{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T23:06:37Z","timestamp":1790723197732,"version":"4.1.0"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T00:00:00Z","timestamp":1711843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Catholic Medical Center Research Foundation made in the program year of 2023","award":["2021R1F1A1063568"],"award-info":[{"award-number":["2021R1F1A1063568"]}]},{"name":"Korean government (Ministry of Science and ICT (MSIT)","award":["2021R1F1A1063568"],"award-info":[{"award-number":["2021R1F1A1063568"]}]},{"name":"Fund of Biomedical Research Institute, Jeonbuk National University Hospital","award":["2021R1F1A1063568"],"award-info":[{"award-number":["2021R1F1A1063568"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Noonan syndrome (NS)\/Noonan syndrome with multiple lentigines (NSML) is commonly characterized by distinct facial features, a short stature, cardiac problems, and a developmental delay of variable degrees. However, as many as 50% of individuals diagnosed with NS\/NSML have a mildly affected parent or relative due to variable expressivity and possibly incomplete penetrance of the disorder, and those who are recognized to have NS only after a diagnosis are established in a more obviously affected index case. Methods: In order to collect intergenerational data reported from previous studies, electronic journal databases containing information on the molecular genetics of PTPN11 were searched from 2000 to 2022. Results: We present a case of a proband with a PTPN11 variant (c.1492C &gt; T\/p.Arg498Trp) inherited from an asymptomatic father, displaying only mild intellectual disability without classical symptoms of NS. Among our cases and the reported NS cases caused by the PTPN11 p.Arg498Trp variant, cardiac abnormalities (6\/11), facial dysmorphism (7\/11), skin pigmentation (4\/11), growth problems (4\/11), and sensorineural hearing loss (2\/11) have been observed. NS\/NSML patients with the PTPN11 p.Arg498Trp variant tend to exhibit relatively lower frequencies of skin pigmentation, facial dysmorphism and cardiac abnormalities and mild symptoms compared to those carrying any other mutated PTPN11. Conclusions: Paternally inherited NS\/NSML caused by a PTPN11 p.Arg498Trp variant, including our cases, may exhibit relatively lower frequencies of abnormal features and mild symptoms. This could be ascribed to potential gene\u2013gene interactions, gene\u2013environment interactions, the gender and phenotype of the transmitting parent, or ethnic differences that influence the clinical phenotype.<\/jats:p>","DOI":"10.3390\/genes15040445","type":"journal-article","created":{"date-parts":[[2024,3,31]],"date-time":"2024-03-31T13:42:30Z","timestamp":1711892550000},"page":"445","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Paternally Inherited Noonan Syndrome Caused by a PTPN11 Variant May Exhibit Mild Symptoms: A Case Report and Literature Review"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4174-5266","authenticated-orcid":false,"given":"Ji Yoon","family":"Han","sequence":"first","affiliation":[{"name":"Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7354-4234","authenticated-orcid":false,"given":"Joonhong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Republic of Korea"},{"name":"Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","author":"Roberts","year":"2013","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1002\/humu.20955","article-title":"Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum","volume":"30","author":"Sarkozy","year":"2009","journal-title":"Hum. Mutat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1159\/000331266","article-title":"RASopathies: Clinical Diagnosis in the First Year of Life","volume":"1","author":"Digilio","year":"2011","journal-title":"Mol. Syndromol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/humu.20005","article-title":"Noonan syndrome-associated SHP2\/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2\/MAPK1 activation","volume":"23","author":"Fragale","year":"2004","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"6785","DOI":"10.1074\/jbc.M513068200","article-title":"PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects","volume":"281","author":"Kontaridis","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.braindev.2011.10.011","article-title":"Involvement of SHP2 in focal adhesion, migration and differentiation of neural stem cells","volume":"34","author":"Huang","year":"2012","journal-title":"Brain Dev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8855","DOI":"10.1523\/JNEUROSCI.0137-12.2012","article-title":"ERK1\/ERK2 MAPK signaling is required to increase myelin thickness independent of oligodendrocyte differentiation and initiation of myelination","volume":"32","author":"Ishii","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1736","DOI":"10.1038\/nn.3863","article-title":"Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome","volume":"17","author":"Lee","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1557","DOI":"10.1128\/MCB.01339-14","article-title":"Shp2 in forebrain neurons regulates synaptic plasticity, locomotion, and memory formation in mice","volume":"35","author":"Kusakari","year":"2015","journal-title":"Mol. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Athota, J.P., Bhat, M., Nampoothiri, S., Gowrishankar, K., Narayanachar, S.G., Puttamallesh, V., Farooque, M.O., and Shetty, S. (2020). Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations. BMC Med. Genet., 21.","DOI":"10.1186\/s12881-020-0986-5"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1159\/000342251","article-title":"LEOPARD Syndrome: Clinical Features and Gene Mutations","volume":"3","year":"2012","journal-title":"Mol. Syndromol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e68","DOI":"10.1136\/jmg.2003.013466","article-title":"Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome","volume":"41","author":"Sarkozy","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"31622","DOI":"10.1038\/srep31622","article-title":"Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss","volume":"6","author":"Bademci","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1093\/cercor\/bhy158","article-title":"PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention","volume":"29","author":"Johnson","year":"2019","journal-title":"Cereb. Cortex"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1002\/ajmg.a.31156","article-title":"LEOPARD syndrome: Clinical diagnosis in the first year of life","volume":"140","author":"Digilio","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s00431-005-0031-x","article-title":"Lethal proliferation of erythroid precursors in a neonate with a germline PTPN11 mutation","volume":"165","author":"Kratz","year":"2006","journal-title":"Eur. J. Pediatr."},{"key":"ref_17","first-page":"1210","article-title":"A novel PTPN11 gene mutation in a patient with LEOPARD Syndrome","volume":"143","author":"Cave","year":"2007","journal-title":"Arch. Dermatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1002\/ajmg.a.32206","article-title":"Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome","volume":"146a","author":"Limongelli","year":"2008","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1002\/ajmg.a.36620","article-title":"A PTPN11 allele encoding a catalytically impaired SHP2 protein in a patient with a Noonan syndrome phenotype","volume":"164a","author":"Edwards","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1146\/annurev.nutr.27.061406.093705","article-title":"Epigenetic epidemiology of the developmental origins hypothesis","volume":"27","author":"Waterland","year":"2007","journal-title":"Annu. Rev. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.1073\/pnas.0502024102","article-title":"Gene regulatory networks","volume":"102","author":"Davidson","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.recesp.2012.09.017","article-title":"LEOPARD syndrome: A variant of Noonan syndrome strongly associated with hypertrophic cardiomyopathy","volume":"66","author":"Carcavilla","year":"2013","journal-title":"Rev. Esp. Cardiol. (Engl. Ed.)"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1750-1172-3-13","article-title":"Leopard syndrome","volume":"3","author":"Sarkozy","year":"2008","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/j.beem.2010.09.002","article-title":"Noonan syndrome and clinically related disorders","volume":"25","author":"Tartaglia","year":"2011","journal-title":"Best. Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"452","DOI":"10.25259\/IJDVL_799_20","article-title":"RASopathies: Dermatologists\u2019 viewpoints","volume":"88","author":"Palit","year":"2022","journal-title":"Indian J. Dermatol. Venereol. Leprol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1146\/annurev-genom-091212-153523","article-title":"The RASopathies","volume":"14","author":"Rauen","year":"2013","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8541","DOI":"10.1038\/s41598-017-08902-1","article-title":"Decoding disease-causing mechanisms of missense mutations from supramolecular structures","volume":"7","author":"Hijikata","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"dmm049344","DOI":"10.1242\/dmm.049344","article-title":"Defining RASopathy","volume":"15","author":"Rauen","year":"2022","journal-title":"Dis. Model. Mech."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"10472","DOI":"10.1074\/jbc.M113.450023","article-title":"Structural and mechanistic insights into LEOPARD syndrome-associated SHP2 mutations","volume":"288","author":"Yu","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"4136","DOI":"10.1021\/bi5002695","article-title":"Molecular basis of gain-of-function LEOPARD syndrome-associated SHP2 mutations","volume":"53","author":"Yu","year":"2014","journal-title":"Biochemistry"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1111\/cge.13904","article-title":"Compound heterozygosity for PTPN11 variants in a subject with Noonan syndrome provides insights into the mechanism of SHP2-related disorders","volume":"99","author":"Lorca","year":"2021","journal-title":"Clin. Genet."},{"key":"ref_32","first-page":"117","article-title":"Familial Noonan Syndrome Confirmed by PTPN11 Gene Test","volume":"13","author":"Kim","year":"2008","journal-title":"Ann. Pediatr. Endocrinol. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3242","DOI":"10.1002\/ajmg.a.62955","article-title":"Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study","volume":"188","author":"Swarts","year":"2022","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1086\/340847","article-title":"PTPN11 mutations in Noonan syndrome: Molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity","volume":"70","author":"Tartaglia","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1146\/annurev.genom.6.080604.162305","article-title":"Noonan syndrome and related disorders: Genetics and pathogenesis","volume":"6","author":"Tartaglia","year":"2005","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1086\/423493","article-title":"Paternal germline origin and sex-ratio distortion in transmission of PTPN11 mutations in Noonan syndrome","volume":"75","author":"Tartaglia","year":"2004","journal-title":"Am. J. Hum. Genet."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/4\/445\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:21:46Z","timestamp":1760106106000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/4\/445"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,31]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["genes15040445"],"URL":"https:\/\/doi.org\/10.3390\/genes15040445","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,31]]}}}