RESUMEN
Pediatric neoplastic diseases account for about 10% of cases of fever of unknown origin (FUO), and most neoplastic disease cases are leukemia, lymphoma, and neuroblastoma. Brain tumors are rarely reported as the cause of FUO, although craniopharyngioma, metastatic brain tumor, and Castleman's disease have been reported. We report a case of intracranial mesenchymal tumor (IMT) with a FET:CREB fusion gene, which had inflammatory phenotype without neurological signs. A 10-year-old girl was admitted with a 2-month history of intermittent fever and headache, whereas her past history as well as her family history lacked special events. Sepsis work-up showed no pathological organism, and empirical antibiotic therapy was not effective. Bone marrow examination showed a negative result. Cerebrospinal fluid examination showed elevated protein as well as cell counts, and head magnaetic resonance imaging showed a hypervascular mass lesion with contrast enhancement in the left cerebellar hemisphere. The patient underwent tumor excision, which made the intermittent fever disappear. Pathological examinations resembled those of classic angiomatoid fibrous histiocytoma (AFH), but the morphological features were distinct from the AFH myxoid variant; then we performed break-apart fluorescence in situ hybridization and confirmed the tumor harbored the rare EWSR1::CREM fusion gene (Ewing sarcoma breakpoint region 1 gene (EWSR1) and cAMP response element binding (CREB) family gene). Consequently, we diagnosed the condition as IMT with EWSR1::CREM fusion. Elevated serum concentration of interleukin 6 (IL-6) was normalized after tumor resection, which suggested the fever could be caused by tumor-derived IL-6. This is the first case of IMT with EWSR1::CREM fusion that showed paraneoplastic symptoms associated with the IL-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway. Although brain tumors are rarely diagnosed as a responsible disease for FUO, they should be considered as a cause of unknown fever even in the absence of abnormal neurological findings.
Asunto(s)
Neoplasias Encefálicas , Interleucina-6 , Femenino , Humanos , Interleucina-6/genética , Hibridación Fluorescente in Situ/métodos , Factor de Transcripción STAT3/genética , Proteína EWS de Unión a ARN/genética , Neoplasias Encefálicas/patología , Inflamación , Fusión Génica , Modulador del Elemento de Respuesta al AMP Cíclico/genéticaRESUMEN
PURPOSE: Heterozygous dominant-negative (DN) STAT1 variants are responsible for autosomal dominant (AD) Mendelian susceptibility to mycobacterial disease (MSMD). In this paper, we describe eight MSMD cases from four kindreds in Japan. METHODS: An inborn error of immunity-related gene panel sequencing was performed using genomic DNA extracted from whole blood samples. The identified variants were validated using Sanger sequencing. Functional analysis was evaluated with a luciferase reporter assay and co-transfection assay in STAT1-deficient cells. RESULTS: Patient 1.1 was a 20-month-old boy with multifocal osteomyelitis and paravertebral abscesses caused by Mycobacterium bovis bacillus Calmette-Guérin (BCG). Although the paravertebral abscess was refractory to antimycobacterial drugs, the addition of IFN-γ and drainage of the abscess were effective. Intriguingly, his mother (patient 1.2) showed an uneventful clinical course except for treatment-responsive tuberculous spondylitis during adulthood. Patient 2.1 was an 8-month-old boy with lymphadenopathy and lung nodules caused by BCG. He responded well to antimycobacterial drugs. His mother (patient 2.2) was healthy. Patient 3.1 was a 11-year-old girl with suspected skin tuberculosis. Her brother (patient 3.2) had BCG-osis, but their mother (patient 3.3) was healthy. Patient 4 was an 8-month-old girl with left axillary and supraclavicular lymphadenopathy associated with BCG vaccination. Kindreds 1, 2, and 3 were shown to have novel heterozygous variants (V642F, R588C, and R649G) in STAT1, respectively. Kindred 4 had previously reported heterozygous variants (Q463H). A luciferase reporter assay in STAT1-deficient cells followed by IFN-γ stimulation confirmed that these variants are loss-of-function. In addition, with co-transfection assay, we confirmed all of these variants had DN effect on WT STAT1. CONCLUSION: Four kindred MSMD subjects with 3 novel variants and 1 known variant in STAT1 were identified in this study. AD STAT1 deficiency might be prevalent in Japanese patients with BCG-associated MSMD.
Asunto(s)
Infecciones por Mycobacterium , Mycobacterium bovis , Masculino , Femenino , Humanos , Adulto , Lactante , Niño , Absceso , Vacuna BCG , Pueblos del Este de Asia , Mutación , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/genética , Antibacterianos , Predisposición Genética a la Enfermedad , Factor de Transcripción STAT1/genéticaAsunto(s)
Síndrome de Hermanski-Pudlak , Enfermedades Pulmonares Intersticiales , Complejo 3 de Proteína Adaptadora/genética , Subunidades beta de Complejo de Proteína Adaptadora/genética , Síndrome de Hermanski-Pudlak/genética , Humanos , Recién Nacido , Enfermedades Pulmonares Intersticiales/genética , MutaciónRESUMEN
As sodium level in diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) is usually low, normal, or slightly elevated, severe hypernatremia with DKA and/or HHS is rare. Case 1 was a 14-year-old boy, presenting with typical laboratory test values and symptoms consistent with DKA and HHS. His corrected sodium level, 172 mEq/L, might have occurred as a result of consuming 6 L/day of highly carbonated, carbohydrate- and sodium-rich drinks during the week preceding the diagnosis. This patient developed right lung artery thrombosis, which did not require treatment. Case 2 was a 10-year-old girl, presenting with typical laboratory test values and symptoms of DKA and HHS. Her corrected sodium level, 175 mEq/L, might have occurred as a result of large electrolyte-free water loss associated with osmotic diuresis. These two cases of patients presenting with DKA-HHS and severe hypernatremia are the first to be reported in Japan.