RESUMEN
Dubin-Johnson syndrome (DJS) is a rare autosomal recessive disorder that typically manifests in young adulthood as jaundice with conjugated hyperbilirubinemia. We report a case presenting as neonatal cholestasis with the unexpected histologic finding of paucity of interlobular bile ducts, a feature that is not typically seen in DJS. The diagnosis was confirmed by absent canalicular multidrug-resistance-associated protein 2 (MRP2) immunohistochemical staining on liver biopsy tissue and molecular genetic testing that demonstrated heterozygous mutations in the ATP-Binding Cassette Subfamily C Member 2 (ABCC2) gene, including a novel missense mutation. This report describes a case of DJS with atypical clinicopathologic findings and suggests that DJS should be considered in patients with neonatal cholestasis and bile duct paucity.
Asunto(s)
Síndrome de Alagille/diagnóstico , Ictericia Idiopática Crónica/diagnóstico , Síndrome de Alagille/genética , Síndrome de Alagille/metabolismo , Síndrome de Alagille/patología , Biomarcadores/metabolismo , Femenino , Marcadores Genéticos , Heterocigoto , Humanos , Recién Nacido , Ictericia Idiopática Crónica/genética , Ictericia Idiopática Crónica/metabolismo , Ictericia Idiopática Crónica/patología , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Mutación MissenseRESUMEN
AIMS: Historically, there has been no consensus on the diagnostic classification of high-grade B-cell lymphoma (HGBCL) with morphological features of Burkitt lymphoma (BL) but no MYC gene rearrangement (MYC-negative). The 2016 WHO classification of tumours of haematopoietic and lymphoid tissues has shed some light on this field with the modification of the grey-zone lymphoma with features intermediate between BL and diffuse large B-cell lymphoma, and the creation of several new entities. The aim of this study was to investigate how the revised WHO classification affects our practice in diagnosing these lymphomas in children. METHODS: We retrospectively reviewed cases of mature HGBCL diagnosed at our hospital between 2015 and 2018. RESULTS: Among 14 mature HGBCL cases with BL morphological features, 11 showed MYC rearrangement consistent with BL and 3 were MYC-negative. Two MYC-negative cases showed regions of 11q gain and loss by microarray consistent with Burkitt-like lymphoma with 11q aberration (BLL-11q). The third MYC-negative case showed diffuse and strong MUM1 expression, translocation involving 6p25 by chromosome analysis and IRF4 rearrangement by fluorescence in situ hybridisation analysis consistent with large B-cell lymphoma with IRF4 rearrangement (LBL-IRF4). All patients were treated according to applicable chemotherapeutic protocols and achieved remission. CONCLUSIONS: BLL-11q and LBL-IRF4, two newly defined entities, should be considered in paediatric MYC-negative mature HGBCL cases. Accurate diagnosis needs careful histopathological examination and proper cytogenetic testing. Since they have unique cytogenetic features, specific treatments for them may emerge in the future. Therefore, accurate diagnosis based on the 2016 WHO classification is clinically significant.
Asunto(s)
Linfoma de Burkitt/clasificación , Aberraciones Cromosómicas , Linfoma de Células B Grandes Difuso/clasificación , Translocación Genética , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Niño , Preescolar , Citogenética , Femenino , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Masculino , Estudios RetrospectivosAsunto(s)
Forma del Núcleo Celular , Eliminación de Gen , Factor de Transcripción Ikaros/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Factores de Edad , Forma del Núcleo Celular/genética , Niño , Hibridación Genómica Comparativa , Análisis Citogenético , Humanos , InmunohistoquímicaRESUMEN
Spitzoid melanoma of childhood is a rare malignancy. The histological features are at the upper end of a range encompassing Spitz nevus and atypical Spitz tumor, the unifying features including large oval, fusiform or polygonal melanocytes with abundant homogeneous-appearing cytoplasma and large vesicular nuclei. The presence of a "bottom-heavy" pattern, strikingly enlarged nuclei and nucleoli in both the upper and lower portions of the lesion, and deep mitotic figures are among the findings that distinguish most of the Spitzoid melanomas from Spitz nevi and atypical Spitz tumors. There are no syndromic associations reported for this malignancy. We report the occurrence of choroid plexus carcinoma, Spitzoid melanoma, and myelodysplasia in a child who was found to carry a germline mutation for TP53. While choroid plexus carcinoma and myelodysplasia have relatively frequently been described, melanomas have been very rarely described in Li-Fraumeni syndrome. The association of Spitzoid melanoma with Li-Fraumeni syndrome, especially in a pediatric patient, has not been reported before.
Asunto(s)
Carcinoma/complicaciones , Neoplasias del Plexo Coroideo/complicaciones , Genes p53 , Síndrome de Li-Fraumeni/complicaciones , Melanoma/etiología , Neoplasias Cutáneas/etiología , Carcinoma/genética , Neoplasias del Plexo Coroideo/genética , Mutación de Línea Germinal , Humanos , Lactante , Cariotipo , Síndrome de Li-Fraumeni/genética , Masculino , Melanoma/patología , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/genética , Piel/patología , Neoplasias Cutáneas/patologíaRESUMEN
Pediatric-onset inflammatory bowel disease (IBD) is known to be associated with severe disease, poor response to therapy, and increased morbidity and mortality. We conducted exome sequencing of two brothers from a non-consanguineous relationship who presented before the age of one with severe infantile-onset IBD, failure to thrive, skin rash, and perirectal abscesses refractory to medical management. We examined the variants discovered in all known IBD-associated and primary immunodeficiency genes in both siblings. The siblings were identified to harbor compound heterozygous mutations in IL10RA (c.784C>T, p.Arg262Cys; c.349C>T, p.Arg117Cys). Upon molecular diagnosis, the proband underwent successful hematopoietic stem cell transplantation and demonstrated marked clinical improvement of all IBD-associated clinical symptoms. Exome sequencing can be an effective tool to aid in the molecular diagnosis of pediatric-onset IBD. We provide additional evidence of the safety and benefit of HSCT for patients with IBD due to mutations in the IL10RA gene.
Asunto(s)
Pruebas Genéticas , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/genética , Subunidad alfa del Receptor de Interleucina-10/genética , Niño , Exoma , Variación Genética , Trasplante de Células Madre Hematopoyéticas , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/terapia , Masculino , Técnicas de Diagnóstico Molecular , Polimorfismo de Nucleótido Simple , Análisis de Secuencia de ADN , Resultado del TratamientoRESUMEN
A new unstable α-globin variant was detected in a child with hypoxemia and anemia. The child's mother was found to carry the same mutation. The hemoglobin (Hb) variant co-eluted with Hb A(2) by cation exchange high performance liquid chromatography (HPLC) and appeared cathodal to Hb A and anodal to Hb F by isoelectric focusing. It represented less than 20% of the total Hb and was unstable by isopropanol testing. Gene sequencing identified a missense mutation on the α2 gene [HBA2:c.140T>C]. Oxygen dissociation and P(50) test results were normal.
Asunto(s)
Hemoglobinas Anormales/genética , Mutación Missense , Globinas alfa/genética , Anemia/genética , Anemia/metabolismo , Sitios de Unión , Niño , Cromatografía Líquida de Alta Presión , Hemo/análogos & derivados , Hemo/química , Hemo/metabolismo , Hemoglobinas Anormales/química , Hemoglobinas Anormales/metabolismo , Humanos , Hipoxia/genética , Hipoxia/metabolismo , Masculino , Modelos Moleculares , Estructura Terciaria de Proteína , Globinas alfa/química , Globinas alfa/metabolismoRESUMEN
Neonatal deaths account for about 67% of all deaths during the first year of life in the USA. Genetic defects are important factors contributing to neonatal deaths and congenital anomalies. Here we report on the identification of a 1.37 Mb de novo deletion of chromosome 16q24.1-q24.2 by microarray-based comparative genomic hybridization (aCGH) technique in a newborn boy with lethal severe alveolar capillary dysplasia and multiple congenital anomalies who died of irreversible pulmonary hypertension, respiratory failure and cor pulmonale at three days of age. The phenotypic findings and causal genes (FOXF1 and FOXC2) involved in producing this unusual syndrome are detailed. Our findings independently confirm the results in a previous publication describing multiple patients with similar clinical and genetic observations, and highlight the importance of scanning human genomes at high resolution for identifications of micro-imbalances as pathogenic causes in neonates with unexplained congenital anomalies. (c) 2010 Wiley-Liss, Inc.
Asunto(s)
Capilares/anomalías , Factores de Transcripción Forkhead/genética , Haploidia , Cardiopatías Congénitas/complicaciones , Cardiopatías Congénitas/genética , Alveolos Pulmonares/anomalías , Hibridación Genómica Comparativa , Variaciones en el Número de Copia de ADN/genética , Resultado Fatal , Femenino , Estudios de Seguimiento , Dosificación de Gen/genética , Humanos , Recién Nacido , Masculino , Padres , Reacción en Cadena de la Polimerasa , Embarazo , Alveolos Pulmonares/patología , Reproducibilidad de los ResultadosRESUMEN
High-resolution microarray comparative genomic hybridization (aCGH) is being adopted for diagnostic evaluation of genomic disorders, but validation for clinical diagnosis has not yet been reported. We present validation data for the Agilent Human Genome Microarray Kit 244K for clinical application. The platform contains approximately 240,000 distinct 60-mer oligonucleotide probes spanning the entire human genome. We studied 45 previously characterized samples (43 abnormal, 2 normal), 32 with knowledge of prior results and 13 in a blinded manner with 11 performed in a reference laboratory providing microarray testing. Array analysis confirmed known aberrations in 43 samples and a normal result in 2. The array analysis corrected 1 karyotype and clarified 2 additional cases. Array data from 6 patients with 22q11.2 deletion found an average of 2.56 megabases (Mb; range, 2.49-2.62 Mb) with a common 2.43-Mb deleted region. Approximately 7 copy number variants from 400 base pairs to 1.6 Mb were identified per sample. Results demonstrate the usefulness of the aCGH-244K platform as a powerful diagnostic tool.
Asunto(s)
Aberraciones Cromosómicas , Hibridación Genómica Comparativa/métodos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sensibilidad y EspecificidadRESUMEN
Immunophenotypic analysis can identify protein epitopes in non-Hodgkin lymphomas (NHL) that may respond to targeted immunotherapies, such as anti-CD20 and anti-CD52. Recent studies suggest additional targets may provide therapeutic benefits in NHL. This study evaluated protein expression of CD25, CD52, CD74 and CD80 in paediatric NHL to determine possible targets for immune-based therapeutic approaches. Patient samples were derived from paediatric NHL clinical trials sponsored by the Children's Cancer Group (CCG, now the Children's Oncology Group, COG) and included Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), disseminated T- and B-cell lymphoblastic lymphoma (T-LBL and B-LBL) and anaplastic large cell (ALCL). Immunophenotypic studies were performed on formalin-fixed, paraffin-embedded diagnostic tissues. CD25 was expressed in 8% of T-LBL and 75% of ALCL cases, but not in BL, DLBCL, or B-LBL. CD52 was expressed in 99% of cases of paediatric NHL of all subtypes. CD74 was expressed in 100% of B-LBL, BL and DLBCL, but was absent in ALCL and T-LBL. CD80 was expressed in 12% of B-LBL, 6% of BL and 10% of DLBCL cases studied, but was not detected in T-cell NHL. These expression patterns suggest that CD25, CD52 and CD74 may represent potential new therapeutic targets in paediatric NHL.
Asunto(s)
Antígenos CD/análisis , Linfoma no Hodgkin/inmunología , Antígenos de Diferenciación de Linfocitos B/análisis , Antígenos de Neoplasias/análisis , Antígeno B7-1/análisis , Antígeno CD52 , Niño , Glicoproteínas/análisis , Antígenos de Histocompatibilidad Clase II/análisis , Humanos , Inmunofenotipificación , Inmunoterapia , Subunidad alfa del Receptor de Interleucina-2/análisis , Linfoma no Hodgkin/terapiaRESUMEN
PURPOSE: Non-Hodgkin's lymphoma (NHL) arising in bone is a heterogeneous histologic type of NHL that includes large-cell lymphoma, lymphoblastic lymphoma, and small noncleaved-cell lymphoma. NHL arising in bone is well recognized in adults but is less well characterized and infrequent in children and adolescents. PATIENTS AND METHODS: We performed a retrospective review of Children's Cancer Group (CCG) studies treating children and adolescents with NHL over a 20-year period (CCG-551, CCG-501, CCG-502, CCG-503, CCG-552, CCG-5911, and CCG-5941) and determined the response and event-free survival (EFS) rates in 31 patients with NHL arising in bone. RESULTS: The patients ranged in age from 3 to 17 years (median, 11 years; mean, 11 years), and 64.5% were male. All 31 (100%) patients achieved complete response. For 31 patients with NHL arising in bone, the product-limit estimated 5-year EFS was 83.8% +/- 6.7%. EFS in 17 patients with localized disease (Murphy stages I and II) was 94.1% +/- 5.7%, and EFS in 14 patients with disseminated disease (Murphy stage III) was 70.7% +/- 12.4% (log-rank P =.10). EFS in 17 patients treated with chemotherapy and radiation was 70.1% +/- 11.2%, and EFS in 14 patients treated with chemotherapy without radiation was 100% (P =.03). EFS in 26 patients with histology-directed treatment (LSA2-L2 or ADCOMP for lymphoblastic, other therapy for nonlymphoblastic) was 92.2% +/- 5.3%, and in five patients with nonhistology-directed treatment it was 40.0% +/- 21.9% (P <.001). CONCLUSION: NHL arising in bone is a heterogeneous type of NHL that makes up approximately 2.0% of NHL in children and adolescents on CCG studies. Response and survival in this young age group seem superb, with histology-directed treatment protocols without radiation in both localized and disseminated disease.