{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:02:33Z","timestamp":1789642953192,"version":"4.0.0"},"reference-count":12,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T00:00:00Z","timestamp":1416873600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"Ministry of Health, Labour and Welfare, Japan"},{"name":"Nagano Children's Hospital Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2015,2]]},"abstract":"<jats:sec><jats:label\/><jats:p>Noonan syndrome with multiple lentigines (NSML), formerly referred to as LEOPARD syndrome, is a rare autosomal\u2010dominant condition, characterized by multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and sensorineural deafness. To date, <jats:italic>PTPN11<\/jats:italic>, <jats:italic>RAF1<\/jats:italic>, and <jats:italic>BRAF<\/jats:italic> have been reported to be causal for NSML. We report on a 13\u2010year\u2010old Japanese boy, who was diagnosed with NSML. He was found to have a novel heterozygous missense variant (c.305A\u2009&gt;\u2009G; p.E102G) in <jats:italic>MAP2K1<\/jats:italic>, a gene mostly causal for cardio\u2010facio\u2010cutaneous syndrome (CFCS). He manifested fetal macrosomia, and showed hypotonia and poor sucking in the neonatal period. He had mild developmental delay, and multiple lentigines appearing at approximately age 3 years, as well as flexion deformity of knees bilaterally, subtle facial characteristics including ocular hypertelorism, sensorineural hearing loss, and precocious puberty. He lacked congenital heart defects or hypertrophic cardiomyopathy, frequently observed in patients with NSML, mostly caused by <jats:italic>PTPN11<\/jats:italic> mutations. He also lacked congenital heart defects, characteristic facial features, or intellectual disability, frequently observed in those with CFCS caused by <jats:italic>MAP2K1<\/jats:italic> or <jats:italic>MAP2K2<\/jats:italic> mutations. This may be the first patient clinically diagnosed with NSML, caused by a mutation in <jats:italic>MAP2K1<\/jats:italic>. \u00a9 2014 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.36842","type":"journal-article","created":{"date-parts":[[2014,11,25]],"date-time":"2014-11-25T20:57:40Z","timestamp":1416949060000},"page":"407-411","source":"Crossref","is-referenced-by-count":28,"title":["A novel heterozygous <i>MAP2K1<\/i> mutation in a patient with Noonan syndrome with multiple lentigines"],"prefix":"10.1002","volume":"167","author":[{"given":"Eriko","family":"Nishi","sequence":"first","affiliation":[{"name":"Division of Medical Genetics Nagano Children's Hospital Azumino Japan"},{"name":"Department of Medical Genetics Shinshu University School of Medicine Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seiji","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Central Hospital Aichi Human Service Center Kasugai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Nanjo","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Tohoku University School of Medicine Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tetsuya","family":"Niihori","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Tohoku University School of Medicine Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshimitsu","family":"Fukushima","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Shinshu University School of Medicine Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoichi","family":"Matsubara","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Tohoku University School of Medicine Sendai Japan"},{"name":"National Research Institute for Child Health and Development Tokyo"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Aoki","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Tohoku University School of Medicine Sendai Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoki","family":"Kosho","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics Nagano Children's Hospital Azumino Japan"},{"name":"Department of Medical Genetics Shinshu University School of Medicine Matsumoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,11,25]]},"reference":[{"key":"e_1_2_6_2_1","unstructured":"Allanson JE Roberts AE. 2011. Noonan syndrome. In: Pagon RA Adam MP Bird TD et al. editors. GeneReviews\u00ae [Internet]. Seattle (WA): University of Washington; 1993\u20132014. Available from:http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1116\/. Accessed March 16 2014. ."},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-012-1239-y"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2008.256"},{"key":"e_1_2_6_5_1","unstructured":"Gelb BD Tartaglia M. 2010. LEOPARD syndrome. In: Pagon RA Adam MP Bird TD et al. editors. GeneReviews\u00ae [Internet]. Seattle (WA): University of Washington; 1993\u20132014. Available from:http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1116\/. Accessed March 16 2014. ."},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2009.04.006"},{"key":"e_1_2_6_7_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1159\/000342251","article-title":"LEOPARD syndrome: Clinical features and gene mutations","volume":"3","author":"Mart\u00ednez\u2010Quintana E","year":"2012","journal-title":"Mol Syndromol"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng2073"},{"key":"e_1_2_6_9_1","unstructured":"Rauen KA. 2012. Cardiofaciocutaneous syndrome. In: Pagon RA Adam MP Bird TD et al. editors. GeneReviews\u00ae [Internet]. Seattle (WA): University of Washington; 1993\u20132014. Available from:http:\/\/www.ncbi.nlm.nih.gov\/books\/NBK1116\/. 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