{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T05:51:08Z","timestamp":1761630668438},"reference-count":24,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T00:00:00Z","timestamp":1386201600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:label \/><jats:p>Recent advances in genetic diagnostic technologies have made the classic disease nosology highly complicated. This situation is exemplified by rasopathies, among which neurofibromatosis type 1 and Noonan syndrome represent prototypic entities. The former condition is characterized by multiple caf\u00e9 au lait spots and neurofibromas, while the latter is characterized by distinct facial features, webbed neck, congenital heart disease, and a short stature. On rare occasions, the features of both neurofibromatosis and Noonan syndrome co\u2010exist within an individual; such patients are diagnosed as having neurofibromatosis\u2013Noonan syndrome. Here, we report familial patients with multiple caf\u00e9 au lait spots and Noonan syndrome\u2010like facial features. A mutation analysis unexpectedly revealed a mutation in <jats:italic>MAP2K2<\/jats:italic> in both the propositus and his mother. The propositus fulfilled the diagnostic criteria for neurofibromatosis type 1, but his mother did not. Their phenotype was not consistent with that of cardio\u2010facio\u2010cutaneous syndrome, which is classically known to be associated with <jats:italic>MAP2K2<\/jats:italic> mutations. The mother of the propositus had cervical cancer at the age of 23 years, consistent with the oncogenic tendency associated with rasopathies. The phenotypic combination of multiple caf\u00e9 au lait spots and Noonan syndrome\u2010like facial features suggested a diagnosis of neurofibromatosis\u2013Noonan syndrome. Whether this condition represents a discrete disease entity or a variable expression of neurofibromatosis type 1 has long been debated. The present observation suggests that some perturbation in the RAS\/MAPK signaling cascade results in multiple caf\u00e9 au lait spots, a key diagnostic phenotype of rasopathies, although the exact mechanism remains to be elucidated. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.36288","type":"journal-article","created":{"date-parts":[[2013,12,5]],"date-time":"2013-12-05T20:18:38Z","timestamp":1386274718000},"page":"392-396","source":"Crossref","is-referenced-by-count":12,"title":["Multiple caf\u00e9 au lait spots in familial patients with <i>MAP2K2<\/i> mutation"],"prefix":"10.1002","volume":"164","author":[{"given":"Toshiki","family":"Takenouchi","sequence":"first","affiliation":[{"name":"Department of Pediatrics Keio University School of Medicine Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology Keio University School of Medicine Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiharu","family":"Torii","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rika","family":"Kosaki","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics National Center for Child Health and Development Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takao","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Keio University School of Medicine Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideyuki","family":"Saya","sequence":"additional","affiliation":[{"name":"Division of Gene Regulation Institute for Advanced Medical Research Keio University School of Medicine Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenjiro","family":"Kosaki","sequence":"additional","affiliation":[{"name":"Center for Medical Genetics Keio University School of Medicine Tokyo 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