Asunto(s)
Cardiomiopatía Hipertrófica , Síndrome LEOPARD , Síndrome de Noonan , Humanos , Síndrome LEOPARD/complicaciones , Síndrome LEOPARD/diagnóstico , Síndrome LEOPARD/genética , Síndrome de Noonan/complicaciones , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Mutación , Cardiomiopatía Hipertrófica/complicaciones , Cardiomiopatía Hipertrófica/diagnóstico , Cardiomiopatía Hipertrófica/genética , Fenotipo , Genotipo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genéticaRESUMEN
PURPOSE: To report a case of Noonan syndrome with multiple lentigines with unusual ocular features. METHODS: The authors describe a case of a 7-year-old girl with Noonan syndrome with multiple lentigines and anomalous optic disks. RESULTS: A 7-year-old girl with genetically proven Noonan syndrome with multiple lentigines ( PTPN11 gene mutation) and anomalous optic disks was referred for treatment of persistent macular detachment after 1 year of conservative follow-up. The right eye demonstrated an optic disk coloboma with the best-corrected visual acuity of 20/32, the left eye demonstrated an optic disk pit with serous macular detachment (best-corrected visual acuity 20/50-20/80). Optical coherence tomography demonstrated a neurosensory detachment. Twenty-five gauge pars plana vitrectomy was performed with posterior hyaloid detachment, drainage over disk pit area, and SF6 20% gas tamponade. Surgery resulted in subretinal fluid reduction and improvement of the visual acuity to 20/32. CONCLUSION: A case of Noonan syndrome with multiple lentigines with optic disk coloboma in the right eye and optic disk pit with related maculopathy in the left eye. To the best of the authors' knowledge, this is the first reported case describing the association of Noonan syndrome with multiple lentigines and congenital optic disk anomalies. Optic disk pit maculopathy was managed surgically because of its longstanding nature with the deteriorating visual acuity.
Asunto(s)
Coloboma , Anomalías del Ojo , Síndrome LEOPARD , Degeneración Macular , Disco Óptico , Trastornos de la Pigmentación , Desprendimiento de Retina , Enfermedades de la Retina , Femenino , Humanos , Niño , Disco Óptico/anomalías , Coloboma/complicaciones , Coloboma/diagnóstico , Coloboma/cirugía , Vitrectomía/métodos , Síndrome LEOPARD/complicaciones , Síndrome LEOPARD/cirugía , Enfermedades de la Retina/complicaciones , Desprendimiento de Retina/cirugía , Anomalías del Ojo/complicaciones , Anomalías del Ojo/diagnóstico , Anomalías del Ojo/cirugía , Degeneración Macular/complicaciones , Tomografía de Coherencia Óptica , Trastornos de la Pigmentación/complicacionesRESUMEN
BACKGROUND: Noonan Syndrome with Multiple Lentigines (NSML) and Noonan Syndrome (NS) can be difficult to differentiate clinically in early childhood. This study aims to describe characteristics of the ventricular septum that may differentiate NSML from NS. We hypothesize that the shape of the ventricular septum determined by echocardiography correlates with genotype and may distinguish patients with NSML from those with NS. METHODS: We analyzed data from 17 NSML and 67 NS patients. Forty normal and 30 sarcomeric hypertrophic cardiomyopathy (HCM) patients were included as controls. Septal morphology was qualitatively evaluated, and septal angle was measured quantitatively at end diastole. We recorded the presence of a ventricular septal bulge (VSB) and reviewed genetic testing results for each patient. RESULTS: The most important findings were a sigmoid septum (71%) and VSB (71%) in NSML. NSML septal angle was decreased compared to the normal and sarcomeric HCM control groups, respectively (149 ± 13 vs. 177 ± 3, p < 0.001; 149 ± 13 vs. 172 ± 7, p < 0.001). NS septal angle was similar to the controls (176 ± 6 vs. 177 ± 3, p > 0.5; 176 ± 6 vs. 172 ± 7, p > 0.5). NSML-linked pathogenic variants were associated with sigmoid septum and VSB. CONCLUSIONS: These findings provide novel phenotypic evidence to clinicians that may offer incremental diagnostic value in counseling families in ambiguous NSML/NS cases. IMPACT: Characteristics of the ventricular septum are linked to specific gene variants that cause NSML and NS. Sigmoid septum and VSB are associated with NSML. This novel echocardiographic association may help clinicians distinguish NSML from NS in ambiguous cases. Early distinction between the two may be important, as syndrome-specific therapies may become available in the near future. This study may encourage further research into genotype-phenotype associations in other forms of HCM.
Asunto(s)
Cardiomiopatía Hipertrófica/diagnóstico por imagen , Ecocardiografía , Síndrome LEOPARD/genética , Mutación , Síndrome de Noonan/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Tabique Interventricular/diagnóstico por imagen , Adolescente , Adulto , Cardiomiopatía Hipertrófica/etiología , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Lactante , Síndrome LEOPARD/complicaciones , Síndrome LEOPARD/diagnóstico , Masculino , Síndrome de Noonan/complicaciones , Síndrome de Noonan/diagnóstico , Fenotipo , Valor Predictivo de las Pruebas , Estudios Retrospectivos , Adulto JovenRESUMEN
Multiple lentigines syndrome is an autosomal dominant inherited condition with variable expressivity that is also known as LEOPARD syndrome. LEOPARD stands for lentigines, electrocardiographic conduction defects, ocular hypertelorism, pulmonary valve stenosis, abnormalities of genitalia, retardation of growth, and deafness. LEOPARD syndrome most frequently develops secondary to a missense mutation of protein-tyrosine phosphatase nonreceptor type 11 gene, which encodes tyrosine phosphatase. The missense mutation p.Tyr279Cys can either occur as a de novo mutation or affect multiple family members. Although hypertrophic cardiomyopathy is not part of the LEOPARD acronym, it is the most frequent cardiac anomaly observed in this syndrome. The recognition of increased left or right ventricular wall thickness in patients with LEOPARD syndrome may have significant impact on their clinical course similar to classic hypertrophic cardiomyopathy, which may require septal reduction procedures for relief of left or right ventricular outflow tract obstruction or implantable cardioverter-defibrillator placement for sudden cardiac death prevention. We describe a case series of a family with diffuse lentigines and hypertrophic cardiomyopathy in which the son carries the protein-tyrosine phosphatase nonreceptor type 11 (p.Tyr279Cys) gene mutation and both the son and daughter underwent left ventricular myectomy at an early age. In conclusion, our case series of a family with LEOPARD syndrome illustrates the importance of recognizing hypertrophic cardiomyopathy as part of this syndrome.
Asunto(s)
Cardiomiopatía Hipertrófica/complicaciones , Síndrome LEOPARD/complicaciones , Adulto , Cardiomiopatía Hipertrófica/diagnóstico por imagen , Femenino , Humanos , Síndrome LEOPARD/genética , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
Noonan syndrome with multiple lentigines (NSML) is a rare autosomal dominant disorder that presents with cardio-cutaneous-craniofacial defects. Hypertrophic cardiomyopathy (HCM) represents the major life-threatening presentation in NSML. Mutations in the PTPN11 gene that encodes for the protein tyrosine phosphatase (PTP), SHP2, represents the predominant cause of HCM in NSML. NSML-associated PTPN11 mutations render SHP2 catalytically inactive with an "open" conformation. NSML-associated PTPN11 mutations cause hypertyrosyl phosphorylation of the transmembrane glycoprotein, protein zero-related (PZR), resulting in increased SHP2 binding. Here we show that NSML mice harboring a tyrosyl phosphorylation-defective mutant of PZR (NSML/PZRY242F) that is defective for SHP2 binding fail to develop HCM. Enhanced AKT/S6 kinase signaling in heart lysates of NSML mice was reversed in NSML/PZRY242F mice, demonstrating that PZR/SHP2 interactions promote aberrant AKT/S6 kinase activity in NSML. Enhanced PZR tyrosyl phosphorylation in the hearts of NSML mice was found to drive myocardial fibrosis by engaging an Src/NF-κB pathway, resulting in increased activation of IL-6. Increased expression of IL-6 in the hearts of NSML mice was reversed in NSML/PZRY242F mice, and PZRY242F mutant fibroblasts were defective for IL-6 secretion and STAT3-mediated fibrogenesis. These results demonstrate that NSML-associated PTPN11 mutations that induce PZR hypertyrosyl phosphorylation trigger pathophysiological signaling that promotes HCM and cardiac fibrosis.
Asunto(s)
Cardiomiopatía Hipertrófica/patología , Modelos Animales de Enfermedad , Péptidos y Proteínas de Señalización Intracelular/fisiología , Síndrome LEOPARD/complicaciones , Mutación , Fosfoproteínas/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Tirosina/metabolismo , Animales , Cardiomiopatía Hipertrófica/etiología , Cardiomiopatía Hipertrófica/metabolismo , Femenino , Síndrome LEOPARD/genética , Síndrome LEOPARD/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , FosforilaciónRESUMEN
BACKGROUND: Animal studies suggested that blocking the activation of the mammalian target of rapamycin (mTOR) pathway might be effective to treat cardiac hypertrophy in LEOPARD syndrome (LS) caused by PTPN11 mutations. RESULTS: In the present study, mTOR pathway activity was examined in human myocardial samples from two patients with LS, four patients with hypertrophic cardiomyopathy (HCM), and four normal controls. The two patients with LS had p.Y279C and p.T468 M mutations of the PTPN11 gene, respectively. Although PTPN11 mutation showed initially positive regulation on phosphoinositide 3-kinase, overall the mTOR complex 1 pathway showed widely attenuated activity in LS. This included mildly hypophosphorylated mTOR and ribosomal protein S6 kinase and significantly hypophosphorylated Akt308 and ribosomal protein S6, which is similar to HCM. Akt473 is a basal molecule of the mTOR complex 2 pathway. Akt473 was less affected and showed hyperactivity in LS compared with HCM and normal controls. Additionally, MAPK/ERK kinase and ERK1/2 were significantly more phosphorylated in both HCM and LS than normal controls. CONCLUSIONS: In LS, the mTOR signaling pathway shows similar activity to HCM and is attenuated compared with normal controls. Thus, caution should be applied when using rapamycin to treat heart hypertrophy in LS.
Asunto(s)
Cardiomegalia/etiología , Cardiomegalia/metabolismo , Síndrome LEOPARD/complicaciones , Síndrome LEOPARD/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adolescente , Adulto , Animales , Cardiomegalia/tratamiento farmacológico , Humanos , Síndrome LEOPARD/tratamiento farmacológico , Masculino , Modelos Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Sirolimus/uso terapéutico , Adulto JovenRESUMEN
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.
Asunto(s)
Síndrome LEOPARD/complicaciones , Síndrome de Noonan/complicaciones , Paro Cardíaco Extrahospitalario/etiología , Reanimación Cardiopulmonar , Niño , Desfibriladores Implantables , Humanos , Masculino , Paro Cardíaco Extrahospitalario/terapiaRESUMEN
Introduction LEOPARD syndrome is a rare genetic disorder characterised by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth and sensorineural deafness. Clinical manifestations are often mild, which may result in difficult and late diagnosis. Cardiac involvement may have a significant impact on the prognosis, however, appearance of severe abnormalities such as hypertrophic cardiomyopathy usually precedes the occurrence of multiple lentigines and may be asymptomatic. Case presentation We report two cases of LEOPARD syndrome with hypertrophic cardiomyopathy in a 10-year-old girl and an 18-year-old boy. In both cases, multiple lentigines, ocular hypertelorism and growth retardation were present. The first patient was followed up at the paediatric cardiology clinic due to the risk of progression of septal hypertrophy and pressure gradient across the left ventricular outflow tract, the second patient underwent surgery for a moderate obstruction of the left ventricular outflow tract with uncomplicated post-operative follow-up. Conclusion In both presented patients, hypertrophic cardiomyopathy was clinically silent and the murmur over the precordium was the sole cardiac abnormality revealed during routine visit. A detailed cardiologic examination should be considered in the patients with suspicion of LEOPARD syndrome since the ventricular hypertrophy is thought to precede the occurrence of lentigines and progress over time.
Asunto(s)
Cardiomiopatía Hipertrófica/etiología , Síndrome LEOPARD/complicaciones , Adolescente , Cardiomiopatía Hipertrófica/diagnóstico , Niño , Femenino , Humanos , MasculinoAsunto(s)
Enfermedad de Darier/complicaciones , Cejas/anomalías , Síndrome LEOPARD/diagnóstico , Anomalías Múltiples/diagnóstico , Adulto , Enfermedad de Darier/diagnóstico , Asesoramiento Genético , Pruebas Genéticas , Humanos , Síndrome LEOPARD/complicaciones , Síndrome LEOPARD/genética , MasculinoRESUMEN
ABSTRACT Multiple lentigines syndrome (MLS) is an autosomal dominant disease which is usually diagnosed clinically by the presence of characteristic features. The molecular genetic testing is an adjuvant diagnostic tool to identify the mutation of particular genes such as PTPN11 genes, RAF1, BRAF or MAP2K1 genes. This syndrome was formerly known as LEOPARD syndrome or Noonan syndrome with multiple lentigines. 'LEOPARD syndrome ' is an acronym of characteristic features (Lentigines, Electrocardiographic conduction abnormalities, Ocular hypertelorism, Pulmonary stenosis, Abnormalities of the genitalia, Retardation of growth, and Deafness). There was no previous case report about any glomerulonephropathy in association with MLS. We present a case of a patient with MLS with recurrent nephrotic syndrome who was found to have histologic evidence of 'full house ' glomerulopathy.
RESUMEN El síndrome de lentigos múltiples (SLM) es una enfermedad autosómica dominante que de modo general se diagnostica clínicamente por la presencia de rasgos característicos. La prueba genética molecular es una herramienta de diagnóstico auxiliar utilizada para identificar la mutación de genes específicos tales como los genes PTPN11, RAF1, BRAF, o los genes MAP2K1. Este síndrome se conocía anteriormente como síndrome del leopardo o síndrome de Noonan con múltiples lentigos. El síndrome toma su nombre del acrónimo en inglés LEOPARD, que describe sus rasgos característicos (L lentigos; E conducción electrocardiográfica de las anormalidades; O hipertelorismo ocular; P estenosis pulmonar; A anormalidades de los genitales; R retardo del crecimiento; y D deafness, 'sordera ' en inglés), y que fuera introducido por Gorlin et al en 1969. No existía ningún reporte de caso anterior sobre glomerulonefropatía asociada con SLM. Presentamos el caso de un paciente con SLM con síndrome nefrótico recurrente en el que se halló evidencia histológica de glomerulopatía 'full house'.
Asunto(s)
Humanos , Masculino , Adolescente , Síndrome LEOPARD/complicaciones , Glomerulonefritis/etiología , Recurrencia , Progresión de la Enfermedad , Síndrome LEOPARD/diagnóstico , Síndrome LEOPARD/genéticaRESUMEN
We present a 3-year old boy with Leopard syndrome. His clinical manifestations included a congenital bilateral sensorineural hearing loss. He underwent cochlear implantation on the right side at age 1 year and on the left side at age 1.5 years. The patient is doing very well and mainstreamed in a regular pre-school program with a teacher of the deaf and home based speech therapy. Bilateral cochlear implantation in the case of a child with Leopard syndrome can be successful.
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Implantación Coclear , Pérdida Auditiva Bilateral/rehabilitación , Pérdida Auditiva Sensorineural/rehabilitación , Síndrome LEOPARD/rehabilitación , Preescolar , Implantes Cocleares , Pérdida Auditiva Bilateral/etiología , Pérdida Auditiva Sensorineural/etiología , Humanos , Síndrome LEOPARD/complicaciones , Integración Escolar , Masculino , Personas con Deficiencia Auditiva , Habla , Percepción del Habla , LogopediaRESUMEN
A sixteen year old girl presented with history of hemoptysis of one week duration. She had history of dyspnea on exertion and frequent respiratory infections in childhood. She had short stature, hypertelorism, neurofibroma, café au lait spots and multiple lentigines. She had features of severe pulmonary hypertension and differential clubbing and cyanosis. A final diagnosis of LEOPARD syndrome with hypertrophic cardiomyopathy and patent ductus arteriosus (PDA) Eisenmenger syndrome was made.
Asunto(s)
Cardiomiopatía Hipertrófica/complicaciones , Conducto Arterioso Permeable/complicaciones , Síndrome LEOPARD/complicaciones , Adolescente , Femenino , HumanosRESUMEN
INTRODUCTION: Noonan syndrome (NS) and other syndromes with a similar phenotype, such as LEOPARD, cardiofaciocutaneous, Costello and Legius, are associated to mutations in genes included in the RAS/MAPK pathway (RASopathies), which is an important signalling pathway related to cell proliferation. Tonsillar descent into the upper cervical spinal canal, known as Arnold-Chiari malformation (ACM), has been reported in patients with NS and this has led some researchers to suggest that ACM could be part of the phenotypic spectrum of NS. We report two cases of NS and ACM. CASE REPORTS: Case 1: 29-year-old female with Noonan phenotype who underwent surgery at the age of nine years due to pulmonary valve stenosis. At the age of 27, she presented symptomatic ACM that required surgical decompression. She presented the c.922A>G (N308D) mutation in the gene PTPN that belongs to the RAS/MAPK pathway. Case 2: a 10-year-old female with Noonan phenotype and asymptomatic ACM detected in magnetic resonance imaging of the brain. She was a carrier of the c.923A>G (N308S) mutation in gene PTPN11. CONCLUSIONS: Six patients with this association have been found in the literature, four with the Noonan phenotype and two with LEOPARD. Our two patients provide supplementary evidence that backs up the hypothesis by which ACM would be part of the phenotypic spectrum of NS. The small number of reported cases of patients with this association does not allow us to draw up recommendations about when and how often neuroimaging studies should be performed; a careful neurological examination, however, should be included in the anticipatory health guidelines in syndromes involving the RAS/MAPK pathway.
TITLE: Malformacion de Arnold-Chiari en el sindrome de Noonan y otros sindromes de la via RAS/MAPK.Introduccion. El sindrome de Noonan (SN) y otros sindromes con fenotipo similar, como LEOPARD, cardiofaciocutaneo, Costello y Legius, estan asociados a mutaciones en genes incluidos en la via RAS/MAPK (rasopatias), una importante via de señalizacion relacionada con la proliferacion celular. El descenso de las amigdalas cerebelares dentro del canal medular cervical, conocido como malformacion de Arnold-Chiari (MAC), se ha descrito en pacientes afectos de SN, lo que ha llevado a sugerir que la MAC podria formar parte del espectro fenotipico del SN. Presentamos dos casos con SN y MAC. Casos clinicos. Caso 1: mujer de 29 años con fenotipo de Noonan. Fue intervenida a los 9 años de estenosis valvular pulmonar. A los 27 años, presento MAC sintomatica que preciso descompresion quirurgica. Presentaba mutacion c.922A>G (N308D) en el gen PTPN perteneciente a la via RAS/MAPK. Caso 2: niña de 10 años con fenotipo de Noonan y MAC asintomatica detectada en resonancia magnetica cerebral. Era portadora de la mutacion c.923A>G (N308S) en el gen PTPN11. Conclusiones. Hemos encontrado en la bibliografia seis pacientes con esta asociacion, cuatro con fenotipo Noonan y dos con LEOPARD. Nuestros dos pacientes aportan evidencia suplementaria a la hipotesis de que la MAC formaria parte del espectro fenotipico del SN. El escaso numero de pacientes publicados con esta asociacion no permite extraer recomendaciones sobre el momento y la frecuencia de estudio de neuroimagen; no obstante, una exploracion neurologica cuidadosa deberia incluirse en la guia anticipatoria de salud en los sindromes de la via RAS/MAPK.
Asunto(s)
Malformación de Arnold-Chiari/etiología , Síndrome de Noonan/complicaciones , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas p21(ras)/fisiología , Transducción de Señal/fisiología , Adulto , Malformación de Arnold-Chiari/cirugía , Niño , Descompresión Quirúrgica , Exones , Femenino , Humanos , Síndrome LEOPARD/complicaciones , Síndrome LEOPARD/genética , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/fisiología , Mutación Missense , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Síndrome de Noonan/metabolismo , Fenotipo , Mutación Puntual , Embarazo , Complicaciones del Embarazo/genética , Diagnóstico Prenatal , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de Señal/genéticaRESUMEN
BACKGROUND: LEOPARD syndrome (LS) belongs to the family of neuro-cardio-facio-cutaneous syndromes, which include Neurofibromatosis-1 (NF1), Noonan syndrome, Costello Syndrome, cardio-facio-cutaneous syndrome, Noonan-like syndrome with loose anagen hair and Legius syndrome. These conditions are caused by mutations in genes encoding proteins involved in the RAS-MAPK cellular pathway. Clinical heterogeneity and phenotype overlaps across those different syndromes is already recognized. CASE PRESENTATION: We hereby report a heterozygous de novo mutation in the PTPN11 gene (c.1403C > T) manifesting with a clinical picture of LS during childhood, and later development of neuropathic pain with hypertrophic plexi, which are typically observed in NF1 but have not been reported in LS. CONCLUSION: LS caused by PTPN11 mutations may be associated with hypertrophic roots and plexi. Consequently, clinicians should be aware of the possible development of neuropathic pain and consider specific diagnostic work-up and management.
Asunto(s)
Síndrome LEOPARD/genética , Neuralgia/fisiopatología , Enfermedades del Sistema Nervioso Periférico/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Adulto , Femenino , Humanos , Síndrome LEOPARD/complicaciones , Mutación , Neuralgia/etiología , Enfermedades del Sistema Nervioso Periférico/etiologíaRESUMEN
Systemic conditions may have pigmentary associations. Prompt recognition of these associations allows the practitioner to initiate the appropriate workup and therapy when indicated. This contribution highlights some of the clinical features of neurofibromatosis 1, LEOPARD syndrome, acanthosis nigricans, hypomelanosis of Ito, incontinentia pigmenti, CHILD syndrome, and piebaldism to assist the dermatologist in making the proper diagnosis.