{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T23:51:56Z","timestamp":1793404316157,"version":"4.5.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neurofibromatosis Type I (NF1), also termed von Recklinghausen disease, is a rare genetic disorder that is transmitted by autosomal dominant inheritance, with complete penetrance and variable expressivity. It is caused by mutation in the NF1 gene on chromosome 17 encoding for neurofibromin, a protein with oncosuppressive activity, and it is 50% sporadic or inherited. The disease is characterized by a broad spectrum of clinical manifestations, mainly involving the nervous system, the eye and skin, and a predisposition to develop multiple benign and malignant neoplasms. Ocular diagnostic hallmarks of NF1 include optic gliomas, iris Lisch nodules, orbital and eyelid neurofibromas, eyelid caf\u00e9-au-lait spots. Choroidal nodules and microvascular abnormalities have recently been identified as additional NF1-related ocular manifestations. The present study was designed to describe the features and clinical significance of a new sign related to the visual apparatus in NF-1, represented by hyperpigmented spots (HSs) of the fundus oculi.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      HSs were detected in 60 (24.1%) out of 249 patients with NF1, with a positive predictive value of 100% and a negative predictive value of 44.2%. None of the healthy subjects (150 subjects) showed the presence of HSs. HSs were visible under indirect ophthalmoscopy, ultra-wide field (UWF) pseudocolor imaging and red-only laser image, near-infrared reflectance (NIR)-OCT, but they were not appreciable on UWF green reflectance. The location and features of pigmentary lesions matched with the already studied NF1-related choroidal nodules. No significant difference was found between the group of patients (n\u2009=\u200960) with ocular HSs and the group of patients (n\u2009=\u2009189) without ocular pigmented spots in terms of age, gender or severity grading of the disease. A statistically significant association was demonstrated between the presence of HSs and neurofibromas (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.047), and between the presence of HSs and NF1-related retinal microvascular abnormalities (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.017).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We described a new ocular sign represented by HSs of the fundus in NF1. The presence of HSs was not a negative prognostic factor of the disease. Following multimodal imaging, we demonstrated that HSs and choroidal nodules were consistent with the same type of lesion, and simple indirect ophthalmoscopy allowed for screening of HSs in NF1.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-021-01773-w","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T06:03:30Z","timestamp":1616479410000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Hyperpigmented spots at fundus examination: a new ocular sign in Neurofibromatosis Type I"],"prefix":"10.1186","volume":"16","author":[{"given":"Antonietta","family":"Moramarco","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabiana","family":"Mallone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Sacchetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Lucchino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele","family":"Miraglia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Roberti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8974-991X","authenticated-orcid":false,"given":"Alessandro","family":"Lambiase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Giustini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,23]]},"reference":[{"key":"1773_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/GIM.0b013e3181bf15e3","volume":"12","author":"K Jett","year":"2010","unstructured":"Jett K, Friedman JM. Clinical and genetic aspects of neurofibromatosis 1. Genet Med. 2010;12:1\u201311.","journal-title":"Genet. Med"},{"key":"1773_CR2","doi-asserted-by":"publisher","first-page":"5873","DOI":"10.18632\/oncotarget.2194","volume":"5","author":"YS Yap","year":"2014","unstructured":"Yap YS, McPherson JR, Ong CK, Rozen SG, Teh BT, Lee ASG, et al. The NF1 gene revisited -from bench to bedside. Oncotarget. 2014;5:5873\u201392.","journal-title":"Oncotarget"},{"key":"#cr-split#-1773_CR3.1","unstructured":"Poyhonen, M. Risk of malignancy and death in neurofibromatosis. search.proquest.com [Internet]. [cited 2020 Oct 13]"},{"key":"#cr-split#-1773_CR3.2","unstructured":"Available from: http:\/\/search.proquest.com\/openview\/aae164438ad6e71247d95e4c78c14e10\/1?pq-origsite=gscholar&cbl=42082 (1997)"},{"key":"1773_CR4","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1007\/s00439-003-1047-9","volume":"114","author":"I Vandenbroucke","year":"2004","unstructured":"Vandenbroucke I, van Doorn R, Callens T, Cobben JM, Starink TM, Messiaen L. Genetic and clinical mosaicism in a patient with neurofibromatosis type 1. Hum Genet. 2004;114:284\u201390.","journal-title":"Hum Genet"},{"key":"1773_CR5","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1002\/neu.480270408","volume":"27","author":"KM Stocker","year":"1995","unstructured":"Stocker KM, Baizer L, Coston T, Sherman L, Ciment G. Regulated expression of neurofibromin in migrating neural crest cells of avian embryos. J Neurobiol. 1995;27:535\u201352.","journal-title":"J Neurobiol"},{"key":"1773_CR6","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1111\/pcmr.12134","volume":"26","author":"CD Van Raamsdonk","year":"2013","unstructured":"Van Raamsdonk CD, Deo M. Links between Schwann cells and melanocytes in development and disease. Pigment Cell Melanoma Res. 2013;26:634\u201345.","journal-title":"Pigment Cell Melanoma Res"},{"key":"1773_CR7","doi-asserted-by":"publisher","first-page":"518","DOI":"10.1016\/j.survophthal.2017.10.007","volume":"63","author":"M Kinori","year":"2018","unstructured":"Kinori M, Hodgson N, Zeid JL. Ophthalmic manifestations in neurofibromatosis type 1. Surv Ophthalmol. 2018;63:518\u201333.","journal-title":"Surv Ophthalmol"},{"key":"1773_CR8","doi-asserted-by":"publisher","first-page":"119","DOI":"10.2147\/EB.S255184","volume":"12","author":"M Nebbioso","year":"2020","unstructured":"Nebbioso M, Moramarco A, Lambiase A, Giustini S, Marenco M, Miraglia E, et al. Neurofibromatosis type 1: Ocular electrophysiological and perimetric anomalies. Eye Brain. 2020;12:119\u201327.","journal-title":"Eye Brain"},{"key":"1773_CR9","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1111\/j.1468-3083.2004.00915.x","volume":"18","author":"A Richetta","year":"2004","unstructured":"Richetta A, Giustini S, Recupero SM, Pezza M, Carlomagno V, Amoruso G, et al. Lisch nodules of the iris in neurofibromatosis type 1. J Eur Acad Dermatology Venereol. 2004;18:342\u20134.","journal-title":"J Eur Acad Dermatology Venereol"},{"key":"1773_CR10","doi-asserted-by":"publisher","first-page":"307","DOI":"10.1007\/s00417-017-3870-z","volume":"256","author":"A Moramarco","year":"2018","unstructured":"Moramarco A, Giustini S, Nofroni I, Mallone F, Miraglia E, Iacovino C, et al. Near-infrared imaging: an in vivo, non-invasive diagnostic tool in neurofibromatosis type 1. Graefe\u2019s Arch Clin Exp Ophthalmol. 2018;256:307\u201311.","journal-title":"Graefe\u2019s Arch Clin Exp Ophthalmol"},{"issue":"9","key":"1773_CR11","doi-asserted-by":"publisher","first-page":"1789","DOI":"10.1007\/s00417-018-4028-3","volume":"256","author":"A Moramarco","year":"2018","unstructured":"Moramarco A, Giustini S, Miraglia E, Sacchetti M. SD-OCT in NIR modality to diagnose retinal microvascular abnormalities in neurofibromatosis type 1. Graefes Arch Clin Exp Ophthalmol. 2018;256(9):1789\u201390. https:\/\/doi.org\/10.1007\/s00417-018-4028-3.","journal-title":"Graefes Arch Clin Exp Ophthalmol."},{"key":"1773_CR12","first-page":"E4","volume":"170","author":"A Moramarco","year":"2019","unstructured":"Moramarco A, Lambiase A, Mallone F, Miraglia E, Giustini S. A characteristic type of retinal microvascular abnormalities in a patient with Neurofibromatosis type 1. Clin Ter. 2019;170:E4-9.","journal-title":"Clin Ter"},{"key":"1773_CR13","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1136\/bjophthalmol-2018-313002","volume":"103","author":"A Moramarco","year":"2019","unstructured":"Moramarco A, Miraglia E, Mallone F, Roberti V, Iacovino C, Bruscolini A, et al. Retinal microvascular abnormalities in neurofibromatosis type 1. Br J Ophthalmol. 2019;103:1590\u20134.","journal-title":"Br J Ophthalmol"},{"key":"1773_CR14","unstructured":"Stumpf, DA. Neurofibromatosis. Conference statement, National Institute of Health development conference. Arch Neurol 1988;45:575\u20138."},{"key":"1773_CR15","unstructured":"Riccardi V, Kleiner B. Neurofibromatosis: a neoplastic birth defect with two age peaks of severe problems. https:\/\/europepmc.org. Available from: https:\/\/europepmc.org\/article\/med\/407957 (1977)"},{"key":"#cr-split#-1773_CR16.1","unstructured":"Ablon J. Gender response to neurofibromatosis 1. [cited 2020 Oct 13]"},{"key":"#cr-split#-1773_CR16.2","unstructured":"Available from: https:\/\/www.sciencedirect.com\/science\/article\/pii\/0277953695000763 (1996)"},{"key":"1773_CR17","doi-asserted-by":"publisher","first-page":"2121","DOI":"10.1007\/s00417-015-2958-6","volume":"253","author":"KT Nam","year":"2015","unstructured":"Nam KT, Yun CM, Kim JT, Yang KS, Kim HJ, Kim SW, et al. Central serous chorioretinopathy fundus autofluorescence comparison with two different confocal scanning laser ophthalmoscopes. Graefe\u2019s Arch Clin Exp Ophthalmol. 2015;253:2121\u20137.","journal-title":"Graefe\u2019s Arch Clin Exp Ophthalmol"},{"key":"#cr-split#-1773_CR18.1","unstructured":"Spaide R, Koizumi H, Pozzoni M. Enhanced depth imaging spectral-domain optical coherence tomography. [cited 2020 Oct 13]"},{"key":"#cr-split#-1773_CR18.2","unstructured":"Available from: https:\/\/www.sciencedirect.com\/science\/article\/pii\/S0002939408004182 (2008)"},{"key":"#cr-split#-1773_CR19.1","unstructured":"Kurosawa A, Kurosawa H. Ovoid bodies in choroidal neurofibromatosis. [cited 2020 Oct 13]"},{"key":"#cr-split#-1773_CR19.2","unstructured":"https:\/\/jamanetwork.com\/journals\/jamaophthalmology\/article-abstract\/634404 (1982)"},{"key":"1773_CR20","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1001\/archopht.1965.00970030698019","volume":"73","author":"JR Wolter","year":"1965","unstructured":"Wolter JR. Nerve fibrils in ovoid bodies: with neurofibromatosis of the choroid. Arch Ophthalmol. 1965;73:696\u20139.","journal-title":"Arch Ophthalmol"},{"key":"1773_CR21","doi-asserted-by":"crossref","unstructured":"Rescaldani C, Nicolini P, Fatigati G, Bottoni F. 1998. Clinical application of digital indocyanine green angiography in choroidal neurofibromatosis. [cited 2020 Oct 13]; Available from: https:\/\/www.karger.com\/Article\/FullText\/27287","DOI":"10.1159\/000027287"},{"key":"1773_CR22","doi-asserted-by":"crossref","unstructured":"Yasunari T, Shiraki K, Hattori H, Miki T. 2000. Frequency of choroidal abnormalities in neurofibromatosis type 1. [cited 2020 Oct 13]; Available from: https:\/\/www.sciencedirect.com\/science\/article\/pii\/S0140673600027161","DOI":"10.1016\/S0140-6736(00)02716-1"},{"key":"1773_CR23","doi-asserted-by":"crossref","unstructured":"Kumar V, Singh S. Multimodal imaging of choroidal nodules in neurofibromatosis type-1. Indian J Ophthalmol 2018;66:586. Available from: http:\/\/www.ijo.in\/text.asp?2018\/66\/4\/586\/228465","DOI":"10.4103\/ijo.IJO_1095_17"},{"key":"1773_CR24","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4613-8525-7","volume-title":"Pathology of the eye","author":"GOH Naumann","year":"1986","unstructured":"Naumann GOH, Apple DJ. Pathology of the eye. New York: Springer; 1986."},{"key":"1773_CR25","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1111\/j.1600-0749.2006.00357.x","volume":"20","author":"WC Ward","year":"2007","unstructured":"Ward WC, Simon JD. The differing embryonic origins of retinal and uveal (iris\/ciliary body and choroid) melanosomes are mirrored by their phospholipid composition. Pigment Cell Res. 2007;20:61\u20139.","journal-title":"Pigment Cell Res"},{"key":"1773_CR26","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1111\/j.1600-0749.2004.00206.x","volume":"18","author":"S De Schepper","year":"2005","unstructured":"De Schepper S, Boucneau J, Lambert J, Messiaen L, Naeyaert JM. Pigment cell-related manifestations in neurofibromatosis type 1: an overview. Pigment Cell Res. 2005;18:13\u201324.","journal-title":"Pigment Cell Res"},{"issue":"10","key":"1773_CR27","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1007\/s00403-006-0644-6","volume":"297","author":"S De Schepper","year":"2006","unstructured":"De Schepper S, Boucneau J, Vander Haeghen Y, Messiaen L, Naeyaert JM, Lambert J. Caf\u00e9-au-lait spots in neurofibromatosis type 1 and in healthy control individuals: hyperpigmentation of a different kind? Arch Dermatol Res. 2006;297(10):439\u201349. https:\/\/doi.org\/10.1007\/s00403-006-0644-6.","journal-title":"Arch Dermatol Res."},{"key":"1773_CR28","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1620\/tjem.118.255","volume":"118","author":"M Takahashi","year":"1976","unstructured":"Takahashi M. Studies on cafe au lait spots in neurofibromatosis and pigmented macules of nevus spilus. Tohoku J Exp Med. 1976;118:255\u201373.","journal-title":"Tohoku J Exp Med"},{"key":"1773_CR29","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1364\/AO.28.001061","volume":"28","author":"FC Delori","year":"1989","unstructured":"Delori FC, Pflibsen KP. Spectral reflectance of the human ocular fundus. Appl Opt. 1989;28:1061.","journal-title":"Appl Opt"},{"key":"1773_CR30","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1136\/bjo.2008.141564","volume":"93","author":"A Ayata","year":"2009","unstructured":"Ayata A, Tatlipinar S, Kar T, Unal M, Ersanli D, Bilge AH. Near-infrared and short-wavelength autofluorescence imaging in central serous chorioretinopathy. Br J Ophthalmol. 2009;93:79\u201382.","journal-title":"Br J Ophthalmol"},{"key":"1773_CR31","doi-asserted-by":"publisher","first-page":"1134","DOI":"10.1136\/bjo.2010.189498","volume":"95","author":"S Schmitz-Valckenberg","year":"2011","unstructured":"Schmitz-Valckenberg S, Lara D, Nizari S, Normando EM, Guo L, Wegener AR, et al. Localisation and significance of in vivo near-infrared autofluorescent signal in retinal imaging. Br J Ophthalmol. 2011;95:1134\u20139.","journal-title":"Br J Ophthalmol"},{"key":"1773_CR32","doi-asserted-by":"crossref","unstructured":"Cotlier E. 1977. Caf\u00e9-au-lait spots of the fundus in neurofibromatosis. [cited 2020 Oct 13]; Available from: https:\/\/jamanetwork.com\/journals\/jamaophthalmology\/article-abstract\/632400","DOI":"10.1001\/archopht.1977.04450110084007"},{"key":"1773_CR33","doi-asserted-by":"publisher","first-page":"2101","DOI":"10.4103\/ijo.IJO_925_19","volume":"67","author":"R Venkatesh","year":"2019","unstructured":"Venkatesh R, Jain K, Pereira A, Jain S, Aseem A, Mahendradas P, et al. Retinal cafe-au-lait macules: A rare retinal finding in a patient with neurofibromatosis type 1. Indian J Ophthalmol. 2019;67:2101.","journal-title":"Indian J Ophthalmol"},{"key":"1773_CR34","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1002\/glia.23262","volume":"66","author":"JB Aquino","year":"2018","unstructured":"Aquino JB, Sierra R. Schwann cell precursors in health and disease. Glia. 2018;66:465\u201376.","journal-title":"Glia"},{"key":"1773_CR35","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1159\/000469702","volume":"8","author":"C Cassiman","year":"2017","unstructured":"Cassiman C, Casteels I, Stalmans P, Legius E, Jacob J. Optical coherence tomography angiography of retinal microvascular changes overlying choroidal nodules in neurofibromatosis type 1. Case Rep Ophthalmol. 2017;8:214\u201320.","journal-title":"Case Rep Ophthalmol"},{"key":"1773_CR36","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/1471-2415-14-146","volume":"14","author":"S Abdolrahimzadeh","year":"2014","unstructured":"Abdolrahimzadeh S, Felli L, Piraino DC, Mollo R, Calvieri S, Recupero SM. Retinal microvascular abnormalities overlying choroidal nodules in neurofibromatosis type 1. BMC Ophthalmol. 2014;14:146. https:\/\/doi.org\/10.1186\/1471-2415-14-146.","journal-title":"BMC Ophthalmol."},{"key":"1773_CR37","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1097\/IAE.0000000000001578","volume":"38","author":"R Parrozzani","year":"2018","unstructured":"Parrozzani R, Pilotto E, Clementi M, Frizziero L, Leonardi F, Convento E, et al. Retinal vascular abnormalities in a large cohort of patients affected by neurofibromatosis type: 1 a study using optical coherence tomography angiography. Retina. 2018;38:585\u201393.","journal-title":"Retina"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-01773-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13023-021-01773-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-021-01773-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T06:03:46Z","timestamp":1616479426000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojrd.biomedcentral.com\/articles\/10.1186\/s13023-021-01773-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,23]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1773"],"URL":"https:\/\/doi.org\/10.1186\/s13023-021-01773-w","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-122662\/v1","asserted-by":"object"}]},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,23]]},"assertion":[{"value":"30 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee of Sapienza University of Rome and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Informed consent to publish personal or clinical details along with any identifying images was obtained from study patients.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"All authors certify that they have no financial or proprietary interest in the subject matter or materials discussed in this manuscript. The authors declare that they do not have any conflicts or potential conflicts of interest.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"147"}}