{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T12:12:19Z","timestamp":1792239139434,"version":"4.4.0"},"reference-count":60,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T00:00:00Z","timestamp":1604534400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers12113277","type":"journal-article","created":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T09:04:34Z","timestamp":1604567074000},"page":"3277","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization"],"prefix":"10.3390","volume":"12","author":[{"given":"A. Beatriz","family":"S\u00e1nchez-Heras","sequence":"first","affiliation":[{"name":"Cancer Genetic Counselling Unit, Medical Oncology Department, Hospital General Universitario de Elche, 03203 Elche, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adela","family":"Castillejo","sequence":"additional","affiliation":[{"name":"Molecular Genetics Unit, Hospital General Universitario de Elche, 03203 Elche, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4492-3996","authenticated-orcid":false,"given":"Juan D.","family":"Garc\u00eda-D\u00edaz","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Department of Internal Medicine, University Hospital Pr\u00edncipe de Asturias, 28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mercedes","family":"Robledo","sequence":"additional","affiliation":[{"name":"Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), 28029 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras, CIBERER, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre","family":"Teul\u00e9","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Program, Catalan Institute of Oncology, Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge, 08908 Hospitalet de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Unidad Multidisciplinar de Enfermedades de Baja Prevalencia, Instituto de Investigaci\u00f3n Sanitaria y Biom\u00e9dica de Alicante (ISABIAL), Hospital General Universitario de Alicante, 03015 Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1ngel","family":"Z\u00fa\u00f1iga","sequence":"additional","affiliation":[{"name":"Unit of Genetics, Hospital Universitario Polit\u00e9cnico La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Lastra","sequence":"additional","affiliation":[{"name":"Unidad de Consejo Gen\u00e9tico en C\u00e1ncer Hereditario, Servicio de Oncolog\u00eda M\u00e9dica, Hospital Universitario de Burgos, 09006 Burgos, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6301-9732","authenticated-orcid":false,"given":"Mercedes","family":"Dur\u00e1n","sequence":"additional","affiliation":[{"name":"Gen\u00e9tica del C\u00e1ncer, Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM-UVA-CSIC), 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gemma","family":"Llort","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Unit, Medical Oncology Department, Corporaci\u00f3 Sanitaria Universit\u00e0ria Parc Taul\u00ed, 08208 Sabadell, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Yag\u00fce","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Unit, Medical Oncology Department, Consorci Sanitari de Terrassa, 08191 Rubi, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Ramon y Cajal","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Santa Creu i Sant Pau, 08091 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Consol","family":"L\u00f3pez San Martin","sequence":"additional","affiliation":[{"name":"Medical Oncology Department, Hospital Santa Creu i Sant Pau, 08091 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00e0","family":"L\u00f3pez-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Genetics Group, Medical Oncology Department (VHIO), Hospital Universitario Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Balma\u00f1a","sequence":"additional","affiliation":[{"name":"Hereditary Cancer Genetics Group, Medical Oncology Department (VHIO), Hospital Universitario Vall d\u2019Hebron, 08035 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Robles","sequence":"additional","affiliation":[{"name":"Unidad de C\u00e1ncer Familiar, Servicio de Oncolog\u00eda M\u00e9dica, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Mesa-Latorre","sequence":"additional","affiliation":[{"name":"Clinical Genetics Unit, Department of Internal Medicine, University Hospital Pr\u00edncipe de Asturias, 28805 Alcal\u00e1 de Henares, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0733-3276","authenticated-orcid":false,"given":"Isabel","family":"Chirivella","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, INCLIVA Biomedical Research Institute, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Fonfria","sequence":"additional","affiliation":[{"name":"Cancer Genetic Counselling Unit, Medical Oncology Department, Consorcio Hospitalario Provincial de Castell\u00f3n, 12002 Castell\u00f3n, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Perea Iba\u00f1ez","sequence":"additional","affiliation":[{"name":"Cancer Genetic Counselling Unit, Medical Oncology Department, Hospital General Universitario de Elche, 03203 Elche, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Isabel","family":"Castillejo","sequence":"additional","affiliation":[{"name":"Molecular Genetics Unit, Hospital General Universitario de Elche, 03203 Elche, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Escandell","sequence":"additional","affiliation":[{"name":"Servicio de Dermatolog\u00eda, Hospital General Universitario de Elda, 03600 Elda, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1396-0484","authenticated-orcid":false,"given":"Luis","family":"Gomez","sequence":"additional","affiliation":[{"name":"Urology Department, Hospital Universitario Sant Joan de Alicante, 03550 Sant Joan de Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pere","family":"Berbel","sequence":"additional","affiliation":[{"name":"Departamento de Histolog\u00eda y Anatom\u00eda, Facultad de Medicina, Universidad Miguel Hern\u00e1ndez, 03550 Sant Joan de Alicante, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0234-9188","authenticated-orcid":false,"given":"Jose Luis","family":"Soto","sequence":"additional","affiliation":[{"name":"Molecular Genetics Unit, Hospital General Universitario de Elche, 03203 Elche, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"409","DOI":"10.2340\/0001555553409416","article-title":"Cutaneous leiomyomata with uterine leiomyomata","volume":"53","author":"Reed","year":"1973","journal-title":"Acta Derm. 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