{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T23:43:16Z","timestamp":1782603796630,"version":"3.54.5"},"reference-count":17,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>Pathogenic variants in the RASopathy-causing <jats:italic>SHOC2<\/jats:italic> gene have been suggested to cause Noonan syndrome-like with loose anagen hair (NS\/LAH). This condition is characterized by facial features resembling Noonan syndrome (NS), short stature, growth hormone deficiency (GHD), cognitive deficits, cardiac defects, and ectodermal abnormalities, including easily pluckable, sparse, thin, slow-growing hair, hyperpigmented skin and hypernasal voice. The mutation spectrum of <jats:italic>SHOC2<\/jats:italic> is narrow, and only 8 pathogenic variants have been identified. Here, we report a 5-year-3-month-old Chinese female who displays characteristics typical of NS and has normal neurodevelopment. Trio-based whole-exome sequencing (WES) revealed a <jats:italic>de novo<\/jats:italic> variant (c.1231A&amp;gt;G, p.Thr411Ala) in <jats:italic>SHOC2<\/jats:italic>. This variant has been recently reported in one subject in the literature who displayed facial features typical of NS and also presented with significant speech delays, moderate intellectual disabilities, epilepsy, bilateral sensorineural deafness and renal dysplasia. The differential phenotypes between these subjects deserve to be further investigated. Next, we reviewed the clinical pictures of NS\/LAH and noticed that a recurrent <jats:italic>SHOC2<\/jats:italic> Ser2Gly variant was more likely to result in delayed neurodevelopment and short stature, compared to other <jats:italic>SHOC2<\/jats:italic> variants. And growth hormone (GH) therapy could improve height prognosis. It was noticed that the slight sleep problems and friendly and relatively mature personality observed in our patient may be a novel phenotype of NS\/LAH. Our study reconfirms the pathogenic nature of the <jats:italic>SHOC2<\/jats:italic> Thr411Ala variant. It also provides insights into the genotype-phenotype relationship in NS\/LAH and a foundation for its genetic counseling, diagnosis and treatment.<\/jats:p>","DOI":"10.3389\/fgene.2022.1040124","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T06:09:30Z","timestamp":1670566170000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Case report: A de novo RASopathy-causing SHOC2 variant in a Chinese girl with noonan syndrome-like with loose anagen hair"],"prefix":"10.3389","volume":"13","author":[{"given":"Qingming","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangxi","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youqing","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiming","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3120","DOI":"10.1002\/ajmg.a.36697","article-title":"Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation","author":"Baldassarre","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"B2","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1002\/ajmg.a.35234","article-title":"Noonan-like syndrome with loose anagen hair associated with growth hormone insensitivity and atypical neurological manifestations","author":"Capalbo","year":"","journal-title":"Am. J. Med. Genet. A"},{"key":"B3","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/1824-7288-38-48","article-title":"Clinical Heterogeneity in two patients with Noonan-like Syndrome associated with the same SHOC2 mutation","volume":"38","author":"Capalbo","year":"","journal-title":"Ital. J. Pediatr."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1038\/ng.425","article-title":"Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair","volume":"41","author":"Cordeddu","year":"2009","journal-title":"Nat. Genet."},{"key":"B5","doi-asserted-by":"publisher","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","author":"Gripp","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1290","DOI":"10.1002\/humu.22634","article-title":"A novel SHOC2 variant in rasopathy","volume":"35","author":"Hannig","year":"2014","journal-title":"Hum. Mutat."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1411","DOI":"10.1002\/ajmg.a.35318","article-title":"Noonan syndrome due to a SHOC2 mutation presenting with fetal distress and fatal hypertrophic cardiomyopathy in a premature infant","author":"Hoban","year":"2012","journal-title":"Am. J. Med. Genet. A"},{"key":"B8","doi-asserted-by":"publisher","first-page":"290","DOI":"10.1111\/cge.13588","article-title":"Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients","volume":"96","author":"Li","year":"2019","journal-title":"Clin. Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1002\/ajmg.c.31869","article-title":"Clinical and molecular analysis of 26 individuals with Noonan syndrome in a reference institution in Colombia","volume":"184","author":"Lores","year":"2020","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"B10","doi-asserted-by":"publisher","first-page":"7818","DOI":"10.1074\/jbc.M109.053975","article-title":"The scaffold protein Shoc2\/SUR-8 accelerates the interaction of Ras and Raf","volume":"285","author":"Matsunaga-Udagawa","year":"2010","journal-title":"J. Biol. Chem."},{"key":"B11","doi-asserted-by":"publisher","first-page":"2756","DOI":"10.1002\/ajmg.a.36255","article-title":"GH Therapy and first final height data in Noonan-like syndrome with loose anagen hair (Mazzanti syndrome)","author":"Mazzanti","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1046","DOI":"10.1002\/humu.23767","article-title":"Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy","volume":"40","author":"Motta","year":"2019","journal-title":"Hum. Mutat."},{"key":"B13","doi-asserted-by":"publisher","first-page":"2766","DOI":"10.1093\/hmg\/ddac071","article-title":"Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome","volume":"31","author":"Motta","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and Genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.molcel.2006.03.027","article-title":"A phosphatase holoenzyme comprised of Shoc2\/Sur8 and the catalytic subunit of PP1 functions as an M-Ras effector to modulate Raf activity","volume":"22","author":"Rodriguez-Viciana","year":"2006","journal-title":"Mol. Cell"},{"key":"B16","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1002\/ajmg.a.37191","article-title":"Improved growth velocity of a patient with Noonan-like syndrome with loose anagen hair (NS\/LAH) without growth hormone deficiency by low-dose growth hormone therapy","author":"Takasawa","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"B17","doi-asserted-by":"publisher","first-page":"E10576","DOI":"10.1073\/pnas.1720352115","article-title":"SHOC2-MRAS-PP1 complex positively regulates RAF activity and contributes to Noonan syndrome pathogenesis","volume":"115","author":"Young","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1040124\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T21:42:45Z","timestamp":1670881365000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1040124\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,9]]},"references-count":17,"alternative-id":["10.3389\/fgene.2022.1040124"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.1040124","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,9]]},"article-number":"1040124"}}