RESUMEN
Children with severe inflammatory diseases are challenging to diagnose and treat, and the etiology of disease often remains unexplained. Here we present DIAPH1 deficiency as an unexpected genetic finding in a child with fatal inflammatory bowel disease who also displayed complex neurological and developmental phenotypes. Bi-allelic mutations of DIAPH1 were first described in patients with a severe neurological phenotype including microcephaly, intellectual disability, seizures, and blindness. Recent findings have expanded the clinical phenotype of DIAPH1 deficiency to include severe susceptibility to infections, placing this monogenic disease amongst the etiologies of inborn errors of immunity. Immune phenotypes in DIAPH1 deficiency are largely driven aberrant lymphocyte activation, particularly the failure to form an effective immune synapse in T cells. We present the case of a child with a novel homozygous deletion in DIAPH1, leading to a premature truncation in the Lasso domain of the protein. Unlike other cases of DIAPH1 deficiency, this patient did not have seizures or lung infections. Her major immune-related clinical symptoms were inflammation and enteropathy, diarrhea and failure to thrive. This patient did not show T or B cell lymphopenia but did have dramatically reduced naïve CD4+ and CD8+ T cells, expanded CD4-CD8- T cells, and elevated IgE. Similar to other cases of DIAPH1 deficiency, this patient had non-hematological phenotypes including microcephaly, developmental delay, and impaired vision. This patient's symptSoms of immune dysregulation were not successfully controlled and were ultimately fatal. This case expands the clinical spectrum of DIAPH1 deficiency and reveals that autoimmune or inflammatory enteropathy may be the most prominent immunological manifestation of disease.
Asunto(s)
Forminas , Mutación , Humanos , Forminas/genética , Femenino , Alelos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Fenotipo , Proteínas Adaptadoras Transductoras de Señales/genéticaRESUMEN
Inborn errors of immunity are a group of rare genetically determined diseases that impair immune system development or function. Many of these diseases include immune dysregulation, autoimmunity or autoinflammation as prominent clinical features. In some children diagnosed with very early onset inflammatory bowel disease (VEOIBD), monogenic inborn errors of immune dysregulation underlie disease. We report a case of VEOIBD caused by a novel homozygous loss of function mutation in IL10RB. We use CyTOF with a broad panel of antibodies to interrogate the immunophenotype of this patient and detect reduced frequencies of CD4 and CD8 T cells with additional defects in some populations of T helper cells, innate-like T cells and memory B cells. Finally, we identify the patient's mutation as a founder allele in an isolated indigenous population and estimate the age of this variant by studying the shared ancestral haplotype.
RESUMEN
Hermansky-Pudlak syndrome (HPS) is a heterogeneous group of autosomal recessive genetic disorders characterized by oculocutaneous albinism, bleeding diathesis, and variable presentation of immune deficiency and dysregulation. The pathogenesis of HPS involves mutations in genes responsible for biogenesis and trafficking of lysosome-related organelles, essential for the function of melanosomes, platelet granules, and immune cell granules. Eleven genes coding for proteins in the BLOC-1, BLOC-2, BLOC-3 and AP-3 complexes have been implicated in the pathogenesis of HPS. To date, the rare subtype HPS-7 associated with bi-allelic mutations in DTNBP1 (dysbindin) has only been reported in 9 patients. We report a novel DTNBP1 splicing mutation in a 15-month-old patient with HPS-7 phenotype and severe inflammatory bowel disease (IBD). This patient's leukocytes have undetectable dysbindin protein. We also identify dysregulated expression of several genes involved in activation of the adaptive immune response. This case underscores the emerging immunological consequences of dysbindin deficiency and suggests that DTNBP1 mutations may underlie some rare cases of very early onset IBD.
Asunto(s)
Síndrome de Hermanski-Pudlak , Enfermedades Inflamatorias del Intestino , Humanos , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Disbindina/genética , Disbindina/metabolismo , Síndrome de Hermanski-Pudlak/genética , Síndrome de Hermanski-Pudlak/patología , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/genética , Mutación , Proteínas/genéticaRESUMEN
Limited evidence exists on real-world adherence to nusinersen for the treatment of spinal muscular atrophy (SMA). Data are presented from a multi-site retrospective chart review of 86 adults with SMA initiating nusinersen at nine US centers between January 2017 and February 2019. Seventy-nine (92%) adults remained on nusinersen during the study; 454 (92%) of 493 total nusinersen doses were received on time. Fifty-eight (67%) adults received all nusinersen doses on time. The majority of patients with at least one nonadherent dose resumed nusinersen on time. Most patients followed the dosing schedule across the loading and maintenance dose periods.
Asunto(s)
Atrofia Muscular Espinal , Adulto , Humanos , Atrofia Muscular Espinal/tratamiento farmacológico , Oligonucleótidos/uso terapéutico , Estudios RetrospectivosRESUMEN
Neonatal multisystem onset inflammatory disorder (NOMID) is a severe autoinflammatory syndrome that can have an initial presentation as infantile urticaria. Thus, an immediate recognition of the clinical symptoms is essential for obtaining a genetic diagnosis and initiation of early therapies to prevent morbidity and mortality. Herein, we describe a neonate presenting with urticaria and systemic inflammation within hours after birth who developed arthropathy and neurologic findings. Pathologic evaluation of the skin revealed an infiltration of lymphocytes, eosinophils, and scattered neutrophils. Genetic analysis identified a novel heterozygous germline variant of unknown significance in the NLRP3 gene, causing the missense mutation M408T. Variants of unknown significance are common in genetic sequencing studies and are diagnostically challenging. Functional studies of the M408T variant demonstrated enhanced formation and activity of the NLRP3 inflammasome, with increased cleavage of the inflammatory cytokine IL-1ß. Upon initiation of IL-1 pathway blockade, the infant had a robust response and improvement in clinical and laboratory findings. Our experimental data support that this novel variant in NLRP3 is causal for this infant's diagnosis of NOMID. Rapid assessment of infantile urticaria with biopsy and genetic diagnosis led to early recognition and targeted anti-cytokine therapy. This observation expands the NOMID-causing variants in NLRP3 and underscores the role of genetic sequencing in rapidly identifying and treating autoinflammatory disease in infants. In addition, these findings highlight the importance of establishing the functional impact of variants of unknown significance, and the impact this knowledge may have on therapeutic decision making.
Asunto(s)
Síndromes Periódicos Asociados a Criopirina/diagnóstico , Síndromes Periódicos Asociados a Criopirina/genética , Mutación , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Fenotipo , Urticaria/diagnóstico , Urticaria/genética , Biomarcadores , Biopsia , Preescolar , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Piel/patologíaRESUMEN
Nerve conduction studies and electromyography are useful diagnostic tools that neurologists use to diagnose diseases of the peripheral nerves, neuromuscular junction, and muscles. These tests are considered an extension of clinical history and examination, and their results should always be interpreted with the clinical context. Neuromuscular diseases are common and affect a large proportion of the elderly population. With an aging population in expansion, these diseases are expected to become even more prevalent. It is important to highlight the basics of electrophysiology and provide a reference for providers who are planning to send their patients to electromyographers for these studies.V.
Asunto(s)
Electrodiagnóstico , Electromiografía/métodos , Polineuropatías/diagnóstico , Neuropatías Cubitales/diagnóstico , Síndrome del Túnel Carpiano , Humanos , RadiculopatíaRESUMEN
INTRODUCTION: Medical institutions are using barrier enclosure devices during intubation procedures and other aerosol-generating medical procedures without evidence of their effectiveness or usability, potentially compromising patient care, and provider safety. Our objective was to determine the degree of protection offered by these devices and explore other usability factors for two popular barrier systems. METHODS: A simulated trial comparing an intubation box, a frame and plastic tarp system, and unprotected intubation was performed in an academic emergency department. Ten emergency physicians were recruited to participate. Our primary outcome was the degree of contamination from secretions measured by average surface area exposed to phosphorescent material. Secondary outcomes included: laryngoscopy time and time to barrier application, unsuccessful intubation attempts, and usability ratings for each system. Descriptive statistics were reported for all variables of interest and a linear mixed model was used to analyze contamination and laryngoscopy time. Usability was captured through electronic questionnaires using a five-point Likert scale. RESULTS: Contamination was more prevalent with the box, compared to the frame and tarp, and no device, however, this did not achieve statistical significance (13.2% versus 8.1% versus 12.2%, P = 0.17). A barrier system delayed intubation when compared to using no system (no system = 24.4 s [95% CI 17.3-27.5], frame = 54.4 s [95% CI 13.8-95.0], box = 33.8 s [95% CI 21.4-46.1], P = 0.02). In assessing usability, 30% of users preferred the use of a box barrier, 40% of users preferred the frame, and 30% would not use either in future intubation. CONCLUSIONS: Compared to no barrier protection, an intubation box enclosure offers limited additional protection. A frame and tarp system reduces exposure at the expense of visibility and operator comfort. Finally, barrier systems do not appear to have a clinically significant impact on airway management.