{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T05:07:37Z","timestamp":1794028057179,"version":"4.8.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T00:00:00Z","timestamp":1690502400000},"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. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Noonan syndrome (NS) is a genetic multisystem disorder characterised by variable clinical manifestations including dysmorphic facial features, short stature, congenital heart disease, renal anomalies, lymphatic malformations, chest deformities, cryptorchidism in males.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this narrative review, we summarized the available data on puberty and gonadal function in NS subjects and the role of the RAS\/mitogen-activated protein kinase (MAPK) signalling pathway in fertility. In addition, we have reported our personal experience on pubertal development and vertical transmission in NS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>According to the literature and to our experience, NS patients seem to have a delay in puberty onset compared to the physiological timing reported in healthy children. Males with NS seem to be at risk of gonadal dysfunction secondary not only to cryptorchidism but also to other underlying developmental factors including the MAP\/MAPK pathway and genetics. Long-term data on a large cohort of males and females with NS are needed to better understand the impact of delayed puberty on adult height, metabolic profile and well-being. The role of genetic counselling and fertility related-issues is crucial.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2023.1213098","type":"journal-article","created":{"date-parts":[[2023,7,28]],"date-time":"2023-07-28T20:43:56Z","timestamp":1690577036000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Abnormalities of pubertal development and gonadal function in Noonan syndrome"],"prefix":"10.3389","volume":"14","author":[{"given":"Giuseppa","family":"Patti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Scaglione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia Gabriella","family":"Maiorano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Rosti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Teresa","family":"Divizia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiziana","family":"Camia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Lucia","family":"De Rose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Zucconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Casalini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Napoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natascia","family":"Di Iorgi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad","family":"Maghnie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/archdischild-2021-322858","article-title":"Noonan syndrome: improving recognition and diagnosis","volume":"107","author":"Zenker","year":"2022","journal-title":"Arch Dis Child"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(12)61023-X","article-title":"Noonan syndrome","volume":"381","author":"Roberts","year":"2013","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-006-9021-1","article-title":"Noonan syndrome and related disorders: alterations in growth and puberty","volume":"7","author":"Noonan","year":"2006","journal-title":"Rev Endocr Metab Disord"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32012","article-title":"The molecular genetics of RASopathies: An update on novel disease genes and new disorders","volume":"190","author":"Tartaglia","year":"2022","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-2-4","article-title":"Noonan syndrome","volume":"2","author":"van der Burgt","year":"2007","journal-title":"Orphanet J Rare Dis"},{"key":"B6","unstructured":"University of ManchesterManagement of Noonan syndrome \u2013 a clinical guideline"},{"key":"B7","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1007\/s00439-018-1951-7","article-title":"Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes","volume":"138","author":"Umeki","year":"2019","journal-title":"Hum Genet"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2421","DOI":"10.1038\/s41598-018-20894-0","article-title":"Integrating functional analysis in the next-generation sequencing diagnostic pipeline of RASopathies","volume":"8","author":"Leung","year":"2018","journal-title":"Sci Rep"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8166-7-28","article-title":"Rare copy number variations containing genes involved in RASopathies: deletion of SHOC2 and duplication of PTPN11","volume":"7","author":"Chen","year":"2014","journal-title":"Mol Cytogenet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-020-0658-0","article-title":"Digenic inheritance of subclinical variants in Noonan Syndrome patients: an alternative pathogenic model","volume":"28","author":"Ferrari","year":"2020","journal-title":"Eur J Hum Genet"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32015","article-title":"Clinical overview on RASopathies","volume":"190","author":"Zenker","year":"2022","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B12","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1159\/000522670","article-title":"Delayed puberty phenotype observed in noonan syndrome is more pronounced in girls than boys","volume":"95","author":"Rezende","year":"2022","journal-title":"Horm Res Paediatr"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2008-2094","article-title":"Growth response, near-adult height, and patterns of growth and puberty in patients with Noonan syndrome treated with growth hormone","volume":"94","author":"Romano","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.761171","article-title":"Growth in children with noonan syndrome and effects of growth hormone treatment on adult height","volume":"12","author":"Libraro","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37260","article-title":"Response to long-term growth hormone therapy in patients affected by RASopathies and growth hormone deficiency: Patterns of growth, puberty and final height data","author":"Tamburrino","year":"2015","journal-title":"Am J Med Genet A"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.c.32013","article-title":"Endocrinological manifestations in RASopathies","volume":"190","author":"Tamburrino","year":"2022","journal-title":"Am J Med Genet C Semin Med Genet"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/adc.2006.104547","article-title":"The natural history of Noonan syndrome: a long-term follow-up study","volume":"92","author":"Shaw","year":"2007","journal-title":"Arch Dis Child"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2020.111040","article-title":"Activation of the MAPK pathway (RASopathies) and partial growth hormone insensitivity","volume":"519","author":"Malaquias","year":"2021","journal-title":"Mol Cell Endocrinol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ando.2022.04.008","article-title":"Gonadal function in Noonan syndrome","volume":"83","author":"Edouard","year":"2022","journal-title":"Ann Endocrinol (Paris)"},{"key":"B20","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1159\/000243775","article-title":"Noonan syndrome: the hypothalamo-adrenal and hypothalamo-gonadal axes","author":"Kelnar","year":"2009","journal-title":"Horm Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-11-0092","article-title":"Testicular size development and reproductive hormones in boys and adult males with Noonan syndrome: a longitudinal study","volume":"165","author":"Ankarberg-Lindgren","year":"2011","journal-title":"Eur J Endocrinol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-18-0582","article-title":"Noonan syndrome males display Sertoli cell-specific primary testicular insufficiency","volume":"179","author":"Moniez","year":"2018","journal-title":"Eur J Endocrinol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1515\/jpem.2008.21.11.1079","article-title":"Impaired Sertoli cell function in males diagnosed with Noonan syndrome","volume":"21","author":"Marcus","year":"2008","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.31.6.468","article-title":"Genital tract function in men with Noonan syndrome","volume":"31","author":"Elsawi","year":"1994","journal-title":"J Med Genet"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62089","article-title":"Noonan syndrome with loose anagen hair with variants in the PPP1CB gene: First familial case reported","volume":"185","author":"Huckstadt","year":"2021","journal-title":"Am J Med Genet"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.2147\/TACG.S372761","article-title":"RASopathy cohort of patients enrolled in a Brazilian reference center for rare diseases: A novel familial LZTR1 variant and recurrent mutations","volume":"15","author":"Chaves Rabelo","year":"2022","journal-title":"Appl Clin Genet"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.35270","article-title":"KRAS gene mutations in Noonan syndrome familial cases cluster in the vicinity of the switch II region of the G-domain: report of another family with metopic craniosynostosis","author":"Brasil","year":"2012","journal-title":"Am J Med Genet A"},{"key":"B28","first-page":"1993","volume-title":"Noonan syndrome. GeneReviews\u00ae","author":"Roberts","year":"2001"},{"key":"B29","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1186\/s12881-015-0239-1","article-title":"Mutation in NRAS in familial Noonan syndrome\u2013case report and review of the literature","volume":"16","author":"Ekvall","year":"2015","journal-title":"BMC Med Genet"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/6891897","article-title":"Role of p38 MAPK signalling in testis development and male fertility","volume":"2022","author":"Luo","year":"2022","journal-title":"Oxid Med Cell Longev"},{"key":"B31","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.semcdb.2016.01.020","article-title":"The regulation of male fertility by the PTPN11 tyrosine phosphatase","volume":"59","author":"Puri","year":"2016","journal-title":"Semin Cell Dev Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/srep12982","article-title":"Deletion of the tyrosine phosphatase Shp2 in Sertoli cells causes infertility in mice","volume":"5","author":"Hu","year":"2015","journal-title":"Sci Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1486","article-title":"MEK\/ERK signaling directly and indirectly contributes to the cyclical self-renewal of spermatogonial stem cells","volume":"31","author":"Hasegawa","year":"2013","journal-title":"Stem Cells"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2019.1656952","article-title":"EGFR promotes the proliferation of quail follicular granulosa cells through the MAPK\/extracellular signal-regulated kinase (ERK) signaling pathway","volume":"18","author":"Wu","year":"2019","journal-title":"Cell Cycle"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/science.1171396","article-title":"MAPK3\/1 (ERK1\/2) in ovarian granulosa cells are essential for female fertility","volume":"324","author":"Fan","year":"2009","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/cells8101272","article-title":"PTPN11 (SHP2) is indispensable for growth factors and cytokine signal transduction during bovine oocyte maturation and blastocyst development","volume":"8","author":"Idrees","year":"2019","journal-title":"Cells"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCGEN.119.002690","article-title":"LZTR1-related hypertrophic cardiomyopathy without typical noonan syndrome features","volume":"13","author":"Jenkins","year":"2020","journal-title":"Circ Genom Precis Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.09.007","article-title":"SPRED2 loss-of-function causes a recessive Noonan syndrome-like phenotype","volume":"108","author":"Motta","year":"2021","journal-title":"Am J Hum Genet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/uog.23756","article-title":"Clinical experience with non-invasive prenatal screening for single-gene disorders","volume":"59","author":"Mohan","year":"2022","journal-title":"Ultrasound Obstet Gynecol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36737","article-title":"Perinatal features of the RASopathies: Noonan syndrome, cardiofaciocutaneous syndrome and Costello syndrome","author":"Myers","year":"2014","journal-title":"Am J Med Genet A"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/genes11080871","article-title":"Preimplantation genetic testing for monogenic disorders","volume":"11","author":"De Rycke","year":"2020","journal-title":"Genes (Basel)"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2014.114595","article-title":"RAS diseases in children","volume":"99","author":"Niemeyer","year":"2014","journal-title":"Haematologica"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.23358","article-title":"Bleeding disorders in Noonan syndrome","volume":"58","author":"Briggs","year":"2012","journal-title":"Pediatr Blood Cancer"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.37","article-title":"Cancer risk in patients with Noonan syndrome carrying a PTPN11 mutation","volume":"19","author":"Jongmans","year":"2011","journal-title":"Eur J Hum Genet"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/gcc.20735","article-title":"Tumor spectrum in children with Noonan syndrome and SOS1 or RAF1 mutations","volume":"49","author":"Denayer","year":"2010","journal-title":"Genes Chromosomes Cancer"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1097\/MPH.0b013e31805d8f57","article-title":"Rhabdomyosarcoma in a patient with Noonan syndrome phenotype and review of the literature","volume":"29","author":"Moschovi","year":"2007","journal-title":"J Pediatr Hematol Oncol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics10080582","article-title":"Low-grade gliomas in patients with noonan syndrome: case-based review of the literature","volume":"10","author":"Lodi","year":"2020","journal-title":"Diagnostics (Basel)"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2015.75","article-title":"Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes","volume":"112","author":"Kratz","year":"2015","journal-title":"Br J Cancer"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-0631","article-title":"Recommendations for cancer surveillance in individuals with RASopathies and other rare genetic conditions with increased cancer risk","volume":"23","author":"Villani","year":"2017","journal-title":"Clin Cancer Res"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-11-3876","article-title":"Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia","volume":"104","author":"Tartaglia","year":"2004","journal-title":"Blood"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001279","article-title":"Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy","volume":"2","author":"Estep","year":"2007","journal-title":"PloS One"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-0099","article-title":"Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma","volume":"68","author":"Marks","year":"2008","journal-title":"Cancer Res"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1136\/adc.51.3.170","article-title":"Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty","volume":"51","author":"Tanner","year":"1976","journal-title":"Arch Dis Child"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp0800459","article-title":"Clinical practice. precocious puberty","volume":"358","author":"Carel","year":"2008","journal-title":"N Engl J Med"},{"key":"B55","first-page":"1","volume-title":"Radiographic atlas of skeletal development of the hand and wrist","author":"Greulich","year":"1959"},{"key":"B56","doi-asserted-by":"publisher","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":"B57","doi-asserted-by":"publisher","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"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1213098\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T17:15:19Z","timestamp":1692638119000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1213098\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,28]]},"references-count":57,"alternative-id":["10.3389\/fendo.2023.1213098"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1213098","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,28]]},"article-number":"1213098"}}