{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T15:43:09Z","timestamp":1789486989345,"version":"build-2803163510"},"reference-count":29,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>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 \u00b1 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&gt;G, p.(Ser145Ter) and c.1256C&gt;G, p.(Ser419Ter)], and one (5.9%) had a variant of uncertain significance (VUS) [c.1090G&gt;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.<\/jats:p>","DOI":"10.3390\/diagnostics16182985","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:33:42Z","timestamp":1789479222000},"page":"2985","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Fumarate Hydratase-Deficient Uterine Leiomyomas: Germline Genetic Findings and Clinical Follow-Up in a Single-Center Cohort"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3818-7945","authenticated-orcid":false,"given":"Nisan Helin","family":"Donmez","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0872-3898","authenticated-orcid":false,"given":"Elif","family":"Yilmaz Gulec","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Faculty of Medicine, Istanbul Medeniyet University, Istanbul 34730, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0837-3146","authenticated-orcid":false,"given":"Hanne","family":"Bulat Cim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2326-1387","authenticated-orcid":false,"given":"Beg\u00fcm Sinem","family":"Kezer Cingoz","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-1292","authenticated-orcid":false,"given":"Melis","family":"Altug Inan","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emine","family":"Bolukbasi Karapinar","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Prof. Dr. S\u00fcleyman Yal\u00e7\u0131n City Hospital, Istanbul 34722, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4448-3863","authenticated-orcid":false,"given":"Ergul","family":"Demircivi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Istanbul Medeniyet University, Istanbul 34730, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canan","family":"Satir Ozel","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Istanbul Medeniyet University, Istanbul 34730, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3156-2116","authenticated-orcid":false,"given":"Abdulkadir","family":"Turgut","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Faculty of Medicine, Istanbul Medeniyet University, Istanbul 34730, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1002\/ijgo.70527","article-title":"The epidemiology and pathogenesis of uterine fibroids","volume":"171","author":"Munro","year":"2025","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.2147\/IJWH.S444069","article-title":"Fumarate hydratase-deficient leiomyoma with double mutation sites in the FH gene: A rare case report and literature review","volume":"16","author":"Wei","year":"2024","journal-title":"Int. J. Womens Health"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/cdd.2016.137","article-title":"Fumarate drives EMT in renal cancer","volume":"24","author":"Sciacovelli","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1038\/s41416-023-02412-w","article-title":"Fumarate hydratase (FH) and cancer: A paradigm of oncometabolism","volume":"129","author":"Frezza","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Giallongo, S., Costa, F., Longhitano, L., Giallongo, C., Ferrigno, J., Tropea, E., Vicario, N., Li Volti, G., Parenti, R., and Barbagallo, I. (2023). The pleiotropic effects of fumarate: From mitochondrial respiration to epigenetic rewiring and DNA repair mechanisms. Metabolites, 13.","DOI":"10.3390\/metabo13070880"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"D\u2019Indinosante, M., Lardino, S., Bruno, M., Stabile, G., Pavone, M., Giannone, G., Lombardi, P., Daniele, G., Fanfani, F., and Ciccarone, F. (2025). Implications of fumarate hydratase deficiency (FHD) and cancer risk: A window into the clinical and oncological implications of a rare disorder in gynecology. Cancers, 17.","DOI":"10.3390\/cancers17040573"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e240073","DOI":"10.1530\/EDM-24-0073","article-title":"Hereditary leiomyomatosis and renal cell cancer (HLRCC), pheochromocytoma (PCC)\/paraganglioma (PGL) and germline fumarate hydratase (FH) variants","volume":"2024","author":"Orrego","year":"2024","journal-title":"Endocrinol. Diabetes Metab. Case Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"791.e9","DOI":"10.1016\/j.urolonc.2021.07.026","article-title":"Hereditary leiomyomatosis and renal cell cancer (HLRCC): Case series and review of the literature","volume":"39","author":"Yu","year":"2021","journal-title":"Urol. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Lindner, A.K., Tulchiner, G., Seeber, A., Siska, P.J., Thurnher, M., and Pichler, R. (2022). Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.906014"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1111\/aogs.14248","article-title":"Uterine leiomyomas in hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome can be identified through distinct clinical characteristics and typical morphology","volume":"100","author":"Uimari","year":"2021","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_11","unstructured":"Adam, M.P., Bick, S., Mirzaa, G.M., Wallace, S.E., and Amemiya, A. (2025). FH tumor predisposition syndrome. GeneReviews\u00ae [Internet], University of Washington, Seattle. updated 8 May 2025."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"154916","DOI":"10.1016\/j.prp.2023.154916","article-title":"The use of clinicopathological, immunohistochemistry and molecular detection in the diagnosis of fumarate hydratase-deficient uterine leiomyomas","volume":"253","author":"Zhang","year":"2024","journal-title":"Pathol. Res. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Alkhrait, S., Ali, M., Kertowidjojo, E., Romero, I.L., Hathaway, F., and Madueke-Laveaux, O.S. (2023). Investigating fumarate hydratase-deficient uterine fibroids: A case series. J. Clin. Med., 12.","DOI":"10.3390\/jcm12175436"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"101963","DOI":"10.1016\/j.tranon.2024.101963","article-title":"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","volume":"45","author":"Wang","year":"2024","journal-title":"Transl. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"207","DOI":"10.3343\/alm.2021.41.2.207","article-title":"Genotypic and phenotypic characteristics of hereditary leiomyomatosis and renal cell cancer syndrome in Korean patients","volume":"41","author":"Seo","year":"2021","journal-title":"Ann. Lab. Med."},{"key":"ref_16","first-page":"33","article-title":"Fumarate Hydratase-Deficient Leiomyomas: A Retrospective Case Series with Clinical and Familial Findings Suggestive of Hereditary Leiomyomatosis and Renal Cell Carcinoma Syndrome","volume":"32","author":"Ismayilov","year":"2026","journal-title":"Gynecol. Obstet. Reprod. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1038\/s41379-020-0596-y","article-title":"Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants","volume":"33","author":"Popp","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1097\/PAS.0000000000000573","article-title":"Fumarate hydratase-deficient uterine leiomyomas occur in both the syndromic and sporadic settings","volume":"40","author":"Harrison","year":"2016","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1093\/humrep\/deaa187","article-title":"Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy","volume":"35","author":"Pasanen","year":"2020","journal-title":"Hum. Reprod."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1158\/1940-6207.CAPR-23-0535","article-title":"Germline and somatic fumarate hydratase testing in atypical uterine leiomyomata","volume":"17","author":"Kipnis","year":"2024","journal-title":"Cancer Prev. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1097\/PAS.0000000000002362","article-title":"Prospective fumarate hydratase tumor predisposition syndrome screening in patients with uterine smooth muscle tumors: Age, morphology, fumarate hydratase\/S-(2-succino)cysteine immunohistochemistry, and germline testing","volume":"49","author":"McHenry","year":"2025","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1002\/path.70016","article-title":"Integrated morphological, immunohistochemical, and genomic profiling identifies uterine leiomyoma patients with hereditary leiomyomatosis and renal cell cancer syndrome: A comprehensive analysis of 252 cases","volume":"268","author":"Liu","year":"2026","journal-title":"J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1097\/PAS.0000000000000520","article-title":"Morphology and immunohistochemistry for 2SC and FH aid in detection of fumarate hydratase gene aberrations in uterine leiomyomas from young patients","volume":"39","author":"Joseph","year":"2015","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1097\/PAS.0000000000001293","article-title":"Detailed morphologic and immunohistochemical characterization of myomectomy and hysterectomy specimens from women with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC)","volume":"43","author":"Chan","year":"2019","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Rogozhina, A., Badlaeva, A., Tregubova, A., Asaturova, A., Kuznetsova, M., and Sukhikh, G. (2025). Diagnostic value and interobserver reproducibility of histopathological features in fumarate hydratase-deficient uterine leiomyomas. Diagnostics, 15.","DOI":"10.3390\/diagnostics15233006"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1177\/10668969231180285","article-title":"Fumarate hydratase-deficient leiomyoma of the uterine corpus: Comparative morphologic analysis of protein-deficient tumors with and without pathogenic germline fumarate hydratase gene mutations","volume":"32","author":"Shi","year":"2024","journal-title":"Int. J. Surg. Pathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1097\/PGP.0000000000000797","article-title":"Fumarate hydratase deficiency should be considered in the differential diagnosis of uterine and extrauterine smooth muscle tumors of uncertain malignant potential (STUMP)","volume":"41","author":"Pors","year":"2022","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1097\/PGP.0000000000000918","article-title":"Fumarate hydratase and S-(2-succinyl)-cysteine immunohistochemistry shows evidence of fumarate hydratase deficiency in 2% of uterine leiomyosarcomas: A cohort study of 348 tumors","volume":"42","author":"Chapel","year":"2023","journal-title":"Int. J. Gynecol. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1016\/j.euo.2019.11.002","article-title":"Hereditary leiomyomatosis and renal cell cancer: Clinical, molecular, and screening features in a cohort of 185 affected individuals","volume":"3","author":"Forde","year":"2020","journal-title":"Eur. Urol. Oncol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/18\/2985\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:42:11Z","timestamp":1789479731000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/16\/18\/2985"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,15]]},"references-count":29,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["diagnostics16182985"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics16182985","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,15]]}}}