{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T12:06:19Z","timestamp":1770897979492,"version":"3.50.1"},"reference-count":35,"publisher":"American Academy of Pediatrics (AAP)","issue":"6","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,12,1]]},"abstract":"<jats:p>RASopathies, such as Noonan, Costello, and cardio-facio-cutaneous syndromes, are developmental disorders caused by mutations in rat sarcoma\u2013mitogen-activated protein kinase pathway genes. Mutations that cause Noonan syndrome have been associated with delayed puberty. Here we report 4 patients with either Costello or cardio-facio-cutaneous syndrome who developed precocious puberty, suggesting complex regulation of the hypothalamic\u2013pituitary\u2013gonadal axis and the timing of puberty by the rat sarcoma\u2013mitogen-activated protein kinase pathway. Additional study of the timing of puberty among patients with RASopathies is warranted to ascertain the incidence of delayed and precocious puberty in these conditions and to examine genotype\u2013phenotype correlations, which may provide insight into pathways that regulate the timing of puberty.<\/jats:p>","DOI":"10.1542\/peds.2016-0182","type":"journal-article","created":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T10:10:10Z","timestamp":1479895810000},"source":"Crossref","is-referenced-by-count":11,"title":["RASopathies Are Associated With Delayed Puberty; Are They Associated With Precocious Puberty Too?"],"prefix":"10.1542","volume":"138","author":[{"given":"Dani\u00eblle C.M.","family":"van der Kaay","sequence":"first","affiliation":[{"name":"Divisions of Endocrinology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bat-Sheva","family":"Levine","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Boston Children\u2019s Hospital, Boston, Massachusetts; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Doyle","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Nemours Alfred I. Dupont Hospital for Children, Wilmington, Delaware"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roberto","family":"Mendoza-Londono","sequence":"additional","affiliation":[{"name":"Divisions of Endocrinology and"},{"name":"Clinical and Metabolic Genetics, The Hospital for Sick Children, and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark R.","family":"Palmert","sequence":"additional","affiliation":[{"name":"Divisions of Endocrinology and"},{"name":"Departments of Pediatrics and"},{"name":"Physiology, The University of Toronto, Toronto, Ontario, Canada;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"417","published-online":{"date-parts":[[2016,12,1]]},"reference":[{"issue":"5\u20136","key":"2021120904591143100_B1","first-page":"405","article-title":"Normosmic idiopathic hypogonadotropic hypogonadism: update on the genetic background and future challenges","volume":"26","author":"Fathi","year":"2013","journal-title":"J Pediatr Endocrinol Metab"},{"issue":"7520","key":"2021120904591143100_B2","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature13545","article-title":"Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.","volume":"514","author":"Perry","year":"2014","journal-title":"Nature"},{"issue":"1\u20132","key":"2021120904591143100_B3","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.mce.2010.01.038","article-title":"Genetic determinants of pubertal timing in the general population.","volume":"324","author":"Gajdos","year":"2010","journal-title":"Mol Cell Endocrinol"},{"key":"2021120904591143100_B4","doi-asserted-by":"crossref","first-page":"e37","DOI":"10.1017\/S1462399408000902","article-title":"Noonan, Costello and cardio-facio-cutaneous syndromes: dysregulation of the Ras-MAPK pathway.","volume":"10","author":"Tidyman","year":"2008","journal-title":"Expert Rev Mol Med"},{"issue":"4","key":"2021120904591143100_B5","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1097\/MOP.0b013e32834881dd","article-title":"Clinical manifestations of mutations in RAS and related intracellular signal transduction factors.","volume":"23","author":"Zenker","year":"2011","journal-title":"Curr Opin Pediatr"},{"issue":"3","key":"2021120904591143100_B6","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.gde.2009.04.001","article-title":"The RASopathies: developmental syndromes of Ras\/MAPK pathway dysregulation.","volume":"19","author":"Tidyman","year":"2009","journal-title":"Curr Opin Genet Dev"},{"key":"2021120904591143100_B7","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 Genomics Hum Genet"},{"issue":"5","key":"2021120904591143100_B8","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1002\/ajmg.a.35292","article-title":"Prevalence and clinical features of Costello syndrome and cardio-facio-cutaneous syndrome in Japan: findings from a nationwide epidemiological survey.","volume":"158A","author":"Abe","year":"2012","journal-title":"Am J Med Genet A"},{"issue":"4","key":"2021120904591143100_B9","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1542\/peds.2009-3207","article-title":"Noonan syndrome: clinical features, diagnosis, and management guidelines.","volume":"126","author":"Romano","year":"2010","journal-title":"Pediatrics"},{"issue":"2","key":"2021120904591143100_B10","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1002\/ajmg.a.30747","article-title":"The adult phenotype in Costello syndrome.","volume":"136","author":"White","year":"2005","journal-title":"Am J Med Genet A"},{"issue":"3","key":"2021120904591143100_B11","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S0022-3476(98)70284-7","article-title":"Costello syndrome: phenotype, natural history, differential diagnosis, and possible cause.","volume":"133","author":"Johnson","year":"1998","journal-title":"J Pediatr"},{"issue":"2","key":"2021120904591143100_B12","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1002\/(SICI)1096-8628(19990115)82:2<187::AID-AJMG17>3.0.CO;2-2","article-title":"Costello syndrome: report and review.","volume":"82","author":"van Eeghen","year":"1999","journal-title":"Am J Med Genet"},{"issue":"1","key":"2021120904591143100_B13","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/ajmg.a.10236","article-title":"Further delineation of the behavioral and neurologic features in Costello syndrome.","volume":"118A","author":"Kawame","year":"2003","journal-title":"Am J Med Genet A"},{"issue":"5","key":"2021120904591143100_B14","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1136\/jmg.2005.040352","article-title":"Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.","volume":"43","author":"Kerr","year":"2006","journal-title":"J Med Genet"},{"issue":"4","key":"2021120904591143100_B15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1136\/jmg.2007.054460","article-title":"Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations.","volume":"45","author":"Armour","year":"2008","journal-title":"J Med Genet"},{"issue":"1","key":"2021120904591143100_B16","doi-asserted-by":"crossref","first-page":"55","DOI":"10.4274\/Jcrpe.1151","article-title":"Cardio-facio-cutaneous syndrome with precocious puberty, growth hormone deficiency and hyperprolactinemia.","volume":"6","author":"\u00c7elik","year":"2014","journal-title":"J Clin Res Pediatr Endocrinol"},{"issue":"15","key":"2021120904591143100_B17","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1002\/ajmg.a.31315","article-title":"Distinguishing Costello versus cardio-facio-cutaneous syndrome: BRAF mutations in patients with a Costello phenotype.","volume":"140","author":"Rauen","year":"2006","journal-title":"Am J Med Genet A"},{"issue":"1","key":"2021120904591143100_B18","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1136\/archdischild-2013-304414","article-title":"Use of local data to enhance uptake of published recommendations: an example from the diagnostic evaluation of precocious puberty.","volume":"99","author":"Harrington","year":"2014","journal-title":"Arch Dis Child"},{"issue":"3","key":"2021120904591143100_B19","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1159\/000336325","article-title":"Recent secular trends in pubertal timing: implications for evaluation and diagnosis of precocious puberty.","volume":"77","author":"S\u00f8rensen","year":"2012","journal-title":"Horm Res Paediatr"},{"issue":"11","key":"2021120904591143100_B20","doi-asserted-by":"crossref","first-page":"1045","DOI":"10.1007\/s00247-005-1512-9","article-title":"MRI of the hypothalamic\u2013pituitary axis in children.","volume":"35","author":"Argyropoulou","year":"2005","journal-title":"Pediatr Radiol"},{"issue":"1","key":"2021120904591143100_B21","doi-asserted-by":"crossref","first-page":"e29829","DOI":"10.1371\/journal.pone.0029829","article-title":"Pathological and incidental findings on brain MRI in a single-center study of 229 consecutive girls with early or precocious puberty.","volume":"7","author":"Mogensen","year":"2012","journal-title":"PLoS One"},{"issue":"12","key":"2021120904591143100_B22","doi-asserted-by":"crossref","first-page":"4455","DOI":"10.1210\/jc.2014-2702","article-title":"Routine screening by brain magnetic resonance imaging is not indicated in every girl with onset of puberty between the ages of 6 and 8 years.","volume":"99","author":"Pedicelli","year":"2014","journal-title":"J Clin Endocrinol Metab"},{"issue":"4","key":"2021120904591143100_B23","doi-asserted-by":"crossref","DOI":"10.1542\/peds.2013-3189","article-title":"Cardio-facio-cutaneous syndrome: clinical features, diagnosis, and management guidelines.","volume":"134","author":"Pierpont","year":"2014","journal-title":"Pediatrics"},{"key":"2021120904591143100_B24","article-title":"Objective studies of the face of Noonan, cardio-facio-cutaneous, and Costello syndromes: a comparison of three disorders of the Ras\/MAPK signaling pathway","author":"Allanson","journal-title":"Am J Med Genet A"},{"issue":"1","key":"2021120904591143100_B25","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.yfrne.2008.07.001","article-title":"Signaling by G-protein-coupled receptor (GPCR): studies on the GnRH receptor.","volume":"30","author":"Naor","year":"2009","journal-title":"Front Neuroendocrinol"},{"issue":"1\u20132","key":"2021120904591143100_B26","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.mce.2013.08.015","article-title":"Outside the box signaling: secreted factors modulate GnRH receptor\u2013mediated gonadotropin regulation.","volume":"385","author":"Pincas","year":"2014","journal-title":"Mol Cell Endocrinol"},{"key":"2021120904591143100_B27","doi-asserted-by":"crossref","first-page":"180","DOI":"10.3389\/fendo.2013.00180","article-title":"Molecular mechanisms of gonadotropin-releasing hormone signaling: integrating cyclic nucleotides into the network.","volume":"4","author":"Perrett","year":"2013","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"4","key":"2021120904591143100_B28","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1159\/000354305","article-title":"Endocrine problems in children and adolescents who have disabilities.","volume":"80","author":"Zacharin","year":"2013","journal-title":"Horm Res Paediatr"},{"issue":"3","key":"2021120904591143100_B29","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1385\/ENDO:12:3:257","article-title":"Stimulation of mitogen-activated protein kinase pathway in rat somatotrophs by growth hormone\u2013releasing hormone.","volume":"12","author":"Zeitler","year":"2000","journal-title":"Endocrine"},{"key":"2021120904591143100_B30","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1159\/000342573","article-title":"New aspects of the physiology of the GH-IGF-1 axis.","volume":"24","author":"Vottero","year":"2013","journal-title":"Endocr Dev"},{"issue":"1","key":"2021120904591143100_B31","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1210\/me.2009-0233","article-title":"In vivo targeting of the growth hormone receptor (GHR) Box1 sequence demonstrates that the GHR does not signal exclusively through JAK2.","volume":"24","author":"Barclay","year":"2010","journal-title":"Mol Endocrinol"},{"issue":"1","key":"2021120904591143100_B32","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.ajhg.2013.05.021","article-title":"Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS\/MAPK pathway syndrome.","volume":"93","author":"Aoki","year":"2013","journal-title":"Am J Hum Genet"},{"issue":"1","key":"2021120904591143100_B33","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/jhg.2015.114","article-title":"Recent advances in RASopathies.","volume":"61","author":"Aoki","year":"2016","journal-title":"J Hum Genet"},{"issue":"2","key":"2021120904591143100_B34","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1002\/ajmg.a.36842","article-title":"A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines.","volume":"167A","author":"Nishi","year":"2015","journal-title":"Am J Med Genet A"},{"issue":"4","key":"2021120904591143100_B35","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1159\/000369802","article-title":"Endocrine implications of neurofibromatosis 1 in childhood.","volume":"83","author":"Bizzarri","year":"2015","journal-title":"Horm Res Paediatr"}],"container-title":["Pediatrics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/doi\/10.1542\/peds.2016-0182\/911022\/peds_20160182.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/publications.aap.org\/pediatrics\/article-pdf\/doi\/10.1542\/peds.2016-0182\/911022\/peds_20160182.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T16:47:41Z","timestamp":1657817261000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.aap.org\/pediatrics\/article\/138\/6\/e20160182\/52587\/RASopathies-Are-Associated-With-Delayed-Puberty"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,1]]},"references-count":35,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2016,12,1]]},"published-print":{"date-parts":[[2016,12,1]]}},"URL":"https:\/\/doi.org\/10.1542\/peds.2016-0182","relation":{},"ISSN":["0031-4005","1098-4275"],"issn-type":[{"value":"0031-4005","type":"print"},{"value":"1098-4275","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,1]]},"article-number":"e20160182"}}