Multiple giant cell lesions in patients with Noonan syndrome and cardio-facio-cutaneous syndrome

Abstract

Noonan syndrome (NS) and cardio-facio-cutaneous syndrome (CFCS) are related developmental disorders caused by mutations in genes encoding various components of the RAS-MAPK signaling cascade. NS is associated with mutations in the genes PTPN11, SOS1, RAF1, or KRAS, whereas CFCS can be caused by mutations in BRAF, MEK1, MEK2, or KRAS. The NS phenotype is rarely accompanied by multiple giant cell lesions (MGCL) of the jaw (Noonan-like/MGCL syndrome (NL/MGCLS)). PTPN11 mutations are the only genetic abnormalities reported so far in some patients with NL/MGCLS and in one individual with LEOPARD syndrome and MGCL. In a cohort of 75 NS patients previously tested negative for mutations in PTPN11 and KRAS, we detected SOS1 mutations in 11 individuals, four of whom had MGCL. To explore further the relevance of aberrant RAS-MAPK signaling in syndromic MGCL, we analyzed the established genes causing CFCS in three subjects with MGCL associated with a phenotype fitting CFCS. Mutations in BRAF or MEK1 were identified in these patients. All mutations detected in these seven patients with syndromic MGCL had previously been described in NS or CFCS without apparent MGCL. This study demonstrates that MGCL may occur in NS and CFCS with various underlying genetic alterations and no obvious genotype -phenotype correlation. This suggests that dysregulation of the RAS-MAPK pathway

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

“…In this Journal, cherubism was reported in four patients with NS and SOS1 mutations, and in three patients with CFC and BRAF mutations. 40 A SOS1 mutation 41 was reported in a single patient with NS and PVS. These reports confirm that MGCL is a rare complication of the deregulated RAS/MAPK pathway.…”

Response to Growth Hormone in Short Children with Noonan Syndrome: Correlation to Genotype

“…JMML tumor cells exhibit increased GM-CSF sensitivity in the presence of mutant SHP2 in vitro [28]. Another tumor associated with NS is the benign giant cell lesion of the jaw, the incidence and pathogenesis of which are unclear [29,30]. These tumors are frequently found by dentists, and they can be painful and may destroy the jaw.…”

Atrioventricular canal defect in patients with RASopathies

“…Table 3 summarizes known mutations in AVCD patients with any RASopathy, including two patients with AVCD and PTPN11 mutation, 22 one patient with cleft mitral valve and KRAS mutation, 33 and one with cleft mitral valve and BRAF mutation. 34 The patients are counted once, accordingly to the primary diagnosis. The percentage of subjects with AVCD among the patients with molecular diagnosis and CHDs and frequency of the different mutations in the total series of patients with mutations is shown in Supplementary Table 4.…”