Síndromes neurocutáneos y leucemia linfoide aguda: a propósito de un caso / Neurocutaneous syndromes and acute lymphoid leukemia: a case report

Introducción: Los síndromes neurocutáneos comprenden un grupo heterogéneo de trastornos hereditarios que comprometen principalmente la piel y el sistema nervioso central. Dentro de estos se incluye la neurofibromatosis, la esclerosis tuberosa y la enfermedad de Von-Hippel Lindau. Se caracterizan por presencia de displasia en distintos tejidos y formación de tumores en diversos órganos. Se ha descrito también un riesgo relativo aumentado para leucemia linfoblástica aguda, leucemia mielomonocítica crónica y linfoma no Hodgkin. Objetivo: Describir caso de paciente con diagnóstico de síndrome neurocutáneo (esclerosis tuberosa) que desarrolló a los 6 años una leucemia linfoide aguda. Caso clínico: Paciente femenina, seis años de edad, con antecedentes de síndrome neurocutáneo tipo esclerosis tuberosa diagnosticado a los dos años de edad- Comenzó con síndrome febril, adenopatías cervicales y hepatoesplenomegalia. El hemograma mostró anemia, trombocitopenia grave y leucocitosis con presencia de blastos. En el medulograma se observó una infiltración de 90 por ciento de blastos linfoides, por lo que se diagnosticó como una leucemia linfoide aguda. Conclusiones: La coexistencia de síndromes neurocutáneos y leucemia linfoide aguda no es frecuente. Se describe una paciente con ambas enfermedades, que fallece a pesar del tratamiento(AU)

Introduction: Neurocutaneous syndromes comprise a heterogeneous set of hereditary disorders mainly affecting the skin and the central nervous system. Among the conditions included are neurofibromatosis, tuberous sclerosis and von Hippel-Lindau disease, characterized by dysplasia in various tissues and the formation of tumors in various organs. Increased relative risk has also been described for acute lymphoblastic leukemia, chronic myelomonocytic leukemia and non-Hodgkin lymphoma. Objective: Describe the case of a patient diagnosed with neurocutaneous syndrome (tuberous sclerosis) who developed acute lymphoid leukemia at age six. Clinical case: A case is presented of a female six-year-old patient with a history of neurocutaneous syndrome, tuberous sclerosis type, diagnosed at age two. The patient started with febrile syndrome, cervical adenopathies and hepatosplenomegaly. The blood count revealed anemia, severe thrombocytopenia and leukocytosis with the presence of blasts, whereas the medullogram showed 90 percent infiltration by lymphoid blasts, leading to the diagnosis of acute lymphoid leukemia. Conclusions: Coexistence of neurocutaneous syndromes and acute lymphoid leukemia is not frequent. A case is described of a patient with both conditions who died despite the treatment indicated(AU)

Utilidad del método clínico en el diagnóstico de algunos síndromes genéticos / Use fulness of the clinical method for diagnosing a group of clinical syndromes

Introducción: El método científico es un método general, constituido por varias etapas necesarias en el desarrollo de toda investigación científica. Es la forma de abordar la realidad y estudiar los fenómenos de la naturaleza, para descubrir su esencia y sus interrelaciones. El método clínico es la aplicación particular del método científico en el ejercicio de la práctica médica, y en las condiciones económicas actuales prevalecientes a nivel mundial resulta de inestimable valor su aplicación por las ventajas que reporta desde ese punto de vista, así como también por el bienestar del paciente que no es sometido a innecesarios y costosos procedimientos diagnósticos. Objetivo: Proporcionar al personal médico los criterios clínicos para lograr, mediante el uso del método clínico, el diagnóstico de algunos síndromes genéticos; los que han sido elaborados luego de una exhaustiva delineación clínica de estos. Métodos: Se realizó una revisión de los textos básicos de genética clínica y sindromología con independencia del año de su publicación y se realizó una búsqueda en las bases de datos Medline, Lilacs y Cochrane en el periodo comprendido entre 2012 y 2016. Conclusiones: Fueron reflejados los criterios establecidos para el diagnóstico clínico de catorce síndromes genéticos(AU)

Introduction: The scientific method is a general method which consists of several stages necessary for the development of all scientific research. It is the way to approach reality and to study the phenomena of nature, to discover their essence and interrelations. The clinical method is the particular application of the scientific method in the medical practice, and in the current economic conditions prevailing worldwide, its application is of inestimable value because of the advantages it brings from that point of view, as well as for the well-being of the patient, who would not be subjected to unnecessary and expensive diagnostic procedures. Objective: To provide the medical personnel with the clinical criteria to achieve, through the use of the clinical method, the diagnosis of some genetic syndromes. Such criteria have been elaborated after an exhaustive clinical description of those conditions. Methods: A review of basic texts of clinical genetics and syndromology was carried out regardless the year of publication. A search was carried out in the databases Medline, Lilacs and Cochrane, in the period between 2012 and 2016. Conclusions: The criteria established for the clinical diagnosis of fourteen genetic syndromes have been presented(AU)

Hallazgos clínicos y epidemiológicos en la neurofibromatosis tipo 1 y el complejo esclerosis tuberosa en una serie de pacientes pediátricos / Clinical and epidemiological findings in neurofibromatosis type 1 and tuberous sclerosis complex in a series of pediatric patients

Resumen: Introducción: La neurofibromatosis tipo 1 (NF1) es una entidad genética con una incidencia de 1 entre 2,500 a 3,500 nacimientos. Por su parte, el complejo esclerosis tuberosa (CET) presenta una incidencia de 1 entre 6,000 a 10,000 nacimientos. Ambas entidades neurocutáneas cursan con un patrón de herencia autosómico dominante, expresividad variable y la morbimortalidad se encuentra asociada a complicaciones multisistémicas. El objetivo de este trabajo fue exponer las características clínicas y epidemiológicas de una serie de pacientes pediátricos con diagnóstico de NF1 y CET atendidos en la Unidad de Genética Médica de la Universidad de Los Andes. Métodos: Este trabajo corresponde a una serie de casos de pacientes menores de 16 años atendidos en un período de 11 años, que cumplan con los criterios diagnósticos de NF1 y CET según los consensos para cada entidad. Resultados: Se estudiaron 89 pacientes, 73 con NF1 y 16 con CET. Presentaron dos criterios para NF1, 58 (79.45%) pacientes, y las máculas café con leche fueron las más frecuentes y presentes en todos los casos; 10 pacientes (62.50 %) presentaron dos criterios mayores para el CET, y las máculas hipocrómicas estuvieron igualmente presentes en todos los casos. Conclusiones: Este estudio muestra la forma de presentación clínica de las dos entidades neurocutáneas más frecuentes. Se discuten los criterios diagnósticos con el objeto de identificarlos a edades más tempranas y poder brindar una evaluación médica interdisciplinaria, tratamiento y un oportuno asesoramiento genético familiar.

Abstract: Background: Neurofibromatosis type 1 (NF1) is a genetic entity with an incidence of 1 in 2,500 to 3,500 births. Tuberous sclerosis complex (TSC) has an incidence between 1 in 6,000 to 10,000 births. Both neurocutaneous entities present an autosomal dominant inheritance pattern, variable expressivity and their morbidity and mortality is associated with multisystemic complications. The aim of this study was to present the clinical and epidemiological characteristics of a series of pediatric patients diagnosed with NF1 and TSC, who were treated in the Medical Genetics Unit of the Universidad of Los Andes. Methods: This work corresponds to a series of cases of patients under 16 years of age served in a period of 11 years, who met the diagnostic criteria of NF1 and CET according to the consensus for each entity. Results: We studied 89 patients, 73 with NF1 and 16 with TSC. 58 (79.45%) of the patients presented two criteria for NF1, with café-au-lait macules being the most frequent and present in all cases. 10 (62.50%) of the patients presented two major criteria for TSC; hypochromic macules were equally present in all cases. Conclusions: This study shows the clinical presentation of the two most frequent neurocutaneous entities. Diagnostic criteria are discussed in order to perform them at younger ages and to provide an interdisciplinary medical evaluation, treatment and timely family genetic counseling.

Tuberous sclerosis complex: review based on new diagnostic criteria

Abstract: Tuberous sclerosis complex is a multisystemic, autosomal dominant genetic disorder with complete penetrance, that can evolve with hamartomas in multiple organs, such as skin, central nervous system, kidney and lung. Due to the wide phenotypic variability, the disease is often not recognized. Tuberous sclerosis complex affects one in 10,000 newborns and most patients are diagnosed during the first 15 months of life. The diagnostic criteria for tuberous sclerosis were reviewed in 2012, at the second International Tuberous Sclerosis Complex Consensus Conference. The diagnosis is based on genetic criteria, by the identification of inactivating pathogenic mutation of tumor suppressor genes TSC1 and TSC2, and clinical criteria, including cutaneous, renal, pulmonary, cardiac and neurological manifestations. The treatment of tuberous sclerosis complex consists, mainly, in management of the symptoms caused by hamartomas and in prevention of organ failure. Multidisciplinary approach is recommended, in order to obtain better clinical outcomes.

Nueva mutación del gen TSC2 en un paciente pediátrico con diagnóstico clínico de esclerosis tuberosa / Novel mutation in TSC2 gene in pediatric patient with clinical diagnosis of tuberous sclerosis

El complejo de esclerosis tuberosa es un desorden neurocutáneo autosómico dominante causado por mutaciones en los genes TSC1 o TSC2. El diagnóstico se basa en criterios clínicos o el criterio genético. La presentación clínica es altamente variable y las manifestaciones de la enfermedad pueden desarrollarse durante toda la vida. Se reporta el caso de un niño que cumple criterios clínicos para el diagnóstico de esclerosis tuberosa y cuyo estudio molecular identificó una variante nueva del gen TSC2. Se trata de una mutación sin sentido, esporádica, no reportada previamente (c.583_586dupATCG) localizada en el exón 6, que provoca un codón de parada temprano y altera la estructura de la proteína. Puede considerarse una variante patogénica por el tipo de mutación y permite ampliar el espectro de variantes del gen TSC2 como causa del complejo de esclerosis tuberosa.

Tuberous sclerosis complex (TSC) is a neurocutaneous autosomal dominant disorder that results from mutations within either the TSC1 gene or the TSC2 gene. Diagnosis is based on well-established clinical criteria or genetic criteria. Clinical features are highly variable and could be developing over the life. We present a case of TSC with a molecular test that identified a novel variant in TSC2 gene. It is a sporadic missense mutation which has not been previously reported in the literature. It is caused by premature termination of protein translation and results in the production of truncated and non-functional proteins. This mutation is considered as a pathogenic variant and allows to broaden the spectrum of variants of TSC2 gene as a cause of TSC.

Respuesta a la rapamicina en un paciente trasplantado renal con esclerosis tuberosa / Response to rapamycin in a kidney transplant patient with tuberous sclerosis

La esclerosis tuberosa (ET) es un síndrome neurocutáneo autosómico dominante causado por mutaciones en los genes de supresión tumoral TSC1/TSC2, con la consecuente formación de hamartomas y tuberomas en múltiples órganos. Reportamos una paciente que a los 21 años de edad es trasplantada por insuficiencia renal crónica idiopática, a la cual se le diagnostica ET posterior a trasplante renal. A nivel mucocutáneo presentaba las manifestaciones características de la enfermedad. Además refería el antecedente de sufrir crisis comiciales que se correlacionaron con el hallazgo de tuberomas corticales en encéfalo, como así también en el parénquima pulmonar. Dentro del esquema terapéutico inmunosupresor post-trasplante que recibió la paciente se encontraba la rapamicina, un inhibidor de la proteína mTOR (mammalian Target of Rapamycin), que participa en la proliferación y muerte celular. Durante el tratamiento se pudo observar una mejoría clínica de los angiofibromas faciales y del tuberoma pulmonar (AU)

Tuberous sclerosis (TS) is an autosomal dominant neurocutaneous syndrome caused by mutations in tumor suppressor genes TSC1/TSC2, with the consequent formation of hamartomas and tuberomas in multiple organs. A female patient diagnosed with TS after kidney transplantation because idiopathic chronic kidney disease at the age of 21-year-old is reported. Characteristic mucocutaneous manifestations of the disease were present at the examination. Patient also referred a history of seizures which were correlated with cortical tuberomas found in brain, as well as in the lung parenchyma. Patient was treated with rapamycin in the post- transplant immunosuppressive scheme, an inhibitor of mTOR (mammalian Target of Rapamycin), which is involved in proliferation and cell death. Clinical improvement of facial angiofibromas and pulmonary tuberoma were observed during treatment (AU)

Esclerosis tuberosa / Tuberous sclerosis

Se presenta el caso de paciente masculino de 15 años de edad que es llevado a sala de urgencia s del Hospital Roosevelt por convulsiones tónico clónico generalizadas de 2 minutos de duración, con período postictal, con antecedentes familiares de convulsiones mostradas en el árbol genealógico (grafico 2 ). Además presenta antecedente de síndrome convulsivo desarrollado a los tres años de edad, tratado con múltiples anticonvulsivantes sin llegar a un dia gnóstico. Paciente al examen físico se presenta normocéfalo, cabello adecuada implantación, alerta, orientado en tiempo, espacio y persona, escleras y mucosas normales, con lesiones angiofibromatosas de distribución en alas de mariposa en región de puente nasal, alas nasales, mejillas y frente , frecuencia respiratoria de 14 por minuto, con ruidos respiratorios conservados, frecuencia cardíaca 70 por minuto, presión arteria l 100/60 mmHg, ritmo cardíaco normal, sincrónico con el pulso, abdomen sin alteraciones, extremidades y evaluación de sistema nervioso central sin presentar alteraciones...(AU)

We present the case of a 15-year-old male patient who is taken to the emergency room s Roosevelt Hospital for generalized 2-minute clonic tonic convulsions, with a period postictal, with family history of seizures shown in the pedigree (chart 2). It also presents a history of convulsive syndrome developed at three years of age, treated with multiple anticonvulsants without reaching a Gnostic day. Patient to the physical examination presents normocephalus, adequate hair implantation, alert, oriented in time, space and person, normal scleras and mucous membranes, with angiofibromatosis lesions of distribution in butterfly wings in nasal bridge region, nasal wings, cheeks and forehead, frequency respiratory rate of 14 per minute, with preserved respiratory sounds, heart rate 70 per minute, artery pressure l 100/60 mmHg, normal heart rate, synchronous with the pulse, abdomen without alterations, extremities and evaluation of the central nervous system without presenting alterations. . (AU)

Partial epilepsy: A pictorial review of 3 TESLA magnetic resonance imaging features

Epilepsy is a disease with serious consequences for patients and society. In many cases seizures are sufficiently disabling to justify surgical evaluation. In this context, Magnetic Resonance Imaging (MRI) is one of the most valuable tools for the preoperative localization of epileptogenic foci. Because these lesions show a large variety of presentations (including subtle imaging characteristics), their analysis requires careful and systematic interpretation of MRI data. Several studies have shown that 3 Tesla (T) MRI provides a better image quality than 1.5 T MRI regarding the detection and characterization of structural lesions, indicating that high-field-strength imaging should be considered for patients with intractable epilepsy who might benefit from surgery. Likewise, advanced MRI postprocessing and quantitative analysis techniques such as thickness and volume measurements of cortical gray matter have emerged and in the near future, these techniques will routinely enable more precise evaluations of such patients. Finally, the familiarity with radiologic findings of the potential epileptogenic substrates in association with combined use of higher field strengths (3 T, 7 T, and greater) and new quantitative analytical post-processing techniques will lead to improvements regarding the clinical imaging of these patients. We present a pictorial review of the major pathologies related to partial epilepsy, highlighting the key findings of 3 T MRI.

Analysis of twenty pediatric cases of tuberous sclerosis complex: Are we doing enough.

Background: Tuberous sclerosis complex (TSC) is a neuro-cutaneous disease characterized by hamartoma formation in various organs particularly the skin, brain, eye, kidney, heart and lungs. Patients usually have multisystem involvement and thus present to different medical specialties with varied complaints while the true nature of the disease and the hidden manifestations may remain unattended. A im: To assess the frequency and characteristics of various cutaneous and systemic manifestations in TSC and the total impact on different system in a cohort of pediatric patients. Methods: The study included 20 patients fulfilling the diagnostic criteria for TSC from dermatology, pediatrics, and neurology department. Detailed history, examination, and investigations such as chest X-ray, electrocardiography (ECG), ultrasonography (USG) abdomen, echocardiography, fundoscopy, computed tomography (CT) scan of brain and abdomen were done. Results: Dermatological manifestations included ash leaf macules, angiofibromas, shagreen patch, and fibrous plaque. Systemic findings observed were subependymal calcified nodules, subependymal giant cell astrocytoma, cortical tubers, renal cysts, angiomyolipomas, lung cyst, retinal hamartomas, mental deficits and epilepsy. Limitation: Wechsler's Intelligence Scale for Children would have been more appropriate for assessing the intelligence. Dental check-up was not done in our group of patients. Conclusion: Our study highlights the wide variety of cutaneous and systemic manifestations of TSC. The study emphasizes the need for comprehensive multidisciplinary treatment and periodic follow-up which are necessary for appropriate management of this multisystem disorder. Counseling regarding education and rehabilitation of the patients and genetic counseling of parents are important.

Haga su diagnóstico / Make your diagnosis

El diagnóstico es Rabdomiomas cardiacos/ Esclerosis tuberosa.

Tuberous sclerosis with rhabdomyoma.

Tuberous sclerosis is a neurocutaneous syndrome characterized by abnormalities of both the integument and central nervous system. We present a case of tuberous sclerosis with rhabdomyoma in the heart. This was a 1½-year-old female child with infantile spasms and rhabdomyoma in heart with mother having neurocutaneous markers of tuberous sclerosis. Magnetic resonance imaging brain and electroencephalography findings were consistent with diagnosis.

Tuberous sclerosis complex diagnosed from oral lesions / Complexo esclerose tuberosa diagnosticado a partir de lesoes orais

CONTEXT: Tuberous sclerosis complex (TSC) is a genetic disease in the group known as neurocutaneous syndromes, with dominant autosomal inheritance. It is characterized by skin and adnexal lesions and central and peripheral nervous system tumors, with neurological and psychiatric findings. It may affect the heart, kidneys, eyes, face, bones, lungs, stomach and dentition. CASE REPORT: We present the case of a 66-year-old man with dermatological signs that included hypopigmented maculae, confetti-like lesions, shagreen plaque, angiofibromas on nasolabial folds, neck and back, nail dystrophy and periungual fibromas on fingers and toes. An electroencephalogram produced normal results, but magnetic resonance imaging showed a nodular image measuring 1.2 x 1.0 cm close to the Monro foramen, which was similar to cerebral parenchyma and compatible with a subependymal giant-cell astrocytoma. A conservative approach was taken, through control imaging examinations on the lesion for seven years, with absence of any expansive process or neurological symptoms. Abdominal ultrasonography revealed a solid, heterogenic and echogenic mass with a calcified focus, measuring 4.6 x 3.4 cm, in the rightkidney, compatible with angiomyolipoma. The patient was treated by means of complete nephrectomy because of malignant areas seen on histopathological examination and died one month after the procedure. This case report illustrates the importance of oral clinical findings such as dental enamel pits and angiofibromas in making an early diagnosis of TSC, with subsequent screening examinations, treatment and genetic counseling. .

CONTEXTO: O complexo esclerose tuberosa é uma doença genética pertencente ao grupo das facomatoses, de herança autossômica dominante, caracterizada por lesões acometendo pele e anexos, além de tumores do sistema nervoso central e periférico, com presença de achados neurólogicos e psiquiátricos, podendo acometer coração, rins, olhos, dentes, mucosa oral e outros órgãos. RELATO DE CASO: Apresentamos o caso de um paciente do sexo masculino, 66 anos de idade, que apresentava diversos sinais dermatol ógicos, como máculas hipopigmentadas, lesões em confete, placas tipo shagreen, angiofibromas nas regiões cervical, nasolabial e dorsal, distrofias ungueais e fibromas nos dedos das mãos e pés. Embora o encefalograma não tenha mostrado alterações, a ressonância nuclear magnética apresentou imagem nodular com aspecto semelhante ao parênquima cerebral, medindo 1.2 x 1.0 cm e próxima ao forame de Monro, compatível com astrocitoma subependimário de células gigantes. Abordagem conservadora foi escolhida por meio de controle imaginológico da lesão por sete anos, com ausência de sintomas neurológicos ou processos expansivos. A ultrassonografia de abdômen total revelou massa medindo 4.6 x 3.4 cm, com áreas ecogênicas e heterogêneas, apresentando focos de calcificação no rim direito, com padrão semelhante ao de um angiomiolipoma. O paciente foi submetido a nefrectomia total, devido à presença de áreas de malignidade ao exame histopatológico, e evoluiu para óbito um mês após o procedimento. Este relato de caso ilustra a importância de achados clínicos orais, tais como lesões no esmalte dentário e angiofibromas, para o diagnóstico precoce dessa doença e posterior rastreamento, tratamento ...

Tuberous sclerosis complex / Esclerose tuberosa

Tuberous Sclerosis Complex, also known as Epiloia or Bourneville-Pringle disease is an autosomal dominant neurocutaneous syndrome with variable clinical expression. It is a multisystem disorder that may be associated with hamartomas in multiple organs in an unpredictable manner. The dermatologist plays an essential role in the history of the disease, since skin manifestations represent the most prevalent clinical features, enabling early diagnosis and intervention in its natural course. This article aims to inform the scientific community about advances made in the study of genetics and molecular biology. Recent findings regarding stimulation of tumor growth have been changing the history of this condition, making therapeutic trials with topical and systemic drugs possible. Knowledge of these topics enables better management of the patients affected, since tissue replacement by tumors can result in significant morbidity and mortality.

A Esclerose Tuberosa, também conhecida como Epilóia ou Facomatose de Pringle-Bourneville, é uma síndrome neurocutânea de caráter autossômico dominante com expressões clínicas variadas. É uma doença multissistêmica que pode cursar com hamartomas em diversos órgãos, de forma imprevisível. O dermatologista tem papel essencial na história da doença, uma vez que as afecções cutâneas representam as mais prevalentes apresentações clínicas, possibilitando assim o diagnóstico precoce da síndrome e intervenção na sua evolução natural. O presente artigo tem o objetivo de atualizar a comunidade científica sobre avanços alcançados no estudo genético e biologia molecular. Recentes descobertas sobre o estímulo do crescimento tumoral vêm mudando a evolução desta patologia, possibilitando ensaios terapêuticos com drogas tópicas e sistêmicas. O conhecimento destes aspectos possibilita melhor condução dos pacientes acometidos, dado que a substituição tumoral dos diversos tecidos pode resultar em relevante morbidade e mortalidade.