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1.
Clin Dermatol ; 38(4): 455-461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32972603

RESUMO

RASopathies are a group of disorders characterized by mutations in the RAS-MAPK pathway. RAS-MAP signaling plays a critical role in cell differentiation, proliferation, and survival. Germline mutations can result in distinctive syndromes, including Noonan syndrome, Costello syndrome, and neurofibromatosis type 1. Mosaic RASopathies can present as localized cutaneous lesions like epidermal nevi and nevus sebaceous, or more extensive conditions such as encephalocraniocutaneous lipomatosis. We review the heterogenous presentation of RAS mutations, discuss new targeted therapies, and highlight areas of uncertainty, including carcinogenesis risk and appropriate screening.


Assuntos
Síndrome de Costello/genética , Oftalmopatias/genética , Mutação em Linhagem Germinativa , Lipomatose/genética , Sistema de Sinalização das MAP Quinases/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Síndromes Neurocutâneas/genética , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Síndrome de Costello/diagnóstico , Síndrome de Costello/terapia , Oftalmopatias/diagnóstico por imagem , Oftalmopatias/terapia , Humanos , Lipomatose/diagnóstico por imagem , Lipomatose/terapia , Terapia de Alvo Molecular , Mutação , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/terapia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/terapia , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/terapia , Risco
4.
Arch Argent Pediatr ; 117(5): 330-337, 2019 10 01.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31560489

RESUMO

INTRODUCTION: RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway. They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer. A molecular diagnosis is a key factor. OBJECTIVE: To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation. Population and methods. Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017. RESULTS: Mutations were identified in 71 % (87/122) of patients. The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome. The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene. A previously undescribed variant in RAF1 was detected: c.1467G>>C (p.Leu489Phe). Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations. Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases. CONCLUSION: The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis. The prevalence of PTPN11 (58 %), SOS1 (10 %), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.


Assuntos
Síndrome de Costello/diagnóstico , Displasia Ectodérmica/diagnóstico , Insuficiência de Crescimento/diagnóstico , Cardiopatias Congênitas/diagnóstico , Síndrome de Noonan/diagnóstico , Adolescente , Argentina , Criança , Pré-Escolar , Síndrome de Costello/genética , Diagnóstico Diferencial , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/genética , Adulto Jovem
5.
Cytogenet Genome Res ; 158(4): 184-191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31394527

RESUMO

Costello syndrome (CS) is a rare genetic disorder characterized by distinctive facial appearance, cardiopulmonary complications, severe growth retardation, skin and skeletal defects, developmental delay, and tumor predisposition. CS is caused by heterozygous de novo mutations in the proto-oncogene HRAS, which is a component of the RAS/mitogen-activated protein kinase pathway. Herein, we reviewed the phenotypic and genetic features of 5 Korean patients who were genetically diagnosed with CS. Atrial tachycardia and polyhydramnios, which are important prenatal features for CS, were observed in 4 and 5 patients, respectively. The distinctive coarse facial appearances of the patients and presence of deep palmoplantar creases supported the clinical diagnosis of CS, which was confirmed by HRAS sequence analysis. Extremely poor postnatal growth was observed in all 5 patients. Further, all patients exhibited cardiac abnormalities; left ventricular hypertrophy and hypertrophic cardiomyopathy were observed in 3 patients. All 5 patients suffered from airway problems; 3 of them required intubation right after birth, and 2 of them received tracheostomy. One patient with a p.Gly12Ser mutation was diagnosed with retroperitoneal rhabdomyosarcoma alveolar type at the age of 5 years. Consistent with previous reports, both patients with p.Gly12Cys mutations died within the first year of life due to cardiopulmonary failure. Our study summarizes the characteristics of these 5 Korean patients with CS and, along with previous studies, provides clues for genotype-phenotype correlation in patients with CS.


Assuntos
Síndrome de Costello/genética , Fenótipo , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , República da Coreia
6.
Mol Cells ; 42(6): 441-447, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31250618

RESUMO

RAS gene mutations are frequently found in one third of human cancers. Affecting approximately 1 in 1,000 newborns, germline and somatic gain-of-function mutations in the components of RAS/mitogen-activated protein kinase (RAS/MAPK) pathway has been shown to cause developmental disorders, known as RASopathies. Since RAS-MAPK pathway plays essential roles in proliferation, differentiation and migration involving developmental processes, individuals with RASopathies show abnormalities in various organ systems including central nervous system. The frequently seen neurological defects are developmental delay, macrocephaly, seizures, neurocognitive deficits, and structural malformations. Some of the defects stemmed from dysregulation of molecular and cellular processes affecting early neurodevelopmental processes. In this review, we will discuss the implications of RAS-MAPK pathway components in neurodevelopmental processes and pathogenesis of RASopathies.


Assuntos
Transtornos do Neurodesenvolvimento/genética , Proteínas ras/genética , Síndrome de Costello/genética , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Humanos , Recém-Nascido , Neoplasias/metabolismo , Neurofibromatose 1/genética , Nevo Sebáceo de Jadassohn/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteína SOS1/genética , Transdução de Sinais/genética
7.
Am J Med Genet A ; 179(9): 1725-1744, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31222966

RESUMO

Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues; however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are based on expert opinion and do not represent evidence-based guidelines due to the lack of data for this rare condition.


Assuntos
Anormalidades Múltiplas/genética , Síndrome de Costello/genética , Coração/fisiopatologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/fisiopatologia , Síndrome de Costello/fisiopatologia , Síndrome de Costello/terapia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Gerenciamento Clínico , Face/anormalidades , Regulação da Expressão Gênica/genética , Genótipo , Mutação em Linhagem Germinativa/genética , Guias como Assunto , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/fisiopatologia , Humanos , Fenótipo
8.
Am J Med Genet C Semin Med Genet ; 181(2): 208-217, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30896080

RESUMO

RASopathies are a group of genetic disorders due to dysregulation of the RAS-MAPK signaling pathway, which is important in regulating cell growth, proliferation, and differentiation. These include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), cardiofaciocutaneous (CFC) syndrome, and Costello syndrome (CS), clinical manifestations include growth retardation, developmental delay, cardiac defects, and specific dysmorphic features. There were abundant publications describing the genotype and phenotype from the Western populations. However, detailed study of RASopathies in Chinese population is lacking. We present here the largest cohort of RASopathies ever reported in Chinese populations, detailing the mutation spectrum and clinical phenotypes of these patients. The Clinical Genetic Service, Department of Health, and Queen Mary Hospital are tertiary referral centers for genetic disorders in Hong Kong. We retrospectively reviewed all the genetically confirmed cases of RASopathies, including NS, NSML, CFC syndrome, and CS, over the past 29 years (from 1989 to 2017). Analyses of the mutation spectrum and clinical phenotypes were performed. One hundred and ninety-one ethnic Chinese patients with genetically confirmed RASopathies were identified, including 148 patients with NS, 23 NSML, 12 CFC syndrome, and eight CS. We found a lower incidence of hypertrophic cardiomyopathy in individuals with NSML (27.3%), and NS caused by RAF1 mutations (62.5%). Another significant finding was for those NS patients with myeloproliferative disorder, the mutations fall within Exon 3 of PTPN11 but not only restricted to the well-known hotspots, that is, p.Asp61 and p.Thr731, which suggested that re-evaluation of the current tumor surveillance recommendation maybe warranted.


Assuntos
Mutação , Fenótipo , Proteínas ras/genética , Síndrome de Costello/genética , Síndrome de Costello/patologia , Displasia Ectodérmica/genética , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Feminino , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Hong Kong , Humanos , Síndrome LEOPARD/genética , Síndrome LEOPARD/patologia , Sistema de Sinalização das MAP Quinases/genética , Masculino , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Estudos Retrospectivos
10.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 53(12): 858-861, 2018 Dec 09.
Artigo em Chinês | MEDLINE | ID: mdl-30522213

RESUMO

The RASopathies are a group of syndromes that have in common germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway and have been a focus of study to understand the role of this pathway in development and disease. These syndromes include Noonan syndrome (NS), NS with multiple lentigines (NSML), neu-rofibromatosis type 1 (NF1), Costello syndrome (CS), cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type 1-like syndrome (NFLS) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). These disorders affect multiple systems, including the craniofacial complex. Although the crani-ofacial features have been well described and can aid in clinical diagnosis, the dental phenotypes have not been analysed in detail for each of the RASopathies. In this review, we summarize the clinical features of the RASopathies, highlighting the reported craniofacial and dental findings.


Assuntos
Síndrome de Costello , Displasia Ectodérmica , Síndrome de Noonan , Proteínas ras , Síndrome de Costello/genética , Anormalidades Craniofaciais/genética , Displasia Ectodérmica/genética , Humanos , Síndrome de Noonan/genética , Proteínas ras/genética
11.
Hum Mutat ; 39(11): 1485-1493, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30311384

RESUMO

The RASopathies are a complex group of conditions regarding phenotype and genetic etiology. The ClinGen RASopathy Expert Panel (RAS EP) assessed published and other publicly available evidence supporting the association of 19 genes with RASopathy conditions. Using the semiquantitative literature curation method developed by the ClinGen Gene Curation Working Group, evidence for each gene was curated and scored for Noonan syndrome (NS), Costello syndrome, cardiofaciocutaneous syndrome, NS with multiple lentigines, and Noonan-like syndrome with loose anagen hair. The curated evidence supporting each gene-disease relationship was then discussed and approved by the ClinGen RASopathy Expert Panel. Each association's strength was classified as definitive, strong, moderate, limited, disputed, or no evidence. Eleven genes were classified as definitively associated with at least one RASopathy condition. Two genes classified as strong for association with at least one RASopathy condition while one gene was moderate and three were limited. The RAS EP also disputed the association of two genes for all RASopathy conditions. Overall, our results provide a greater understanding of the different gene-disease relationships within the RASopathies and can help in guiding and directing clinicians, patients, and researchers who are identifying variants in individuals with a suspected RASopathy.


Assuntos
Proteínas ras/metabolismo , Síndrome de Costello/genética , Displasia Ectodérmica/genética , Facies , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Mutação/genética , Síndrome de Noonan/genética , Proteínas ras/genética
12.
Am J Med Genet A ; 176(8): 1711-1722, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30055033

RESUMO

Multifocal atrial tachycardia (MAT) has a well-known association with Costello syndrome, but is rarely described with related RAS/MAPK pathway disorders (RASopathies). We report 11 patients with RASopathies (Costello, Noonan, and Noonan syndrome with multiple lentigines [formerly LEOPARD syndrome]) and nonreentrant atrial tachycardias (MAT and ectopic atrial tachycardia) demonstrating overlap in cardiac arrhythmia phenotype. Similar overlap is seen in RASopathies with respect to skeletal, musculoskeletal and cutaneous abnormalities, dysmorphic facial features, and neurodevelopmental deficits. Nonreentrant atrial tachycardias may cause cardiac compromise if sinus rhythm is not restored expeditiously. Typical first-line supraventricular tachycardia anti-arrhythmics (propranolol and digoxin) were generally not effective in restoring or maintaining sinus rhythm in this cohort, while flecainide or amiodarone alone or in concert with propranolol were effective anti-arrhythmic agents for acute and chronic use. Atrial tachycardia resolved in all patients. However, a 4-month-old boy from the cohort was found asystolic (with concurrent cellulitis) and a second patient underwent cardiac transplant for heart failure complicated by recalcitrant atrial arrhythmia. While propranolol alone frequently failed to convert or maintain sinus rhythm, fleccainide or amiodarone, occasionally in combination with propranolol, was effective for RASopathy patient treatment for nonreentrant atrial arrhythmia. Our analysis shows that RASopathy patients may have nonreentrant atrial tachycardia with and without associated cardiac hypertrophy. While nonreentrant arrhythmia has been traditionally associated with Costello syndrome, this work provides an expanded view of RASopathy cardiac arrhythmia phenotype as we demonstrate mutant proteins throughout this signaling pathway can also give rise to ectopic and/or MAT.


Assuntos
Cardiomiopatia Hipertrófica/genética , Síndrome de Costello/genética , Síndrome de Noonan/genética , Taquicardia Atrial Ectópica/genética , Proteínas ras/genética , Amiodarona/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Arritmias Cardíacas/genética , Arritmias Cardíacas/fisiopatologia , Cálcio/metabolismo , Cardiomiopatia Hipertrófica/tratamento farmacológico , Cardiomiopatia Hipertrófica/fisiopatologia , Síndrome de Costello/tratamento farmacológico , Síndrome de Costello/fisiopatologia , Digoxina/uso terapêutico , Feminino , Humanos , Lactente , Recém-Nascido , Síndrome LEOPARD/genética , Síndrome LEOPARD/fisiopatologia , Masculino , Síndrome de Noonan/tratamento farmacológico , Síndrome de Noonan/fisiopatologia , Propranolol/uso terapêutico , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/genética , Taquicardia Atrial Ectópica/tratamento farmacológico , Taquicardia Atrial Ectópica/fisiopatologia , Proteínas ras/classificação
13.
Am J Med Genet B Neuropsychiatr Genet ; 177(4): 434-446, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29659143

RESUMO

Personality is a complex, yet partially heritable, trait. Although some Mendelian diseases like Williams-Beuren syndrome are associated with a particular personality profile, studies have failed to assign the personality features to a single gene or pathway. As a family of monogenic disorders caused by mutations in the Ras/MAPK pathway known to influence social behavior, RASopathies are likely to provide insight into the genetic basis of personality. Eighty subjects diagnosed with cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis type 1, and Noonan syndrome were assessed using a parent-report BFQ-C (Big Five Questionnaire for Children) evaluating agreeableness, extraversion, conscientiousness, intellect/openness, and neuroticism, along with 55 unaffected sibling controls. A short questionnaire was added to assess sense of humor. RASopathy subjects and sibling controls were compared for individual components of personality, multidimensional personality profiles, and individual questions using Student tests, analysis of variance, and principal component analysis. RASopathy subjects were given lower scores on average compared to sibling controls in agreeableness, extraversion, conscientiousness, openness, and sense of humor, and similar scores in neuroticism. When comparing the multidimensional personality profile between groups, RASopathies showed a distinct profile from unaffected siblings, but no difference in this global profile was found within RASopathies, revealing a common profile for the Ras/MAPK-related disorders. In addition, several syndrome-specific strengths or weaknesses were observed in individual domains. We describe for the first time an association between a single pathway and a specific personality profile, providing a better understanding of the genetics underlying personality, and new tools for tailoring educational and behavioral approaches for individuals with RASopathies.


Assuntos
Transtornos da Personalidade/fisiopatologia , Personalidade/fisiologia , Proteínas ras/fisiologia , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Costello/genética , Síndrome de Costello/fisiopatologia , Displasia Ectodérmica/fisiopatologia , Facies , Insuficiência de Crescimento/fisiopatologia , Família , Feminino , Cardiopatias Congênitas/fisiopatologia , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Mutação , Neurofibromatose 1/fisiopatologia , Síndrome de Noonan/fisiopatologia , Irmãos , Proteínas ras/genética
14.
Sci Rep ; 8(1): 2421, 2018 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-29402968

RESUMO

RASopathies are a group of heterogeneous conditions caused by germline mutations in RAS/MAPK signalling pathway genes. With next-generation sequencing (NGS), sequencing capacity is no longer a limitation to molecular diagnosis. Instead, the rising number of variants of unknown significance (VUSs) poses challenges to clinical interpretation and genetic counselling. We investigated the potential of an integrated pipeline combining NGS and the functional assessment of variants for the diagnosis of RASopathies. We included 63 Chinese patients with RASopathies that had previously tested negative for PTPN11 and HRAS mutations. In these patients, we performed a genetic analysis of genes associated with RASopathies using a multigene NGS panel and Sanger sequencing. For the VUSs, we evaluated evidence from genetic, bioinformatic and functional data. Twenty disease-causing mutations were identified in the 63 patients, providing a primary diagnostic yield of 31.7%. Four VUSs were identified in five patients. The functional assessment supported the pathogenicity of the RAF1 and RIT1 VUSs, while the significance of two VUSs in A2ML1 remained unclear. In summary, functional analysis improved the diagnostic yield from 31.7% to 36.5%. Although technically demanding and time-consuming, a functional genetic diagnostic analysis can ease the clinical translation of these findings to aid bedside interpretation.


Assuntos
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , Cardiopatias Congênitas/genética , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas ras/genética , Adolescente , Animais , Bioensaio , Criança , Pré-Escolar , Biologia Computacional , Síndrome de Costello/patologia , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , MAP Quinase Quinase 1/genética , Masculino , Mutação de Sentido Incorreto , Neurofibromatose 1/patologia , Síndrome de Noonan/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína SOS1/genética , Peixe-Zebra , alfa-Macroglobulinas/genética
16.
Eur J Dermatol ; 27(6): 641-645, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29165300

RESUMO

Cardio-facio-cutaneous syndrome (CFC), Noonan syndrome (NS), and Costello syndrome are a group of diseases that belong to the RASopathies. The syndromes share clinical features making diagnosis a challenge. To investigate the phenotype and genotype of a 10-year-old Iraqi girl with overlapping features of CFC, NS, and Costello syndromes, with additional features of ectodermal dysplasia. DNA was examined by exome sequencing and protein expression by immunohistochemistry. Exome sequencing identified a mutation in the SOS1 gene and a de novo deletion in the FOXI2 gene which was neither present in the international databases, nor in 400 chromosomes from the same population. Based on immunohistochemical staining, FOXI2 was identified in the basal cell layer of the skin and overlapped with the expression of P63, a major player in ectodermal dysplasia. We therefore suggest screening for FOXI2 mutation in the setting of ectodermal features that are not associated with genes known to contribute to ectodermal dysplasia.


Assuntos
Displasia Ectodérmica/genética , Mutação , Criança , Síndrome de Costello/diagnóstico , Síndrome de Costello/genética , Displasia Ectodérmica/diagnóstico , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/diagnóstico , Insuficiência de Crescimento/genética , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Humanos , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Proteína SOS1 , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética
17.
Clin Cancer Res ; 23(12): e83-e90, 2017 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-28620009

RESUMO

In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific PTPN11 or KRAS mutations are present, and in patients with CBL syndrome. Also, the high brain tumor risk in patients with L-2 hydroxyglutaric aciduria may warrant regular screening with brain MRIs. For most syndromes, surveillance may be needed for nonmalignant health problems. Clin Cancer Res; 23(12); e83-e90. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.


Assuntos
Anormalidades Múltiplas/epidemiologia , Hipotireoidismo Congênito/epidemiologia , Anormalidades Craniofaciais/epidemiologia , Deformidades Congênitas da Mão/epidemiologia , Deficiência Intelectual/epidemiologia , Unhas Malformadas/epidemiologia , Síndrome de Rubinstein-Taybi/epidemiologia , Síndrome de Sotos/epidemiologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Hipotireoidismo Congênito/genética , Hipotireoidismo Congênito/patologia , Síndrome de Costello/epidemiologia , Síndrome de Costello/genética , Síndrome de Costello/patologia , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/patologia , Deformidades Congênitas da Mão/genética , Deformidades Congênitas da Mão/patologia , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação , Unhas Malformadas/genética , Unhas Malformadas/patologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/patologia , Síndrome de Noonan/epidemiologia , Síndrome de Noonan/genética , Síndrome de Noonan/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Fatores de Risco , Síndrome de Rubinstein-Taybi/genética , Síndrome de Rubinstein-Taybi/patologia , Síndrome de Sotos/genética , Síndrome de Sotos/patologia , Fator Nuclear 1 de Tireoide/genética
18.
Eur J Hum Genet ; 25(7): 823-831, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28594414

RESUMO

RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c.35G>A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c.34G>C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.


Assuntos
Síndrome de Costello/genética , Displasia Ectodérmica/genética , Insuficiência de Crescimento/genética , GTP Fosfo-Hidrolases/genética , Mutação em Linhagem Germinativa , Cardiopatias Congênitas/genética , Proteínas de Membrana/genética , Síndrome de Noonan/genética , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Costello/patologia , Displasia Ectodérmica/patologia , Facies , Insuficiência de Crescimento/patologia , Feminino , Genótipo , Cardiopatias Congênitas/patologia , Humanos , Lactente , Recém-Nascido , Masculino , Mutação de Sentido Incorreto , Síndrome de Noonan/patologia , Fenótipo
19.
Am J Med Genet A ; 173(5): 1294-1300, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28374929

RESUMO

Dysregulation of the mitogen activated protein kinase (MAPK) pathway in Costello syndrome (CS) may contribute to increased risk for autism-spectrum disorder (ASD). We examined prevalence of ASD symptoms in 14 individuals (six females) age 1-18 years with molecularly confirmed CS. Caregivers completed the Modified Checklist for Autism in Toddlers (M-CHAT) for ages 0-4 years (n = 7), and the Social Communication Questionnaire (SCQ) for ages 4 and older (n = 7). Age was associated with meeting ASD criteria: 5/7 (71.4%) younger children met the ASD cut-off on the MCHAT, compared to 0/7 older children on the SCQ. The following medical and developmental factors were strongly associated with ASD criteria on the M-CHAT: having a gastrostomy tube at time of assessment, not eating solid food, not walking, and not being toilet trained. Two children who met stricter ASD criteria had significantly lower adaptive functioning and were physically much more impaired. Among older participants, SCQ subscale scores in communication, socialization, and repetitive behavior domains were comparable to the typically-developing normative sample. ASD symptoms were highly elevated in younger CS individuals. Older children did not differ from typically developing samples in prevalence of ASD symptoms. CS individuals may appear to fall on the autism spectrum in early childhood due to severe feeding and orthopedic problems that improve by age four, suggesting many of these children may eventually emerge out of an ASD presentation.


Assuntos
Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/fisiopatologia , Síndrome de Costello/epidemiologia , Síndrome de Costello/fisiopatologia , Adolescente , Fatores Etários , Transtorno do Espectro Autista/genética , Criança , Pré-Escolar , Síndrome de Costello/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Comportamento Social , Inquéritos e Questionários
20.
Am J Med Genet A ; 173(5): 1309-1318, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28371260

RESUMO

Costello syndrome is part of the RASopathies, a group of neurocardiofaciocutaneous syndromes caused by deregulation of the RAS mitogen-activated protein kinase pathway. Heterozygous mutations in HRAS are responsible for Costello syndrome, with more than 80% of the patients harboring the specific p.Gly12Ser variant. These individuals show a homogeneous phenotype. The clinical characteristics of the Costello syndrome individuals harboring rarer HRAS mutations are less understood, due to the small number of reported cases. Here, we describe the phenotypic spectrum of five additional individuals with HRAS c.38G>A; p.Gly13Asp, including one with somatic mosaicism, and review five previously described cases. The facial and hair abnormalities of the HRAS p.Gly13Asp individuals differ from the typical pattern observed in those showing the common HRAS (p.Gly12Ser) mutation, with less coarse facial features and slow growing, sparse hair with abnormal texture, the latter resembling the pattern observed in Noonan syndrome-like disorder with loose anagen hair and individuals harboring another amino acid substitution in HRAS (p.Gly13Cys). Although some individuals with HRAS p.Gly13Asp developed papillomata and vascular proliferation lesions, no malignant tumors occurred, similar to what was reported for individuals harboring the HRAS p.Gly13Cys. The fact that no malignant tumors were described in these individuals does not allow definitive conclusions about the risk for cancer development. It remains to be determined if substitutions of amino acid 13 in HRAS (p.Gly13Asp and p.Gly13Cys) increase the risk of tumor development.


Assuntos
Anormalidades Múltiplas/genética , Síndrome de Costello/genética , Neoplasias/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Substituição de Aminoácidos/genética , Aminoácidos/genética , Criança , Pré-Escolar , Síndrome de Costello/complicações , Síndrome de Costello/fisiopatologia , Feminino , Mutação em Linhagem Germinativa , Humanos , Masculino , Mosaicismo , Neoplasias/complicações , Neoplasias/fisiopatologia , Fenótipo
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