Hipertrofia grave del ventrículo derecho secundaria a estenosis valvular pulmonar en lactante mayor con síndrome de Noonan: reporte de caso / Severe right ventricular hypertrophy secondary to pulmonary valve stenosis in an older infant with Noonan syndrome: a case report

Introducción: El Síndrome de Noonan se caracterizada por alteraciones del crecimiento, retraso psicomotor y mental, dismorfia facial, alteraciones musculo-esqueléticas y alteraciones cardíacas hasta en el 80 % de los pacientes, miocardiopatía hipertrófica 30%, estenosis valvular pulmonar 50 % y defectos septales, estenosis de ramas pulmonares, tetralogía de Fallot o coartaciones aórticas. Caso clínico: lactante de 8 meses con hipertelorismo, ptosis palpe-bral, orejas con implantación baja, cuello corto y escoliosis. Se presenta con cianosis y disnea asociada a hipotonía muscular. Peso: score Z: -3, talla: score Z: -3, a la auscultación cardiaca: soplo meso-sistólico grado 4/6 en segundo espacio intercostal izquierdo, línea para-esternal. En el ecocardiograma se observa estenosis pulmonar valvular de grado moderado (gradiente sistólico de 52 mmHg) y dilatación del tronco arterial pulmonar. Evolución: Se efectúa cateterismo cardíaco con evidencia estenosis valvular pulmonar grave, reacción infundibular, hipertrofia del ventrículo derecho, apertura valvular en domo y conducto arterioso persistente filiforme "tipo E", estos hallazgos justificaban el desarrollo de hipertrofia cardíaca. Se realizó una valvuloplastia pulmonar con balón que mejoró las presiones cardíacas. Conclusiones: Las alteraciones cardíacas presentes en un lactante con síndrome de Noonan fueron: Hipertrofia biventricular, hipertensión pulmonar, estenosis valvular pulmonar, conducto arterioso persistente.

Introduction: Noonan syndrome is characterized by growth disorders, psychomotor and mental retardation, facial dysmorphia, musculoskeletal disorders, and cardiac disorders in up to 80% of patients, hypertrophic cardiomyopathy in 30%, pulmonary valve stenosis in 50%, septal defects, pulmonary branch stenosis, tetralogy of Fallot, and aortic coarctations. Clinical case: 8-month-old infant with hypertelorism, palpebral ptosis, low-set ears, short neck, and scoliosis. It presents with cyanosis and dyspnea associated with muscle hypotonia. Weight: Z score: -3, height: Z score: -3, on cardiac auscultation: mid-systolic murmur grade 4/6 in the second left intercostal space, parasternal line. The echocardiogram shows moderate valvular pulmonary stenosis (52 mmHg systolic gradient) and dilatation of the pulmonary arterial trunk. Evolution: Cardiac catheterization was performed with evidence of severe pulmonary valve stenosis, infundibular reaction, right ventricular hypertrophy, dome valve opening, and "type E" filiform patent ductus arteriosus. These findings justified the development of cardiac hypertrophy. Pulmonary balloon valvuloplasty was performed, which improved cardiac pressure. Conclusions: The cardiac alterations present in an infant with Noonan syndrome were biventricular hypertrophy, pulmonary hypertension, pulmonary valve stenosis, and patent ductus arteriosus.

Síndrome de Noonan asociado a mutación del gen SOS1, reporte de caso / Noonan syndrome associated with a mutation of the SOS1 gene, case report

Introducción: El síndrome de Noonan es un trastorno genético de herencia autosómica dominante con una expresión fenotípica variable. Se encuentra dentro de las enfermedades conocidas como rasopatías, producidas por las mutaciones en los genes RAS. Los pacientes se caracterizan por dismorfismo facial, talla baja, enfermedad cardíaca congénita, alteraciones músculos esqueléticas y en algunos casos discapacidad intelectual. Caso clínico: En el presente reporte se describe el caso de un paciente masculino de un mes de edad que acude a consulta externa, presentando dismorfismo facial y estenosis pulmonar, por lo que se realiza un seguimiento multidisciplinario por sospecha de Síndrome de Noonan. A partir del cuarto mes desarrolló linfedema en la zona del deltoides. Evolución: A los 7 meses de vida se realiza secuenciación de exoma, encontrando una variante patogénica en el gen SOS1, confirmando el diagnóstico de dicho síndrome. Conclusión: Este caso documenta la presencia de síndrome de Noonan con mutación del gen SOS1 con dismorfología facial típica, estenosis de la válvula pulmonar, criptorquidia y displasia linfática con linfedema del deltoides, hallazgo no descrito en casos previos.

Introduction: Noonan syndrome is a dominant autosomal inherited ge-netic disorder with variable phenotypic expression. It is found within diseases known as rasopathies and is pro-duced by mutations in RAS genes. Patients are character-ized by facial dysmorphism, short stature, congenital heart disease, musculoskeletal disorders, and, in some cases, intellectual disability. Clinical case: This report describes the case of a one-month-old male patient who comes to the outpatient clinic, presenting with facial dysmorphism and pulmonary steno-sis, for which a multidisciplinary follow-up is carried out due to suspicion of Noonan syndrome. From the fourth month, the patient developed lymphedema in the deltoid area. Evolution: At 7 months of age, exome sequencing was per-formed, finding a pathogenic vari-ant in the SOS1 gene and confirming the diagnosis of this syndrome. Conclusion: This case documents the presence of Noonan syndrome with a mutation of the SOS1 gene with typical facial dysmorphology, pulmonary valve stenosis, cryptor-chidism and lymphatic dysplasia with deltoid.

Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Highlights - The Ras (Rat Sarcoma) gene family is a group of small G proteins - Ras is regulated by growth factors and neurohormones affecting cardiomyocyte growth and hypertrophy - Ras directly affects cardiomyocyte physiological and pathological hypertrophy - Genetic alterations of Ras and its pathways result in various cardiac phenotypes? - Ras and its pathway are differentially regulated in acquired heart disease - Ras modulation is a promising therapeutic target in various cardiac conditions.

Síndrome de Noonan e insuficiencia aórtica severa en un paciente adulto / Noonan Syndrome and Severe Aortic Regurgitation in an Adult Patient

Introducción: El síndrome de Noonan es una enfermedad congénita con una incidencia de 1:1000-2500 recién nacidos vivos. Se encuentra subdiagnosticada en nuestro medio debido a la variabilidad clínica, lo cual no permite un adecuado control y seguimiento para detectar complicaciones consecuentes a los defectos cardiovasculares congénitos. En Perú no existen reportes de casos sobre el síndrome de Noonan y sus complicaciones. Objetivo: Discutir la importancia del examen clínico para su adecuado diagnóstico a partir de las características del síndrome de Noonan en un adulto. Caso clínico: Presentamos el caso de un varón de 33 años con síndrome de Noonan, endocarditis infecciosa e insuficiencia aórtica severa. Conclusiones: Se resalta la importancia del examen físico y el uso de criterios diagnósticos para realizar el diagnóstico del síndrome de Noonan(AU)

Introduction: Noonan syndrome is a congenital disease with an incidence of 1: 1000-2500 live newborns. Due to its clinical variability, it is underdiagnosed in our setting, which does not allow adequate control and follow-up to detect complications resulting from congenital cardiovascular defects. In Peru, there are no case reports on Noonan syndrome and its complications. Objective: To discuss the importance of clinical examination for adequate diagnosis of Noonan syndrome, based on the characteristics of the disease in an adult. Clinical case: We present the case of a 33-year-old male patient with Noonan syndrome, infective endocarditis, and severe aortic regurgitation. Conclusions: The importance of physical examination and the use of diagnostic criteria to diagnose Noonan syndrome are highlighted(AU)

Integración de la Bioinformática en la caracterización Clínica y Genómica de Retinitis Pigmentosa, Síndrome de Noonan y Síndrome de Retraso Mental Martin-Probs, en un mismo individuo. Reporte de un Caso / Integration of Bioinformatics in the Clinical and Genomic Characterization of Retinitis Pigmentosa, Noonan Syndrome and Martin-Probs Mental Retardation Syndrome, in the Same Individual. Case report

Introducción: El avance en las técnicas bioinformáticas ha permitido realizar acercamientos y mejoras en los diagnósticos clínicos, correlacionando genotipo ­ fenotipo y permitiendo el acercamiento a una terapia personalizada. Objetivo: Realizar mediante técnicas bioinformáticas, la caracterización molecular y de expresión génica de una paciente con manifestaciones clínicas (dismorfias, retraso en el desarrollo) de una enfermedad compleja (poligénica). Materiales y métodos: Se realizó la secuenciación de exoma completo a partir de una muestra de sangre periférica. Se analizaron los datos obtenidos mediante análisis in-sílico, utilizando programas como SIFT, Mutation Tester, UMD y Provean, para determinar la significancia clínica de variantes encontradas; además se usó programa GeneMania para determinar las interacciones génicas. Resultados:Se encontraron 3 variantes en los genes SEMA4A, PTPN11 y RAB40A, asociados a Retinitis pigmentosa 35, Síndrome de Noonan y Sindrome de retraso mental Martin-Probs, respectivamente; encontrando según los softwares predictores, en el primer caso un significado clínico aparentemente benigno, y en los dos últimos genes un significado clínico patogénico. El análisis de redes génicas reveló alteraciones en funciones biológicas como la señalización mediada por fosfatidilinositol, respuesta al factor del crecimiento fibroblástico, vía de señalización de neutrofina y la morfogénesis de vasos sanguíneo que permitieron explicar gran parte de la sintomatología observada. Conclusión: El análisis personalizado de las patologías complejas mediante el uso de la clínica, herramientas genómicas y bioinformaticas han permitido un avance significativo en las técnicas para el procesamiento y análisis de datos, beneficiando los estudios científicos que permiten el acercamiento a un correcto diagnóstico y adecuada consejería genética.

Introduction: Advances in bioinformatics techniques have allowed approaches and improvements in clinical diagnoses, correlating genotype - phenotype and allowing the approach to personalized therapy. Objective: In order to perform the molecular characterization and gene expression in a patient with complex clinical manifestations through bioinformatics techniques, complete exome sequencing was performed by a peripheral blood sample to a woman with facial dysmorphisms and developmental disorders. Material and methods: We analyzed the data obtained by in-silico analysis, using programs such as SIFT, Mutation Tester, UMD and Provean, to determine the clinical significance of the found variants and GeneMania program was used to determine gene interactions. Results: 3 variants were found in the genes SEMA4A, PTPN11 and RAB40A, associated with Retinitis pigmentosa 35, Noonan Syndrome and Mental Retardation Syndrome Martin-Probs, respectively; according to the predictive softwares, in the first case an apparently benign clinical meaning, and in the last two genes a clinical pathogenic meaning. The analysis of gene networks revealed alterations in biological functions such as signaling mediated by phosphatidylinositol, response to the fibroblastic growth factor, neutrophin signaling pathway and blood vessel morphogenesis that allowed us to explain a large part of the observed symptomatology. Conclusion: The personalized analysis of complex pathologies through the use of clinical, genomic and bioinformatic tools has allowed a significant advance in techniques for processing and analyzing data, benefiting scientific studies that allow the approach to a correct diagnosis and adequate genetic counseling.

Reporte de un caso de síndrome de Noonan diagnosticado en atención primaria / A case report of Noonan syndrome diagnosed in primary healthcare

El síndrome de Noonan es un trastorno genético de herencia autosómica dominante, de expresión fenotípica variable. Pertenece al grupo de las enfermedades conocidas como rasopatías, trastornos producido por las mutaciones en los genes RAS. Los pacientes desarrollan síntomas como dismorfismo facial, talla baja, enfermedad cardíaca congénita, alteraciones músculos esqueléticas y discapacidad intelectual. En el presente reporte, se describe un caso de diagnóstico del síndrome de Noonan en un paciente de 14 años, realizado a nivel de atención primaria en Ecuador. El síndrome se identificó mediante diagnóstico clínico, permitiendo su derivación al segundo y tercer nivel de salud para una atención especializada.

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.

Caracterización clínica y molecular de niños con síndrome de Noonan y otras RASopatías en Argentina / Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina

Introducción. Las RASopatías son un conjunto de síndromes fenotípicamente superpuestos causados por mutaciones en genes implicados en la vía RAS/MAPK. La herencia es autosómica dominante, presentan características clínicas comunes, como baja talla, dismorfias craneofaciales, cardiopatia congénita, manifestaciones ectodérmicas y mayor riesgo de cáncer. El diagnóstico molecular es clave. Objetivo. Identificar mutaciones en los genes PTPN11, SOS1,RAF1, BRAFy HRAS,y comparar las principales características clínicas en pacientes con confirmación molecular. Población y métodos. Se estudiaron niños con diagnóstico clínico de RASopatía evaluados entre agosto de 2013 y febrero de 2017. Resultados. Se identificaron mutaciones en el 71 % (87/122) de los pacientes. El estudio molecular confirmó el diagnóstico en el 73 % de los pacientes con síndrome de Noonan. La mutación más prevalente fue c.922A>G (p.Asn308Asp) en el gen PTPN11. Se detectó una variante no descrita en RAF1, c.1467G>C (p.Leu489Phe). Se confirmó el sindrome cardiofaciocutáneo en el 67 % de los casos con mutaciones en el gen BRAF. El síndrome de Costello y el síndrome de Noonan con múltiples lentigos se confirmaron en todos los casos. Conclusión. La confirmación del diagnóstico clínico permitió un diagnóstico diferencial más preciso. Se determinó la prevalencia de las mutaciones en PTPN11 (el 58 %), SOS1 (el 10 %) y RAF1 (el 5 %) en niños con síndrome de Noonan, en PTPN11 (el 100 %) en el sindrome de Noonan con múltiples lentigos, en BRAF (el 67 %) en el síndrome cardiofaciocutáneo y en HRAS (el 100 %) en el sindrome de Costello.

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.

Estudo descritivo molecular de pacientes com RASopatia / Descriptive molecular study of patients with RASopathy

As RASopatias são um grupo de doenças cujos pacientes apresentam alterações constitucionais em genes que participam de uma mesma via de sinalização celular denominada Ras/MAPK, que desempenha um papel importante na proliferação, diferenciação, migração celular e apoptose, além de estar associada a processos carcinogênicos. Apesar dos avanços em métodos diagnósticos, cerca de 20 a 25% dos casos permanecem inconclusivos, o que impulsiona pesquisas que buscam alterações em outros níveis de regulação da via, como RNAs não codificantes e proteínas. O primeiro capítulo deste estudo, avalia um grupo de 6 pacientes diagnosticados clinicamente com RASopatia e com exomas sequenciados. Foram obtidos dados sobre mutações em seus miRNAs. O segundo capítulo relata o caso de um paciente com suspeita clínica de síndrome de Costello, mas sem mutações detectadas. Foram avaliados, in silico, dados sobre miRNAs reguladores do gene HRAS, bem como os diferentes tecidos nos quais o HRAS é expresso. Para o capítulo 3 foi realizado um estudo comparativo entre gêmeas com diagnóstico clínico de síndrome de Noonan, mas com fenótipo discordante. Foi realizado um array por RT-qPCR para diferentes RNAs reguladores e um estudo comparativo de proteoma com análise de vias biológicas, processos biológicos e genes alvo da regulação de fatores de transcrição putativos. No estudo de miRNAs foram encontradas mutações em heterozigose, que são de difícil avaliação em ensaios de expressão. No estudo de caso do paciente S4 (síndrome de Costello), não foram encontradas mutações nos miR-181d-5p, let-7a-5p, miR-143-3p, miR-181a-5p, miR-139-5p, miR-663a e let-7b-5p, descritos como reguladores do HRAS. Também não foram encontrados tecidos viáveis para coleta e análise da expressão do HRAS. Na expressão de RNAs reguladores nas gêmeas (S16 e S17) foram encontrados níveis de expressão aumentados em S17 para Lnc-C21orf33-1, ERBS3/SBNO2e, miR-200be, CTBP1-AS e Lnc_DC. Na análise do proteoma, foram encontradas diferenças de expressão em vias de integrinas, proteoglicanos e trombinas, além de diferenças em processos de transdução de sinal, crescimento e manutenção celular e metabolismo. Os genes com sítio de ligação para os fatores de transcrição como RREB1, ETS1, EGR1 e TBX5 também possuíam expressão diferente entre as gêmeas. Os resultados aqui apresentados apontam novos caminhos para estudos moleculares das RASopatias que possam preencher as lacunas diagnósticas ainda pendentes.

RASopathies are a group of diseases whose patients present constitutional changes in genes that participate in the same cellular signaling pathway called the Ras/MAPK, which plays an important role in proliferation, differentiation, cell migration and apoptosis, in addition to being associated with carcinogenic processes. Despite advances in diagnostic methods, about 20 to 25% of cases remain inconclusive, which drives research that seeks changes in other levels of pathway regulation, such as non-coding RNAs and proteins. The first chapter of this study evaluates a group of 6 patients clinically diagnosed with RASopathy and sequenced exomes. Data were obtained on mutations in their miRNAs. The second chapter reports the case of a patient with clinical suspicion of Costello syndrome, but without mutations detected. Data on the miRNAs regulating the HRAS gene, as well as the different tissues in which HRAS is expressed, were evaluated in silico. For chapter 3 a comparative study was performed between twins with clinical diagnosis of Noonan syndrome, but with a discordant phenotype. An array was performed by RT-qPCR for different regulatory RNAs and a comparative proteome study with analysis of biological pathways, biological processes and genes targeting the regulation of putative transcription factors. In the study of miRNAs, mutations were found in heterozygosis, which are difficult to evaluate in expression assays. In the case study of S4 patient (Costello syndrome), no mutations were found in miR-181d-5p, let-7a-5p, miR-143-3p, miR-181a-5p, miR-139-5p, miR-663a and let-7b -5p, described as HRAS regulators. No available tissues were also found for collection and analysis of HRAS expression. In expression of regulatory RNAs in the S16 and S17 twins, increased levels of S17 expression were found for Lnc-C21orf33-1, ERBS3 / SBNO2e, miR-200b, CTBP1-AS and Lnc_DC. In the proteome analysis, expression differences were found in integrins, proteoglycans and thrombin pathways, as well as differences in signal transduction processes, cell growth and maintenance, and metabolism. Genes with binding site for transcription factors such as RREB1, ETS1, EGR1 and TBX5 also had different expression between the twins. The results presented here point out new ways for molecular studies of RASopathies that may close the remaining diagnostic gaps.

Niños y adolescentes con patología orgánica: experiencias desde la clínica psicopedagógica / Children and adolescents with organic pathology: experiences from the psychopedagogical clinic

Ateneo de los residentes de Psicopedagogía del Hospital de Niños Dr Ricardo Gutiérrez, de la Ciudad de Buenos Aires, donde a partir de la práctica psicopedagógica con niños y adolescentes con patología orgánica se desarrollan cuatro ejes temáticos para describir algunas de las patologías o condiciones con las cuales se han ido encontrando en su labor cotidiana. Se relatan algunas viñetas clínicas que surgen de la experiencia en el Consultorio Interdisciplinario de Espina Bífida, con el fin de reflejar la intervención y los aportes de la psicopedagogía en ese campo. Se presenta el caso de una paciente que presentó un cuadro de Encefalitis Autoinmune por anticuerpos contra el receptor NMDAR, patología que despertó un gran interés al interior del equipo y que debido a su creciente recurrencia en los últimos tiempos, convoca a ampliar el conocimiento en ese campo, que aún se encuentra poco investigado. A continuación, se caracterizan dos patologías genéticas a través de casos de Agustín y Matías, considerando la importante incidencia de diversas condiciones genéticas en la población con la cual trabajamos. A partir de los casos clínicos seleccionados, no solo perseguimos el fin de describir y caracterizar algunos cuadros específicos, sino que a través de los mismos buscaremos plasmar los pilares fundamentales sobre los cuales asentamos nuestra mirada e intervención frente a pacientes que exigen un abordaje complejo, integral e interdisciplinario.

Síndrome de Noonan / Noonan syndrome

Se presenta un caso de Síndrome de Noonan, enfermedad genética poco frecuente con manifestaciones clínicas diversas, con una característica afectación cardiovascular como es la estenosis valvular pulmonar. La paciente ingresa en insuficiencia cardiaca y durante la observación se detectan datos clínicos típicamente descritos en la enfermedad, tales como talla baja, hipertelorismo, pterigium coli y tórax carinatum. Se evalúa de manera conjunta con genética y se identifican los criterios diagnósticos. La paciente es compensada y egresada por mejoría

A case of Noonan´s Syndrome, is reported here. This is a rare genetic disease with diverse clinical manifestations, with a characteristic cardiovascular involvement of pulmonary valve stenosis. The patient was admitted with heart failure. Typical clinical features were found such as short stature, hypertelorism, pterygium coli and thorax carinatum. The patient was evaluated with the genetic specialists and diagnostic criteria were identified

Manifestaciones otorrinolaringológicas del síndrome de Noonan / Otorhinolaryngologic manifestations of Noonan síndrome / Manifestações otorrinolaringológicas da síndrome de noonan

El síndrome de Noonan (SN) es un trastorno genético de herencia autosómica dominante relativamente frecuente. Clásicamente se ha descrito como la asociación de talla baja, dismorfias craneofaciales (fundamentalmente hipertelorismo, inclinación hacia abajo de las hendiduras palpebrales, ptosis palpebral, pabellones auriculares rotados y de implantación baja, hélix grueso), cardiopatía congénita (característicamente estenosis pulmonar valvular -EP- y miocardiopatía hipertrófica -MCH-), malformaciones torácicas(pectus excavatum/carinatum, tórax amplio) y criptorquidia en los varones. Tiene una incidencia alta, de 1/1.000- ½.500 neonatos.

Noonan syndrome (NS) is a genetic disorder relatively common autosomal dominant inheritance. Classically described as the association of short stature, craniofacial dysmorphia (hypertelorism, palpebral ptosis, ear low – set ears), congenital heart disease (typically valvular pulmonary stenosis -PSand hypertrophic cardiomyopathy -HCM-), thoracic malformations (pectus excavatum / carinatum, broad chest) and cryptorchidism in men. It has a high incidence of 1 / 1,000- 1 / 2,500 newborns.(1).

A síndrome de Noonan (SN) é um transtorno genético de herança autossômica dominante relativamente frequente. Classicamente, foi descrita como a associação de baixa estatura, dismorfias craniofaciais (fundamentalmente hipertelorismo, inclinação para baixo das fendas palpebrais, ptose palpebral, pavilhões auriculares rotados e de implantação baixa, hélix grosso), cardiopatia congênita (caracteristicamente estenose pulmonar valvular -EP- e miocardiopatia hipertrófica -MCH-), más formações torácicas (pectus excavatum/carinatum, tórax amplo) e criptorquidia nos meninos. (1) Tem uma incidência alta de 1/1.000- ½.500 neo-natos.

Síndrome de Noonan / Noonan syndrome

El Síndrome de Noonan fue descrito por Noonan y Ehmke en 1963. La incidencia se ha estimado en 1 de 1000 y 1 de 2500 nacimientos vivos.1 El gen se encuentra localizado en el cromosoma 12q22 y se hereda en forma autosómica dominante y tiene una expresividad muy variable. La principal característica incluye estatura baja, defectos cardiacos, dismorfismo facial entre otros. Estatura La severidad de los síntomas varían mucho en estos pacientes. Lo que no siempre es fácil hacer el diagnóstico en los primeros años, y muchas veces son subdiagnosticados, condición que nos motivo a revisar el caso.

Noonan Syndrome is a relative common autosomic dominant congenital disorder, with an incidence between 1:1,000 and 1:2,500 children worldwide. The gen is in 12q22 chromosome. The principal features include short stature, typical facial dysmorphology and congenital heart disease, among others. The range and severity of features can vary greatly in patients with NS, therefore, establishing a diagnose is difficult. The syndrome is not always identified at an early age, and many times misdiagnosed.

Do you know this syndrome? / Voce conhece esta sindrome?

Noonan Syndrome is one of the most common genetic syndromes and also an important differential diagnosis in children presenting with syndromic facies similar to Turner's syndrome phenotype. This syndrome is characterized by facial dysmorphism, congenital heart defects, short stature and also a wide phenotypic variation. This article discusses the case of a 10 year-old patient with Noonan syndrome that presented typical facies, cardiac defects (pulmonary dilatation and mitral regurgitation), dental malocclusion, micrognatism, short stature and a certain degree of learning disability.

Síndrome de Noonan é uma das mais frequentes síndromes genéticas e importante diagnóstico diferencial em crianças com fácies sindrômica similar ao fenótipo da síndrome de Turner. É caracterizada por dismorfismo facial, defeitos cardíacos congênitos, baixa estatura e uma ampla variação fenotípica. Esse artigo apresenta um caso de uma paciente de 10 anos de idade com síndrome de Noonan que apresentava fácies tiípica além de defeitos cardíacos (dilatação de artéria pulmonar e insufiência mitral), má oclusão dentária, micrognatismo, baixa estatura e dificuldade de aprendizado.

Tegumentary manifestations of Noonan and Noonan-related syndromes

OBJECTIVES: Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement. METHODS: A standard questionnaire was administered. A focused physical examination and a systematic review of clinical records was performed on all patients to verify the presence of tegumentary alterations. The molecular analysis of this cohort included sequencing of the following genes in all patients: PTPN1, SOS1, RAF1, KRAS, SHOC2 and BRAF. RESULTS: The most frequent tegumentary alterations were xeroderma (46%), photosensitivity (29%), excessive hair loss (24%), recurrent oral ulcers (22%), curly hair (20%), nevi (17%), markedly increased palmar and plantar creases (12%), follicular hyperkeratosis (12%), palmoplantar hyperkeratosis (10%), café-au-lait spots (10%) and sparse eyebrows (7%). Patients with mutations in PTPN11 had lower frequencies of palmar and plantar creases and palmar/plantar hyperkeratosis compared with the other patients. CONCLUSIONS: We observed that patients with mutations in genes directly involved in cell proliferation kinase cascades (SOS1, BRAF, KRAS and RAF1) had a higher frequency of hyperkeratotic lesions compared with patients with mutations in genes that have a more complex interaction with and modulation of cell proliferation kinase cascades (PTPN11). .

Estudio clínico y molecular del síndrome de Noonan / Clinical and molecular study of the Noonan syndrome

El síndrome de Noonan es una entidad autosómica dominante relativamente común, clínicamente variable y genéticamente heterogénea, caracterizado por reducción del crecimiento postnatal, dismorfismo facial distintivo, alteraciones cardíacas y déficit cognitivo variable. El gen PTPN11 se encuentra localizado en el brazo largo del cromosoma 12 y es el principal responsable de los casos clínicamente diagnosticados de esta entidad. Se reporta el caso de un lactante mayor masculino, de 18 meses de edad, evaluado de forma multidisciplinaria con diagnóstico clínico y molecular de síndrome de Noonan, con la mutación en sentido errado del gen PTPN11, G503R (c.1507 G>A). Se discutieron los diversos hallazgos clínicos y las alteraciones genéticas asociadas con esta mutación.

Noonan syndrome is a relatively common autosomal dominant entity, clinically variable and genetically heterogeneous; characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. The PTPN11 gene is located on the long arm of chromosome 12 and is primarily responsible for the clinically diagnosed cases of this entity. We report the case of a 18 month-old boy, evaluated in a multidisciplinary way, with clinic and molecular diagnosis of Noonan syndrome, with the missense mutation in PTPN11 gene, G503R (c.1507 G>A). Several clinical features and the genetic alterations associated with this mutation are discussed.

A de novo em ~1.3 Mb microdeletion at 17q11.2 associated with Neurofibromatosis-Noonan syndrome

Introduction: Neurofibromatosis-Noonan syndrome is a clinical entity considered an extended Neurofibromatosis phenotype generally caused by different types of intragenic mutations at the NF1 gene. About 5%-10% of patients with neurofibromatosis diagnosis carry chromosomal microdeletions involving NF1, often presenting with a more severe phenotype than that observedin the patients carrying intragenic mutations; however, anticipating the presence of a deletion based only in the phenotype is not straightforward. Patient and Methods: Here we investigated by oligoarray-CGH (aCGH) the presence of a submicroscopic genomic rearrangement in a patientwith a clinical picture of Neurofibromatosis, and other characteristics compatible with Noonansyndrome. Results: The aCGH analysis revealed a germline de novo ~1.3 Mb microdeletion at 17q11.2 encompassing other coding genes besides the NF1 gene. Discussion: Up to now, thenumber of reported patients with Neurofibromatosis-Noonan syndrome carrying NF1 microdeletions is quite small. The continuous identification of patients carrying 17q11.2 deletions canhelp to establish a reliable genotype-phenotype relationship in this syndrome

Avaliação do padrão de crescimento na síndrome de Noonan em pacientes com mutações identificadas nos genes PTPN11, SOS1, RAF1 e KRAS / Growth pattern of patients with Noonan syndrome with identified mutations in PTPN11, SOS1, RAF1 e KRAS genes

A Síndrome de Noonan (SN) é caracterizada por baixa estatura proporcionada de início pós-natal, dismorfismos faciais, cardiopatia congênita e deformidade torácica. A frequência da SN é estimada entre 1:1000 e 1:2500 nascidos vivos, com distribuição semelhante em ambos os sexos. A herança é autossômica dominante com penetrância completa, porém a maioria dos casos é esporádica. Até o momento, mutações em genes da via RAS-MAPK (PTPN11, KRAS, SOS1, RAF1, MEK1, NRAS e SHOC2) foram identificadas em aproximadamente 70% dos pacientes. Uma das principais características fenotípicas da SN é a baixa estatura pós-natal, embora o mecanismo fisiopatológico do déficit de crescimento nesta síndrome ainda não esteja totalmente esclarecido. Estudos que avaliaram o padrão de crescimento linear em crianças com SN foram realizados anteriormente ao conhecimento do diagnóstico molecular dessa síndrome. No presente estudo, avaliamos a frequência de mutação nos genes PTPN11, SOS1, RAF1 e KRAS em 152 pacientes com SN e o padrão de crescimento linear (altura) e ponderal [índice de massa corpórea (IMC)] dos pacientes com mutação identificada. No total, mutações nos genes relacionados foram encontradas em 99 pacientes (65%) do nosso estudo, com predominância do gene PTPN11 (47%), seguido do SOS1 (9%), RAF1 (7%) e KRAS (3%). Foram construídas curvas específicas para SN de Altura e IMC para idade e sexo utilizando o método LMS. Os pacientes com SN apresentaram crescimento pré-natal preservado, porém o comprometimento do crescimento pós-natal foi observado desde o primeiro ano de vida, atingindo uma altura final de -2,5 e -2,2 desvios-padrão da média para população brasileira em homens e mulheres, respectivamente. O prejuízo da altura foi maior nos pacientes com mutação no gene RAF1 em comparação com os genes PTPN11 e SOS1. O IMC dos pacientes com SN apresentou queda de 1 desvio-padrão em relação à média da população brasileira normal. O comprometimento do IMC foi menor...

Noonan Syndrome (NS) is characterized by distinctive facial features, short stature and congenital heart defects. The estimated prevalence is 1:1000 to 1:2500 live births, affecting equally both sexes. It is an autosomal dominant disorder with complete penetrance, but most cases are sporadic. To date, mutations in the RAS/MAPK pathway genes (PTPN11, KRAS, SOS1, RAF1, MEK1, NRAS and SHOC2) were identified in approximately 70% of patients. One of the cardinal signs of NS is proportional postnatal short stature although the physiopathological mechanism of growth impairment remains unclear. The current knowledge about the natural history of growth associated with NS was described before molecular diagnosis era. In this study, we performed PTPN11, SOS1, RAF1, and KRAS mutation analysis in a cohort of 152 NS patients and studied the natural linear (height) and ponderal growth [body mass index (BMI)] of NS patients with related mutations. Mutations in NS-causative genes were found in 99 patients (65%) of our cohort. The most common mutated gene was PTPN11 (47%), followed by SOS1 (9%), RAF1 (7%) and KRAS (3%). Sex-specific percentile curves for height and BMI were constructed using the LMS method. NS patients had birth weight and length within normal ranges but the postnatal growth impairment was observed during the first year of life, reaching a final height of -2.3 and -2.2 standard deviations from the mean for Brazilian healthy men and women, respectively. Postnatal growth impairment was higher in RAF1 mutation patients than in patients with SOS1 and PTPN11 mutations. BMI values in NS patients were lower in comparison with normal Brazilian population. BMI values were higher in patients with RAF1 mutations than in patients with other genotypes. Patients with mutations in PTPN11 and SOS1 genes were more likely to have pulmonary valve stenosis, whereas hypertrophic cardiomyopathy was more common in patients with mutations in the gene RAF1...