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. 2011 May 15;157C(2):83-9.
doi: 10.1002/ajmg.c.30300. Epub 2011 Apr 15.

Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes

Christian P Kratz  1 , Suthee Rapisuwon, Helen Reed, Henrik Hasle, Philip S Rosenberg
Affiliations

Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes

Christian P Kratz et al. Am J Med Genet C Semin Med Genet. .

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.

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Figures

Figure 1
Figure 1. Cumulative incidence and annual hazard rates and by age
(a, b) Cumulative incidence for cancer and cancer-free death by age in patients with Noonan syndrome (a) and Costello syndrome (b) and 95% CIs (shaded regions). (c, d) Annual hazard rates (incidence rate per year among subjects who are still susceptible) of cancer-free death or cancer, and 95% point-wise confidence envelopes (shaded regions) for Noonan syndrome (c) and Costello syndrome (d).
See this image and copyright information in PMC

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