RESUMO
OBJECTIVE: To evaluate the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in 3 hospitalized patients with Noonan syndrome. STUDY DESIGN: Pharmacologic MEK1/2 inhibition has been used to treat conditions associated with Noonan syndrome, given that activation of RAS-MAPK pathway variants leads to downstream MEK activation. We describe our experience with 3 patients with Noonan syndrome (owing to variants in 3 distinct genes) and refractory chylous effusions treated successfully with MEK inhibition. A monitoring protocol was established to standardize medication dosing and monitoring of outcome measures. RESULTS: Subjects demonstrated improvement in lymphatic leak with additional findings of improved growth and normalization of cardiac and hematologic measurements. Trametinib was administered safely, with only moderate skin irritation in 1 subject. CONCLUSIONS: Improvements in a variety of quantifiable measurements highlight the potential utility of MEK1/2 inhibition in patients with Noonan syndrome and life-threatening lymphatic disease. Larger, prospective studies are needed to confirm efficacy and assess long-term safety.
Assuntos
Antineoplásicos , Síndrome de Noonan , Criança , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno , Síndrome de Noonan/complicações , Síndrome de Noonan/tratamento farmacológico , Síndrome de Noonan/genética , Piridonas/uso terapêutico , Pirimidinonas/uso terapêuticoRESUMO
Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.
Assuntos
Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Síndrome de Noonan/tratamento farmacológico , Animais , Modelos Animais de Doenças , Transtornos do Crescimento/etiologia , Humanos , Camundongos , Síndrome de Noonan/complicações , Resultado do TratamentoRESUMO
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)
Assuntos
Humanos , Masculino , Adulto , Insuficiência da Valva Aórtica/cirurgia , Endocardite/diagnóstico , Síndrome de Noonan/complicações , Síndrome de Noonan/genética , Síndrome de Noonan/epidemiologia , PeruRESUMO
OBJECTIVE: To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. STUDY DESIGN: Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations. RESULTS: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers. CONCLUSIONS: Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.
Assuntos
Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/genética , Mutação , Hipertensão Arterial Pulmonar/epidemiologia , Hipertensão Arterial Pulmonar/genética , Receptores de Activinas Tipo II/genética , Adolescente , Aracnodactilia/complicações , Aracnodactilia/epidemiologia , Aracnodactilia/genética , Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Criança , Pré-Escolar , Contratura/complicações , Contratura/epidemiologia , Contratura/genética , Síndrome de Down/epidemiologia , Síndrome de Down/genética , Feminino , Dosagem de Genes , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Humanos , Lactente , Masculino , Proteínas do Tecido Nervoso/genética , Países Baixos/epidemiologia , Síndrome de Noonan/complicações , Síndrome de Noonan/epidemiologia , Síndrome de Noonan/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Estudos Prospectivos , Proteínas Serina-Treonina Quinases/genética , Sistema de Registros , Proteínas com Domínio T/genética , Vitamina B 12/metabolismo , Deficiência de Vitamina B 12/epidemiologia , Deficiência de Vitamina B 12/genéticaRESUMO
OBJECTIVES: To assess the potential impact of using screening recommendations for bleeding disorders in patients with Noonan syndrome on perioperative bleeding complications. STUDY DESIGN: We performed a retrospective, single-site cohort study; patients were identified by query of the electronic medical record. All patients with a clinical diagnosis of Noonan syndrome over a 10-year period were included. Data on surgeries, hematologic evaluation, bleeding symptoms, and bleeding complications were extracted. Surgeries were graded as major or minor. RESULTS: We identified 101 patients with Noonan syndrome, 70 of whom required surgery for a total of 164 procedures. Nine patients (9/70; 12.8%) had bleeding complications, occurring in those without comprehensive testing or perioperative intervention and undergoing major or dental surgery. Based on these findings, the risk of a bleeding complication for patients with Noonan syndrome who did not have comprehensive testing or perioperative intervention was 6.2% (95% CI 2.3%-10.1%), indicating the number needed to treat or screen would be 16 to prevent 1 bleeding complication (95% CI 9.9-43.9). The majority of patients had either no or incomplete evaluation (59 of 101; 58.4%). CONCLUSIONS: With proper evaluation and management, the bleeding risk in patients with Noonan syndrome can be minimized. Efforts are needed to address the knowledge and implementation gap in this evaluation.