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

Abstract

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.