{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:01:35Z","timestamp":1791295295783,"version":"4.1.0"},"reference-count":28,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2016,6,5]],"date-time":"2016-06-05T00:00:00Z","timestamp":1465084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM114736 (COBRE)"],"award-info":[{"award-number":["P30GM114736 (COBRE)"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103446 (INBRE)"],"award-info":[{"award-number":["P20GM103446 (INBRE)"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:sec>\n                    <jats:label\/>\n                    <jats:p>\n                      Noonan syndrome is a rasopathy caused by mutations in multiple genes encoding components of the RAS\/MAPK pathway. Despite its variable phenotype, limited genotype\u2013phenotype correlations exist. Noonan syndrome with loose anagen hair (NS\u2010LAH) is characterized by its distinctive hair anomalies, developmental differences, and structural brain abnormalities and is caused by a single recurrent missense\n                      <jats:italic>SHOC2<\/jats:italic>\n                      mutation. SHOC2 forms a complex with protein phosphatase 1 (PP1C). Protein phosphatases counterbalance kinases and control activation of signaling proteins, such as the mitogen\u2010activated protein kinases of the RAS\/MAPK pathway. Here we report four patients with de novo missense mutations in protein phosphatase one catalytic subunit beta (PPP1CB), sharing a recognizable phenotype. Three individuals had the recurrent PPP1CB c.146G&gt;C, p.Pro49Arg mutation, the fourth had a c.166G&gt;C, p.Ala56Pro change. All had relative or absolute macrocephaly, low\u2010set and posteriorly angulated ears, and developmental delay. Slow growing and\/or sparse hair and\/or an unruly hair texture was present in all. Three individuals had feeding difficulties requiring feeding tubes. One of two males had cryptorchidism, another had pectus excavatum. Short stature was present in three. A female with the recurrent mutation had a Dandy\u2013Walker malformation and optic nerve hypoplasia. Mild ventriculomegaly occurred in all, cerebellar tonsillar ectopia was seen in two and progressed to Chiari 1 malformation in one individual. Based on the combination of phenotypic findings and PPP1CB's effect on RAF dephosphorylation within the RAS\/MAPK pathway, this novel condition can be considered a rasopathy, most similar to NS\u2010LAH. Collectively, these mutations meet the standardized criteria for pathogenicity. \u00a9 2016 Wiley Periodicals, Inc.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ajmg.a.37781","type":"journal-article","created":{"date-parts":[[2016,6,5]],"date-time":"2016-06-05T23:58:41Z","timestamp":1465171121000},"page":"2237-2247","source":"Crossref","is-referenced-by-count":129,"title":["A novel rasopathy caused by recurrent de novo missense mutations in\n                    <i>PPP1CB<\/i>\n                    closely resembles Noonan syndrome with loose anagen hair"],"prefix":"10.1002","volume":"170","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":"Kimberly A.","family":"Aldinger","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James T.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Center for Integrative Brain Research Seattle Children's Research Institute Seattle Washington"},{"name":"Department of Pediatrics University of Washington Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Baker","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics A. I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Tusi","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics A. I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Powell\u2010Hamilton","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics A. I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Stabley","sequence":"additional","affiliation":[{"name":"Center for Applied Clinical Genomics A. I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Sol\u2010Church","sequence":"additional","affiliation":[{"name":"Center for Applied Clinical Genomics A. I. duPont Hospital for Children Wilmington Delaware"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew E.","family":"Timms","sequence":"additional","affiliation":[{"name":"Center for Developmental Biology and Regenerative Medicine Seattle Children's Research Institute Seattle Washington"}],"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"}]}],"member":"311","published-online":{"date-parts":[[2016,6,5]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M003259200"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.spen.2009.06.003"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36697"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/NRL.0b013e31817833c4"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.425"},{"key":"e_1_2_7_7_1","first-page":"408","article-title":"Arnold\u2010Chiari malformation in Noonan syndrome and other syndromes of the RAS\/MAPK pathway","volume":"60","author":"Ejarque I","year":"2015","journal-title":"Rev Neurol"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35449"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33391"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33884"},{"key":"e_1_2_7_11_1","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1002\/ajmg.a.36098","article-title":"Expanding the SHOC2 mutation associated phenotype of Noonan syndrome with loose anagen hair: Structural brain anomalies and myelofibrosis","volume":"161","author":"Gripp KW","year":"2013","journal-title":"Am J Med Genet A"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004772"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00019605-200310000-00013"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2009.03.027"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00381-012-2000-9"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2892"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.10923"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.4103\/2152\u20107806.125546"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2013-3189"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.148"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61023-X"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2006.03.027"},{"key":"e_1_2_7_24_1","unstructured":"VincentLM Mason\u2010SuaresH MaoR DillonMW WilliamsB SmpokouP GrippKW RauenKA RobertsAE GelbBD BaleS.Optimization and utilization of ACMG variant classification criteria for the rasopathies: A ClinGen initiative. 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