problendoПроблемы ЭндокринологииProblems of Endocrinology0375-96602308-1430Endocrinology Research Centre10.14341/probl201460645-52problendo-7055Research ArticleСтатьиArticlesRAS-патии: синдром Нунан и другие родственные заболевания. Обзор литературыRAS-pathies: Noonan syndrome and other related diseases. The literature reviewФаассенМ ВFaassenMariya Vmariafaassen@icloud.comФГБУ «Эндокринологический научный центр» Минздрава России, МоскваРоссияEndocrinology Research Centre, MoscowRussian Federation201415122014606ТОМ 60, №6 (2014)4552Copyright © Фаассен М.В., 20142014Фаассен М.В.Faassen M.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.probl-endojournals.ru/jour/article/view/7055

Рассмотрена сформированная в 2010 г. группа заболеваний - Ras-патии. Одним из представителей группы является синдром Нунан, известный в педиатрической практике в первую очередь как синдром, сопровождающийся правосторонними кардиологическими нарушениями и низкорослостью. Известны множественные молекулярно-генетические механизмы, обусловливающие синдром Нунан (гены PTPN11, SOS1 и др.). Группа Ras-патий включает: синдром Нунан, нейрофиброматоз 1-го типа, синдром Нунан с множественными лентиго (LEOPARD), кранио-фацио-кожный синдром, синдром капиллярной и артериовенозной мальформации, синдром Костелло, синдром Легиуса. Все эти синдромы объединяют молекулярные нарушения в каскаде Ras/MAPK-пути, что приводит к характерной клинической картине, включая множественные стигмы дисэмбриогенеза, низкорослость, кардиальные нарушения и склонность к новообразованиям.

The present review considers a group of diseases, known as Ras-pathies, formed in 2010. One of its representatives is Noonan syndrome is encountered in the pediatric practice in the first place as a syndrome accompanied by right-hand side cardiological disorders and short stature. The multiple molecular-genetic mechanisms underlying Noonan syndrome are associated with the activity of PTPN11, SOS1, and other genes. The group of RAS-pathies includes, besides Noonan syndrome, type 1 neurofibromatosis, Noonan syndrome with multiple lentigo (LEOPARD), craniofaciocutaneous syndrome, capillary and arteriovenous malformation syndrome, Costello syndrome, and Legius syndrome. All these conditions are associated with the molecular disturbances in the Ras/MAPK cascade that produce the characteristic clinical picture apparent as multiple dysembryogenic stigmata, short stature, cardiac disorders, and predisposition to the neoplastic growth.

синдром Нунаннейрофиброматоз 1-го типалентигокранио-фацио-кожный синдромсиндром капиллярной и артериовенозной мальформациисиндром Костеллосиндром ЛегиусанизкорослостьNoonan syndrometype 1 neurofibromatosislentigocraniofaciocutaneous syndromecapillary and arteriovenous malformation syndromeCostello syndromeLegius syndromeshort statureReferencesYoon S, Seger R. The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24(1):21-44. doi: 10.1080/02699050500284218Yoon S, Seger R. The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions. Growth Factors. 2006;24(1):21-44. doi: 10.1080/02699050500284218Rauen KA. The RASopathies. Annual Review of Genomics and Human Genetics. 2013;14(1):355-369. doi: 10.1146/annurev-genom-091212-153523Rauen KA. The RASopathies. Annual Review of Genomics and Human Genetics. 2013;14(1):355-369. doi: 10.1146/annurev-genom-091212-153523Bos JL. RAS Oncogenes in Human Cancer: A Review. Cancer Research. 1989 September 1, 1989;49(17):4682-4689.Bos JL. RAS Oncogenes in Human Cancer: A Review. Cancer Research. 1989 September 1, 1989;49(17):4682-4689.Carragher L, Pritchard C, Aldridge V, Giblett S, Jin H, Foster C, et al. Mouse models for BRAF-induced cancers. Biochemical Society Transactions. 2007;35(5):1329. doi: 10.1042/bst0351329Carragher L, Pritchard C, Aldridge V, Giblett S, Jin H, Foster C, et al. Mouse models for BRAF-induced cancers. Biochemical Society Transactions. 2007;35(5):1329. doi: 10.1042/bst0351329Wallace M, Marchuk D, Andersen L, Letcher R, Odeh H, Saulino A, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990;249(4965):181-186. doi: 10.1126/science.2134734Wallace M, Marchuk D, Andersen L, Letcher R, Odeh H, Saulino A, et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990;249(4965):181-186. doi: 10.1126/science.2134734Cizmarova M, Kostalova L, Pribilincova Z, Lasabova Z, Hlavata A, Kovacs L, et al. Rasopathies – dysmorphic syndromes with short stature and risk of malignancy. Endocrine Regulations. 2013;47(04):217-222. doi: 10.4149/endo_2013_04_217Cizmarova M, Kostalova L, Pribilincova Z, Lasabova Z, Hlavata A, Kovacs L, et al. Rasopathies – dysmorphic syndromes with short stature and risk of malignancy. Endocrine Regulations. 2013;47(04):217-222. doi: 10.4149/endo_2013_04_217Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2011;157(2):83-89. doi: 10.1002/ajmg.c.30300Kratz CP, Rapisuwon S, Reed H, Hasle H, Rosenberg PS. Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. 2011;157(2):83-89. doi: 10.1002/ajmg.c.30300Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Practice & Research Clinical Endocrinology & Metabolism. 2011;25(1):161-179. doi: 10.1016/j.beem.2010.09.002Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Practice & Research Clinical Endocrinology & Metabolism. 2011;25(1):161-179. doi: 10.1016/j.beem.2010.09.002Malaquias AC, Brasil AS, Pereira AC, Arnhold IJP, Mendonca BB, Bertola DR, et al. Growth standards of patients with Noonan and Noonan-like syndromes with mutations in the RAS/MAPK pathway. American Journal of Medical Genetics Part A. 2012;158A(11):2700-2706. doi: 10.1002/ajmg.a.35519Malaquias AC, Brasil AS, Pereira AC, Arnhold IJP, Mendonca BB, Bertola DR, et al. Growth standards of patients with Noonan and Noonan-like syndromes with mutations in the RAS/MAPK pathway. American Journal of Medical Genetics Part A. 2012;158A(11):2700-2706. doi: 10.1002/ajmg.a.35519Noordam K, van der Bürgt I, Brunner HG, Otten BJ. The Relationship between Clinical Severity of Noonan's Syndrome and Growth, Growth Hormone (GH) Secretion and Response to GH Treatment. Journal of Pediatric Endocrinology and Metabolism. 2002;15(2). doi: 10.1515/jpem.2002.15.2.175Noordam K, van der Bürgt I, Brunner HG, Otten BJ. The Relationship between Clinical Severity of Noonan's Syndrome and Growth, Growth Hormone (GH) Secretion and Response to GH Treatment. Journal of Pediatric Endocrinology and Metabolism. 2002;15(2). doi: 10.1515/jpem.2002.15.2.175Binder G, Neuer K, Ranke MB, Wittekindt NE. PTPN11Mutations Are Associated with Mild Growth Hormone Resistance in Individuals with Noonan Syndrome. The Journal of Clinical Endocrinology & Metabolism. 2005;90(9):5377-5381. doi: 10.1210/jc.2005-0995Binder G, Neuer K, Ranke MB, Wittekindt NE. PTPN11Mutations Are Associated with Mild Growth Hormone Resistance in Individuals with Noonan Syndrome. The Journal of Clinical Endocrinology & Metabolism. 2005;90(9):5377-5381. doi: 10.1210/jc.2005-0995van der Burgt I. Orphanet Journal of Rare Diseases. 2007;2(1):4. doi: 10.1186/1750-1172-2-4van der Burgt I. Orphanet Journal of Rare Diseases. 2007;2(1):4. doi: 10.1186/1750-1172-2-4Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genetics. 2001;29(4):465-468. doi: 10.1038/ng772Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genetics. 2001;29(4):465-468. doi: 10.1038/ng772Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature Genetics. 2006;39(1):75-79. doi: 10.1038/ng1939Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature Genetics. 2006;39(1):75-79. doi: 10.1038/ng1939Zenker M, Horn D, Wieczorek D, Allanson J, Pauli S, van der Burgt I, et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. Journal of Medical Genetics. 2007;44(10):651-656. doi: 10.1136/jmg.2007.051276Zenker M, Horn D, Wieczorek D, Allanson J, Pauli S, van der Burgt I, et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. Journal of Medical Genetics. 2007;44(10):651-656. doi: 10.1136/jmg.2007.051276Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics. 2007;39(8):1007-1012. doi: 10.1038/ng2073Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics. 2007;39(8):1007-1012. doi: 10.1038/ng2073Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nature Genetics. 2007;39(8):1013-1017. doi: 10.1038/ng2078Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nature Genetics. 2007;39(8):1013-1017. doi: 10.1038/ng2078Gremer L, Merbitz-Zahradnik T, Dvorsky R, Cirstea IC, Kratz CP, Zenker M, et al. Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. Human Mutation. 2011;32(1):33-43. doi: 10.1002/humu.21377Gremer L, Merbitz-Zahradnik T, Dvorsky R, Cirstea IC, Kratz CP, Zenker M, et al. Germline KRAS mutations cause aberrant biochemical and physical properties leading to developmental disorders. Human Mutation. 2011;32(1):33-43. doi: 10.1002/humu.21377Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nature Genetics. 2009;42(1):27-29. doi: 10.1038/ng.497Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nature Genetics. 2009;42(1):27-29. doi: 10.1038/ng.497Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, et al. GermlineBRAFmutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum. Human Mutation. 2009;30(4):695-702. doi: 10.1002/humu.20955Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, et al. GermlineBRAFmutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: Molecular diversity and associated phenotypic spectrum. Human Mutation. 2009;30(4):695-702. doi: 10.1002/humu.20955Komatsuzaki S, Aoki Y, Niihori T, Okamoto N, Hennekam RCM, Hopman S, et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. Journal of Human Genetics. 2010;55(12):801-809. doi: 10.1038/jhg.2010.116Komatsuzaki S, Aoki Y, Niihori T, Okamoto N, Hennekam RCM, Hopman S, et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. Journal of Human Genetics. 2010;55(12):801-809. doi: 10.1038/jhg.2010.116Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nature Genetics. 2009;41(9):1022-1026. doi: 10.1038/ng.425Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nature Genetics. 2009;41(9):1022-1026. doi: 10.1038/ng.425Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, et al. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype. The American Journal of Human Genetics. 2010;87(2):250-257. doi: 10.1016/j.ajhg.2010.06.015Martinelli S, De Luca A, Stellacci E, Rossi C, Checquolo S, Lepri F, et al. Heterozygous Germline Mutations in the CBL Tumor-Suppressor Gene Cause a Noonan Syndrome-like Phenotype. The American Journal of Human Genetics. 2010;87(2):250-257. doi: 10.1016/j.ajhg.2010.06.015Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genetics. 2010;42(9):794-800. doi: 10.1038/ng.641Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nature Genetics. 2010;42(9):794-800. doi: 10.1038/ng.641Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, et al. Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome. The American Journal of Human Genetics. 2013;93(1):173-180. doi: 10.1016/j.ajhg.2013.05.021Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, et al. Gain-of-Function Mutations in RIT1 Cause Noonan Syndrome, a RAS/MAPK Pathway Syndrome. The American Journal of Human Genetics. 2013;93(1):173-180. doi: 10.1016/j.ajhg.2013.05.021Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis Type 1 Revisited. Pediatrics. 2009;123(1):124-133. doi: 10.1542/peds.2007-3204Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis Type 1 Revisited. Pediatrics. 2009;123(1):124-133. doi: 10.1542/peds.2007-3204Sarkozy A, Digilio M, Dallapiccola B. Leopard syndrome. Orphanet Journal of Rare Diseases. 2008;3(1):13. doi: 10.1186/1750-1172-3-13Sarkozy A, Digilio M, Dallapiccola B. Leopard syndrome. Orphanet Journal of Rare Diseases. 2008;3(1):13. doi: 10.1186/1750-1172-3-13Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, et al. RASA1Mutations and Associated Phenotypes in 68 Families with Capillary Malformation-Arteriovenous Malformation. Human Mutation. 2013;34(12):1632-1641. doi: 10.1002/humu.22431Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, et al. RASA1Mutations and Associated Phenotypes in 68 Families with Capillary Malformation-Arteriovenous Malformation. Human Mutation. 2013;34(12):1632-1641. doi: 10.1002/humu.22431Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype with capillary and arteriovenous malformations. Current Opinion in Genetics & Development. 2005;15(3):265-269. doi: 10.1016/j.gde.2005.03.004Boon LM, Mulliken JB, Vikkula M. RASA1: variable phenotype with capillary and arteriovenous malformations. Current Opinion in Genetics & Development. 2005;15(3):265-269. doi: 10.1016/j.gde.2005.03.004Rauen KA. HRAS and the Costello syndrome. Clinical Genetics. 2007;71(2):101-108. doi: 10.1111/j.1399-0004.2007.00743.xRauen KA. HRAS and the Costello syndrome. Clinical Genetics. 2007;71(2):101-108. doi: 10.1111/j.1399-0004.2007.00743.xSiegel DH, Mann JA, Krol AL, Rauen KA. Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development. British Journal of Dermatology. 2012;166(3):601-607. doi: 10.1111/j.1365-2133.2011.10744.xSiegel DH, Mann JA, Krol AL, Rauen KA. Dermatological phenotype in Costello syndrome: consequences of Ras dysregulation in development. British Journal of Dermatology. 2012;166(3):601-607. doi: 10.1111/j.1365-2133.2011.10744.xNiihori T, Aoki Y, Narumi Y, Neri G, Cavé H, Verloes A, et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nature Genetics. 2006;38(3):294-296. doi: 10.1038/ng1749Niihori T, Aoki Y, Narumi Y, Neri G, Cavé H, Verloes A, et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nature Genetics. 2006;38(3):294-296. doi: 10.1038/ng1749Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M, McCormick F. A Phosphatase Holoenzyme Comprised of Shoc2/Sur8 and the Catalytic Subunit of PP1 Functions as an M-Ras Effector to Modulate Raf Activity. Molecular Cell. 2006;22(2):217-230. doi: 10.1016/j.molcel.2006.03.027Rodriguez-Viciana P, Oses-Prieto J, Burlingame A, Fried M, McCormick F. A Phosphatase Holoenzyme Comprised of Shoc2/Sur8 and the Catalytic Subunit of PP1 Functions as an M-Ras Effector to Modulate Raf Activity. Molecular Cell. 2006;22(2):217-230. doi: 10.1016/j.molcel.2006.03.027Nava C, Hanna N, Michot C, Pereira S, Pouvreau N, Niihori T, et al. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype phenotype relationships and overlap with Costello syndrome. Journal of Medical Genetics. 2007;44(12):763-771. doi: 10.1136/jmg.2007.050450Nava C, Hanna N, Michot C, Pereira S, Pouvreau N, Niihori T, et al. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype phenotype relationships and overlap with Costello syndrome. Journal of Medical Genetics. 2007;44(12):763-771. doi: 10.1136/jmg.2007.050450Yoon G, Rosenberg J, Blaser S, Rauen KA. Neurological complications of cardio-facio-cutaneous syndrome. Developmental Medicine and Child Neurology. 2007;49(12):894-899. doi: 10.1111/j.1469-8749.2007.00894.xYoon G, Rosenberg J, Blaser S, Rauen KA. Neurological complications of cardio-facio-cutaneous syndrome. Developmental Medicine and Child Neurology. 2007;49(12):894-899. doi: 10.1111/j.1469-8749.2007.00894.xBrems H, Legius E. Legius Syndrome, an Update.Molecular Pathology of Mutations in SPRED1. The Keio Journal of Medicine. 2013;62(4):107-112. doi: 10.2302/kjm.2013-0002-REBrems H, Legius E. Legius Syndrome, an Update.Molecular Pathology of Mutations in SPRED1. The Keio Journal of Medicine. 2013;62(4):107-112. doi: 10.2302/kjm.2013-0002-RERoberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nature Genetics. 2006;39(1):70-74. doi: 10.1038/ng1926Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nature Genetics. 2006;39(1):70-74. doi: 10.1038/ng1926Narumi Y, Aoki Y, Niihori T, Sakurai M, Cavé H, Verloes A, et al. Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. Journal of Human Genetics. 2008;53(9):834-841. doi: 10.1007/s10038-008-0320-0Narumi Y, Aoki Y, Niihori T, Sakurai M, Cavé H, Verloes A, et al. Clinical manifestations in patients with SOS1 mutations range from Noonan syndrome to CFC syndrome. Journal of Human Genetics. 2008;53(9):834-841. doi: 10.1007/s10038-008-0320-0Fabretto A, Kutsche K, Harmsen M-B, Demarini S, Gasparini P, Fertz MC, et al. Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I. European Journal of Medical Genetics. 2010;53(5):322-324. doi: 10.1016/j.ejmg.2010.07.011Fabretto A, Kutsche K, Harmsen M-B, Demarini S, Gasparini P, Fertz MC, et al. Two cases of Noonan syndrome with severe respiratory and gastroenteral involvement and the SOS1 mutation F623I. European Journal of Medical Genetics. 2010;53(5):322-324. doi: 10.1016/j.ejmg.2010.07.011Wennerberg K. The RAS superfamily at a glance. Journal of Cell Science. 2005;118(5):843-846. doi: 10.1242/jcs.01660Wennerberg K. The RAS superfamily at a glance. Journal of Cell Science. 2005;118(5):843-846. doi: 10.1242/jcs.01660Kratz CP, Zampino G, Kriek M, Kant SG, Leoni C, Pantaleoni F, et al. Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. American Journal of Medical Genetics Part A. 2009;149A(5):1036-1040. doi: 10.1002/ajmg.a.32786Kratz CP, Zampino G, Kriek M, Kant SG, Leoni C, Pantaleoni F, et al. Craniosynostosis in patients with Noonan syndrome caused by germline KRAS mutations. American Journal of Medical Genetics Part A. 2009;149A(5):1036-1040. doi: 10.1002/ajmg.a.32786Stark Z, Gillessen-Kaesbach G, Ryan MM, Cirstea IC, Gremer L, Ahmadian MR, et al. Two novel germline KRAS mutations: expanding the molecular and clinical phenotype. Clinical Genetics. 2012;81(6):590-594. doi: 10.1111/j.1399-0004.2011.01754.xStark Z, Gillessen-Kaesbach G, Ryan MM, Cirstea IC, Gremer L, Ahmadian MR, et al. Two novel germline KRAS mutations: expanding the molecular and clinical phenotype. Clinical Genetics. 2012;81(6):590-594. doi: 10.1111/j.1399-0004.2011.01754.xOliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proceedings of the National Academy of Sciences. 2007;104(21):8953-8958. doi: 10.1073/pnas.0702975104Oliveira JB, Bidere N, Niemela JE, Zheng L, Sakai K, Nix CP, et al. NRAS mutation causes a human autoimmune lymphoproliferative syndrome. Proceedings of the National Academy of Sciences. 2007;104(21):8953-8958. doi: 10.1073/pnas.0702975104Kobayashi T, Aoki Y, Niihori T, Cavé H, Verloes A, Okamoto N, et al. Molecular and clinical analysis ofRAF1in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Human Mutation. 2010;31(3):284-294. doi: 10.1002/humu.21187Kobayashi T, Aoki Y, Niihori T, Cavé H, Verloes A, Okamoto N, et al. Molecular and clinical analysis ofRAF1in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation. Human Mutation. 2010;31(3):284-294. doi: 10.1002/humu.21187Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Current Opinion in Genetics & Development. 2009;19(3):230-236. doi: 10.1016/j.gde.2009.04.001Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Current Opinion in Genetics & Development. 2009;19(3):230-236. doi: 10.1016/j.gde.2009.04.001Swaminathan G, Tsygankov AY. The Cbl family proteins: Ring leaders in regulation of cell signaling. Journal of Cellular Physiology. 2006;209(1):21-43. doi: 10.1002/jcp.20694Swaminathan G, Tsygankov AY. The Cbl family proteins: Ring leaders in regulation of cell signaling. Journal of Cellular Physiology. 2006;209(1):21-43. doi: 10.1002/jcp.20694Flynn DC. Adaptor proteins. Oncogene. 2001;20(44):6270-6272. doi: 10.1038/sj.onc.1204769Flynn DC. Adaptor proteins. Oncogene. 2001;20(44):6270-6272. doi: 10.1038/sj.onc.1204769Stowe IB, Mercado EL, Stowe TR, Bell EL, Oses-Prieto JA, Hernandez H, et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes & Development. 2012;26(13):1421-1426. doi: 10.1101/gad.190876.112Stowe IB, Mercado EL, Stowe TR, Bell EL, Oses-Prieto JA, Hernandez H, et al. A shared molecular mechanism underlies the human rasopathies Legius syndrome and Neurofibromatosis-1. Genes & Development. 2012;26(13):1421-1426. doi: 10.1101/gad.190876.112

The authors declare that there are no conflicts of interest present.