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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    • "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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    • "In our patient, growth velocity increased to 6 cm/year at the end of the first year of GH treatment in comparison to the rate of 3.8 cm/year prior to GH treatment. Although the first-year GH response was less than expected for a GH-deficient patient, we hesitated to augment the dose of GH in our case due to relatively increased tendency of such cases to develop a cancer in comparison to healthy controls (18). No GH-related side effects were detected in our case during his six-year follow-up. "
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    ABSTRACT: Cardio-facio-cutaneous (CFC) syndrome is a rare disorder characterized by craniofacial dysmorphia, ectodermal abnormalities, cardiac malformations, as well as growth and developmental delay. Although some endocrine abnormalities have been reported in this syndrome, very little is known about CFC syndrome-related endocrine disorders. A 7.5-year-old boy was admitted to our endocrinology clinic with the complaint of short stature. He had a height of 103 cm [-4 standard deviation (SD)], a weight of 16 kg (<3th percentile, -1.7 SD), a facial appearance typical for the CFC syndrome, optic nerve hypoplasia and pulmonary stenosis. Genetic investigation revealed a heterozygous mutation in exon 3 of the MEK1 gene, c.389A>G (p. Y130C). During his long-term follow-up, the patient developed a variety of endocrine disorders including precocious puberty, growth hormone deficiency and hyperprolactinemia.
    Journal of Clinical Research in Pediatric Endocrinology 03/2014; 6(1):55-8. DOI:10.4274/Jcrpe.1151
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    ABSTRACT: Recent advances in molecular genetic research have led to the definition of the new group of genetic syndromes, the RAS-mitogen-activated protein kinase (MAPK) pathway disorders or 'RASopathies'. They comprise Noonan syndrome and related disorders (cardio-facio-cutaneous and Costello syndromes), as well as neurofibromatosis type 1. This review summarizes the recent literature with a special focus on genotype-phenotype correlations. Although the picture is still incomplete, and additional genes are likely to exist, the underlying genetic alteration can now be found in a large majority of patients with a RASopathy phenotype. The most recently discovered novel genes for Noonan syndrome or Noonan syndrome-like disorders, NRAS, SHOC2, and CBL, account for small fractions of the patient population. The increasing knowledge about the spectrum of gene mutations and associated clinical manifestations has led to a refinement of genotype-phenotype correlations. Recent studies have added new insights into tumor predisposition and prenatal manifestations. Model systems are being developed to investigate innovative treatment approaches. Constitutional overactivation at various levels of the RAS-MAPK pathway causes overlapping syndromes, comprising characteristic facial features, cardiac defects, cutaneous abnormalities, growth deficit, neurocognitive delay, and predisposition to malignancies. Each syndrome also exhibits unique features that probably reflect genotype-related specific biological effects.
    Current opinion in pediatrics 08/2011; 23(4):443-51. DOI:10.1097/MOP.0b013e32834881dd · 2.53 Impact Factor
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