{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T20:24:19Z","timestamp":1790627059198,"version":"4.1.0"},"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T00:00:00Z","timestamp":1620172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bundesverband Neurofibromatose e.V."}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Neurofibromatosis type-1 (NF1) patients suffer from cutaneous and subcutaneous neurofibromas (CNF) and large plexiform neurofibromas (PNF). Whole gene deletions of the\n                    <jats:italic>NF1<\/jats:italic>\n                    gene can cause a more severe phenotype compared to smaller intragenic changes. Two distinct groups of\n                    <jats:italic>NF1<\/jats:italic>\n                    whole gene deletions are type-1 deletions and atypical deletions. Our aim was to assess volumes and averaged annual growth-rates of CNF and PNF in patients with\n                    <jats:italic>NF1<\/jats:italic>\n                    whole gene deletions and to compare these with NF1 patients without large deletions of the\n                    <jats:italic>NF1<\/jats:italic>\n                    gene.\n                  <\/jats:p>\n                  <jats:p>\n                    We retrospectively evaluated 140 whole-body MR examinations of 38 patients with\n                    <jats:italic>NF1<\/jats:italic>\n                    whole gene deletions (type-1 group: n = 27\/atypical group n = 11) and an age- and sex matched collective of 38 NF1-patients. Age-dependent subgroups were created (0\u201318 vs &gt;18 years). Sixty-four patients received follow-up MRI examinations (\n                    <jats:italic>NF1<\/jats:italic>\n                    whole gene deletion n = 32\/control group n = 32). Whole-body tumor-volumes were semi-automatically assessed (MedX, V3.42). Tumor volumes and averaged annual growth-rates were compared.\n                  <\/jats:p>\n                  <jats:p>\n                    Median tumor-burden was significantly higher in the type-1 group (418ml; IQR 77 \u2013 950ml, p = 0.012) but not in the atypical group (356ml;IQR 140\u20131190ml, p = 0.099) when compared to the controls (49ml; IQR 11\u2013691ml). Averaged annual growth rates were significantly higher in both the type-1 group (14%\/year; IQR 45\u201336%\/year, p = 0.004) and atypical group (11%\/year; IQR 5\u201323%\/year, p = 0.014) compared to the controls (4%\/year; IQR1\u20138%\/year). Averaged annual growth rates were significantly higher in pediatric patients with type-1 deletions (21%\/year) compared with adult patients (8%\/year, p = 0.014) and also compared with pediatric patients without large deletions of the\n                    <jats:italic>NF1<\/jats:italic>\n                    gene (3.3%\/year, p = 0.0015).\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:italic>NF1<\/jats:italic>\n                    whole gene deletions cause a more severe phenotype of NF1 with higher tumor burden and higher growth-rates compared to NF1 patients without large deletions of the\n                    <jats:italic>NF1<\/jats:italic>\n                    gene. In particular, pediatric patients with type-1 deletions display a pronounced tumor growth.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1009517","type":"journal-article","created":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T13:57:40Z","timestamp":1620223060000},"page":"e1009517","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":25,"title":["Genotype-phenotype correlation in neurofibromatosis type-1: NF1 whole gene deletions lead to high tumor-burden and increased tumor-growth"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2491-1346","authenticated-orcid":true,"given":"Lennart","family":"Well","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly","family":"D\u00f6bel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9919-4551","authenticated-orcid":true,"given":"Lan","family":"Kluwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7102-534X","authenticated-orcid":true,"given":"Peter","family":"Bannas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3596-5932","authenticated-orcid":true,"given":"Said","family":"Farschtschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Adam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor-Felix","family":"Mautner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Salamon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,5,5]]},"reference":[{"key":"pgen.1009517.ref001","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1136\/jmg.26.11.712","article-title":"A genetic study of von Recklinghausen neurofibromatosis in south east Wales. 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Guidelines for genetic counselling","volume":"26","author":"SM Huson","year":"1989","journal-title":"J Med Genet"},{"key":"pgen.1009517.ref002","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1001\/archderm.141.1.71","article-title":"Prevalence of neurofibromatosis 1 in German children at elementary school enrollment","volume":"141","author":"M Lammert","year":"2005","journal-title":"Arch Dermatol"},{"key":"pgen.1009517.ref003","first-page":"562","volume-title":"Journal of Child Neurology","author":"D Viskochil","year":"2002"},{"key":"pgen.1009517.ref004","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/s00439-017-1766-y","article-title":"Emerging genotype\u2013phenotype relationships in patients with large NF1 deletions","volume":"136","author":"H Kehrer-Sawatzki","year":"2017","journal-title":"Hum Genet"},{"key":"pgen.1009517.ref005","first-page":"9","article-title":"Deletions Spanning the Neurofibromatosis Type 1 Gene: Implications for Genotype-Phenotype Correlations in Neurofibromatosis Type 1?","author":"C MH","year":"1997","journal-title":"Hum Mutat"},{"key":"pgen.1009517.ref006","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1136\/jmg.35.6.468","article-title":"Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1","volume":"35","author":"SA Rasmussen","year":"1998","journal-title":"J Med Genet"},{"key":"pgen.1009517.ref007","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1002\/humu.10299","article-title":"Screening 500 unselected neurofibromatosis 1 patients for deletions of theNF1 gene","volume":"23","author":"L Kluwe","year":"2004","journal-title":"Hum Mutat"},{"key":"pgen.1009517.ref008","first-page":"5","article-title":"Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population","author":"J Zhang","year":"2015","journal-title":"Sci Rep"},{"key":"pgen.1009517.ref009","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1093\/hmg\/9.1.35","article-title":"NF1 microdeletion breakpoints are clustered at flanking repetitive sequences","volume":"9","author":"MO Dorschner","year":"2000","journal-title":"Hum Mol Genet"},{"key":"pgen.1009517.ref010","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1086\/323043","article-title":"Molecular characterization and gene content of breakpoint boundaries in patients with neurofibromatosis type 1 with 17q11.2 microdeletions","volume":"69","author":"DE Jenne","year":"2001","journal-title":"Am J Hum Genet"},{"key":"pgen.1009517.ref011","doi-asserted-by":"crossref","first-page":"1387","DOI":"10.1093\/hmg\/10.13.1387","article-title":"Recombination hotspot in NF1 microdeletion patients","volume":"10","author":"C L\u00f3pez-Correa","year":"2001","journal-title":"Hum Mol Genet"},{"key":"pgen.1009517.ref012","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/humu.21418","article-title":"Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1).","volume":"32","author":"L Messiaen","year":"2011","journal-title":"Hum Mutat"},{"key":"pgen.1009517.ref013","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1007\/s00439-018-1961-5","article-title":"Ultra-deep amplicon sequencing indicates absence of low-grade mosaicism with normal cells in patients with type-1 NF1 deletions","volume":"138","author":"A Summerer","year":"2019","journal-title":"Hum Genet"},{"key":"pgen.1009517.ref014","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1136\/jmg.2009.075937","article-title":"Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions","volume":"47","author":"VF Mautner","year":"2010","journal-title":"J Med Genet"},{"key":"pgen.1009517.ref015","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1136\/jmg.2003.014761","article-title":"Mental retardation and cardiovascular malformations in NF1 microdeleted patients point to candidate genes in 17q11.2","volume":"41","author":"M Venturin","year":"2004","journal-title":"J Med Genet"},{"key":"pgen.1009517.ref016","first-page":"31","article-title":"NF1 microdeletions in neurofibromatosis type 1: From genotype to phenotype","author":"E Pasmant","year":"2010","journal-title":"Hum Mutat"},{"key":"pgen.1009517.ref017","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1111\/cge.12072","article-title":"Cardiac characterization of 16 patients with large NF1 gene deletions","volume":"84","author":"R Nguyen","year":"2013","journal-title":"Clin Genet"},{"key":"pgen.1009517.ref018","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.1002\/1097-0142(19860515)57:10<2006::AID-CNCR2820571022>3.0.CO;2-6","article-title":"Malignant peripheral nerve sheath tumors. 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Available: http:\/\/www.ncbi.nlm.nih.gov\/pubmed\/3152465"},{"key":"pgen.1009517.ref032","article-title":"Null phenotype of neurofibromatosis type 1 in a carrier of a heterozygous atypical NF1 deletion due to mosaicism","author":"L Kluwe","year":"2020","journal-title":"Hum Mutat"},{"key":"pgen.1009517.ref033","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1002\/humu.9193","article-title":"Constitutional NF1 mutations in neurofibromatosis 1 patients with malignant peripheral nerve sheath tumors","volume":"22","author":"L Kluwe","year":"2003","journal-title":"Hum Mutat"},{"key":"pgen.1009517.ref034","first-page":"949","article-title":"Growth type of plexiform neurofibromas in NF1 determined on magnetic resonance images","volume":"23","author":"RE Friedrich","year":"2003","journal-title":"Anticancer Res"},{"key":"pgen.1009517.ref035","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1055\/s-0035-1553505","article-title":"Multimodal Imaging in Neurofibromatosis Type 1-associated Nerve Sheath Tumors","volume":"187","author":"J Salamon","year":"2015","journal-title":"Rofo"},{"key":"pgen.1009517.ref036","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1212\/01.wnl.0000168830.79997.13","article-title":"Association between benign and malignant peripheral nerve sheath tumors in NF1","volume":"65","author":"T Tucker","year":"2005","journal-title":"Neurology"},{"key":"pgen.1009517.ref037","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.ccr.2008.01.002","article-title":"Induction of Abnormal Proliferation by Nonmyelinating Schwann Cells Triggers Neurofibroma Formation","volume":"13","author":"H Zheng","year":"2008","journal-title":"Cancer Cell"},{"key":"pgen.1009517.ref038","article-title":"Longitudinal evaluation of peripheral nerve sheath tumors in neurofibromatosis type 1: Growth analysis of plexiform neurofibromas and distinct nodular lesions.","author":"S Akshintala","year":"2020","journal-title":"Neuro Oncol"},{"key":"pgen.1009517.ref039","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1136\/jmg.2008.061051","article-title":"Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas","volume":"46","author":"T Tucker","year":"2009","journal-title":"J Med Genet"},{"key":"pgen.1009517.ref040","article-title":"Selumetinib in Children with Inoperable Plexiform Neurofibromas","author":"AM Gross","year":"2020","journal-title":"N Engl J Med"},{"key":"pgen.1009517.ref041","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s11060-013-1293-1","article-title":"Benign whole body tumor volume is a risk factor for malignant peripheral nerve sheath tumors in neurofibromatosis type 1","volume":"116","author":"R Nguyen","year":"2014","journal-title":"J Neurooncol"},{"key":"pgen.1009517.ref042","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1086\/374821","article-title":"Elevated risk for MPNST in NF1 microdeletion patients","volume":"72","author":"T De Raedt","year":"2003","journal-title":"Am J Hum Genet"}],"container-title":["PLOS Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1009517","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,5]],"date-time":"2021-05-05T13:58:39Z","timestamp":1620223119000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pgen.1009517"}},"subtitle":[],"editor":[{"given":"Amanda J.","family":"Myers","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2021,5,5]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5,5]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pgen.1009517","relation":{},"ISSN":["1553-7404"],"issn-type":[{"value":"1553-7404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,5]]}}}