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1.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(3): 324-328, 2020 Mar 10.
Artigo em Chinês | MEDLINE | ID: mdl-32128752

RESUMO

Noonan syndrome is a common genetic disease characterized by peculiar face, short stature, congenital heart disease and thoracic deformity. The pathogenesis of Noonan syndrome is mainly related to abnormal Ras-MAPK signal pathway which involves more than 16 genes including (PTPN11, SOS1, RAF1)] and KRAS. At present, there is a lack of experience in the diagnosis and treatment of Noonan syndrome in China. This guideline has summarized the clinical manifestation, pathogenesis, diagnostic criteria and treatment for Noonan syndrome, with an aim to improve the diagnostic level and clinical management of patients with this syndrome.


Assuntos
Síndrome de Noonan/diagnóstico , Síndrome de Noonan/terapia , Guias de Prática Clínica como Assunto , China , Nanismo , Humanos , Mutação , Transdução de Sinais
2.
Blood ; 134(25): 2231-2232, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856271
3.
Artigo em Chinês | MEDLINE | ID: mdl-31446693

RESUMO

Summary Noonan syndrome with multiple lentigines(NSML) is a disorder with syndromic hearing loss. Abnormalities of other systems in NSML have received increasing attention, but hearing loss is rarely concerned. And due to the incomplete phenotype, some patients with NSML maybe missed or maybe confused with other syndromic deafness such as Waardenburg syndrome. Our study will familiarize more otolaryngologists with Leopard syndrome. A 5-year-old boy with bilateral sensorineural hearing loss and numerous symmetrically distributed dark brown macules that had good effect of cochlear implantation was collected in this study. And his father had bilateral sensorineural hearing loss and numerous symmetrically distributed dark brown macules. Waardenburg syndrome was initially diagnosed by clinical phenotype and its molecular etiology was confirmed by gene diagnosis. Waardenburg syndrome-related deafness genes and 131 known deafness genes were not identified by second-generation sequencing. Whole-exon sequencing was performed for 4 individuals in the family and the results were confirmed by Sanger sequencing. This study confirmed the diagnosis by identifying a disease-causing mutation in the PTPN11 gene, which was a heterozygous missense mutation at p. Tyr279Cys(c. 836A>G). The mutation co-segregated with hearing loss in the family. Our results demonstrated that hearing loss in this family was caused by heterozygous mutations in PTPN11. These cases will familiarize more otolaryngologists with NSML, and they emphasize the importance of considering NSML as a possible cause of hearing problems.


Assuntos
Surdez/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Pré-Escolar , Heterozigoto , Humanos , Masculino , Mutação , Síndrome de Waardenburg
4.
Artigo em Chinês | MEDLINE | ID: mdl-31446698

RESUMO

Summary PTPN11 gene encodes tyrosine phosphatase SHP-2 which locates on chromosome 12(12q24.1), expresses in most embryonic and adult tissues, and plays pivotal roles in cell proliferation, differentiation, survival and cell death. SHP-2 apparently participates in signaling events downstream of RAS-MAPK and JAK/STAT. Diseases related to PTPN11 gene mutations include the Noonan syndrome(NS) and the NS with Multiple Lentigines(NSML). Both NS and NSML contain the phenotypes of deafness, craniofacial anomalies, short stature, congenital heart defects, skin disorders, ophthalmologic abnormalities and cancer predisposition.


Assuntos
Surdez/genética , Síndrome de Noonan/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Humanos , Mutação , Síndrome de Noonan/classificação , Fenótipo , Transdução de Sinais
5.
Cardiol Young ; 29(9): 1214-1216, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31378211

RESUMO

We present a case of sudden cardiac arrest in the field with complete neurological recovery in an 18-year-old athlete with phenotypic Noonan syndrome. Evaluation revealed interventricular septal thickness of 18 mm without left ventricular outflow tract obstruction and no other identifiable structural, electrophysiologic, or genetic abnormality except isolated heterozygous variant for desmoplakin DSP variant p.Lys2103Glu, with unknown clinical significance.


Assuntos
Atletas , Morte Súbita Cardíaca/etiologia , Síndrome de Noonan/complicações , Adolescente , Desfibriladores Implantáveis , Ecocardiografia , Seguimentos , Humanos , Masculino , Síndrome de Noonan/diagnóstico , Fatores de Tempo , Septo Interventricular/diagnóstico por imagem
6.
Ceska Gynekol ; 84(3): 195-200, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31324109

RESUMO

OBJECTIVE: Noonan syndrome (NS), one of the most common RASopathies, has an estimated incidence of 1 in 1,000-2,500 live births. In the prenatal period increased nuchal translucency, hygroma colli, hydrops fetus, congenital heart disease, kidney defects, larger amount of amniotic fluid can be observed in affected fetuses with this syndrome. In the fetuses with normal karyotype and no microdeletion/microduplication syndromes the examination of selected genes for RASopathies was added. The aim of the study was to evaluate the clinical benefit of massively parallel sequencing (MPS) of susceptible fetal DNA for NS, i.e., the diagnostic yield on the one hand and the proportion of detected variants of unknown significance (VOUS) on the other. DESIGN: Clinically diagnostic. SETTING: Centrum prenatální diagnostiky, Brno, s.r.o; Cytogenetická laboratoř Brno, s.r.o. METHODS: Samples of amniotic fluid or chorionic villus were analyzed. Selected genes associated with RASopathies were analyzed in case of the negative result of karyotype and array-CGH. A panel of twenty genes was investigated by MPS. RESULTS: In the two-years period, Noonan syndrome was detected in 10 from 95 investigated fetuses. This represents a 10.5% diagnostic efficiency of the method. DNA variants of unknown significance were detected in 10 fetuses. A segregation analysis helped to clarify their meaning in six fetuses. CONCLUSION: MPS allows fast molecular-genetic diagnosis of RASopathies already in the prenatal period. This method contributes to the clarification not only of phenotypic manifestations in already born individuals but also of ultrasound findings in fetuses with both normal karyotype and aCGH.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Medição da Translucência Nucal , Diagnóstico Pré-Natal , Ultrassonografia Pré-Natal , Edema , Feminino , Feto , Variação Estrutural do Genoma , Humanos , Cariótipo , Gravidez
8.
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
9.
J Med Case Rep ; 13(1): 194, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31208451

RESUMO

BACKGROUND: A 9-year-old Arabic boy attending middle school presented with an out-of-hospital cardiac arrest due to ventricular fibrillation recorded by Holter electrocardiographic monitoring. He had a background history of Noonan syndrome with multiple lentigines (also known as LEOPARD syndrome), a rare condition of autosomal dominant inheritance with approximately 200 cases reported worldwide. CASE PRESENTATION: Apart from characteristic features, the boy was known to have asymmetric septal hypertrophy with a maximum wall thickness of 24 mm measured by cardiovascular magnetic resonance imaging. A day prior to the event, he attended cardiology follow-up at our institution, and Holter monitoring was commenced. Following cardiopulmonary resuscitation by bystanders and paramedics, he reverted back into sinus rhythm after a total downtime of 24 min. He was initially treated in the intensive care unit and underwent implantable cardioverter defibrillator implantation. He has made a full recovery and remains at the top of his class. CONCLUSION: This case demonstrates that sudden cardiac arrest in patients with secondary forms of hypertrophic cardiomyopathy is not necessarily protected by apparently favorable phenotypes and that events may be preceded by non-sustained ventricular tachycardia observed by Holter monitoring. Implantable cardioverter defibrillator implantation plays a critical role in both primary and secondary prevention in patients at high risk of out-of-hospital cardiac arrest.


Assuntos
Síndrome LEOPARD/complicações , Síndrome de Noonan/complicações , Parada Cardíaca Extra-Hospitalar/etiologia , Reanimação Cardiopulmonar , Criança , Desfibriladores Implantáveis , Humanos , Masculino , Parada Cardíaca Extra-Hospitalar/terapia
11.
Pediatr Endocrinol Rev ; 16(Suppl 2): 424-427, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31115193

RESUMO

Early in her career, Jacqueline Noonan, a pediatric cardiologist, recognized that a number of children with valvular pulmonary stenosis had similar facial features. Dr. Noonan reported the clinical characteristics of this condition including short stature, hypertelorism, ptosis, mild mental retardation, undescended testes, and skeletal malformations. Further characterization of Noonan Syndrome led to the development of clinical criteria for the diagnosis of the condition. Identification of the first genetic cause of Noonan Syndrome, mutation of ptpn11 was reported in 2001. Multiple subsequent genes have been identified as causes of Noonan Syndrome and the related Rasopathies.


Assuntos
Deficiência Intelectual , Síndrome de Noonan , Humanos , Mutação
12.
Pediatr Endocrinol Rev ; 16(Suppl 2): 428-434, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31115194

RESUMO

Noonan syndrome represents a heterogeneous group of genetic disorders caused by mutations in genes of the RAS/MAPK pathway. Related syndromes include cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines and Costello syndrome. The common phenotypic features of Noonan syndrome include facial dysmorphisms, short stature, congenital heart defects and genitourinary abnormalities. These and other findings as well as features of related disorders are discussed. In addition we briefly review clinical diagnosis and prenatal findings of these syndromes and genetic counseling implications.


Assuntos
Síndrome de Costello , Displasia Ectodérmica , Síndrome de Noonan , Insuficiência de Crescimento , Humanos , Proteínas ras
13.
Pediatr Endocrinol Rev ; 16(Suppl 2): 435-446, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31115195

RESUMO

The RAS/MAPK signaling pathway plays an essential role in development and tumorigenesis by regulating cell proliferation, differentiation, apoptosis, migration, and metabolism. Therefore, it is not surprising that germline mutations in genes encoding components or regulators of this signaling pathway cause numerous human genetic conditions, including Noonan syndrome and related disorders. The term "RASopathies" has been used to describe these disorders collectively due to their common underlying RAS/MAPK pathway dysregulation and overlapping clinical features. Taken together, the RASopathies represent one of the most common groups of genetic disorders, affecting approximately 1 in 1,000 individuals. This review describes the RAS/MAPK signaling pathway, summarizes multiple molecular genetic approaches used during the last several decades to discover genes responsible for different RASopathies, and finally focuses on several major disease genes associated with Noonan syndrome and related disorders with regard to genomic locations, structure, mutations, and genotype-phenotype correlations.


Assuntos
Síndrome de Noonan , Mutação em Linhagem Germinativa , Humanos , Transdução de Sinais , Proteínas ras
14.
Pediatr Endocrinol Rev ; 16(Suppl 2): 447-458, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31115196

RESUMO

The RASopathies are a group of developmental genetic syndromes that are caused by germline mutations in genes encoding proteins of the Ras-Mitogen-Activated Protein kinase (RAS-MAPK) pathway. RASopathies include Noonan Syndrome (NS), Neurofibromatosis Type 1 (NF1), Noonan syndrome with multiple lentigines (NSML/LEOPARD), Costello syndrome (CS), Cardio-facio-cutaneous syndrome (CFC), capillary malformation-arteriovenous malformation syndrome (CM-AVM) and Legius Syndrome. These syndromes have many overlapping features; however, the most persistent feature common to all is the postnatal growth failure. The mechanism of growth failure in Rasopathies is highly complex and there are many proposed hypotheses including partial growth hormone insensitivity, growth hormone deficiency, neurosecretory dysfunction of growth hormone secretion, delayed puberty, poor feeding and skeletal abnormalities. Amongst these causes, the most widely accepted is partial growth hormone insensitivity due to a post-receptor signaling defect. Growth hormone therapy seems to be effective in improving height velocity in these syndromes, although the long-term effects on final height remain unproven. However, it is important to consider the potential risk of tumors and cardiomyopathy before and during growth hormone therapy.


Assuntos
Síndrome de Costello , Displasia Ectodérmica , Insuficiência de Crescimento , Síndrome de Noonan , Humanos , Proteínas ras
15.
Pediatr Endocrinol Rev ; 16(Suppl 2): 459-464, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31115197

RESUMO

Short stature is a common characteristic of Noonan Syndrome (NS), a genetic condition caused by mutations affecting the RAS / mitogen-activated protein kinase (MAPK) cascade. Growth hormone (GH) has been used to normalize childhood growth and increase adult height in NS. GH is effective in increasing growth velocity, and significantly improves height SDS at adult height. Studies of GH treatment to adult height have shown height gains of 9.5-13.0 cm for males and 9.0 - 9.8 cm for females. Factors associated with improved height outcomes are earlier initiation of therapy, a greater height SDS at pubertal onset, and a longer duration of GH therapy. The safety data to date is reassuring and includes no evidence of adverse cardiac effects or increased occurrence of malignancies. Further studies will likely clarify the role of different RAS/MAPK pathway aberrations in growth and GH responsiveness. Continued surveillance is needed to assure the long term safety of GH therapy.


Assuntos
Hormônio do Crescimento Humano/uso terapêutico , Síndrome de Noonan , Estatura , Feminino , Humanos , Masculino , Mutação , Síndrome de Noonan/tratamento farmacológico
16.
Pediatr Endocrinol Rev ; 16(Suppl 2): 465-470, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31115198

RESUMO

Noonan syndrome (NS) is a diagnosis that is made clinically based on features including typical facies, congenital heart defects, short stature and developmental delay. Approximately 50% of the patients have identified mutations in the PTPN11 gene, and a smaller percentage of mutations have been reported in other genes such as SOS1, RAF1 and RIT1 Despite normal birth length, patients typically reach adult height below normal. Other than growth, endocrine complications of NS are not as commonly reported. These include possible pathology in thyroid function, pubertal development and bone metabolism. Some investigators have looked to see if genetic mutations in these patients could pose a risk for future endocrinopathies. This chapter reviews reports on endocrine dysfunction other than growth in patients with NS. The information is meant to enhance awareness in those providers who care for these patients to the possibility of other existing endocrinopathies. Most importantly, it supports and highlights the endocrinologist's role in the care of patients with NS.


Assuntos
Nanismo , Síndrome de Noonan , Humanos , Mutação , Proteínas ras
17.
Pediatr Endocrinol Rev ; 16(Suppl 2): 471-476, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31115199

RESUMO

Noonan syndrome NS, a RASopathy, is commonly seen in association with cardiovascular abnormalities, with structural defects and/or cardiomyopathy present in 80-90-% of cases. Though a wide spectrum of cardiac pathology has been reported, pulmonary stenosis is the most common structural abnormality and more likely to be seen in PTPN11 mutations. Hypertrophic cardiomyopathy is the second most common and is more often associated with RAF1 mutations. Cardiac disease tends to be more progressive in infants and children with NS and therefore close cardiology follow-up is indicated. In general, the earlier the presentation, the more severe the phenotype and worse the long term prognosis. As genotype phenotype associations are being better understood, the mechanisms for development of cardiomyopathy are also becoming elucidated, raising the possibility of medical therapies targeted at the involved pathway.


Assuntos
Cardiomiopatia Hipertrófica , Síndrome de Noonan , Humanos , Mutação , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11
18.
Horm Res Paediatr ; 91(4): 252-261, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31132774

RESUMO

OBJECTIVES: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). MATERIALS AND METHODS: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). RESULTS: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were -3.1 ± 0.7 and -0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11- patients. GV SDS increased from -1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from -1.9 ± 2.6 to -0.1 ± 2.6 in PTPN11- patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11- (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were -2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. CONCLUSIONS: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11- patients showed a poor response to rhGH. However, this PTPN11- group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.


Assuntos
Estatura/efeitos dos fármacos , Hormônio do Crescimento Humano/administração & dosagem , Mutação , Síndrome de Noonan , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Adulto , Estatura/genética , Feminino , Humanos , Estudos Longitudinais , Masculino , Síndrome de Noonan/tratamento farmacológico , Síndrome de Noonan/genética , Síndrome de Noonan/fisiopatologia , Estudos Retrospectivos
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(6): 588-591, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31055812

RESUMO

OBJECTIVE: To identify potential mutation in a child clinically diagnosed as Noonan syndrome and to provide genetic counseling and prenatal diagnosis for his family. METHODS: Genomic DNA was extracted from peripheral blood samples of the patient and his parents, and amniotic fluid was taken from the mother during the second trimester. Next generation sequencing (NGS) was used to screen potential mutations from genomic DNA. Suspected mutation was verified by Sanger sequencing. RESULTS: A heterozygous c.4A>G (p.Ser2Gly) mutation of the SHOC2 gene was identified in the patient but not among other family members including the fetus. CONCLUSION: The Noonan syndrome is probably caused by the c.4A>G mutation of the SHOC2 gene. NGS is helpful for the diagnosis of complicated genetic diseases. SHOC2 gene mutation screening is recommended for patient suspected for Noonan syndrome.


Assuntos
Síndrome de Noonan , Criança , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Mutação , Gravidez , Diagnóstico Pré-Natal
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