RESUMEN
Introducción. Sobre la base de un caso clínico, se presenta la descripción del cuadro intersticial por deficiencia de ABCA3, de una paciente de catorce años de edad, en seguimiento durante doce años. Método. Evaluación clínica con extensos estudios para descartar otras patologías semejantes. El diagnóstico definitivo fue determinado por el estudio genético para deficiencias de ABCA3 y otros defectos genéticos realizados por el Dr. Larry Nogee, Hospital Johns Hopkins, EE. UU. Objetivos. Describir detalladamente la evolución de la paciente durante doce años, con énfasis en los estudios anteriormente mencionados. Sugerir la presencia de un cambio de paradigma pronóstico en lo que se conocía sobre la evolución de esta enfermedad intersticial pulmonar grave, tratar de mejorar la calidad de vida y posiblemente el pronóstico. Presentar los hallazgos de genética, anatomía patológica y radiología en consultas y evaluaciones por centros de referencia. Resultados. Realizado su diagnóstico de deficiencia genética de ABCA3, presentamos su seguimiento actualizado hasta el año 2020. Esta debe ser sospechada en niños pequeños desde el nacimiento y durante los primeros años ante la persistencia de cuadros pulmonares crónicos con desaturación de oxígeno e imágenes tomográficas que sugieren cuadro intersticial. Se decidió tratar el cuadro en los años 2019-2020, durante seis meses, según bibliografía y consultas con centros de referencia en los Estados Unidos, con la finalidad de determinar la posible mejoría de su patología y decidir la continuación o suspensión de la medicación. Se usaron pulsos con metilprednisolona- hidroxicloroquina y azitromicina. Se logró mantener estable su función pulmonar y mejorar notablemente su calidad de vida. (AU)
Introduction. A clinical case diagnosed with ABCA3 deficiency is described. Patient is now fourteen years old. She´s being followed up since she was two years old. Methodology. clinical follow up with extensive studies to rule out other similar pathologies. Final diagnosis was done through genetic studies done at Johns Hopkins Hospital by Nogee LM. Objective. To present a detailed evolution description of twelve years' follow-up with the support of the aforementioned studies, to suggest a change in diagnostic prognostic paradigm on what was known of mortality in this severe pulmonary interstitial pathology to improve life quality and possibly prognosis. Present the findings of genetics, pathological anatomy and radiology in consultations and evaluations by reference centers. Results. Having made her diagnosis of genetic ABCA3 deficiency, we present her up dated follow-up until 2020. This should be suspected in young children from birth and during the first years due to the persistence of chronic pulmonary symptoms with oxygen desaturation and tomographic images that suggest interstitial symptoms. It was decided to treat the condition in the years 2019-2020, for six months, according to the bibliography and consultations with reference centers in the United States, in order to determine the possible improvement of her pathology and decide to continue or suspend the medication. Pulses with methylprednisolone hydroxychloroquine and azithromycin were used. Her lung function was stable and her quality of life significantly improved. (AU)
Asunto(s)
Humanos , Femenino , Adolescente , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/genética , Transportadoras de Casetes de Unión a ATP/genética , Estudios de Seguimiento , Enfermedades Pulmonares Intersticiales/terapia , Diagnóstico Diferencial , Estudios de Asociación GenéticaRESUMEN
Interstitial lung disease (ILD) in the connective tissue diseases (CTD) is amongst the most challenging aspect of care of patients with rheumatic diseases and is the source of significant morbidity and mortality. While there has been progress in our understanding of the natural history of these complications, we still suffer from a limited reservoir of data to confidently determine which patients are at highest risk for disease and those who are at highest risk for disease progression. Treatment options until recently have been limited to anti-inflammatory therapies but with the emerging availability of anti-fibrotic therapies, a shift in strategy is emerging to target therapies based on the specific radiographic, histopathologic features and biomarker profiles that are unique to patients with rheumatic diseases and ILD.
Asunto(s)
Enfermedades del Tejido Conjuntivo , Enfermedades Pulmonares Intersticiales , Biomarcadores , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedades del Tejido Conjuntivo/tratamiento farmacológico , Enfermedades del Tejido Conjuntivo/genética , Enfermedades del Tejido Conjuntivo/patología , Humanos , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/patología , Pronóstico , Factores de RiesgoRESUMEN
Fibrotic lung diseases involve subject-environment interactions, together with dysregulated homeostatic processes, impaired DNA repair and distorted immune functions. Systems medicine-based approaches are used to analyse diseases in a holistic manner, by integrating systems biology platforms along with clinical parameters, for the purpose of understanding disease origin, progression, exacerbation and remission.Interstitial lung diseases (ILDs) refer to a heterogeneous group of complex fibrotic diseases. The increase of systems medicine-based approaches in the understanding of ILDs provides exceptional advantages by improving diagnostics, unravelling phenotypical differences, and stratifying patient populations by predictable outcomes and personalised treatments. This review discusses the state-of-the-art contributions of systems medicine-based approaches in ILDs over the past 5â years.
Asunto(s)
Enfermedades Pulmonares Intersticiales , Pulmón , Biología de Sistemas/métodos , Animales , Biomarcadores/sangre , Progresión de la Enfermedad , Interacción Gen-Ambiente , Predisposición Genética a la Enfermedad , Genómica , Interacciones Huésped-Patógeno , Humanos , Pulmón/metabolismo , Pulmón/patología , Pulmón/fisiopatología , Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares Intersticiales/metabolismo , Enfermedades Pulmonares Intersticiales/patología , Enfermedades Pulmonares Intersticiales/fisiopatología , Metabolómica , Microbiota , Fenotipo , Factores de RiesgoRESUMEN
We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.
Asunto(s)
Enfermedades Pulmonares Intersticiales/genética , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/patología , Proteinosis Alveolar Pulmonar/genética , Proteína B Asociada a Surfactante Pulmonar/deficiencia , Factor Nuclear Tiroideo 1/genética , Adolescente , Adulto , Atetosis/complicaciones , Atetosis/genética , Atetosis/patología , Líquido del Lavado Bronquioalveolar/química , Niño , Corea/complicaciones , Corea/genética , Corea/patología , Hipotiroidismo Congénito/complicaciones , Hipotiroidismo Congénito/genética , Hipotiroidismo Congénito/patología , Femenino , Francia/epidemiología , Genes Homeobox , Humanos , Enfermedades Pulmonares/complicaciones , Enfermedades Pulmonares/terapia , Enfermedades Pulmonares Intersticiales/complicaciones , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/fisiopatología , Enfermedades Pulmonares Intersticiales/terapia , Masculino , Mutación , Pronóstico , Proteinosis Alveolar Pulmonar/complicaciones , Proteína B Asociada a Surfactante Pulmonar/genética , Surfactantes Pulmonares/metabolismo , Síndrome de Dificultad Respiratoria del Recién Nacido/complicaciones , Síndrome de Dificultad Respiratoria del Recién Nacido/etiología , Síndrome de Dificultad Respiratoria del Recién Nacido/genética , Síndrome de Dificultad Respiratoria del Recién Nacido/patología , Pruebas de Función Respiratoria/métodos , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Resultado del TratamientoAsunto(s)
Dermatoglifia del ADN/métodos , Litiasis/genética , Enfermedades Pulmonares Intersticiales/genética , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIb/genética , Calcio/metabolismo , Mapeo Cromosómico/métodos , Humanos , Iones , Mutación , Fósforo/metabolismo , Alveolos Pulmonares/metabolismoRESUMEN
Human surfactant protein C (hSP-C(1-197)) is synthesized as a 197 amino acid proprotein and cleaved to a mature 3.7 kD form. Although interstitial lung disease in patients with mutations of the hSP-C gene is becoming increasingly recognized, the mechanisms linking molecular events with clinical pathogenesis are not fully defined. We describe a full-term infant with respiratory insufficiency associated with a spontaneous heterozygous mutation resulting in a substitution of lysine for glutamic acid at position 66 (= E66K) of the proximal hSP-C COOH flanking propeptide. Lung histology and biochemical studies of the index patient (hSP-C(E66K)) revealed nonspecific interstitial pneumonia, increased alveolar total phospholipid lacking phosphatidylglycerol, and increased surfactant protein A. Localization of proSP-C from lung sections prepared from this patient using immunofluorescence and immunogold electron microscopy revealed abnormal proSP-C staining in endosomal-like vesicles of type II cells distinct from SP-B. To evaluate the effect of the E66K substitution on intracellular trafficking of proSP-C, fusion proteins consisting of enhanced green fluorescent protein (EGFP) and hSP-C(1-197) (wild type) or mutant hSP-C(E66K) were generated and transfected into A549 cells. EGFP/hSP-C(1-197) was expressed within CD-63-positive, EEA-1-negative vesicles, whereas EGFP/hSP-C(E66K) localized to EEA-1 positive vesicles. The E66K substitution is representative of a new class of SP-C mutation associated with interstitial lung disease that is diverted from the normal biosynthetic pathway. We propose that, similar to other storage disorders, lung injury results from induction of a toxic gain of function induced by the mutant product that is subject to genetic modifiers and environmental influences.