Cancer in Noonan, Costello, Cardiofaciocutaneous, and LEOPARD syndromes

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Boulevard, EPS/7018, Rockville, MD 20892, USA.
American Journal of Medical Genetics Part C Seminars in Medical Genetics (Impact Factor: 3.91). 05/2011; 157(2):83-9. DOI: 10.1002/ajmg.c.30300
Source: PubMed


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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    • "consists of sparse curly hair, absent or sparse eyelashes and eyebrows , high forehead, relative macrocephaly, bitemporal narrowing , hypoplastic supraorbital ridges, hypertelorism with downslanting palpebral fissures, ptosis, short nose with anteverted nares, deep philtrum, and low-set posteriorly rotated ears. The risk of malignancies (acute lymphoblastic leukemia, lymphoma) appears marginally increased [Reynolds et al., 1986; Rauen, 1993; Roberts et al., 2006; Allanson et al., 2011; Kratz et al., 2011]. Intellectual disability, ranging from moderate to severe, is almost constant in patients with BRAF mutations [Yoon et al., 2007]. "
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    ABSTRACT: Our study was designed to analyze prenatal manifestations in patients affected with cardio-facio-cutaneous syndrome (CFCS), in order to define indications of DNA testing in utero. Prenatal features were extracted from a national database and additional data were collected from 16 families contacted through the French association of CFC-Costello syndrome. We collected results of ultrasound scan (USS) biometrics, presence of congenital birth defects, and polyhydramnios. From the database, increased nuchal translucency was present in 13% of pregnancies, polyhydramnios in 52%, macrosomia and/or macrocephaly in 16%. Of the 16 pregnancies, 81% were complicated by abnormal USS findings. Polyhydramnios was reported in 67%. Head circumference, biparietal diameter, and abdominal circumference were above the 90th centile in 72%, 83% and, 81% of fetuses, respectively. Contrasting with macrosomia, femur length was below the 10th centile in 38%. Urinary tract abnormalities were found in 47% of fetuses. Most CFCS fetuses showed a combination of macrocephaly, macrosomia, and polyhydramnios, contrasting with relatively short femora. This growth pattern is also seen in Costello syndrome. We suggest that screening for CFCS and Costello gene mutations could be proposed in pregnancies showing this unusual pattern of growth parameters. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 10/2015; DOI:10.1002/ajmg.a.37420 · 2.16 Impact Factor
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    • "The alterations that cause these conditions do not increase the signaling of the RAS/MAPK pathway to the same extent as oncogenic alterations such as KRAS c.35G>A (p. Gly12Asp), nevertheless, individuals with these conditions are more likely to have various forms of cancer [Kratz et al., 2011; Rauen, 2013] as well as giant cell granulomas [Neumann et al., 2009b; Karbach et al., 2012]. As noted above, the risk of malignancy in OES remains unknown due to a lack of longitudinal reporting in this cohort; the median age at report is 2 years (see Table I). "
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    ABSTRACT: Oculoectodermal syndrome (OES) is a rare disease characterized by a combination of congenital scalp lesions and ocular dermoids, with additional manifestations including non-ossifying fibromas and giant cell granulomas of the jaw occurring during the first decade of life. To identify the genetic etiology of OES, we conducted whole-genome sequencing of several tissues in an affected individual. Comparison of DNA from a non-ossifying fibroma to blood-derived DNA allowed identification of a somatic missense alteration in KRAS NM_033360.3(KRAS):c.38G>A, resulting in p.Gly13Asp. This alteration was also observed in the patient's other affected tissues including the skin and muscle. Targeted sequencing in a second, unrelated OES patient identified an NM_033360.3(KRAS):c.57G>C, p.Leu19Phe alteration. Allelic frequencies fell below 40% in all tissues examined in both patients, suggesting that OES is a mosaic RAS-related disorder, or RASopathy. The characteristic findings in OES, including scalp lesions, ocular dermoids, and benign tumors, are found in other mosaic and germline RASopathies. This discovery also broadens our understanding of the spectrum of phenotypes resulting from KRAS alterations. Future research into disease progression with regard to malignancy risk and investigation of RAS-targeted therapies in OES is warranted. KRAS sequencing is clinically available and may also now improve OES diagnostic criteria. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 03/2015; 167(7). DOI:10.1002/ajmg.a.37048 · 2.16 Impact Factor
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    • "Clinical manifestations of RASopathies include postnatal reduced growth, a wide spectrum of cardiac defects, facial dysmorphism, ectodermal and skeletal anomalies and variable cognitive deficits (5,8,10). Consistent with the key role of most RASopathy genes in oncogenesis, these disorders are also characterized by variably increased risk for certain haematologic malignancies and other paediatric cancers (6,7,11,12). Most of these conditions are genetically heterogeneous, and the underlying disease gene has not been identified yet for a still significant fraction of cases. "
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    ABSTRACT: RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2S2G mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.
    Human Molecular Genetics 04/2014; 23(16). DOI:10.1093/hmg/ddu148 · 6.39 Impact Factor
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