Our search strategy led to the compilation of 892 suitable publications describing 1941 cases contributing 23,756 person-years with sufficient information for this analysis (). Of the 1941 patients, 87 had 88 cancers (excluding MPDs), for crude rates of 3.8% (NS), 10.8% (CS), 3.5% (CFCS) and 1.6% (NSML) of reported cases (references for patients with cancer or MPD: Online Supplementary file
Cancer in NS, CS, CFCS, and NSML literature cases
Forty-six cases of cancer were reported in 45 subjects with NS (): There were 8 patients with neuroblastoma and 8 with acute lymphoblastic leukemia. The next most frequent neoplasms were 6 with glioma (1 with low-grade hypothalamic glioma, 1 with leptomeningeal dissemination of a low-grade mixed glioneuronal tumor, 1 with bilateral optic nerve pathway gliomas – this patient had deleterious mutations in 2 genes, PTPN11 and NF1, 2 with pilocytic astrocytoma [PA], 1 with glioma unclassified); 6 with RMS (1 botryoid, 5 embryonal); 3 with acute myeloid leukemia (including 1 therapy-related leukemia); 3 with testicular cancer (1 embryonal cell carcinoma, 1 seminoma, 1 Sertoli cell tumor); 2 with non-Hodgkin lymphoma; and 2 with colon cancer. There were single reports of Wilms tumor, hepatoblastoma, Hodgkin disease, chronic myelomonocytic leukemia, chronic lymphocytic leukemia, breast cancer, malignant schwannoma, and bile duct cancer. The ages of the patients at the time of cancer diagnosis were comparable to the ages expected for sporadic cancers.
We also identified 40 cases of NS (or Noonan-like syndrome) associated MPD in the literature. The disease had a benign course in 16 (40%) and an aggressive course in 6 (15%) cases. Twelve patients underwent hematopoietic bone marrow transplantation. Follow-up information was not available in the remaining cases. Two additional cases of MPD have been described, one in NSML and one in CFCS.
Twenty-nine cases of cancer were reported in 29 subjects with CS (): There were 19 RMS at a median age of 2.3 years (9 embryonal RMS, 1 alveolar RMS, 1 mixed histology, 1 pleomorphic RMS, 1 spindle cell type, and 6 with RMS unclassified). The next most frequent neoplasms were: neuroblastoma (n=5, including 4 with ganglioneuroblastoma); bladder cancer (n=4, including 3 with transitional cell carcinoma, 1 with low-grade papillary bladder carcinoma); and fibrosarcoma (n=1). The ages of the patients at the time of diagnosis of bladder cancer were substantially younger (mean=13.5 years) than the ages expected for sporadic cancers (mean=73 years).
Eight cases of cancer were reported in 8 subjects with CFCS (): There were 4 acute lymphoblastic leukemias. The next most frequent neoplasms were non-Hodgkin lymphoma (n=2); hepatoblastoma (n=1); and embryonal RMS (n=1; there has been debate in the literature whether this patient with RMS had CS rather than CFCS). Five cases of cancer were reported in 5 subjects with NSML (), including 2 acute myeloid leukemias; 1 acute lymphoblastic leukemia; 1 neuroblastoma; and 1 melanoma.
For NS, the cumulative incidence of cancer by age 20 years was 4% (95% CI: 3% – 6%) versus 10% (95% CI: 7 – 12%) for cancer-free death . Hence, 14% of NS subjects had developed a cancer or died prior to developing one by age 20 years. Noonan syndrome associated MPDs were excluded from this analysis because of their often benign course. For CS, the corresponding cumulative incidences were 15% (95% CI: 10 – 21%) and 12% (95% CI: 8 – 16%), respectively, and 27% had developed cancer or died . For NS, the annual cause-specific hazard (incidence rate per year among subjects who are still susceptible) of cancer showed an early peak during infancy of approximately 0.6%/year (with a large margin of error) . Subsequently, the cancer risk was stable at ~0.25%/year (also with a large margin of error).
Cumulative incidence and annual hazard rates and by age
For CS, the cause-specific cancer hazard also showed an early childhood peak of ~2-3%/year (also with a large margin of error) prior to the age of 5 years. Subsequently, the cancer risk was stable at around 0.7%/year (also with a large margin of error) . Note that the early childhood cancer hazard appears to be greater for CS than NS  due to the high risk of RMS in young children with CS.