Abstract

The RAS/Mitogen-Activated Protein Kinase (MAPK) pathway is a core developmental signaling cascade that regulates proliferation, differentiation, survival, and tissue growth across multiple organ systems. Germline dysregulation of this pathway results in RASopathies. Although the causal variants affect different components of the pathway, they converge on abnormal downstream signaling. This explains why these disorders share a recognizable clinical core despite clear syndrome-specific differences. The most prevalent and well-known entity is Noonan syndrome, while other major subtypes include cardiofaciocutaneous syndrome, Costello syndrome, and Noonan syndrome with multiple lentigines.

RASopathies are characterized by distinctive craniofacial features and multisystem involvement. Congenital heart disease is a significant cause of morbidity. Neurodevelopmental difficulties are common across the spectrum and may be particularly pronounced in Cardiofaciocutaneous and Costello syndromes. Short stature, pectus anomalies, scoliosis, and other musculoskeletal findings are also recurrent features. Another important concern is the malignancy risk, which varies significantly by genotype.

Although these disorders share a common pathway, genotype-phenotype correlations are increasingly relevant in daily practice. Molecular findings now directly inform risk assessment and long-term follow-up. In parallel, early experience with pathway-directed therapies is beginning to influence the management of selected complications. MEK inhibitors have shown promising results in selected manifestations, particularly hypertrophic cardiomyopathy and refractory lymphatic complications.

In this review, we discuss the biological organization of the RAS/MAPK pathway and relate it to the clinical spectrum of RASopathies. We focus on shared and distinguishing phenotypic features, clinically relevant genotype-phenotype correlations, and the emerging role of targeted therapies.

Keywords: Genotype-Phenotype Correlation, Noonan syndrome, MAP Kinase Signaling System, RASopathies

References

  1. Simanshu DK, Nissley DV, McCormick F. RAS Proteins and Their Regulators in Human Disease. Cell. 2017;170(1):17-33. https://doi.org/10.1016/j.cell.2017.06.009
  2. Ram A, Murphy D, DeCuzzi N, et al. A guide to ERK dynamics, part 1: mechanisms and models. Biochem J. 2023;480(23):1887-907. https://doi.org/10.1042/BCJ20230276
  3. Martin-Vega A, Cobb MH. Navigating the ERK1/2 MAPK Cascade. Biomolecules. 2023;13(10):1555. https://doi.org/10.3390/biom13101555
  4. Hebron KE, Hernandez ER, Yohe ME. The RASopathies: from pathogenetics to therapeutics. Dis Model Mech. 2022;15(2):dmm049107. https://doi.org/10.1242/dmm.049107
  5. Ram A, Murphy D, DeCuzzi N, et al. A guide to ERK dynamics, part 2: downstream decoding. Biochem J. 2023;480(23):1909-28. https://doi.org/10.1042/BCJ20230277
  6. Pudewell S, Wittich C, Kazemein Jasemi NS, Bazgir F, Ahmadian MR. Accessory proteins of the RAS-MAPK pathway: moving from the side line to the front line. Commun Biol. 2021;4(1):696. https://doi.org/10.1038/s42003-021-02149-3
  7. Rauen KA. Defining RASopathy. Dis Model Mech. 2022;15(2):dmm049344. https://doi.org/10.1242/dmm.049344
  8. Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19(3):230-6. https://doi.org/10.1016/j.gde.2009.04.001
  9. Zenker M. Clinical overview on RASOPATHİES. American J of Med Genetics Pt C. 2022;190(4):414-24. https://doi.org/10.1002/ajmg.c.32015
  10. Rauen KA. The RASopathies. Annu Rev Genom Hum Genet. 2013;14(1):355-69. https://doi.org/10.1146/annurev-genom-091212-153523
  11. Tartaglia M, Zampino G, Gelb BD. Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis. Mol Syndromol. 2010;1(1):2-26. https://doi.org/10.1159/000276766
  12. Reynolds G, Gazzin A, Carli D, et al. Update on the Clinical and Molecular Characterization of Noonan Syndrome and Other RASopathies: A Retrospective Study and Systematic Review. IJMS. 2025;26(8):3515. https://doi.org/10.3390/ijms26083515
  13. Tidyman WE, Rauen KA. Pathogenetics of the RASopathies. Hum Mol Genet 2016;25(R2):R123-R132. https://doi.org/10.1093/hmg/ddw191
  14. Aoki Y, Niihori T, Banjo T, et al. Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome. Am J Hum Genet 2013;93(1):173-80. https://doi.org/10.1016/j.ajhg.2013.05.021
  15. Noonan Syndrome Guideline Development Group. Management of Noonan Syndrome: A Clinical Guide. 2010.
  16. Van Der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007;2(1):4. https://doi.org/10.1186/1750-1172-2-4
  17. Zenker M, ed. Genotype-Phenotype Correlations in Noonan Syndrome. In: Monographs in Human Genetics. Vol 17. KARGER; 2008:40-54. https://doi.org/10.1159/000164838
  18. Tangshewinsirikul C, Wattanasirichaigoon D, Tim-Aroon T, et al. Prenatal Sonographic Features of Noonan Syndrome: Case Series and Literature Review. JCM. 2024;13(19):5735. https://doi.org/10.3390/jcm13195735
  19. Fowlkes JL, Thrailkill KM, Bunn RC. RASopathies: The musculoskeletal consequences and their etiology and pathogenesis. Bone. 2021;152:116060. https://doi.org/10.1016/j.bone.2021.116060
  20. Ilic N, KRASic S, Maric N, et al. Noonan Syndrome: Relation of Genotype to Cardiovascular Phenotype-A Multi-Center Retrospective Study. Genes (Basel). 2024;15(11):1463. https://doi.org/10.3390/genes15111463
  21. Pandit B, Sarkozy A, Pennacchio LA, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39(8):1007-12. https://doi.org/10.1038/ng2073
  22. Kobayashi T, Aoki Y, Niihori T, et al. Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Hum Mutat. 2010;31(3):284-94. https://doi.org/10.1002/humu.21187
  23. Saint-Laurent C, Mazeyrie L, Yart A, Edouard T. Novel therapeutic perspectives in Noonan syndrome and RASopathies. Eur J Pediatr. 2024;183(3):1011-9. https://doi.org/10.1007/s00431-023-05263-y
  24. De Brouchoven I, Lorand J, Bofferding L, Sorlin A, Van Damme A, Danhaive O. Trametinib as a targeted treatment in cardiac and lymphatic presentations of Noonan syndrome. Front Pediatr. 2025;13:1475143. https://doi.org/10.3389/fped.2025.1475143
  25. Sleutjes J, Kleimeier L, Leenders E, Klein W, Draaisma J. Lymphatic Abnormalities in Noonan Syndrome Spectrum Disorders: A Systematic Review. Mol Syndromol. 2022;13(1):1-11. https://doi.org/10.1159/000517605
  26. Naylor PE, Bruno JL, Shrestha SB, et al. Neuropsychiatric phenotypes in children with Noonan syndrome. Dev Med Child Neurol. 2023;65(11):1520-9. https://doi.org/10.1111/dmcn.15627
  27. Pascual-Morena C, Martínez-García I, Lucerón-Lucas-Torres M, et al. Prevalence of neurodevelopmental and psychiatric disorders in Noonan syndrome: a systematic review and meta-analysis. Eur J Pediatr. 2025;184(12):800. https://doi.org/10.1007/s00431-025-06648-x
  28. Perrino MR, Das A, Scollon SR, et al. Update on Pediatric Cancer Surveillance Recommendations for Patients with Neurofibromatosis Type 1, Noonan Syndrome, CBL Syndrome, Costello Syndrome, and Related RASopathies. Clinical Cancer Research. 2024;30(21):4834-43. https://doi.org/10.1158/1078-0432.CCR-24-1611
  29. Sodero G, Cipolla C, Pane LC, et al. Efficacy and safety of growth hormone therapy in children with Noonan syndrome. Growth Hormone & IGF Research. 2023;69-70:101532. https://doi.org/10.1016/j.ghir.2023.101532
  30. Pierpont MEM, Magoulas PL, Adi S, et al. Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines. Pediatrics. 2014;134(4):e1149-e1162. https://doi.org/10.1542/peds.2013-3189
  31. Roberts A, Allanson J, Jadico SK, et al. The cardiofaciocutaneous syndrome. J Med Genet. 2006;43(11):833-42. https://doi.org/10.1136/jmg.2006.042796
  32. Abe Y, Aoki Y, Kuriyama S, et al. Prevalence and clinical features of Costello syndrome and cardio‐facio‐cutaneous syndrome in Japan: Findings from a nationwide epidemiological survey. American J of Med Genetics Pt A. 2012;158A(5):1083-94. https://doi.org/10.1002/ajmg.a.35292
  33. Feng B, Li X, Zhang Q, et al. Molecular and phenotypic spectrum of cardio-facio-cutaneous syndrome in Chinese patients. Orphanet J Rare Dis. 2023;18(1):284. https://doi.org/10.1186/s13023-023-02878-0
  34. Scorrano G, David E, Calì E, et al. The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications. Genes. 2023;14(12):2111. https://doi.org/10.3390/genes14122111
  35. Bessis D, Morice‐Picard F, Bourrat E, et al. Dermatological manifestations in cardiofaciocutaneous syndrome: a prospective multicentric study of 45 mutation‐positive patients. Br J Dermatol. 2019;180(1):172-80. https://doi.org/10.1111/bjd.17077
  36. Pierpont EI, Kenney-Jung DL, Shanley R, et al. Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study. Genetics in Medicine. 2022;24(7):1556-66. https://doi.org/10.1016/j.gim.2022.04.004
  37. Battaglia DI, Gambardella ML, Veltri S, et al. Epilepsy and BRAF Mutations: Phenotypes, Natural History and Genotype-Phenotype Correlations. Genes (Basel). 2021;12(9):1316. https://doi.org/10.3390/genes12091316
  38. Di Majo BE, Leoni C, Cartisano E, et al. Cardiofaciocutaneous syndrome and immunodeficiency: data from an international multicenter cohort. Front Immunol. 2025;16:1598896.https://doi.org/10.3389/fimmu.2025.1598896
  39. Gripp KW, Morse LA, Axelrad M, et al. Costello syndrome: Clinical phenotype, genotype, and management guidelines. American J of Med Genetics Pt A. 2019;179(9):1725-44. https://doi.org/10.1002/ajmg.a.61270
  40. Rauen K. HRAS and the Costello syndrome. Clinical Genetics. 2007;71(2):101-8. https://doi.org/10.1111/j.1399-0004.2007.00743.x
  41. Bessis D, Bursztejn A, Morice‐Picard F, et al. Dermatological manifestations in Costello syndrome: A prospective multicentric study of 31 HRAS ‐positive variant patients. Acad Dermatol Venereol. 2024;38(9):1818-27. https://doi.org/10.1111/jdv.19996
  42. Machida M, Rocos B, Taira K, et al. Costello syndrome-associated orthopaedic manifestations focussed on kyphoscoliosis: a case series describing the natural course. J Pediatr Orthop B. 2023;32(4):357-62. https://doi.org/10.1097/BPB.0000000000001013
  43. Shankar SP, Fallurin R, Watson T, et al. Ophthalmic manifestations in Costello syndrome caused by Ras pathway dysregulation during development. Ophthalmic Genetics. 2022;43(1):48-57. https://doi.org/10.1080/13816810.2021.1978103
  44. Peschiaroli S, Viscogliosi G, Salerni A, et al. Costello Syndrome and Ophthalmologic Issues: Unveiling the Unseen. American J of Med Genetics Pt A. 2025;197(7):e64049. https://doi.org/10.1002/ajmg.a.64049
  45. Astiazaran-Symonds E, Ney GM, Higgs C, et al. Cancer in Costello syndrome: a systematic review and meta-analysis. Br J Cancer. 2023;128(11):2089-96. https://doi.org/10.1038/s41416-023-02229-7
  46. Narumi Y, Aoki Y, Niihori T, et al. Molecular and clinical characterization of cardio‐facio‐cutaneous (CFC) syndrome: Overlapping clinical manifestations with Costello syndrome. American J of Med Genetics Pt A. 2007;143A(8):799-807. https://doi.org/10.1002/ajmg.a.31658
  47. Gelb BD, Tartaglia M. Noonan Syndrome with Multiple Lentigines. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, eds. GeneReviews®. University of Washington, Seattle; 1993. Accessed March 4, 2026. http://www.ncbi.nlm.nih.gov/books/NBK1383/
  48. Monda E, Prosnitz A, Aiello R, et al. Natural History of Hypertrophic Cardiomyopathy in Noonan Syndrome With Multiple Lentigines. Circ: Genomic and Precision Medicine. 2023;16(4):350-8. https://doi.org/10.1161/CIRCGEN.122.003861
  49. Gao X, Huang SS, Qiu SW, et al. Congenital sensorineural hearing loss as the initial presentation of PTPN11-associated Noonan syndrome with multiple lentigines or Noonan syndrome: clinical features and underlying mechanisms. J Med Genet. 2021;58(7):465-74. https://doi.org/10.1136/jmedgenet-2020-106892
  50. Liu Z, Lai J, Song F. Noonan syndrome and Noonan-like syndrome with loose anagen hair: rare phenotypes may emerge during follow-up. Transl Pediatr. 2024;13(7):1161-8. https://doi.org/10.21037/tp-24-113
  51. Wang XO, Liu ZQ, Shangguan SF, et al. [Clinical characteristics analysis of children with Noonan-like syndrome with loose anagen hair]. Zhonghua Er Ke Za Zhi. 2025;63(4):405-10. https://doi.org/10.3760/cma.j.cn112140-20241010-00706
  52. Gripp KW, Aldinger KA, Bennett JT, et al. A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair. Am J Med Genet A. 2016;170(9):2237-47. https://doi.org/10.1002/ajmg.a.37781
  53. Leoni C, Viscogliosi G, Tartaglia M, Aoki Y, Zampino G. Multidisciplinary Management of Costello Syndrome: Current Perspectives. J Multidiscip Healthc. 2022;15:1277-96. https://doi.org/10.2147/JMDH.S291757
  54. Wolf CM, Zenker M, Boleti O, et al. Impact of MEK Inhibition on Childhood RASopathy-Associated Hypertrophic Cardiomyopathy. JACC: Basic to Translational Science. 2025;10(2):152-66. https://doi.org/10.1016/j.jacbts.2024.10.002
  55. Dionysiou M, Makri SC, Ahlawat S, et al. Case report: MEK inhibitor as treatment for multi-lineage mosaic KRAS G12D-associated epidermal nevus syndrome in a pediatric patient. Front Neurol. 2024;15:1466946. https://doi.org/10.3389/fneur.2024.1466946
  56. D’Onofrio G, Delrue MA, Lortie A, et al. Treatment of Refractory Epilepsy With MEK Inhibitor in Patients With RASopathy. Pediatric Neurology. 2023;148:148-51. https://doi.org/10.1016/j.pediatrneurol.2023.08.019
  57. Krishna MR, Sennaiyan UN. Everolimus therapy in an infant with Noonan syndrome with multiple lentigines. Ann Pediatr Cardiol. 2025;18(1):72-4. https://doi.org/10.4103/apc.apc_26_25
  58. Cormier F, Lara-Corrales I, Sauder M, Levy R. Therapeutic Advances in Neurofibromatosis Type 1: A Focus on Selumetinib. Skin Therapy Lett. 2025;30(5):1-4.
  59. De Blank PMK, Gross AM, Akshintala S, et al. MEK inhibitors for neurofibromatosis type 1 manifestations: Clinical evidence and consensus. Neuro-Oncology. 2022;24(11):1845-56. https://doi.org/10.1093/neuonc/noac165
  60. Khalid A, Denton K, Paria N, et al. MEK inhibitor Mirdametinib promotes fracture healing in osteofibrous dysplasia RASopathy. J Clin Invest. 2026;136(9):e199048. https://doi.org/10.1172/JCI199048.

Copyright and license

Copyright © 2026 The Author(s). This is an open access article distributed under the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is properly cited.

How to cite

1.
Genç A, Kılıç E. RAS/MAPK Pathway and RASopathies. Turk J Pediatr Dis. 2026;20(3):211-218. https://doi.org/10.12956/TJPD.2025.1329