739c0aaafdb719adcf226d74be858d28 284412.pdf cfe566c43c47fba9595b0d63f195f6700df96f9e 284412.pdf d20f51ab2c7690ed2b981255ce4cb8933ff312fa13beffe399eb07d3bfbb74e0 284412.pdf Title: Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization Subject: 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. Keywords: leiomyomas; hereditary leiomyomatosis; FH gene; missense pathogenic variants, renal cell cancer Author: A. Beatriz Sánchez-Heras, Adela Castillejo, Juan D. García-Díaz, Mercedes Robledo, Alexandre Teulé, Rosario Sánchez, Ángel Zúñiga, Enrique Lastra, Mercedes Durán, Gemma Llort, Carmen Yagüe, Teresa Ramon y Cajal, Consol López San Martin, Adrià López-Fernández, Judith Balmaña, Luis Robles, José M. Mesa-Latorre, Isabel Chirivella, María Fonfria, Raquel Perea Ibañez, M. Isabel Castillejo, Inés Escandell, Luis Gomez, Pere Berbel and Jose Luis Soto Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.18 CreationDate: Sat Nov 14 09:34:53 2020 CET ModDate: Sat Nov 14 09:37:44 2020 CET Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 16 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1208670 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SDIDBK+VnURWPalladioL Type 1 Custom yes yes no 10 0 NLCXCA+URWPalladioL-Ital Type 1 Custom yes yes no 15 0 CVVFMS+URWPalladioL-Bold Type 1 Custom yes yes no 20 0 VQUJCT+URWPalladioL-Roma Type 1 Custom yes yes no 24 0 QANVCD+Rpxr Type 1 Builtin yes yes no 28 0 CBZCTW+VnURWPalladioL-Bold Type 1 Custom yes yes no 32 0 LCJEVJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 41 0 MCBCCI+SourceSansRoman-Regular Type 1C Custom yes yes no 66 0 MCBCCM+SourceSansRoman.613wght Type 1C Custom yes yes no 70 0 MCBCCO+SourceSansRoman-Bold Type 1C Custom yes yes no 74 0 WOZBHT+Rpxb Type 1 Builtin yes yes no 84 0 RDFBCX+Pxsy Type 1 Builtin yes yes no 88 0 HYHBGH+Rpxi Type 1 Builtin yes yes no 92 0 NXCHQG+URWPalladioL-BoldItal Type 1 Custom yes yes no 96 0 FFPDAC+Calibri,Bold CID TrueType Identity-H yes yes yes 130 0 FFOMGP+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 136 0 FFOMIA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 139 0 FFOMIC+PalatinoLinotype TrueType WinAnsi yes yes no 142 0 FFONEA+Calibri CID TrueType Identity-H yes yes yes 145 0 IBDNLO+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 172 0 IBDNMA+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 175 0 IBDNNC+PalatinoLinotype TrueType WinAnsi yes yes no 178 0 QDCWHF+EURM10 Type 1 Builtin yes yes no 186 0 VSHNAE+Rpcxr Type 1 Builtin yes yes no 212 0 Jhove (Rel. 1.22.1, 2019-04-17) Date: 2023-11-10 02:35:33 CET RepresentationInformation: 284412.pdf ReportingModule: PDF-hul, Rel. 1.12.1 (2019-04-17) LastModified: 2023-11-09 12:57:20 CET Size: 1208670 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 421 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4d3167f4 Item: Title: Materials and Methods Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@ed9d034 Children: Item: Title: Patients and Data Collection Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@6121c9d6 Item: Title: Detection of Germline Mutations Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@87f383f Item: Title: Statistics Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@4eb7f003 Item: Title: Results Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@eafc191 Children: Item: Title: Cutaneous Leiomyomas Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612fc6eb Item: Title: Uterine Leiomyomas Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1060b431 Item: Title: Renal Cysts Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@612679d6 Item: Title: Renal Cell Cancers Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@11758f2a Item: Title: Other Tumours Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@e720b71 Item: Title: Discussion Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@1b26f7b2 Item: Title: Conclusions Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@491cc5c9 Item: Title: References Destination: edu.harvard.hul.ois.jhove.module.pdf.PdfSimpleObject@74ad1f1f Info: Title: Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome in Spain: Clinical and Genetic Characterization Author: A. Beatriz Sánchez-Heras, Adela Castillejo, Juan D. García-Díaz, Mercedes Robledo, Alexandre Teulé, Rosario Sánchez, Ángel Zúñiga, Enrique Lastra, Mercedes Durán, Gemma Llort, Carmen Yagüe, Teresa Ramon y Cajal, Consol López San Martin, Adrià López-Fernández, Judith Balmaña, Luis Robles, José M. Mesa-Latorre, Isabel Chirivella, María Fonfria, Raquel Perea Ibañez, M. Isabel Castillejo, Inés Escandell, Luis Gomez, Pere Berbel and Jose Luis Soto Subject: 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. 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