CLINICAL REPORT Case Report: Noonan Syndrome With Multiple Giant Cell Lesions and Review of the Literature Julia Karbach, 1 * Wiltrud Coerdt, 2 Wilfried Wagner, 1 and Oliver Bartsch 3 1 Department of Oral and Maxillofacial Surgery, Plastic Reconstruction, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany 2 Institute of Pathology, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany 3 Institute of Human Genetics, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany Manuscript Received: 17 November 2011; Manuscript Accepted: 7 May 2012 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 complica- tion 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. Ó 2012 Wiley Periodicals, Inc. Key words: Noonan syndrome; multiple giant cell lesions; PTPN11 INTRODUCTION Noonan syndrome (NS, OMIM 163950, frequency 1 in 2.500 newborns) is an autosomal dominant dysmorphic syndrome char- acterized by short stature, craniofacial anomalies (ptosis, hyper- telorism, downslanting palpebral fissures, low-set and posteriorly rotated ears), short and/or webbed neck, with low posterior hairline, cardiac abnormalities, cryptorchidism, and occasionally bleeding tendency (coagulation factor deficiency). The syndrome was first described by Noonan and Ehmke in 1963 [Noonan and Ehmke, 1963] and was recently found be a part of the syndromes of the RAS/MAPK pathway, which also include the LEOPARD syndrome, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, and other RASopathies [Tidyman and Rauen, 2009; Tartaglia and Gelb, 2010]. A small subset of patients with NS develop multiple giant cell lesions (MGCL) of the jaw and these patients were originally reported as a distinct entity, Noonan-like/MGCL syndrome [Cohen and Gorlin, 1991]. 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 syn- drome 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]. There is increasing evidence that neurofibromatosis-NS is allelic to neurofibromatosis type 1 (NF1) in most patients [H€ uffmeier et al., 2006]. Conflicts of interest: None. *Correspondence to: Dr. Julia Karbach, DMD, MD, Department for Oral and Maxillofacial Surgery and Plastic Reconstruction, University Medical Center, Augustusplatz 2, D-55131 Mainz, Germany. E-mail: jkarbach@uni-mainz.de Article first published online in Wiley Online Library (wileyonlinelibrary.com): DOI 10.1002/ajmg.a.35493 How to Cite this Article: Karbach J, Coerdt W, Wagner W, Bartsch O. 2012. Case report: Noonan syndrome with multiple giant cell lesions and review of the literature. Am J Med Genet Part A. Ó 2012 Wiley Periodicals, Inc. 1