title: Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes.
abstract: Noonan syndrome (NS), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and LEOPARD syndrome (now also referred to as Noonan syndrome with multiple lentigines or NSML) are clinically overlapping dominant disorders that are caused by mutations in RAS signaling pathway genes. The spectrum of cancer susceptibility in this group of disorders has not been studied in detail. We identified more than 1900 cases of NS, CS, CFCS, or NSML reported in the literature between 1937 and 2010; 88 cancers were reported. The most common cancers reported in 1051 NS subjects were neuroblastoma (n = 8), acute lymphoblastic leukemia (n = 8), low grade glioma (n = 6), and rhabdomyosarcoma (n = 6). These associations are biologically plausible, given that somatic RAS pathway mutations are known to occur in these specific cancers. In addition, 40 childhood cases of myeloproliferative disease were described in individuals with NS, several of whom experienced a benign course of this hematologic condition. We confirmed the previously described association between CS and cancer in 268 reported individuals: 19 had rhabdomyosarcoma, 4 had bladder cancer, and 5 had neuroblastoma. By age 20, the cumulative incidence of cancer was approximately 4% for NS and 15% for CS; both syndromes had a cancer incidence peak in childhood. The cancers described in CFCS and NSML overlapped with those reported in NS and CS. Future epidemiologic studies will be required to confirm the described cancer spectrum and to estimate precise cancer risks.
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Boulevard, EPS/7018, Rockville, MD 20892, USA. kratzcp@mail.nih.gov
authors.forename: Christian P
authors.initials: CP
authors.lastname: Kratz
authors.forename: Suthee
authors.initials: S
authors.lastname: Rapisuwon
authors.forename: Helen
authors.initials: H
authors.lastname: Reed
authors.forename: Henrik
authors.initials: H
authors.lastname: Hasle
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rosenberg
mesh_terms: D056685:Costello Syndrome / Q000235:genetics*; D004476:Ectodermal Dysplasia / Q000235:genetics; D019066:Facies; D005183:Failure to Thrive / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006330:Heart Defects, Congenital / Q000235:genetics; D006801:Humans; D044542:LEOPARD Syndrome / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000453:epidemiology* / Q000235:genetics*; D009634:Noonan Syndrome / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)