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1.
Mymensingh Med J ; 29(4): 1004-1009, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33116109

RESUMO

Noonan's syndrome is a developmental disorder characterized by short stature, typical facial dysmorphia, congenital heart defects and skeletal deformity. It may be sporadic or inherited as an autosomal dominant or recessive trait which occurs, one in 1000-2500 live births. We report a case of 16 years young girl presented to the hospital with short stature, Shortness of breath, morphologic features and congenital heart defect of Noonan Syndrome who has no similar history in the family and admitted in Bangabandhu Sheikh Mujib Medical University on 12th August 2018.


Assuntos
Cardiopatias Congênitas , Síndrome de Noonan , Feminino , Humanos , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo
2.
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
3.
Medwave ; 20(2): e7826, 2020 Feb 26.
Artigo em Espanhol | MEDLINE | ID: mdl-32119651

RESUMO

Noonan syndrome is an autosomal dominant inherited disorder with variable phenotypic expression. It belongs to the group of diseases known as RASopathies, which are characterized by mutations in the RAS genes. Patients develop symptoms such as facial dysmorphism, short stature, congenital heart disease, musculoskeletal disorders and mental retardation. In this article, we report a case of Noonan syndrome in a 14-year-old patient, diagnosed in a primary health center in Ecuador. The syndrome was identified through clinical diagnosis, after which the patient was referred to the secondary and tertiary levels for specialized care.


Assuntos
Síndrome de Noonan/diagnóstico , Atenção Primária à Saúde , Adolescente , Equador , Humanos , Mutação , Síndrome de Noonan/genética , Síndrome de Noonan/terapia , Proteínas ras/genética
4.
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
5.
Eur J Med Genet ; 63(1): 103617, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30664951

RESUMO

Mutations in LZTR1, already known to be causal in familial schwannomatosis type 2, have been recently involved in a small proportion of patients with autosomal dominant and autosomal recessive Noonan syndrome. LZTR1 is also a driver gene in non syndromal glioblastoma. We report a 26-year-old patient with typical Noonan syndrome, and the dominantly transmitted c.850C > T (p.(Arg284Cys)) variant in LZTR1. An oligoastrocytoma was diagnosed in the patient at the age of 22 years; recurrence of the tumor occurred at age 26, as a ganglioblastoma. The patient had been transiently treated with growth hormone between ages 15 and 17. Considering the implication of LZTR1 in sporadic tumors of the nervous system, we hypothesize that gliomas are a possible complication of LZTR1-related Noonan syndrome. This report also supports a possible link between occurrence of a cerebral tumor in Noonan syndrome and a previous treatment with growth hormone.


Assuntos
Astrocitoma/genética , Glioblastoma/genética , Síndrome de Noonan/genética , Fatores de Transcrição/genética , Adolescente , Adulto , Astrocitoma/complicações , Astrocitoma/diagnóstico , Astrocitoma/patologia , Feminino , Predisposição Genética para Doença , Glioblastoma/complicações , Glioblastoma/diagnóstico , Glioblastoma/patologia , Humanos , Masculino , Mutação , Síndrome de Noonan/complicações , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/patologia , Linhagem
7.
J Clin Res Pediatr Endocrinol ; 12(1): 113-116, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31088041

RESUMO

Neurofibromatosis Noonan syndrome (NFNS) is a rare RASopathy syndrome, resulting from NF1 gene mutations. NFNS is characterized by phenotypic features of both neurofibromatosis type 1 (NF1) and Noonan syndrome. Plexiform neurofibromas (PNFs) are an unusual finding in NFNS. A seven year-old girl with typical clinical features of NF1 was referred to our clinic due to short stature and abnormal genital appearance. Due to dysmorphic features, a clinical diagnosis of NFNS was considered in the patient and, following molecular analysis, revealed a novel heterozygous c.3052_3056delTTAGT (p.L1018X) variant in the NF1 gene. Although evaluation for genital virilization, including karyotype and hormonal studies were normal, imaging studies revealed a diffuse genital PNF. Although PNFs are seen rarely in NFNS, this should be considered in the differential diagnosis of genital virilization in these patients to prevent unnecessary testing.


Assuntos
Genitália Feminina/anormalidades , Neurofibromatoses/diagnóstico , Síndrome de Noonan/diagnóstico , Criança , Feminino , Humanos
8.
Am J Med Genet A ; 179(12): 2433-2446, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31566897

RESUMO

While neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are clinically distinct genetic syndromes, they have overlapping features because they are caused by pathogenic variants in genes encoding molecules within the Ras-mitogen-activated protein kinase signaling pathway. Increased risk for emotional and behavioral challenges has been reported in both children and adults with these syndromes. The current study examined parent-report and self-report measures of emotional functioning among children with NF1 and NS as compared to their unaffected siblings. Parents and children with NS (n = 39), NF1 (n = 39), and their siblings without a genetic condition (n = 32) completed well-validated clinical symptom rating scales. Results from parent questionnaires indicated greater symptomatology on scales measuring internalizing behaviors and symptoms of attention deficit hyperactivity disorder (ADHD) in both syndrome groups as compared with unaffected children. Frequency and severity of emotional and behavioral symptoms were remarkably similar across the two clinical groups. Symptoms of depression and anxiety were higher in children who were also rated as meeting symptom criteria for ADHD. While self-report ratings by children generally correlated with parent ratings, symptom severity was less pronounced. Among unaffected siblings, parent ratings indicated higher than expected levels of anxiety. Study findings may assist with guiding family-based interventions to address emotional challenges.


Assuntos
Emoções , Neurofibromatose 1/diagnóstico , Síndrome de Noonan/diagnóstico , Adolescente , Fatores Etários , Criança , Comportamento Infantil , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Neurofibromatose 1/genética , Síndrome de Noonan/genética , Pais , Fenótipo , Autorrelato , Irmãos , Inquéritos e Questionários
10.
Am J Med Genet A ; 179(12): 2474-2480, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31584751

RESUMO

Noonan syndrome-like disorder with loose anagen hair (NS/LAH) is one of the RASopathies, a group of clinically related developmental disorders caused by germline mutations in genes that encode components acting in the RAS/MAPK pathway. Among RASopathies, NS/LAH (OMIM 607721) is an extremely rare, multiple anomaly syndrome characterized by dysmorphic facial features similar to those observed in Noonan syndrome along with some distinctive ectodermal findings including easily pluckable, sparse, thin, and slow-growing hair. ADA2 deficiency (DADA2, OMIM 615688) is a monogenic autoinflammatory disorder caused by homozygous or compound heterozygous mutations in ADA2, with clinical features including recurrent fever, livedo racemosa, hepatosplenomegaly, and strokes as well as immune dysregulation. This is the first report of NS/LAH and ADA2 deficiency in the same individual. We report on a patient presenting with facial features, recurrent infections and ectodermal findings in whom both the clinical and molecular diagnoses of NS/LAH and ADA2 deficiency were established, respectively.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Síndrome dos Cabelos Anágenos Frouxos/diagnóstico , Síndrome dos Cabelos Anágenos Frouxos/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/genética , Adenosina Desaminase/genética , Alelos , Estudos de Associação Genética/métodos , Predisposição Genética para Doença , Genótipo , Humanos , Mutação , Radiografia , Avaliação de Sintomas
11.
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
12.
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
13.
Orphanet J Rare Dis ; 14(1): 163, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277675

RESUMO

The concomitant occurrence of hypertrophic cardiomyopathy and congenital heart defect in patients with RASopathies has previously been reported as associated to a worse clinical outcome, particularly closed to cardiac surgery. Different mechanisms of disease have been demonstrated to be associated with the two classes of PTPN11 mutations underlying Noonan syndrome and Noonan syndrome with multiple lentigines (also known as LEOPARD syndrome). Although differential diagnosis between these two syndromes could be difficult, particularly in the first age of life, we underline the relevance in discriminating these two disorders in terms of affected signaling pathway to allow an effective targeted pharmacological treatment.


Assuntos
Cardiomiopatia Hipertrófica/genética , Mutação/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Cardiomiopatia Hipertrófica/diagnóstico , Feminino , Cardiopatias Congênitas/genética , Humanos , Masculino , Mutação de Sentido Incorreto/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
14.
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
16.
Am J Med Genet A ; 179(8): 1628-1630, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31173466

RESUMO

Activation of the RAS pathway through either the activation of genes that accelerate the pathway or the suppression of genes that inhibit the pathway leads to a group of disorders collectively referred to as RASopathies. The key molecules of the RAS pathway are KRAS, HRAS, and NRAS. Mutations in these three RAS homolog genes have been shown to be associated with RASopathies. Recently, two patients with a Noonan syndrome phenotype were shown to carry mutations in the yet another RASopathy gene, MRAS (muscle RAS oncogene homolog). Here, we report a patient with a severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant, which represents a recurrent substitution in RAS homologs in various cancers. The patient's dysmorphic features included relative macrocephaly, a down-slanted palpebral fissure, hypertelorism, a depressed nasal bridge, and low-set ears with thick lobes; these facial features are strongly associated with RASopathy. We confirmed that the MRAS gene represents a causative gene for RASopathy.


Assuntos
Alelos , Substituição de Aminoácidos , Mutação em Linhagem Germinativa , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Proteínas ras/genética , Sequência de Aminoácidos , Pré-Escolar , Genes ras , Predisposição Genética para Doença , Humanos , Masculino , Mutação
17.
Clin Genet ; 96(4): 290-299, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31219622

RESUMO

Noonan syndrome (NS) is a common autosomal dominant/recessive disorder. No large-scale study has been conducted on NS in China, which is the most populous country in the world. Next-generation sequencing (NGS) was used to identify pathogenic variants in patients that exhibited NS-related phenotypes. We assessed the facial features and clinical manifestations of patients with pathogenic or likely pathogenic variants in the RAS-MAPK signaling pathway. Gene-related Chinese NS facial features were described using artificial intelligence (AI).NGS identified pathogenic variants in 103 Chinese patients in eight NS-related genes: PTPN11 (48.5%), SOS1 (12.6%), SHOC2 (11.7%), KRAS (9.71%), RAF1 (7.77%), RIT1 (6.8%), CBL (0.97%), NRAS (0.97%), and LZTR1 (0.97%). Gene-related facial representations showed that each gene was associated with different facial details. Eight novel pathogenic variants were detected and clinical features because of specific genetic variants were reported, including hearing loss, cancer risk due to a PTPN11 pathogenic variant, and ubiquitous abnormal intracranial structure due to SHOC2 pathogenic variants. NGS facilitates the diagnosis of NS, especially for patients with mild/moderate and atypical symptoms. Our study describes the genotypic and phenotypic spectra of NS in China, providing new insights into distinctive clinical features due to specific pathogenic variants.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Adolescente , Alelos , Criança , Pré-Escolar , China , Facies , Feminino , Estudos de Associação Genética/métodos , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Recém-Nascido , Masculino , Fenótipo , Ultrassonografia
19.
J Med Genet ; 56(10): 654-661, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31040167

RESUMO

BACKGROUND: This study evaluates 6 years of prenatal rasopathy testing in the Netherlands, updates on previous data and gives recommendations for prenatal rasopathy testing. METHODS: 424 fetal samples, sent in for prenatal rasopathy testing in 2011-2016, were collected. Cohort 1 included 231 samples that were sequenced for 1-5 rasopathy genes. Cohort 2 included 193 samples that were analysed with a 14-gene next generation sequencing (NGS) panel. For all mutation-positive samples in both cohorts, the referring physician provided detailed ultrasound findings and postnatal follow-up. For 168 mutation-negative samples in cohort 2, solely clinical information on the requisition form was collected. RESULTS: In total, 40 (likely) pathogenic variants were detected (9.4%). All fetuses showed a variable degree of involvement of prenatal findings: increased nuchal translucency (NT)/cystic hygroma, distended jugular lymph sacs (JLS), hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies. An increased NT was the most common finding. Eight fetuses showed solely an increased NT/cystic hygroma, which were all larger than 5.5 mm. Ascites and renal anomalies appeared to be poor predictors of pathogenic outcome. CONCLUSION: Fetuses with a rasopathy show in general multiple ultrasound findings. The larger the NT and the longer it persists, the more likely it is to find a pathogenic variant. Rasopathy testing is recommended when the fetus shows an isolated increased NT ≥5.0 mm or when NT of ≥3.5 mm and at least one of the following ultrasound anomalies is present: distended JLS, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects and renal anomalies.


Assuntos
Linfangioma Cístico/genética , Síndrome de Noonan/genética , Estudos de Coortes , Feminino , Feto , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Países Baixos , Síndrome de Noonan/diagnóstico , Gravidez , Diagnóstico Pré-Natal , Análise de Sequência de DNA
20.
Cesk Patol ; 55(1): 48-52, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30939887

RESUMO

We present our experience with four cases of fetal autopsies with abnormal prenatal ultrasound findings and suspicion of Noonan syndrome. These were fetuses from the 17th to the 24th age of gestation (GA). In all cases, prenatal ultrasound examination recorded increased nuchal translucency (NT) and presence of lymphatic neck sacs. Some fetuses showed signs of fetal hydrops and polyhydramnion was found. Similar signs and congenital developmental defects were confirmed in the autopsy examination. These were primarily signs of developing fetal hydrops with increased nuchal edema, in some cases up to the character of cystic hygroma, pleural and abdominal effusions, congenital heart and kidney defects, skeletal defects and facial dysmorphism. A karyotype was examined in all cases without chromosome aneuploidy. The diagnosis of NS was confimed by subsequent genetic analysis of causal gene mutations (mainly PTPN11, KRAS, RAF 1,). Our cases demonstrate a wide range of signs of prenatal presentation of this syndrome. Because of wide differential diagnosis, summarizing prenatal ultrasound findings, autopsy examination and molecular genetic testing is essential.


Assuntos
Doenças Fetais , Hidropisia Fetal , Linfangioma Cístico , Síndrome de Noonan , Feminino , Doenças Fetais/diagnóstico , Humanos , Hidropisia Fetal/diagnóstico , Linfangioma Cístico/diagnóstico , Síndrome de Noonan/diagnóstico , Medição da Translucência Nucal , Gravidez , Ultrassonografia Pré-Natal
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