Abstract
We report five cases of multiple giant cell lesions in patients with typical Noonan syndrome. Such association has frequently been referred to as Noonan-like/multiple giant cell (NL/MGCL) syndrome before the molecular definition of Noonan syndrome. Two patients show mutations in PTPN11 (p.Tyr62Asp and p.Asn308Asp) and three in SOS1 (p.Arg552Ser and p.Arg552Thr). The latter are the first SOS1 mutations reported outside PTPN11 in NL/MGCL syndrome. MGCL lesions were observed in jaws (‘cherubism’) and joints (‘pigmented villonodular synovitis’). We show through those patients that both types of MGCL are not PTPN11-specific, but rather represent a low penetrant (or perhaps overlooked) complication of the dysregulated RAS/MAPK signaling pathway. We recommend discarding NL/MGCL syndrome from the nosology, as this presentation is neither gene-nor allele-specific of Noonan syndrome; these patients should be described as Noonan syndrome with MGCL (of the mandible, the long bone…). The term cherubism should be used only when multiple giant cell lesions occur without any other clinical and molecular evidence of Noonan syndrome, with or without mutations of the SH3BP2 gene.
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References
Tartaglia M, Martinelli S, Stella L et al: Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet 2006; 78: 279–290.
Gelb BD, Tartaglia M : Noonan syndrome and related disorders: dysregulated RAS-mitogen activated protein kinase signal transduction. Hum Mol Genet 2006; 15 (Spec No 2): R220–R226.
Schubbert S, Shannon K, Bollag G : Hyperactive Ras in developmental disorders and cancer. Nat Rev Cancer 2007; 7: 295–308.
Bentires-Alj M, Kontaridis MI, Neel BG : Stops along the RAS pathway in human genetic disease. Nat Med 2006; 12: 283–285.
Tartaglia M, Mehler EL, Goldberg R et al: Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet 2001; 29: 465–468.
Roberts AE, Araki T, Swanson KD et al: Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet 2007; 39: 70–74.
Tartaglia M, Pennacchio LA, Zhao C et al: Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet 2007; 39: 75–79.
Razzaque MA, Nishizawa T, Komoike Y et al: Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet 2007; 8: 1013–1017.
Schubbert S, Zenker M, Rowe SL et al: Germline KRAS mutations cause Noonan syndrome. Nat Genet 2006; 38: 331–336.
Nava C, Hanna N, Michot C et al: CFC and Noonan syndromes due to mutations in RAS/MAPK signaling pathway: genotype/phenotype relationships and overlap with Costello syndrome. J Med Genet 2007; 12: 763–771.
Idowu BD, Thomas G, Frow R et al: Mutations in SH3BP2, the cherubism gene, were not detected in central or peripheral giant cell tumours of the jaw. Br J Oral Maxillofac Surg 2008; 46: 229–230.
Cohen Jr MM, Gorlin RJ : Noonan-like/multiple giant cell lesion syndrome. Am J Med Genet 1991; 40: 159–166.
Lee JS, Tartaglia M, Gelb BD et al: Phenotypic and genotypic characterisation of Noonan-like/multiple giant cell lesion syndrome. J Med Genet 2005; 42: e11.
Wolvius EB, de LJ, Smeets EE et al: Noonan-like/multiple giant cell lesion syndrome: report of a case and review of the literature. J Oral Maxillofac Surg 2006; 64: 1289–1292.
Cancino CM, Gaiao L, Sant’Ana FM et al: Giant cell lesions with a Noonan-like phenotype: a case report. J Contemp Dent Pract 2007; 8: 67–73.
Lee SM, Cooper JC : Noonan syndrome with giant cell lesions. Int J Paediatr Dent 2005; 15: 140–145.
Addante RR, Breen GH : Cherubism in a patient with Noonan's syndrome. J Oral Maxillofac Surg 1996; 54: 210–213.
Betts NJ, Stewart JC, Fonseca RJ et al: Multiple central giant cell lesions with a Noonan-like phenotype. Oral Surg Oral Med Oral Pathol 1993; 76: 601–607.
Levine B, Skope L, Parker R : Cherubism in a patient with Noonan syndrome: report of a case. J Oral Maxillofac Surg 1991; 49: 1014–1018.
Dunlap C, Neville B, Vickers RA et al: The Noonan syndrome/cherubism association. Oral Surg Oral Med Oral Pathol 1989; 67: 698–705.
Minisola G, Porzio V, Ceralli F et al: Polyarticular pigmented villonodular synovitis associated with multiple congenital anomalies. A case of Noonan-like/multiple giant cell lesion syndrome. Clin Exp Rheumatol 1996; 14: 207–210.
Tartaglia M, Kalidas K, Shaw A et al: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002; 70: 1555–1563.
Bertola DR, Pereira AC, Albano LM et al: PTPN11 gene analysis in 74 Brazilian patients with Noonan syndrome or Noonan-like phenotype. Genet Test 2006; 10: 186–191.
Jafarov T, Ferimazova N, Reichenberger E : Noonan-like syndrome mutations in PTPN11 in patients diagnosed with cherubism. Clin Genet 2005; 68: 190–191.
Bertola DR, Pereira AC, Passetti F et al: Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. Am J Med Genet A 2005; 136: 242–245.
Maheshwari M, Belmont J, Fernbach S et al: PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exons 3 and 13. Hum Mutat 2002; 20: 298–304.
Tartaglia M, Kalidas K, Shaw A et al: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002; 70: 1555–1563.
Bertola DR, Kim CA, Pereira AC et al: Are Noonan syndrome and Noonan-like/multiple giant cell lesion syndrome distinct entities? Am J Med Genet 2001; 98: 230–234.
Kirk JM, Betts PR, Butler GE et al: Short stature in Noonan syndrome: response to growth hormone therapy. Arch Dis Child 2001; 84: 440–443.
Wendt RG, Wolfe F, McQueen D et al: Polyarticular pigmented villonodular synovitis in children: evidence for a genetic contribution. J Rheumatol 1986; 13: 921–926.
Sarkozy A, Obregon MG, Conti E et al: A novel PTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet 2004; 12: 1069–1072.
Ruggieri M, Pavone V, Polizzi A et al: Unusual form of recurrent giant cell granuloma of the mandible and lower extremities in a patient with neurofibromatosis type 1. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 87: 67–72.
Edwards PC, Fantasia JE, Saini T et al: Clinically aggressive central giant cell granulomas in two patients with neurofibromatosis 1. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006; 102: 765–772.
Krammer U, Wimmer K, Wiesbauer P et al: Neurofibromatosis 1: a novel NF1 mutation in an 11-year-old girl with a giant cell granuloma. J Child Neurol 2003; 18: 371–373.
Van Damme PA, Mooren RE : Differentiation of multiple giant cell lesions, Noonan-like syndrome, and (occult) hyperparathyroidism. Case report and review of the literature. Int J Oral Maxillofac Surg 1994; 23: 32–36.
Yazdizadeh M, Tapia JL, Baharvand M et al: A case of neurofibromatosis-Noonan syndrome with a central giant cell granuloma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2004; 98: 316–320.
Ueki Y, Tiziani V, Santanna C et al: Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat Genet 2001; 28: 125–126.
Ueki Y, Lin CY, Senoo M : Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 ‘cherubism’ mice. Cell 2007; 128: 71–83.
Lietman SA, Yin L, Levine MA : SH3BP2 is an activator of NFAT activity and osteoclastogenesis. Biochem Biophys Res Commun 2008; 371: 644–648.
Neumann TE, Allanson J, Kavamura I et al: Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome. Eur J Hum Genet 2008.
Mascheroni E, Digilio MC, Cortis E et al: Pigmented villonodular synovitis in a patient with Noonan syndrome and SOS1 gene mutation. Am J Med Genet A 2008; 146A: 2966–2967.
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Beneteau, C., Cavé, H., Moncla, A. et al. SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions. Eur J Hum Genet 17, 1216–1221 (2009). https://doi.org/10.1038/ejhg.2009.44
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DOI: https://doi.org/10.1038/ejhg.2009.44
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