Case report: response to immunotherapy and association with the fh gene in hereditary leiomyomatosis and renal cell cancer-associated renal cell cancer.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal dominant syndrome caused by a germline mutation in the fumarate hydratase (FH) gene that manifests with cutaneous leiomyomas, uterine fibroids, and renal cell cancer (RCC). Patients with HLRCC-associated RCC (HLRCC-RCC) have aggressive clinical courses, but there is no standardized therapy for advanced HLRCC-RCC. In this study, we described a case of aggressive HLRCC in a 33-year-old female who exhibited a novel heterozygous germline insertion mutation in exon 8 of the FH gene (c.1126 C > T; p.Q376*). The patient underwent laparoscopic resection of the right kidney, but metastases appeared within 3 months after surgery. Histological staining of the resected tumor revealed high expression levels of programmed cell death-ligand 1 (PD-L1). Therefore, the patient was treated with immunotherapy. The patient achieved a partial response to immunotherapy, and the treatment of metastatic lesions has continued to improve. A thorough literature review pinpointed 76 historical cases of HLRCC-RCC that had undergone immunotherapy. From this pool, 46 patients were selected for this study to scrutinize the association between mutations in the FH gene and the effectiveness of immunotherapy. Our results indicate that immunotherapy could significantly improve the overall survival (OS) of patients with HLRCC-RCC. However, no influence of different mutations in the FH germline gene on the therapeutic efficacy of immunotherapy was observed. Therefore, our study suggested that immunotherapy was an effective therapeutic option for patients with HLRCC regardless of the type of FH germline mutation.

The use of Clinicopathological, immunohistochemistry and molecular detection in the diagnosis of fumarate hydratase-deficient uterine leiomyomas.

BACKGROUND: Fumarate hydratase-deficient uterine leiomyomas (FH-dUL) are rare, accounting for only 0.4-1.6% of uterine leiomyomas. FH germline mutation gene is associated with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC). METHODS: In this study, we aim to investigate Clinicopathological features and FH mutation in FH-dUL. We performed a retrospective analysis of 300 cases of uterine leiomyoma, diagnosed from January 2017 to December 2021, within the archives of the Department of Pathology at Peking University People's Hospital. In our review of the immunohistochemical(IHC) staining was performed on 300 uSMTs to detect FH deficiency. RESULTS: We identified 21cases (21/300,7%) of FH-dUL. Nineteen cases (6.33%) displayed negative FH. Twenty-one cases (7%) displayed 2SC diffuse plasma and nuclear staining. The most common FH-d morphological features included staghorn vasculature ( 100%,21/21), alveolar-pattern oedema (71.43%, 15/21), scattered bizarre nuclei (23.81%, 5/21), eosinophilic cytoplasmic (rhabdoid) inclusions (47.62%, 10/21), significant eosinophilic nucleolus with peri-nucleolus hollowing (23.81%, 5/21), ovoid nuclei sometimes arranged in chains (9.52%, 2/21). DNA sequencing for the 21 cases was performed using Next Generation Sequencing (NGS). 6 cases were detected significant variations for the FH gene, 11 cases were detected FH gene mutation forvariants of uncertain significance (VUS), and 2 cases were detected a TP53 gene mutation. No related mutations were detected in the other two cases. CONCLUSIONS: FH-dUL is rare. The combination of predictive Clinicopathological evaluation,FH and 2SC IHC test, and molecular test were helpful for the screening of FH-dUL from uSMTs,or even the screening of HLRCC.

A new missense mutation c.1240A>G in fumarate hydratase gene leads to uterine leiomyoma associated hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome in Chinese.

OBJECTIVE: This study presents a detailed analysis of the clinical and genetic characteristics of uterine leiomyoma associated with Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC), combined with exploration of family history, pathology, and management procedures, supported by thorough evidence collection. METHODS: Blood samples were collected from the proband, and the pathogenic variant was verified using Sanger sequencing. A comprehensive review of family history, FH deficiency pathology, FH and 2SC immunohistochemistry staining was conducted. Functional evidence was derived from clinical and genetic information, supplemented by a literature collection and mutation was reclassified based on ACMG/AMP guidelines. RESULTS: The study successfully identifies a novel missense mutation (c.1240A>G; p.Lys414Glu) in exon 9 of FH, with no prior reports in existing databases. The patient's phenotype and family history, coupled with evidence collected from the literature, contribute to the preliminary determination of the variant as likely pathogenic. We also emphasize that the importance of combining FH-deficient morphology and immunohistochemical staining with 2SC for enhanced sensitivity. CONCLUSION: This research adds a novel missense mutation to the repertoire of FH gene variants, emphasizing its likely pathogenic nature based on a multidimensional analysis of phenotype, family history, and literature evidence. The findings enhance our understanding of the genetic landscape associated with FH and underscore the importance of thorough characterization for accurate variant classification.

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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Fumarate hydratase-deficient renal cell carcinoma in extended remission with bevacizumab and erlotinib.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant syndrome associated with fumarate hydratase (FH) gene mutation leading to defective DNA double-strand break repair mechanism. Although these tumours have an aggressive presentation, they respond well to targeted therapy with fewer adverse effects. Here we present a case of a 42-year-old female having isolated renal cell carcinoma, papillary type 2, carrying a mutation in the FH gene without cutaneous and uterine involvement. Her tumour responded well to erlotinib and bevacizumab combination and she was on treatment for 23 months. This report adds to the current literature and can help to define treatment protocols for HLRCC.

Fumarase Deficiency: A Case With a New Pathogenic Mutation and a Review of the Literature.

Fumarase deficiency (FD) is a rare and severe autosomal disorder, caused by inactivity of the enzyme fumarase, due to biallelic mutations of the fumarase hydratase (FH) gene. Several pathogenic mutations have been published. The article describes an infant with failure to thrive, microcephaly, axial hypotonia, and developmental retardation with increased excretion of fumarate, no activity of fumarase and a homozygous mutation of the FH gene, which was until recently only known as a variant of unknown significance. Carriers of pathogenic mutations in the FH gene are at risk for developing renal cell carcinoma and should therefore be screened. Both parents were healthy carriers of the mutation and had decreased levels of enzyme activity. In addition, the article presents an overview and analysis of all cases of FD reported thus far in the literature.

Paraganglioma of the organ of Zuckerkandl and FH gene mutation.

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Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.