also mandatory.
 Due to the existing probability of the hereditary nature of Reeds syndrome, a thorough examination of the patients relatives is necessary.
 We report a case of a 58-year-old woman with Reeds syndrome: multiple cutaneous leiomyomas, uterine leiomyoma and renal cysts.

Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma.

Fumarate hydratase (FH) - deficient renal cell carcinoma (FHdRCC) is a rare aggressive subtype of RCC caused by a germline or sporadic loss-of-function mutation in the FH gene. Here, we summarize how FH deficiency results in the accumulation of fumarate, which in turn leads to activation of hypoxia-inducible factor (HIF) through inhibition of prolyl hydroxylases. HIF promotes tumorigenesis by orchestrating a metabolic switch to glycolysis even under normoxia, a phenomenon well-known as the Warburg effect. HIF activates the transcription of many genes, including vascular endothelial growth factor (VEGF). Crosstalk between HIF and epidermal growth factor receptor (EGFR) has also been described as a tumor-promoting mechanism. In this review we discuss therapeutic options for FHdRCC with a focus on anti-angiogenesis and EGFR-blockade. We also address potential targets that arise within the metabolic escape routes taken by FH-deficient cells for cell growth and survival.

Fumarate hydratase gene germline variants and mosaicism associated with pheochromocytoma and paraganglioma.

Fumarate hydratase (FH) catalyzes the conversion of fumaric acid to L-malic acid. Heterozygous variants of the human fumarate hydratase gene (FH) predispose to hereditary leiomyomatosis and renal cell cancer and, rarely, pheochromocytoma/paraganglioma (PPGL). No mosaic variant in FH has been reported yet. Using next-generation sequencing, five individuals with FH variants were found in 319 PPGL patients. Immunohistochemistry staining and loss of heterozygosity analysis in tumor tissues were performed to determine the pathogenicity of the variants. Deep targeted sequencing was performed on the peripheral blood DNA of a pheochromocytoma (PCC) patient with uterine leiomyomas. Finally, two of the five variants were found to be pathogenic. A germline variant (c.817G>A, p.Ala273Thr) was found in a patient with a PPGL family history. A mosaic variant (c.206G>A, p.Gly69Asp) with an allelic ratio of 5% in blood DNA was confirmed in the PCC patient with uterine leiomyomas. No metastatic PPGL was observed in the two PPGL patients with FH pathogenic variants. In summary, we report mosaicism in FH and the first PPGL pedigree with an FH pathogenic germline variant. Both germline variantsand mosaicism should be taken into account during genetic testing.

Abstract 3112: Metabolic hallmarks of rare renal cell carcinoma patient-derived xenograft models

Abstract Renal medullary carcinoma (RMC) and fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) are rare but highly aggressive malignancies that are often refractory to the therapies used for the more common RCCs. FH-deficient RCC most often occurs in individuals with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) and is characterized by loss of FH activity, a key metabolic enzyme. Bevacizumab plus erlotinib (B+E) is a preferred first-line therapy for FH-deficient RCC. RMC is characterized by loss of SMARCB1, which is involved in ATP-dependent chromatin remodeling. Platinum-based chemotherapy consisting of either cisplatin or carboplatin plus paclitaxel is the preferred first-line therapy for RMC. We developed patient-derived xenograft (PDX) models of tumors exposed to the commonly used first-line therapies to allow functional characterization of the metabolic hallmarks of treatment-experienced RMC and FH-deficient RCC. Methods: Resected tumor tissue was immediately implanted into NSG male and female mice. After tumor engraftment, animals were euthanized, and the tumor tissue implanted into another set of NSG mice. PDX tissues were confirmed to be genetically identical to the original patient tissue by short tandem repeat analysis. Histology was confirmed to be identical between original patient tumor and PDX by a trained clinical pathologist. Four tumors from each PDX model and four normal human kidney tissue samples were analyzed using reverse phase protein array (RPPA). Expression of proteins shown to be highly expressed by RPPA were further validated by Western blots. Results: We successfully generated one PDX model for RMC and one for FH-deficient RCC, respectively. The RMC model was generated from a 28-year old male with sickle cell trait, who had previously received cisplatin plus paclitaxel followed carboplatin plus paclitaxel. His lesion was characterized as ypT3apN1pMx and histology was consistent with RMC. The FH-deficient RCC model was generated from a 24-year-old female with HLRCC, who had been previously treated with B+E. Her lesion was characterized as pT3apN1pM1 and histology consistent with FH-deficient RCC. Germline testing revealed a R233H pathogenic mutation in the FH gene. RPPA revealed higher expression of hexokinase II (10x HLRCC, 16x RMC), lactate dehydrogenase A (27x HLRCC, 17x RMC), and glutaminase (4x HLRCC) in PDX tissue compared to normal kidney tissue. Western blots confirmed higher expression of glutaminase 1 in both HLRCC and RMC compared to normal kidney. Furthermore, we observed substantially higher hypoxia inducible factor 2α (HIF2α) protein expression in PDX tissue from FH-deficient RCC compared to RMC PDX tumors and normal kidney. Conclusions: Our study revealed distinct metabolic features in PDX models of FH-deficient RCC following treatment with B+E, and of platinum-experienced RMC, these differences may confer targetable vulnerabilities. Citation Format: Manuel Ozambela, Alberto Pieretti, Graciela M. Nogueras Gonzalez, Tapati Maity, Lei Wang, Carolyn De La Cerda, Breanna Alonzo, Luis Segarra, Angelita Alaniz, Priya Rao, Nizar Tannir, Jose A. Karam, Christopher G. Wood, Pavlos Msaouel, Niki M. Zacharias. Metabolic hallmarks of rare renal cell carcinoma patient-derived xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3112.

Clinicopathological and molecular characteristics of fumarate hydratase–deficient uterine smooth muscle tumors: a single-center study of 52 cases

The fumarate hydratase (FH) gene germline mutations cause hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), predisposing carriers to uterine and cutaneous leiomyomas and renal cell carcinoma. In this study, we aim to investigate morphology and the correlation between FH mutation in FH-deficient (FH-d) uterine smooth muscle tumors (uSMTs). We conducted immunohistochemical staining in 161 cases of uSMTs to detect FH deficiency. We identified 52 cases (52/161, 32%)of FH-d, including 34 leiomyomas with bizarre nuclei, 10 uSMTs of uncertain malignant potential (STUMPs), 4 cellular leiomyomas, 3 usual type leiomyomas, and 1 leiomyosarcoma. Patients with FH-d were aged 24-67 years (median, 40 years). The most common FH-d morphological features included staghorn-shaped blood vessels (87%), bizarre nuclei (81%), alveolar pattern edema (65%), macronucleoli surrounded by a halo (65%), cytoplasmic eosinophilic globules (56%), and chain-like distribution of smooth muscle cells (52%). A targeted next-generation sequence was performed in 11 of 52 FH-d tumors. Five cases (5/11, 45%) were found with FH germline mutations, including 4 leiomyomas with bizarre nuclei and 1 STUMP. The median age of patients with germline FH mutation was 30 years. The germline mutations included 3 pathogenic, 1 likely pathogenic, and 1 rare uncertain clinical significance variants. Our results revealed that FH-d uSMTs usually exhibit the distinct morphology features and high frequency of FH germline mutations. The combination of predictive morphology evaluation, FH immunotype, and molecular testing is helpful for the screening of HLRCC in uSMTs.

Approach for reclassification of collecting duct carcinoma and comparative histopathological analysis with SMARCB1/INI1-deficient renal cell carcinoma and fumarate hydratase-deficient renal cell carcinoma

Collecting duct carcinoma (CDC) is a rare subset of high-grade renal cell carcinoma (RCC). To diagnose CDC, it is necessary to rule out other renal tumors including renal medullary carcinoma and fumarate hydratase (FH)-deficient RCC. However, there is overlap in the morphology of these three tumors, which all have poor outcomes. There is also still a need to sufficiently examine the therapeutic strategies for each of these tumors. In this study, we retrospectively reclassified invasive/infiltrating high-grade RCC and investigated its pathological features. We reviewed 18 cases previously diagnosed as "CDC," "FH-deficient RCC," and "unclassified RCC," which were reclassified as SMARCB1/INI1-deficient RCC, FH-deficient RCC, and CDC by SMARCB1/INI1, FH, and 2SC immunohistochemistry (IHC) and FH gene mutational status. As the result, 18 cases were reclassified into 2 cases of SMARCB1/INI1-deficient RCC, 7 cases of FH-deficient RCC, and 9 cases of CDC. The morphological features of each group overlapped, and no specific immunohistochemical expression except for SMARCB1/INI1, FH, and 2SC was detected. These results suggest that invasive/infiltrating high-grade RCC should be diagnosed by the combination of immunohistochemistry and molecular biological technique.

Hereditary leiomyomatosis and renal cell carcinoma syndrome-associated renal cell carcinoma: A case report

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome-associated renal cell carcinoma (RCC) is a rare but significant diagnosis due to the need to genetically screen close family members and its aggressive behaviour.1 Patients with HLRCC syndrome carry a germline mutation of the Fumarate Hydratase (FH) gene, resulting in accumulation of fumarate. Other manifestations of this syndrome include uterine leiomyomas.2

Reed Syndrome in Eighteen Patients: A Genodermatosis Where Piloleiomyomas May Be the Diagnostic Clue

Introduction: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is caused by germline heterozygous mutations of the fumarate hydratase (FH) gene. Materials and Methods: A retrospective observational study was conducted, aimed at characterizing the clinical features, histopathology, and genetic mutations in eighteen patients with confirmed HLRCC diagnosis. Results: FH gene mutations were identified in the seven families studied, including a previously undescribed mutation. All index cases of the families included were suspected on skin manifestations. Thirteen of the 18 patients (72%) presented cutaneous leiomyomas. The chief complaint was pain, with complete but transient response to botulinum toxin in one. No evidence of malignant transformation was observed. Uterine leiomyomas were present in seven of the eight women studied (88%). There was no evidence of renal cell carcinoma in any of the patients in the study. The most frequently found mutations were missense type (43%), followed by large rearrangements (24%), intronic deletions (14%) and nonsense (14%). A novel mutation not previously described in the literature is presented. Conclusions: HLRCC is a rare disease but it is also probably underdiagnosed. Dermatologists have an essential role in its diagnosis, by recognizing the clinical characteristics of the syndrome and investigating the family history.

Different Fumarate Hydratase Gene Variants Are Associated With Distinct Cancer Phenotypes.

Whether individuals with monoallelic FH pathogenic variants (PVs) associated with autosomal recessive fumarate hydratase (FH) deficiency are also at risk of autosomal dominant FH-associated tumors is of paramount clinical importance. A retrospective study of individuals with a PV in the FH gene identified via multigene panel testing from 2012 to 2019 through a single testing laboratory was performed. Cancer histories of individuals with PVs in FH (FH PV) were compared to those with PVs associated only with autosomal recessive FH deficiency (FH-d PV) and to FH-negative controls. Cancer histories of individuals with truncating versus nontruncating FH PV were also compared. Individuals with FH PV were more likely to have kidney cancer than those with FH-d PV (odds ratio, 9.0; 95% CI, 4.4 to 20.0; P < .001) or FH-negative controls (odds ratio, 7.6; 95% CI, 5.2 to 11.2; P value < .001). The FH PV cohort had kidney cancer at a significantly younger age (median age: 35.0 years; interquartile range, 26.0-45.0 years) than the FH-d PV cohort (median age: 44.5 years; interquartile range, 43.5-53.5 years; P = .011). Within the FH PV cohort, there were no differences in the frequency or age at kidney cancer between those with truncating versus nontruncating PV. Unlike FH PV, FH-d PV are not associated with kidney cancers at early ages of onset. The FH-d PV cohort had a cancer phenotype that resembled FH-negative controls. These data may inform genetic counseling and risk assessment of individuals with FH-d PV.

The Gynecologist's Role in the Workup and Management of Patients with Leiomyomas Demonstrating Fumarate Hydratase Deficiency

Study Objective Fumarate hydratase (FH) tumor predisposition syndrome or hereditary leiomyomatosis renal cell cancer (HLRCC) is caused by an autosomal-dominant heterozygous mutation in the FH gene. It is characterized by uterine or cutaneous leiomyomas and renal tumors. Timely diagnosis of HLRCC allows for cancer surveillance. Yet, delays in diagnosis are common in patients with isolated uterine findings. Given that leiomyomas are the most common benign tumors in reproductive-aged women, gynecologists are in an opportunistic position to detect HLRCC earlier. In this series, we present three patients with FH-deficient leiomyomas, and review the gynecologist's unique role in screening, workup, and diagnosis of HLRCC. Design Case Series. Setting Academic institution. Patients or Participants Three patients. Interventions Surgery and genetic screening. Measurements and Main Results Case 1 A 33-year-old with heavy menstrual bleeding and an 18cm uterine lesion presents for abdominal myomectomy. Pathological evaluation was suggestive of FH-deficient leiomyoma, which was confirmed by immunohistochemistry (IHC). She was lost to follow up. Case 2 A 32-year-old with pelvic pain, infertility, and a submucosal fibroid presents for robotic myomectomy. Pathology and IHC confirmed a diagnosis of FH-deficient leiomyoma. Genetic testing for FH mutation was negative. Case 3 A 52-year-old with adenomyosis unresponsive to conservative management presents for hysterectomy. Pathological evaluation was suggestive of FH-deficient leiomyoma, however IHC did not support this diagnosis. Genetic testing was negative. Conclusion HLRCC presents with a variation of phenotypes ranging from leiomyomas to metastatic renal cell carcinoma. Our cases underscore the gynecologist's unique role in the diagnosis of HLRCC. The majority of uterine fibroids are not associated with an increased risk malignancy. FH-deficient leiomyomas can occur in both syndromic and sporadic settings. A thorough history can identify patients at risk. Characteristic histopathological features should prompt genetic evaluation. Management requires a multidisciplinary approach and surveillance can be offered to individuals with even a suspected diagnosis in whom an FH mutation has not been identified. Fumarate hydratase (FH) tumor predisposition syndrome or hereditary leiomyomatosis renal cell cancer (HLRCC) is caused by an autosomal-dominant heterozygous mutation in the FH gene. It is characterized by uterine or cutaneous leiomyomas and renal tumors. Timely diagnosis of HLRCC allows for cancer surveillance. Yet, delays in diagnosis are common in patients with isolated uterine findings. Given that leiomyomas are the most common benign tumors in reproductive-aged women, gynecologists are in an opportunistic position to detect HLRCC earlier. In this series, we present three patients with FH-deficient leiomyomas, and review the gynecologist's unique role in screening, workup, and diagnosis of HLRCC. Case Series. Academic institution. Three patients. Surgery and genetic screening. Case 1 A 33-year-old with heavy menstrual bleeding and an 18cm uterine lesion presents for abdominal myomectomy. Pathological evaluation was suggestive of FH-deficient leiomyoma, which was confirmed by immunohistochemistry (IHC). She was lost to follow up. Case 2 A 32-year-old with pelvic pain, infertility, and a submucosal fibroid presents for robotic myomectomy. Pathology and IHC confirmed a diagnosis of FH-deficient leiomyoma. Genetic testing for FH mutation was negative. Case 3 A 52-year-old with adenomyosis unresponsive to conservative management presents for hysterectomy. Pathological evaluation was suggestive of FH-deficient leiomyoma, however IHC did not support this diagnosis. Genetic testing was negative. HLRCC presents with a variation of phenotypes ranging from leiomyomas to metastatic renal cell carcinoma. Our cases underscore the gynecologist's unique role in the diagnosis of HLRCC. The majority of uterine fibroids are not associated with an increased risk malignancy. FH-deficient leiomyomas can occur in both syndromic and sporadic settings. A thorough history can identify patients at risk. Characteristic histopathological features should prompt genetic evaluation. Management requires a multidisciplinary approach and surveillance can be offered to individuals with even a suspected diagnosis in whom an FH mutation has not been identified.

Uterine leiomyomas in hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome can be identified through distinct clinical characteristics and typical morphology.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) constitute a tumor susceptibility syndrome caused by germline mutations in the fumarate hydratase (FH) gene. The most common features are leiomyomas of the uterus and the skin. The syndrome includes a predisposition to early-onset, aggressive renal cell cancer. It is important to identify women with HLRCC among other uterine leiomyoma patients in order to direct them to genetic counseling and to identify other affected family members. We conducted a nationwide historical study to identify typical clinical characteristics, uterine leiomyoma morphology, and immunohistochemistry for diagnosing HLRCC. The study included 20 women with a known FH germline mutation and 77 women with sporadic uterine leiomyomas. The patient records of all women were reviewed to obtain clinical details regarding their leiomyomas. Uterine leiomyoma tissue specimens from 43 HLRCC-related leiomyomas and 42 sporadic leiomyomas were collected and prepared for histology analysis. A morphologic description was performed on hematoxylin & eosin-stained tissue slides, and immunohistochemical analysis was carried out for CD34, Bcl-2, and p53 stainings. The women with HLRCC were diagnosed with uterine leiomyomas at a young age compared with the sporadic leiomyoma group (mean 33.8years vs. 45.4years, P<0.0001), and their leiomyomas occurred as multiples compared with the sporadic leiomyoma group (more than four tumors 88.9% vs. 30.8%, P<0.0001). Congruently, these women underwent surgical treatment at younger age compared with the sporadic leiomyoma group (mean 37.3years vs. 48.3years, P<0.0001). HLRCC leiomyomas had denser microvasculature highlighted by CD34 immunostaining when compared with the sporadic leiomyoma group (112.6mean count/high-power field, SD 20.8 vs. 37.4 mean count/high-power field, SD 21.0 P<0.0001) and stronger anti-apoptotic protein Bcl-2 immunostaining when compared with the sporadic leiomyoma group (weak 4.7%, moderate 44.2%, strong 51.2% vs. 26.2%, 52.4%, 21.4%, respectively, P=0.003). No differences were observed in p53 staining. Women with HLRCC may be identified through the distinct clinical characteristics: symptomatic and numerous leioymyomas at young age, and morphologic features of FH-mutant leiomyomas, aided by Bcl-2 and CD34 immunohistochemistry. Further, distinguishing individuals with a germline FH mutation enables proper genetic counseling and regular renal monitoring.

Hereditary leiomyomatosis and renal cell cancer (HLRCC): Case series and review of the literature

BackgroundHereditary leiomyomatosis and renal cell cancer (HLRCC) is an autosomal dominant syndrome caused by heterozygous pathogenic germline variants in the fumarate hydratase (FH) gene. It is characterized by cutaneous and uterine leiomyomas and an increased risk of developing renal cell carcinoma (RCC). HLRCC-related RCC tends to be aggressive. To date, only a few publications have described HLRCC-related RCC, and the clinical, morphological and molecular aspects of HLRCC-related RCC need to be further studied. MethodsWe retrospectively analyzed the clinical and pathological data of 3 patients with HLRCC recently diagnosed. Immunohistochemistry and Whole-exome sequencing was performed on 3 patients. The function of the DNA variant was predicted in silico. ResultsWe reported 3 patients from unrelated Chinese families, with HLRCC-related RCC and identified 3 different germline FH mutations (2 missense and 1 nonsense). A novel missense mutation of FH gene (c.454A>G, p.N152D) was predicted to be probably pathogenic and deleterious by multiple protein function predicting software. This study indicated that the novel mutation may be responsible for the occurrence of HLRCC-related RCC. 100% (2/2) female RCC patients had uterine fibroids. No cutaneous manifestations were identified. ConclusionWe indicate that germline screening should be encouraged in early-onset patients. Clinicopathological data, such as family history and immunohistochemical results can provide valuable clinical information for the differential diagnosis of HLRCC-associated RCC in advance.

FH-deficient renal cell carcinoma expands the spectrum of renal papillary tumors

Das Fumarat-Hydratase(FH)-defiziente Nierenzellkarzinom (NZK) ist eine distinkte Entität, welche eine biallelische Inaktivierung des FH-Gens zeigt, die konsekutiv mit einem Expressions- bzw. Funktionsverlust des FH-Proteins einhergeht. Diese Alteration führt zu einer Akkumulation des Onkometaboliten Fumarat im Citratzyklus und vielfältigen Störungen des Zellhaushaltes und der DNA-Prozessierung. Das FH-defiziente NZK zeigt häufig ein morphologisch überlappendes Spektrum mit papillären NZK (Typ 2), wobei typischerweise ein Wechsel verschiedener Wachstumsmuster inkl. tubulozystischer, kribriformer und/oder solider Differenzierung zu beobachten ist. Eine typische, jedoch nicht spezifische morphologische Eigenschaft sind die prominenten eosinophilen, Viruseinschlußkörperchen-artigen Nukleolen mit perinukleolärem Halo. Der immunhistochemische Verlust der FH-Expression untermauert die Diagnose, kann in seltenen Fällen jedoch erhalten sein. Zumeist zeigen FH-defiziente NZK ein sehr aggressives biologisches Verhalten mit oftmalig primärer Metastasierung bei Diagnosestellung. Die initiale Beschreibung erfolgte als NZK in Assoziation mit dem Hereditären-Leiomyomatose-und-Nierenzellkarzinom(HLRCC)-Syndrom, welches zusätzlich kutane und uterine Leiomyome umfasst. Aktuelle Daten zeigen jedoch auch einen steigenden Anteil an sporadischen Fällen, sodass eine Unterscheidung (hereditär vs. sporadisch) angemessen erscheint. Bisher sind wenige, aber vielversprechende Daten bezüglich wirksamer systemischer therapeutischer Optionen beschrieben. Zusammenfassend ist eine korrekte Diagnose aufgrund des typischerweise biologisch aggressiven Verhaltens, gegebenenfalls vom Standard abweichender therapeutischer Optionen und möglichem Indikator einer hereditären Erkrankung von großer Bedeutung.

Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient’s family was advised to undergo genetic counseling to consider additional RCC screening.