Implementación asistencial de estudios genómicos aplicados al diagnóstico molecular / Implementation of genomic studies applied to molecular diagnostics

El Hospital Garrahan ha sido pionero en el diagnóstico molecular de patologías pediátricas en Argentina. Los avances tecnológicos de las últimas décadas en el área de la biología molecular, sentaron las bases para la optimización y ampliación del diagnóstico molecular a partir de la secuenciación masiva en paralelo de múltiples genes. El presente trabajo describe el proceso de implementación de los estudios de secuenciación de nueva generación y el desarrollo de la Unidad de Genómica en un hospital público pediátrico de alta complejidad, así como su impacto en las capacidades diagnósticas de enfermedades poco frecuentes de origen genético. La creación del Grupo Interdisciplinario de Estudios Genómicos constituyó la vía institucional para la toma de decisiones que implican la implementación de nuevos estudios genómicos y el establecimiento de prioridades diagnósticas, extendiendo la disponibilidad del diagnóstico molecular a más disciplinas. La Unidad de Genómica trabaja en diseñar las estrategias que permitan la mayor optimización de los recursos con los que cuenta el hospital, teniendo en cuenta el equipamiento disponible, las prioridades establecidas y la frecuencia de las distintas patologías. Se demuestra el salto significativo operado en nuestras capacidades diagnósticas, tanto en la variedad de enfermedades como en el número de genes analizados, habiendo estudiado a la fecha alrededor de 2.000 pacientes, muchos de los cuales ven de este modo finalizada su odisea diagnóstica. Los estudios de NGS se han convertido en una herramienta de la práctica diaria para la atención de un número importante de pacientes de nuestro hospital. Continuaremos trabajando para ampliar su aplicación a la mayor cantidad de patologías, a través de los mecanismos institucionales ya existentes (AU)

The Garrahan Hospital has been a pioneer in the molecular diagnosis of pediatric diseases in Argentina. The technological advances of the last decades in the area of molecular biology have laid the foundations for the optimization and expansion of molecular diagnostics through massive parallel sequencing of multiple genes. This study describes the process of implementation of next-generation sequencing studies and the development of the Genomics Unit in a public pediatric tertiary hospital, and its impact on the capacity to diagnose rare diseases of genetic origin. The creation of the Interdisciplinary Group of Genomic Studies constituted the institutional pathway for decision-making involving the implementation of new genomic studies and the establishment of diagnostic priorities, extending the availability of molecular diagnostics to additional disciplines. The Genomics Unit is working to design strategies that allow for optimization of the resources available to the hospital, taking into account the equipment available, the priorities established, and the frequency of the different diseases. It demonstrates the significant leap in our diagnostic capabilities, both in the variety of diseases and in the number of genes analyzed. To date, around 2,000 patients have been studies, many of whom have thus completed their diagnostic odyssey. NGS studies have become a tool in daily practice for the care of a significant number of patients in our hospital. We will continue working to expand its application to as many diseases as possible, through the existing institutional mechanisms (AU)

Síndrome de Axenfeld-Rieger. Presentación de un caso / Axenfeld-Rieger syndrome. Presentation of a case

RESUMEN El síndrome de Axenfeld-Rieger es una enfermedad de origen genético de muy baja prevalencia que se hace acompañar de manifestaciones clínicas variables con afectación ocular y no ocular. Por tales razones se decidió presentar el caso de una paciente de 14 años de edad, antecedente familiar (en este caso su madre) de dicha enfermedad, con historia de retraso mental ligero, hipoacusia y mala visión en ambos ojos que se acompaña de alteraciones oculares: malformaciones a nivel del segmento anterior: deformidad de la pupila, prominencia blanquecina perilímbica que se corresponde con un embriotoxón posterior. Presenta otros signos de afectación no oculares: dismorfismo craneofacial leve, hipertelorismo, hipoplasia maxilar con aplanamiento del tercio medio facial, frente prominente, puente nasal ancho y aplastado así como anomalías dentales. Sufre complicaciones propias de la evolución de la entidad como es el glaucoma secundario, por lo que se trató con triple terapia con hipotensores oculares, en espera de la respuesta al tratamiento para, en el caso de una evolución tórpida, proceder al tratamiento quirúrgico: trabeculectomía.

ABSTRACT Axenfeld-Rieger syndrome is a very low prevalence disease of genetic origin that is accompanied by variable clinical manifestations with ocular and non-ocular involvement. For these reasons, it was decided to present the case of a 14-years-old patient with a family history (in this case her mother) of this disease, with a history of mild mental retardation, hearing loss and poor vision in both eyes that is accompanied by ocular alterations: malformations at the level of the anterior segment: pupil deformity, perilimbic whitish prominence corresponding to a posterior embryotoxon. He presents other non-ocular signs of involvement: mild craniofacial dysmorphism, hypertelorism, maxillary hypoplasia with flattening of the midface, prominent forehead, wide and flattened nasal bridge, as well as dental anomalies. He suffers from complications inherent to the evolution of the entity, such as secondary glaucoma, for which he was treated with triple therapy with ocular hypotensive agents, pending the response to treatment, and in the case of a torpid evolution, proceed to surgical treatment: trabeculectomy.

Ictiosis arlequín: presentación de un caso / Harlequin ichthyosis: presentation of a case

RESUMEN Las genodermatosis ictiosiformes constituyen un grupo heterogéneo de trastornos de la cornificación caracterizados por hiperqueratosis y descamación de la piel. La ictiosis arlequín es la forma más grave y agresiva de las ictiosis congénitas, presenta una baja prevalencia (1/300 000 nacimientos) con expresividad clínica variable, una evolución desfavorable y pronóstico reservado. Se presenta con un patrón autosómico recesivo y su diagnóstico prenatal es aún difícil. Se presentó el caso de un recién nacido masculino pretérmino de 34 semanas gestacionales, sin historia familiar de trastornos de piel, con un cuadro característico de ictiosis arlequín, quien falleció a los 11 días de vida. Se realizó la caracterización clínica y anatomopatológica de la enfermedad y se ofrece una revisión sobre esta rara entidad (AU).

ABSTRACT Ichthyosiform genodermatoses are a heterogeneous group of cornification disorders characterized by hyperkeratosis and skin flaking. Harlequin ichthyosis is the most aggressive and serious form of congenital ichthyoses, presenting a low prevalence (1/300 000 births), with variable clinical expressivity, an unfavorable evolution and reserved prognosis. It appears with an autosomal recessive pattern and its prenatal diagnosis is still difficult. The authors present the case of a male preterm newborn, of 34 gestational weeks, without family history of skin disorders, and clinical characteristics of Harlequin ichthyosis, who died at the 11 day of birth. The disease clinical and anatomopathologic characterization was carried out and a review of this rare entity is made (AU).

Exostosis múltiple hereditaria presentación de caso / Multiple hereditary exostosis. Case report

RESUMEN La exostosis hereditaria múltiple es un trastorno autosómico dominante que se suele presentar en las dos primeras décadas de la vida. Caracterizada por el remodelado metafisaria alterado y crecimiento óseo asimétrico con acortamiento secundario de los huesos de las extremidades. Estas exostosis óseas rodeadas de cartílagos se hacen prominentes a las partes blandas, se diferencia de la enfermedad de Ollier en que esta última no es hereditaria. Se presentó el caso de una mujer de 36 años, que presentaba acortamiento de los miembros especialmente, cubito y radio, metacarpianos y metatarsianos. Su hijo de 18 años afectado también de dicha enfermedad presentaba una deformidad de Madelung asociada (acortamiento de cubito y radio con arqueamiento del radio) (AU).

ABSTRACT Multiple hereditary exostosis is an autosomal dominant disorder, usually found in the first two decades of life. It is characterized by the altered metaphyseal remodeling and asymmetric bone growth with a secondary shortening of extremities bones. These bone exostoses surrounded by cartilages become prominent to the soft parts, and are different from the Ollier disease because this last one is not hereditary. The authors present the case of a woman, aged 36 years, presenting a shortening of the members, especially ulna and radius, metacarpus and metatarsus. Her 18-years-old son was also affected by this disease, having an associated Madelug deformity (shortening of ulna and radius, and radius bowing) (AU).

Rare inherited kidney diseases: an evolving field in Nephrology / Doenças renais hereditárias raras: um campo em evolução na Nefrologia

Abstract There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.

Resumo As doenças renais genéticas raras compreendem mais de 150 desordens. Elas podem ser classificadas segundo achados diagnósticos como (i) distúrbios do crescimento e estrutura, (ii) doenças glomerulares, (iii) tubulares e (iv) metabólicas. Nos últimos anos, houve uma mudança de paradigma nesse campo. Os testes moleculares tornaram-se mais acessíveis, nossa compreensão sobre os mecanismos fisiopatológicos subjacentes a essas doenças evoluiu e novas estratégias terapêuticas foram propostas. Portanto, o papel do nefrologista mudou progressivamente de mero espectador a participante ativo, parte de uma equipe multidisciplinar, no diagnóstico e tratamento desses distúrbios. O presente artigo oferece um panorama geral dos recentes avanços a respeito dos distúrbios renais hereditários raros, discutindo aspectos genéticos, manifestações clínicas e abordagens diagnósticas e terapêuticas de alguns desses distúrbios, mais especificamente a glomeruloesclerose segmentar e focal familiar, complexo da esclerose tuberosa, nefropatia de Fabry e doença relacionada ao MYH9.

Algoritmo para el diagnóstico de pacientes con trastornos del neurodesarrollo y sospecha de un síndrome genético / Algorithm for the diagnosis of patients with neurodevelopmental disorders and suspicion of a genetic syndrome

El amplio espectro de aberraciones cromosómicas observable en los trastornos del neurodesarrollo no siempre puede ser caracterizado por análisis cromosómico. El objetivo del trabajo fue determinar la etiología genética de estos trastornos en pacientes con afecciones neurológicas congénitas y sospecha clínica de un síndrome genético, aplicando un algoritmo de estudio clínico-molecular. En 71 de 111 niños analizados, se hallaron aberraciones submicroscópicas asociadas a síndromes de microdeleción-microduplicación: DiGeorge (22 casos), Prader-Willi (26 casos), Angelman (2 casos), Williams-Beuren (17 casos), Smith-Magenis (1 caso), Miller-Dieker (1 caso) y síndrome cri du chat (1 caso). Adicionalmente, se detectó una inserción desbalanceada de novo de la región 17p12p11.2, en el punto 5p13.1, en un niño de tres años. La utilización del método clínico unido a técnicas moleculares, como hibridación fluorescente in situ, ha permitido, en la mayoría de los casos, el diagnóstico certero de pacientes y/o familias con trastornos del neurodesarrollo.

The wide range of chromosome aberrations seen in neurodevelopmental disorders may not always be characterized by means of a chromosome analysis. The objective of this study was to determine the genetic etiology of these disorders in patients with congenital neurological conditions and clinical suspicion of a genetic disorder using a clinical and molecular testing algorithm. Among 111 studied children, 71 showed submicroscopic chromosome aberrations associated with microdeletion/microduplication syndromes: DiGeorge (22 cases), Prader-Willi (26 cases), Angelman (2 cases), Williams-Beuren (17 cases), Smith-Magenis (1 case), Miller-Dieker (1 case), and cri du chat syndrome (1 case). Additionally, a de novo trisomy 17p12p11.2 due to an unbalanced insertion into 5p13.1 was identified in a 3-year-old child. In most cases, the use of a clinical method together with molecular techniques, such as fluorescence in situ hybridization, has allowed to make an accurate diagnosis in patients and/or families with neurodevelopmental disorders.

Genetic disease in the family: trajectories and experiences in public health services / Enfermedad genética en la familia: trajetorias y experiencias en servicios públicos de salud / Doença genética na família: trajetórias e experiências em serviços públicos de saúde

Abstract Objective: To identify the trajectories and experiences of families of children with genetic diseases in health services. Method: A qualitative study, with data collected through interviews with 15 families and caregivers of children with Genetic Disease, living in the northern region of Rio Grande do Sul. Interviews were conducted from March to May 2018. Data analysis was based on thematic analysis. Results: A genetic disease diagnosis led to families' changes due to the demands of treatment, and also the needs of the child for being met by health services. To access specialized services, some families needed to travel to referral centers in larger cities. Families experienced difficulties such as unprepared health professionals, lack of organization of services, judicialization of resources, and need for structured Health Care Networks. Conclusion: The professional has the fundamental role of providing families with access to information and are responsible for decision making and for the organization and management of health and nursing services to meet the demands imposed on the individual and the family by the genetic disease.

Resumen Objetivo: Identificar trayectorias y experiencias en servicios de salud de familias que poseen hijos con enfermedades genéticas. Método: Estudio de abordaje cualitativo, cuyos datos fueron recolectados por medio de entrevistas con 15 familias representadas por las madres cuidadoras que poseen hijos con enfermedad genética, residentes en la región norte de Rio Grande do Sul, de marzo a mayo de 2018. El análisis de los datos ocurrió a través del análisis temático. Resultados: El diagnóstico de la enfermedad genética trajo cambios en las familias, por la demanda de tratamiento junto a los servicios de salud para atender a las necesidades del hijo. Para acceder a servicios especializados, algunas familias necesitaban desplazarse a centros de referencia en ciudades más grandes. Las familias experimentaron dificultades como la falta de preparo de los profesionales de salud, falta de organización de los servicios, procesos de judicialización de los recursos y necesidad de Redes de Atención a la salud estructuradas. Conclusión: El profesional enfermero asume un papel fundamental para proporcionar a las familias acceso a la información, a la toma de decisiones y a la organización de la gestión y gestión de los servicios de salud y enfermería para satisfacer a las demandas que las enfermedades genéticas condicionan al individuo y a la familia.

Resumo Objetivo: Identificar trajetórias e experiências em serviços de saúde de famílias que possuem filhos com doenças genéticas. Método: Estudo de abordagem qualitativa, cujos dados foram coletados por meio de entrevistas com 15 famílias representadas pelas mães cuidadoras que possuem filhos com Doença Genética, residentes na região norte do Rio Grande do Sul, de março a maio de 2018. A análise dos dados ocorreu através da análise temática. Resultados: O diagnóstico da doença genética acarretou mudanças nas famílias, pela procura de tratamento junto aos serviços de saúde para atender as necessidades do filho. Para ter acesso a serviços especializados, algumas famílias precisaram deslocar-se para centros de referência em cidades maiores. As famílias vivenciaram dificuldades como despreparo dos profissionais de saúde, falta de organização dos serviços, processos de judicialização dos recursos e necessidade de Redes de Atenção à Saúde estruturadas. Conclusão: O profissional enfermeiro assume papel fundamental para prover às famílias o acesso à informação, à tomada de decisão e à organização da gestão e do gerenciamento dos serviços de saúde e de enfermagem para atender às demandas que a doença genética condiciona ao indivíduo e à família.

Interview with Susan Kelly. Co-coordinator of the 1st workshop about the Sociology of Diagnosis in Brazil / Entrevista com Susan Kelly. Co-coordenadora do I Workshop sobre a Sociologia do Diagnóstico no Brasil

Abstract In this interview, Susan Kelly, professor and researcher at the Center for Life Sciences - Egenis, and the University of Exeter, England, discusses her academic career, involvement with the Sociology of Diagnosis and the work involved with the first activity on the Sociology of Diagnosis carried out in Brazil.

Resumo Nessa entrevista, Susan Kelly, professora e pesquisador do Centro sobre as Ciências da Vida - Egenis, e da Universidade de Exeter, em Inglaterra, aborda a sua trajetória acadêmica, o envolvidomento com a Sociologia do Diagnóstico e os trabalhos envolvidos com a primeira atividade sobre a Sociologia do Diagnóstico realizada no Brasil.

A pessoa com o diagnóstico de uma condição genética como informante-chave do campo das doenças raras - uma perspectiva pela sociologia do diagnóstico / The individual with the diagnosis of a genetic condition as a key informant in the field of rare diseases - a perspective from the sociology of diagnosis

Resumo Em um panorama diferente da maioria dos trabalhos do campo das chamadas doenças raras, esse artigo transpõe os limites das associações para chegar até as pessoas que vivem com o diagnóstico de uma condição genética e entendida como doença rara, a Neurofibromatose (NF). Nesse trajeto, utiliza-se da ainda nascente Sociologia do Diagnóstico para identificar tanto o impacto quanto as consequências do diagnóstico na vida das pessoas. Como resultado entende-se que devemos superar o olhar caritativo sobre as pessoas que vivenciam o diagnóstico de uma condição genética, o doente, para, como um informante-chave, captar as contribuições para melhorar os serviços de saúde e as nossas relações sociais.

Abstract Adopting a different viewpoint from most of the work in the field of so-called rare diseases, this paper crosses the boundaries of the associations to reach people living with the diagnosis of a genetic condition, which is understood as being a rare disease, namely neurofibromatosis (NF). In this respect, the incipient Sociology of Diagnosis is utilized to identify both the impact and the consequences of the diagnosis in people's lives. As a result, the consensus is that it is necessary to transcend the charitable outlook on people who experience the diagnosis of a genetic condition, by perceiving the patient as a key informant in order to collect input to improve health services and our social relations.

Da busca pelo diagnóstico às incertezas do tratamento: desafios do cuidado para as doenças genéticas raras no Brasil / From the search for diagnosis to treatment uncertainties: challenges of care for rare genetic diseases in Brazil

Resumo As doenças genéticas raras constituem um importante problema de saúde pública, mas ainda são pouco estudadas na perspectiva da Saúde Coletiva. Este artigo tem por objetivo analisar os itinerários terapêuticos de pacientes com doenças genéticas raras nas cidades do Rio de Janeiro, Salvador e Porto Alegre, tendo por foco os desafios materiais, emocionais e estruturais enfrentados na busca por diagnóstico e tratamento. Foram realizadas entrevistas semiestruturadas com pacientes/cuidadores e profissionais de saúde em serviços públicos de genética médica. Observou-se que a experiência da doença genética rara, além de ser um desafio em si pelo caráter debilitante e incapacitante, é agravada por problemas de ordem prático-relacionais e burocrático-institucionais que não se resolvem com a chegada a um serviço especializado. A existência de longos itinerários terapêuticos até o diagnóstico, o desconhecimento dos médicos não geneticistas sobre as doenças raras, as dificuldades de transporte e de acesso a especialistas, a exames diagnósticos e complementares e o acesso a medicamentos e insumos alimentares de alto custo foram comuns às narrativas nas três cidades. A adesão aos cuidados oferecidos exigem estratégias de ação que dependem de arranjos envolvendo familiares, médicos, associações de pacientes e o Estado.

Abstract Rare genetic diseases are an important public health problem, but they are still little studied in Collective Health. This article aims to analyze the 'therapeutic itineraries' of patients in search of a diagnosis and treatment for rare genetic diseases in the cities of Rio de Janeiro, Salvador and Porto Alegre. It focuses on the material challenges, emotional and structural problems faced in these trajectories. Semi-structured interviews were conducted with patients/caregivers and health professionals in the context of public health medical genetics. Our findings suggest that the experience of the rare genetic disease is aggravated by practical, inter-relational and bureaucratic/institutional problems. The reality of long and circuitous journeys to obtain a diagnosis, non-geneticists' lack of knowledge about rare diseases, difficulties in transportation and access to specialists, diagnostic and complementary examinations, and access to high-cost medicines and food supplies were common challenges in all the narratives examined in the three Brazilian cities. In addition, adherence to care provided by medical genetics requires action and strategies that depend on arrangements involving family members, physicians, patient associations, and the state.

Fibrose hepática congênita e venopatia portal obliterativa sem hipertensão portal - revisão da literatura com base em um caso assintomático / Congenital hepatic fibrosis and obliterative portal venopathy without portal hypertension - a review of literature based on an asymptomatic case

ABSTRACT The disease and the case reported here are relevant especially because of their varied clinical presentation, possibility of being associated with other disorders affecting several organs and possible differential diagnoses. Congenital Hepatic Fibrosis is an autosomal recessive disease due to mutation in the PKHD1 gene, which encodes the fibrocystin/polyductine protein. It is a cholangiopathy, characterized by varying degrees of periportal fibrosis and irregular proliferation of bile ducts. Affected patients are typically diagnosed in childhood, but in some cases the disease may remain asymptomatic for many years. The exact prevalence and incidence of the disease are not known, but it is consider a rare disease, with a few hundred cases described worldwide. It can affect all ethnic groups and occur associated with various hereditary and non-hereditary disorders. The clinical presentation is quite variable, with melena and hematemesis being initial symptoms in 30%-70% of the cases. More rarely, they may present episodes of cholangitis. The disease has been classified into four types: portal hypertension, cholestasis / cholangitis, mixed and latent. Diagnosis begins with imaging tests, but the definition is made by the histopathological sample. So far, there is no specific therapy that can stop or reverse the pathological process. Currently, the therapeutic strategy is to treat the complications of the disease.

RESUMO A patologia e o caso aqui reportados são relevantes especialmente devido sua variada apresentação clínica, possibilidade de estar associada com outras desordens acometendo diversos órgãos e pelos possíveis diagnósticos diferenciais. A fibrose hepática congênita é uma doença autossômica recessiva, devido mutação no gene PKHD1, que codifica a proteína fibrocistina/poliductina. É uma colangiopatia, caracterizada por variados graus de fibrose periportal e proliferação irregular de ductos biliares. Os pacientes acometidos são tipicamente diagnosticados na infância, mas em alguns casos a doença pode permanecer assintomática por muitos anos. Exatas prevalência e incidência da doença não são conhecidas, mas sabe-se que é uma doença bastante rara, com algumas centenas de casos descritos no mundo. Pode afetar todos grupos étnicos e ocorrer associada com diversas desordens hereditárias e não-hereditárias. A apresentação clínica é bastante variável, com melena e hematêmese sendo sintomas iniciais em 30%-70% dos casos. Mais raramente, podem apresentar episódios de colangite. A doença tem sido classificada em quatro tipos: hipertensão portal, colestática/colangite, mista e latente. O diagnóstico inicia com exames de imagem, mas a definição é feita pela amostra histopatológica. Até o momento, não há terapia específica que possa parar ou reverter o processo patológico e a estratégia terapêutica atual é tratar as complicações da doença.

Taquicardia ventricular polimórfica catecolaminérgica com necessidade de implante de cardiodesfibrilador implantável (CDI): Um relato de caso / Ventricular Catecolaminergic Polymorphic Tachycardia (VCPT) with ICD implantation requirement: A case report

Relato de caso de uma paciente do sexo feminino, com 16 anos de idade à ocasião de sua admissão no Instituto de Cardiologia. A mesma foi encaminhada por serviço de saúde externo devido a síncopes durante atividade física e foi submetida à investigação, com diagnóstico final de taquicardia ventricular catecolaminérgica. Após a definição diagnóstica, foi realizado tratamento medicamentoso com betabloqueador, sendo necessário o implante de marcapasso definitivo por conta da incompetência cronotrópica secundária ao tratamento farmacológico instituído. Posteriormente, por persistência das arritmias ventriculares mesmo com o uso de terapia otimizada, optou-se por realizar um implante de CDI

Case report of a 16-year-old female patient at the time of her admission to the Institute of Cardiology. She was referred by an external healthcare service due to syncope during physical activity and was submitted to the investigation with a final diagnosis of catecholaminergic ventricular tachycardia. Once the diagnosis was established, the patient was administered a beta-blocker and definitive pacemaker implant was required due to chronotropic incompetence secondary to drug therapy. Subsequently, due to the persistence of ventricular arrhythmias despite the use of optimized therapy, we decided to implant an ICD

Ventajas y limitaciones de la citogenética en la medicina actual / Advantages and limitations of cytogenetics in current medicine

La citogenética es el estudio de los cromosomas tanto en número como en estructura. En 1882 Flemming publica las primeras primeras ilustraciones de los cromosomas humanos a partir de observaciones al microscopio y recién en el año 1953, Tjio y Levan determinaron el número real de cromosomas humanos por célula diploide (2n=46). El propósito de este trabajo es presentar el valor, uso actual e importancia de los estudios citogenéticos en aquellos casos en que el profesional de salud se enfrente a un paciente con una probable enfermedad de causa genética o síndrome dismórfico, además de exponer algunas experiencias de un laboratorio de Citogenética en el Paraguay, donde se realiza el estudio cromosómico. Aún con el advenimiento de la Biología Molecular y de la Citogenética Molecular, la citogenética convencional sigue siendo una herramienta de gran importancia, ya que permite realizar el diagnóstico de una enfermedad genética en pacientes con sospecha clínica de ser portadores de anomalías cromosómicas, y por tanto asesorar a las familias respecto de dicha enfermedad, proveer un pronóstico, riesgo de recurrencia y en casos que se requiera, un tratamiento(AU)

Cytogenetics is the study of chromosomes both in number and structure. The first publications about human cytogenetics were provided towards the end of the 19th century with the publication of Flemming in 1882 of the first figures of human chromosomes from observations under the microscope and only in 1953, Tjio and Levan determined the actual number of human chromosomes per diploid cell (2n = 46). The purpose of this paper is to present the value, current use and importance of cytogenetic studies in those cases in which the health professional faces a patient with a probable disease of genetic causes or dysmorphic syndrome, in addition to exposing some experiences from a Cytogenetics laboratory in Paraguay, where chromosomal study is carried out. Even with the arrival of Molecular Biology and Molecular Cytogenetics, conventional cytogenetics is a tool with a great importance, which allows the genetic disease diagnosis in patients with clinical suspicion of being carriers of chromosomal abnormalities, allowing to advice families about the disease, as well as to provide a prognosis, risk of recurrence and, in cases that requires it, a treatment(AU)

Enfermedades neurometabólicas: Orientación diagnóstica a partir de la clínica neurológica / Neurometabolic diseases: Diagnostic orientation based on neurological symptoms

Resumen Las Enfermedades Neurometabólicas (ENM) son trastornos bioquímicos en la estructura y/o función de proteínas, de origen genético, por mutaciones en el ADN, causando un déficit enzimático con acumulación del sustrato o producción de metabolitos anormales. Consideradas enfermedades raras por su escasa incidencia, en su conjunto constituyen un motivo de admisión, consulta y morbimortalidad infantil frecuente. Las formas clínicas de presentación incluyen la forma de "intoxicación", las que afectan el metabolismo energético y las que afectan las moléculas complejas con compromiso de las organelas celulares (lisosomas, peroxisomas). El diagnóstico preciso y oportuno de las ENM es crucial, especialmente para aquellos trastornos que son tratables o manejables, con menor impacto en los pacientes, evitando no solo la muerte sino secuelas irreversibles. El diagnóstico clínico es el primer paso para su abordaje partiendo de la elaboración de una adecuada historia clínica, recolección detallada de antecedentes familiares y personales, considerando la edad de la aparición de los síntomas, siendo el periodo neonatal donde la mayoría debutan. La exploración física completa por aparatos y sistemas con especial énfasis en el examen neurológico, permite solicitar con mayor precisión los exámenes complementarios correspondientes para realizar una aproximación diagnóstica más acertada. El uso de herramientas diagnósticas mediante programas electrónicos, algunos de ellos disponibles gratuitamente como el Programa NeurometPlus ( www.neurometplus.com ), permite alcanzar de forma rápida y efectiva el diagnóstico más probable, así como manejo médico y tratamiento disponible actual.

Abstract Neurometabolic Disorders are conditions caused by alterations in the biochemical structure and function of proteins resulting from changes in DNA, causing a lack or dysfunction of an enzyme leading to an accumulation of a substrate or production of abnormal metabolites. Though considered rare diseases, due to low incidence, together they constitute a frequent cause for pediatric admissions and consultations with significant morbidity and mortality in childhood. Neurometabolic disorders may be classified as disorders of intoxication, energy metabolism, or those disorders affecting complex molecules compromising the cellular organelles (lysosomes and peroxisomes). A timely and precise diagnosis is crucial especially in treatable conditions in order to avoid irreversible sequelae and even death. When encountering a child with a potential neurometabolic disorder, making a clinical diagnosis is the rst step which should include an adequate clinical history, taking into consideration the age of onset of symptoms, and a detailed family history. The neonatal period is when the majority of these conditions make their debut. A complete physical exam with special emphasis on the neurological exam allows for greater precision to help guide the complementary exams that correspond to each condition in order to reach the most probable diagnosis. The use of diagnostic tools including electronic programs and databases, some of which are free of charge such as NeurometPlus ( www.neurometplus.com ), allow a quick and effective diagnosis, along with a guide for medical management and current treatment regimens available.

Compromiso renal en la Enfermedad de Fabry en la edad pediátrica / RENAL INVOLVEMENT IN CHILDREN WITH FABRY'S DISEASE

La Enfermedad de Fabry (EF) es un trastorno hereditario, ligado al cromosoma X, con una incidencia de 1/40.000 nacidos vivos. Se sabe que afecta tanto a varones como a mujeres y sus primeras manifestaciones clínicas comienzan en edades pediátricas. La actividad reducida o nula de la enzima lisosomal alfa-galactosidasa A (α-Gal A), que es la comprometida en la EF, genera la acumulación progresiva de su sustrato, principalmente la globotriosilceramida (Gb3) en las diferentes estirpes celulares de los distintos órganos. El fallo renal es una de las complicaciones serias de la enfermedad.efropatía por Fabry, pese a que la enfermedad está presente desde la infancia, suele manifestarse de forma silente, aún en los estudios clínicos de rutina. Un diagnóstico precoz y oportuno es crucial dado que la demora en el inicio de la terapia de reemplazo enzimático parece no lograr detener la enfermedad renal progresiva. Esta revisión tiene como objetivo proporcionar una actualización de la comprensión actual, los desafíos y las necesidades para abordar mejor las complicaciones renales de la enfermedad de Fabry en niños. Intentar comprender la fisiopatología de éste compromiso puede ayudar a prevenir su progresión

Fabry´s disease is an x-chromosome hereditary disease with an incidence of 1/40000 newborns. Nowadays it is present in males as in females , and its first clinical symptoms are seen in pediatric patients. Patients have reduced or no activity of alpha-galactosidase which leads to progressive accumulation of Gb3 in lysosomes of all types of cells. Renal failure is a serious complication of this disease. Fabry´s nephropathic lesions are present and progress in childhood while the disease commonly remains silent by routine clinical measures. Early and timely diagnosis is crucial since late initiation of enzyme replacement therapy may not halt progressive renal dysfunction. This review aims to provide an update of the current understanding, challenges, and needs to better approach renal complications of Fabry´s disease in children. Trying to understand the pathophysiology of this compromise may help prevent its progression

Síndrome Kenny-Caffey en varios miembros de una familia / Kenny-Caffey Syndrome in several members of a family

El síndrome Kenny-Caffey es una enfermedad hereditaria, extremadamente rara, que se transmite de forma autosómica dominante y se caracteriza por retraso del crecimiento, anomalías oculares, hipocalcemia y engrosamiento cortinal de los huesos largos, cuyo diagnóstico precoz e intervención temprana ayudarán a mejorar la calidad de vida de los afectados. Se presenta a 2 miembros de una familia (la madre y un hijo), atendidos en la consulta de genética clínica de la provincia de Holguín, con características clínicas que se correspondían con dicho síndrome, para compartir estos hallazgos con la comunidad médica en general, pues llamó la atención que estuvieran afectados 3 personas de una misma familia, aunque solo se describe a 2 de ellos

The Kenny-Caffey syndrome is a hereditary, extremely strange disease that is transmitted in an autosomal dominant way and is characterized by growth failure, ocular anomalies, hypocalcemia and cortinal swelling of the long bones whose early diagnosis and intervention will help to improve the life quality of affected patients. Two members of a family are presented (mother and a son), assisted in the clinical genetics service in Holguín, with clinical characteristics that fitted with this syndrome, to share these findings with the medical community in general, because the fact that 3 people of the same family were affected attracted attention, although just 2 of them are described

Hemocromatosis herediataria Tipo I. Presentación de un caso / Type I hereditary hemocrhomatosis. Case presentation

La hemocromatosis hereditaria es una enfermedad genética de difícil diagnóstico, en estadios iniciales, ocasionada por alteraciones en el metabolismo del hierro; que conllevan a su depósito en diversos tejidos y como resultado una gran morbilidad en los pacientes afectados. A través de este trabajo se realizó la presentación del primer caso diagnosticado por gastroenterólogos, en el Hospital Faustino Pérez de Matanzas. El paciente debutó con síntomas relacionados con la esfera endocrina como: impotencia, pérdida de la líbido y de la eyaculación. Después de efectuar los estudios correspondientes se concluyó como un hipogonadismo hipogonadotrópico post puberal, por presentar elevación de las enzimas hepáticas. Fue remitido a consulta de Hepatología donde se completó su estudio, confirmándose el diagnóstico de hemocromatosis hereditaria tipo I, a través de biopsia hepática y estudios genéticos (AU).

Hereditary hemocrhomatosis is a genetic disease of difficult diagnosis in its early stages, caused by alterations in the iron metabolism; it leads to iron storage in several tissues and consequently to a great morbidity in affected patients. In this work, we presented the first case diagnosed by gastroenterologists in the Hospital Faustino Pérez, of Matanzas. The patient began with symptoms related with the endocrine sphere like impotence, and lost of libido and ejaculation. After finishing the correspondent studies, we arrived to the conclusion of post-pubertal hypogonadotropic hypogonadism: the patient presented hepatic enzymes elevation. He was referred to Hepatology consultation where the study was finished, confirming the diagnosis of Type I hereditary hemocrhomatosis through biopsy and genetic studies (AU).

Carcinoma escamocelular de labio superior en paciente con síndrome nevoide basocelular. Reporte de caso clínico / Upper-Lip Squamous Cell Carcinoma in Patients with Nevoid Basal Cell Carcinoma Syndrome. A Clinical Case Report

Antecedentes: El síndrome de Gorlin-Goltz, o síndrome nevoide de células básales (SNCB), es un trastorno autosómico dominante de baja incidencia. Su etiología se relaciona con una mutación en el gen PTCH y afecta los sistemas esquelético, oftalmológico y neurológico. Su prevalencia es de 1:60.000 y las mutaciones de novo se presentan aproximadamente en un 20 % a 30 % de los casos. Objetivo: Describir el proceso diagnóstico y manejo de un caso de esporádica presentación de una paciente con SNCB con carcinoma escamocelular (CEC) en labio superior. Descripción del caso: Se trató de una mujer de 58 años, quien asistió a consulta odontológica por motivos estéticos y funcionales. Se encontró un CEC (confirmado por inmunohistoquímica) asintomático delimitado en el lado izquierdo del labio superior, con erosiones de color rojizo y costra. No se encontraron linfoadenopatías asociadas. También evidenció fisuras palmoplantares y múltiples carcinomas basocelulares en la espalda y el dorso de la mano izquierda (con antecedentes familiares similares). Radiográficamente, no se observaron queratoquistes mandibulares que usualmente se asocian con el síndrome de Gorlin-Goltz. Conclusiones: Se diagnosticó SNCB en la paciente, pues presentaba dos criterios mayores (dos o más CBC y piqueteado palmoplantar) y dos menores (calcificación laminar de la hoz del cerebro y antecedente de fibromas ováricos). El tratamiento odontológico se planeó y se remitió a la paciente a la institución pertinente para manejar su condición sistémica.

Background: Gorlin-Goltz syndrome or nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with low incidence. The etiology' is associated with a PTCH gene mutation and affects the skeletal, ophthalmic and neurological systems. The prevalence is 1:60,000 and de novo mutations occur approximately in 20% to 30% of the cases. Objective: To describe the diagnosis and management process for a rare case of a NBCCS patient who developed squamous cell carcinoma (SCC) in the upper lip. Case Description: The patient is a 58 year-old woman who attended to the dental office for aesthetic and functional reasons. An asymptomatic SCC was found (confirmed after immunohistochemical evidence) with defined limits to the left of the upper lip. It showed reddish erosions and some scab. No associated lymphadenopathies were found. The patient had some plantar foot fissures and multiple carcinoma basal cells in the back and in the left hand dorsum (with similar family previous cases). No maxillary keratocyst were observed in the radiographs, notwithstanding they are always associated with the Gorlin-Goltz syndrome. Conclusions: The patient was diagnosed with NBCCS based on two main criteria (two or more SCC lesions and plantar foot fissures) and two mild criteria (laminar calcification in the cerebral falx and family background of ovarian fibromas). A dental treatment was designed, and the patient was referred to another institution for a systemic treatment of her disease.

Adrenoleucomielodistrofia como causa de paraparesia espástica en adulto joven. Reporte de caso / Adrenoleukomelodystrophy as a cause of spastic paraparesis in young adult. Case report

La adrenoleucodistrofia ligada al X (X-ALD), trastorno genético progresivo que afecta la sustancia blanca del SNC y la corteza suprarrenal, causa desde insuficiencia adrenal aislada y mielopatia lentamente progresiva hasta desmielinización cerebral devastadora. Presentamos un paciente masculino, 21 años de edad, tabaquista, con trastorno de la marcha de un año de evolución, paraparesia espástica e hiperreflexia en miembros inferiores. El análisis del líquido cefalorraquídeo (LCR) reveló proteinorraquia elevada, resultados negativos de bandas oligoclonales y virus Epstein Barr. Niveles de cortisol, ACTH, ácidos grasos de cadena muy larga en suero, fueron anormales. La RNM cerebral evidenció lesiones en sustancia blanca en región parietooccipital bilateral, comprometiendo el esplenio del cuerpo calloso, que realzaban con gadolinio. En RNM de columna cervical se observó lesión hiperintensa en secuencia T2 a nivel C7. Fue tratado con reemplazo adrenal. Presentamos un caso de X-ALD de inicio en adulto, con retraso en el diagnóstico debido a recursos limitados. Palabras claves: adrenoleucodistrofia ligada al X, paraparesia espástica, ácidos grasos de cadena muy larga, adrenomieloneuropatia

X- Linked adrenoleukodystrophy (X-ALD) is a progressive genetic disorder that affects CNS white matter and adrenal gland cortex, and causes from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. We present a 21 years old male patient, smoker, with one year history of gradually progressive trouble walking, unsteady gait, asymmetric spastic paraparesis, lower extremity deep tendon reflexes were increased. Cerebrospinal fluid (CSF) analysis revealed elevated CSF protein, CSF oligoclonal bands and Epstein Barr virus negative results. Basal cortisol, ACTH and very-long- chain fatty acids in plasma with abnormal results. All other laboratory tests were normal. Cerebral MRI showed parietooccipital white matter abnormalities involving the splenium of the callosum that enhanced with gadolinium. Cervical spinal cord MRI showed a short-segment T2 hyperintense lesion at C7. He was treated with adrenal replacement. We present a case of adult onset X-ALD and diagnostic delay owed to limited resources