{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T04:39:14Z","timestamp":1774327154583,"version":"3.50.1"},"reference-count":32,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T00:00:00Z","timestamp":1748563200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Noonan syndrome (NS) is a genetic disorder characterized by distinctive craniofacial and skeletal features, short stature, mild to moderate developmental impairment, and multisystem involvement, notably affecting the cardiovascular, musculoskeletal, and endocrine systems. Although abnormalities of the bone matrix, as well as osteopenia and osteoporosis, are well recognized in individuals with NS and other RASopathies, the specific impact of RAS\/MAPK pathway dysregulation on bone health remains poorly understood. Objectives: The aim of this study was to evaluate bone turnover and bone remodeling markers in a cohort of children with NS, to gain further insights into the bone status of these patients. Methods: In this cross-sectional, case-control study, we analyzed 28 children (20 males) with a molecular diagnosis of NS and 35 healthy subjects (21 males), matched by age and sex. We assessed markers of bone metabolism and bone turnover (calcium, phosphate, PTH, 25(OH)-vitamin D, osteocalcin, procollagen I N-propeptide-P1NP, bone alkaline phosphatase-BALP, C-telopeptides of type I collagen-CTX) and bone remodeling (RANKL, OPG, and sclerostin). Bone mineralization was measured at the lumbar spine (L2\u2013L4) using dual-energy X-ray absorptiometry (DEXA). Results: Serum CTX levels were significantly higher in NS patients compared to controls (1.8 \u00b1 0.7 vs. 1.3 \u00b1 0.5 ng\/mL, p = 0.0004). RANKL levels were higher in NS patients, although the difference did not reach statistical significance. No significant differences were found for OPG, sclerostin, or other markers of bone metabolism between patients and controls. Conclusions: Children with NS exhibit increased bone resorption, as indicated by elevated CTX levels, suggesting a potential imbalance in bone remodeling processes. Further studies are warranted to better define the impact of RAS\/MAPK pathway dysregulation on bone health in this population.<\/jats:p>","DOI":"10.3390\/genes16060668","type":"journal-article","created":{"date-parts":[[2025,5,30]],"date-time":"2025-05-30T08:07:58Z","timestamp":1748592478000},"page":"668","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Serum Markers of Bone Turnover and Bone Remodeling in Children with Noonan Syndrome: Genotype-Phenotype Correlation"],"prefix":"10.3390","volume":"16","author":[{"given":"Mariangela","family":"Chiarito","sequence":"first","affiliation":[{"name":"Giovanni XXIII Pediatric Hospital, University of Bari \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0002-7396","authenticated-orcid":false,"given":"Ilaria","family":"Farella","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, LUM University, 70010 Casamassima, Italy"},{"name":"Neonatology Department, Regional General Hospital \u201cF. Miulli\u201d, 70021 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Crescenza","family":"Lattanzio","sequence":"additional","affiliation":[{"name":"Giovanni XXIII Pediatric Hospital, University of Bari \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossella","family":"Vitale","sequence":"additional","affiliation":[{"name":"Giovanni XXIII Pediatric Hospital, University of Bari \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavia","family":"Urbano","sequence":"additional","affiliation":[{"name":"Giovanni XXIII Pediatric Hospital, University of Bari \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Guida","sequence":"additional","affiliation":[{"name":"Neonatology Department, Regional General Hospital \u201cF. Miulli\u201d, 70021 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Piacente","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8813-3200","authenticated-orcid":false,"given":"Paola","family":"Muggeo","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology and Hematology, University Hospital of Policlinic, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1899-8337","authenticated-orcid":false,"given":"Maria Felicia","family":"Faienza","sequence":"additional","affiliation":[{"name":"Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University \u201cA. Moro\u201d, 70124 Bari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,30]]},"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","unstructured":"Libraro, A., D\u2019Ascanio, V., Cappa, M., Chiarito, M., Digilio, M.C., Einaudi, S., Grandone, A., Maghnie, M., Mazzanti, L., and Mussa, A. (2021). Growth in children with noonan syndrome and effects of growth hormone treatment on adult height. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.761171"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Faienza, M.F., Meliota, G., Mentino, D., Ficarella, R., Gentile, M., Vairo, U., and D\u2019amato, G. (2024). Cardiac phenotype and gene mutations in RASopathies. 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