SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions

Bénéteau, Claire; Cavé, Hélène; Moncla, Anne; Dorison, Nathalie; Münnich, Arnold; Verloes, Alain; Leheup, Bruno

doi:10.1038/ejhg.2009.44

Cited by 45 publications

(40 citation statements)

References 38 publications

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“…NL/MGCLS-associated PTPN11 mutations have been observed in individuals with NS, LS or CFCS, including families segregating the trait without any bony involvement. Consistent with this view, this trait is genetically heterogeneous with documented germline mutations affecting other NS/CFCS disease genes coding for transducers participating in the RAS-MAPK signaling pathway (see below) [Beneteau et al, 2009;Hanna et al, 2009;Neumann et al, 2009]. Children with NS are predisposed to a spectrum of hematologic abnormalities and malignancies, including juvenile myelomonocytic leukemia (JMML), a clonal myeloproliferative disorder of childhood characterized by a hypersensitive pattern of myeloid progenitor colony growth in response to GM-CSF, which is due to a selective inability to down-regulate RAS function [Niemeyer and Kratz, 2008].…”

Section: Ptpn11mentioning

confidence: 67%

“…In these subjects, cognitive deficits are generally absent or minor, but at least 1 case with mental retardation was reported [Narumi et al, 2008]. Recently, SOS1 mutations have been identified in 9 individuals with NS associated with MGCL of jaws or joints (pigmented villonodular synovitis) [Mascheroni et al, 2008;Beneteau et al, 2009;Hanna et al, 2009;Neumann et al, 2009]. All of the mutations had previously been documented in subjects with NS without MGCL, confirming the view that MGCL represent a feature of NS, and that the use of NL/MGCLS should be avoided.…”

Section: Sos1mentioning

confidence: 99%

“…While an impaired cata-lytic activity has been established as biochemical behavior shared by these SHP2 mutants [Hanna et al, 2006;Kontaridis et al, 2006;Tartaglia et al, 2006], they do not appear to perturb intracellular signaling by a merely dominant negative effect [Hanna et al, 2006;Martinelli et al, 2008;Oishi et al, 2009], as supposed in the past [Kontaridis et al, 2006]. PTPN11 mutation-positive NS/LS are rarely accompanied by multiple giant cell lesions of the jaw and/or other bone/soft tissues [Tartaglia et al, 2002;Sarkozy et al, 2004;Jafarov et al, 2005;Lee et al, 2005;Beneteau et al, 2009]. This association, which was originally introduced as a distinct nosologic entity and denominated Noonanlike/multiple giant cell lesion syndrome (NL/MGCLS, OMIM 163955) [Cohen and Gorlin, 1991], is now considered as part of the NS/LS/CFCS phenotypic spectrum.…”

Section: Ptpn11mentioning

confidence: 99%

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Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

2010

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Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.

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Section: Ptpn11mentioning

confidence: 67%

Section: Sos1mentioning

confidence: 99%

Section: Ptpn11mentioning

confidence: 99%

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Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

2010

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“…This is consistent with the fact that patients with RIT1 mutations have few general or cognitive problems and are thus likely to show greater reproductive fitness. Interestingly, RIT1 mutations share some rare complications with other RASopathy genes: JMML, aggressive giant cell tumor of the jaw, 28 and autoimmune disorders (Graves disease and lupus erythematosus). 29 RIT1 and cancer NS patients in general have an increased risk of developing several types of childhood malignancies, 1-3 including acute leukemia or MPDs such as JMML.…”

Section: Rit1-related Noonan Syndrome H Cavé Et Almentioning

confidence: 99%

Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

et al. 2016

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Noonan syndrome is a heterogeneous autosomal dominant disorder caused by mutations in at least eight genes involved in the RAS/MAPK signaling pathway. Recently, RIT1 (Ras-like without CAAX 1) has been shown to be involved in the pathogenesis of some patients. We report a series of 44 patients from 30 pedigrees (including nine multiplex families) with mutations in RIT1. These patients display a typical Noonan gestalt and facial phenotype. Among the probands, 8.7% showed postnatal growth retardation, 90% had congenital heart defects, 36% had hypertrophic cardiomyopathy (a lower incidence compared with previous report), 50% displayed speech delay and 52% had learning difficulties, but only 22% required special education. None had major skin anomalies. One child died perinatally of juvenile myelomonocytic leukemia. Compared with the canonical Noonan phenotype linked to PTPN11 mutations, patients with RIT1 mutations appear to be less severely growth retarded and more frequently affected by cardiomyopathy. Based on our experience, we estimate that RIT1 could be the cause of 5% of Noonan syndrome patients. Because mutations found constitutionally in Noonan syndrome are also found in several tumors in adulthood, we evaluated the potential contribution of RIT1 to leukemogenesis in Noonan syndrome. We screened 192 pediatric cases of acute lymphoblastic leukemias (96 B-ALL and 96 T-ALL) and 110 cases of juvenile myelomonocytic leukemias (JMML), but detected no variation in these tumoral samples, suggesting that Noonan patients with germline RIT1 mutations are not at high risk to developing JMML or ALL, and that RIT1 has at most a marginal role in these sporadic malignancies.

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“…However, more recently the MGCL were shown to be a phenotypic variation within the NS and the other syndromes of the Ras/MAPK pathway [Tartaglia et al, 2002]. Till date, 19 patients with NS/MGCL and PTPN11, SOS1, or RAF1 mutations [Bertola et al, 2001;Tartaglia et al, 2002;Jafarov et al, 2005;Lee et al, 2005;Wolvius et al, 2006;Beneteau et al, 2009;Hanna et al, 2009;Bufalino et al, 2010;Denayer et al, 2010], one patient with LEOPARD/MGCL syndrome and PTPN11 mutation [Sarkozy et al, 2004], and three patients with CFC/MGCL syndrome and BRAF or MAP2K1 mutations [Neumann et al, 2009] have been reported. Another report described neurofibromatosis-NS/MGCL but without molecular confirmation [Yazdizadeh et al, 2004].…”

Section: Introductionmentioning

confidence: 97%

Case report: Noonan syndrome with multiple giant cell lesions and review of the literature

Karbach

Coerdt

Wagner

et al. 2012

American J of Med Genetics Pt A

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Noonan syndrome with multiple giant cell lesions (NS/MGCL) was recently shown to be a phenotypic variation within the syndromes of the Ras/MAPK pathway and not an independent entity as previously thought. Here we report on a 13-year-old boy with a typical phenotype of NS including atrial septal defect, pulmonic stenosis, short stature, and combined pectus carinatum/excavatum, pronounced MGCL of both jaws, and a de novo mutation in PTPN11, c.236A>G (which predicts p.Q79R). Mutations in PTPN11 are the most frequent cause of NS and p.Q79R is a recurrent mutation in exon 3. Including this patient, 24 patients with molecularly confirmed NS, LEOPARD, or CFC/MGCL syndrome have been reported to date, of these 21 patients have PTPN11, SOS1, or RAF1 mutations and three have BRAF or MAP2K1 mutations, confirming that MGCL is a rare complication of the deregulated RAS/MAPK pathway. In all patients, the lesions of the mandible and to a lesser extent of the maxilla were first noted between ages 2 and 19 years (median 11 years), and were combined with enlargement of the jaws in 11/24 patients (46%). In this case and, with one exception (mutation not reported), all previous cases the NS/MGCL was caused by known mutations in the PTPN11, SOS1, RAF1, BRAF1, and MAP2K1 genes that were previously reported with RASopathies without MGCL.

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SOS1 and PTPN11 mutations in five cases of Noonan syndrome with multiple giant cell lesions

Cited by 45 publications

References 38 publications

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

Mutations in RIT1 cause Noonan syndrome with possible juvenile myelomonocytic leukemia but are not involved in acute lymphoblastic leukemia

Case report: Noonan syndrome with multiple giant cell lesions and review of the literature

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