RESUMO
RASopathies are phenotypically overlapping genetic disorders caused by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) signaling pathway. RASopathies include Noonan syndrome, cardio-facio-cutaneous (CFC) syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, Noonan syndrome with multiple lentigines, Noonan-like syndrome, hereditary gingival fibromatosis, and capillary malformation/arteriovenous malformation syndrome. Recently, six patients with craniosynostosis and Noonan syndrome involving KRAS mutations were described in a review, and a patient with craniosynostosis and Noonan syndrome involving a SHOC2 mutation has also been reported. Here, we describe patients with craniosynostosis and Noonan syndrome due to de novo mutations in PTPN11 and patients with craniosynostosis and CFC syndrome due to de novo mutations in BRAF or KRAS. All of these patients had cranial deformities in addition to the typical phenotypes of CFC syndrome and Noonan syndrome. In RASopathy, patients with cranial deformities, further assessments may be necessary to look for craniosynostosis. Future studies should attempt to elucidate the pathogenic mechanism responsible for craniosynostosis mediated by the RAS/MAPK signaling pathway.
Assuntos
Craniossinostoses/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Criança , Pré-Escolar , Craniossinostoses/fisiopatologia , Displasia Ectodérmica/fisiopatologia , Fácies , Insuficiência de Crescimento/fisiopatologia , Feminino , Cardiopatias Congênitas/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação , Síndrome de Noonan/fisiopatologia , Fenótipo , Transdução de Sinais , Proteínas ras/genéticaRESUMO
RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype-phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.
Assuntos
Estudos de Associação Genética/métodos , Síndrome de Noonan/genética , Proteínas ras/genética , Pré-Escolar , Quilotórax/genética , Éxons , Feminino , Regulação da Expressão Gênica , Cardiopatias Congênitas/genética , Humanos , Hidropisia Fetal/genética , Lactente , Recém-Nascido , Masculino , Mutação , Medição da Translucência Nucal , Derrame Pleural/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína SOS1/genética , Proteína SOS1/metabolismo , Proteínas ras/metabolismoRESUMO
CASE: A nine-year-old boy had multiple osteochondromas in the hands, feet, and tibiae, many of which pointed toward the adjacent joint. Although several were treated surgically, others resolved spontaneously. A heterozygous mutation in the PTPN11 gene was identified by genetic analysis of peripheral blood, so the patient was diagnosed with metachondromatosis despite the absence of enchondromatous lesions. CONCLUSION: To the best of our knowledge, this is the first reported case of a patient with metachondromatosis without any enchondromatous lesions.
