{"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":1789642953372,"version":"4.0.0"},"reference-count":36,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2013,8,5]],"date-time":"2013-08-05T00:00:00Z","timestamp":1375660800000},"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":[[2013,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:label\/><jats:p>Noonan syndrome is a heterogenous rasopathy typically presenting with short stature, characteristic facial features, cardiac abnormalities including pulmonic valve stenosis, ASD and hypertrophic cardiomyopathy (HCM), cryptorchidism, ectodermal abnormalities, and learning differences. The phenotype is variable, and limited genotype phenotype correlation exists with <jats:italic>SOS1<\/jats:italic> mutations often associated with normal cognition and stature, <jats:italic>RAF1<\/jats:italic> mutations entailing a high HCM risk, and certain <jats:italic>PTPN11<\/jats:italic> mutations predisposing to juvenile myelomonocytic leukemia. The recently identified <jats:italic>SHOC2<\/jats:italic> mutation (p.Ser2Gly) causes Noonan syndrome with loose anagen hair. We report five patients with this mutation. All had skin hyperpigmentation, sparse light colored hair, increased fine wrinkles, ligamentous laxity, developmental delay, and 4\/4 had a structural cardiac anomaly. Hypotonia and macrocephaly occurred in 4\/5 (80%); 3\/5 (60%) had polyhydramnios, increased birth weight or required use of a feeding tube. Distinctive brain abnormalities included relative megalencephaly and enlarged subarachnoid spaces suggestive of benign external hydrocephalus, and a relatively small posterior fossa as indicated by a vertical tentorium. The combination of a large brain with a small posterior fossa likely resulted in the high rate of cerebellar tonsillar ectopia (3\/4; 75%). Periventricular nodular heterotopia was seen in one patient with a thick and dysplastic corpus callosum. We report on the first hematologic neoplasm, myelofibrosis, in a 2\u2010year\u2010old patient with <jats:italic>SHOC2<\/jats:italic> mutation. Myelofibrosis is exceedingly rare in children and young adults. The absence of a somatic <jats:italic>JAK2<\/jats:italic> mutation, seen in the majority of patients with myelofibrosis, is noteworthy as it suggests that germline or somatic <jats:italic>SHOC2<\/jats:italic> mutations are causally involved in myelofibrosis. \u00a9 2013 Wiley Periodicals, Inc.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.36098","type":"journal-article","created":{"date-parts":[[2013,8,5]],"date-time":"2013-08-05T17:23:22Z","timestamp":1375723402000},"page":"2420-2430","source":"Crossref","is-referenced-by-count":66,"title":["Expanding the SHOC2 mutation associated phenotype of noonan syndrome with loose anagen hair: Structural brain anomalies and myelofibrosis"],"prefix":"10.1002","volume":"161","author":[{"given":"Karen W.","family":"Gripp","sequence":"first","affiliation":[{"name":"Division of Medical Genetics A. I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dina J.","family":"Zand","sequence":"additional","affiliation":[{"name":"Division of Genetics and Metabolism Children's National Medical Center Washington District of Columbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Demmer","sequence":"additional","affiliation":[{"name":"Division of Clinical Genetics Levine Children's Hospital Charlotte North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol E.","family":"Anderson","sequence":"additional","affiliation":[{"name":"Section of Clinical Genetics St. Christopher's Hospital for Children Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William B.","family":"Dobyns","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine H.","family":"Zackai","sequence":"additional","affiliation":[{"name":"Division of Genetics The Children's Hospital of Philadelphia Philadelphia Pennsylvania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Denenberg","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics A. I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Jenny","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics A. I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah L.","family":"Stabley","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research Nemours' Children's Clinic Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Sol\u2010Church","sequence":"additional","affiliation":[{"name":"Department of Biomedical Research Nemours' Children's Clinic Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,8,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.seizure.2011.07.013"},{"key":"e_1_2_7_3_1","unstructured":"AllansonJE RobertsAE.2011.Noonan syndrome. In: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. 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