RESUMEN
BACKGROUND: Investigation of patients, particularly children, with unexplained global developmental delay (GDD)/learning disability (LD) has been challenging due to a lack of clear guidance from specialised centres. Limited knowledge of rare diseases and a poor understanding of the purpose or limitations of appropriate investigations have been some of the principal reasons for this difficulty. AIMS: A guideline development group was formed to recommend on appropriate, first line metabolic, genetic and radiological investigations for children and adults with unexplained GDD/ID. METHODS AND RECOMMENDATIONS: A comprehensive literature search was conducted, evaluated and reviewed by the guideline committee and a best practice protocol for first line assessment and genetic, metabolic and radiological investigations was decided upon after considering diagnostic yield, practicality, treatability and costs. CONCLUSION: It is hoped that these recommendations will become national guidelines for the first line metabolic, genetic and radiological investigation of patients presenting with unexplained GDD/ID.
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Discapacidades del Desarrollo/diagnóstico , Discapacidades para el Aprendizaje/diagnóstico , Errores Innatos del Metabolismo/diagnóstico , Adulto , Niño , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/metabolismo , Humanos , Discapacidades para el Aprendizaje/genética , Discapacidades para el Aprendizaje/metabolismo , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/metabolismo , Enfermedades RarasRESUMEN
We report a case of Albright hereditary osteodystrophy (AHO) in a three-year-old girl with a microduplication at 17q11.2. The child developed obesity within the first 6 months of life. A diagnosis of Albright was made at age 2 years when biochemical evidence of parathyroid resistance was found. No mutations were identified in guanine nucleotide-binding protein G (s) subunit alpha (GNAS1). Subsequent investigations revealed methylation disturbance at GNAS1A, neuroendocrine secretory protein antisense (NESPAS) and neuroendocrine secretory protein 55 (NESP55) confirming a diagnosis of pseudohypothyroidism type 1B. A deletion of NESP55 and uniparental disomy chromosome 20 were excluded which suggested that the features of AHO arose through a purely epigenetic mechanism. Further investigation revealed a de novo microduplication at 17q11.2 encompassing the neurofibromatosis type 1 (NF1) gene. The combination of two rare de novo events in the same child raises the possibility that duplication of a gene within the 17q11.2 region may have triggered abnormal methylation in the GNAS cluster region on chromosome 20.
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Proteínas de Ciclo Celular/genética , Proteínas de Unión al ADN/genética , Predisposición Genética a la Enfermedad , Leucemia-Linfoma de Células T del Adulto/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas Supresoras de Tumor/genética , Proteínas de la Ataxia Telangiectasia Mutada , Estudios de Casos y Controles , Niño , Heterocigoto , Humanos , Polimorfismo Genético , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Several studies involving identical twins with concordant leukemia and retrospective scrutiny of archived neonatal blood spots have shown that the TEL-AML1 fusion gene in childhood acute lymphoblastic leukemia (ALL) frequently arises before birth. A prenatal origin of childhood leukemia was further supported by the detection of clonotypic immunoglobulin gene rearrangements on neonatal blood spots of children with various other subtypes of ALL. However, no comprehensive study is available linking these clonotypic events. We describe a pair of 5-year-old monozygotic twins with concordant TEL-AML1-positive ALL. Separate leukemic clones were identified in the diagnostic samples since distinct IGH and IGK-Kde gene rearrangements could be detected. Additional differences characterizing the leukemic clones included an aberration of the second, nonrearranged TEL allele observed in one twin only. Interestingly, both the identical TEL-AML1 fusion sequence and distinct immunoglobulin gene rearrangements were identified on the neonatal blood spots indicating that separate preleukemic clones evolved already before birth. Finally, we compared the reported twins with an additional 31 children with ALL by using the microarray technology. Gene expression profiling provided evidence that leukemia in twins harbours the same subtype-typical feature as TEL-AML1-positive leukemia in singletons suggesting that the leukemogenesis model might also be applicable generally.
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Enfermedades en Gemelos/genética , Reordenamiento Génico , Genes de Inmunoglobulinas , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Gemelos Monocigóticos , Secuencia de Bases , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Femenino , Perfilación de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Datos de Secuencia Molecular , Filogenia , Leucemia-Linfoma Linfoblástico de Células Precursoras/embriología , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Homología de Secuencia de Ácido NucleicoRESUMEN
Although greater than 50% of Ewing tumours contain non-random cytogenetic aberrations in addition to the pathognomonic 22q12 rearrangements, little is known about their prognostic significance. To address this question, tumour samples from 134 Ewing tumour patients were analysed using a combination of classical cytogenetics, comparative genomic and fluorescence in situ hybridisation. The evaluation of the compiled data revealed that gain of chromosome 8 occurred in 52% of Ewing tumours but was not a predictive factor for outcome. Gain of 1q was associated with adverse overall survival and event-free survival in all patients, irrespective of whether the tumour was localised or disseminated (overall survival: P=0.002 and P=0.029; event-free survival: P=0.018 and P=0.010). Loss of 16q was a significant predictive factor for adverse overall survival in all patients (P=0.008) and was associated with disseminated disease at diagnosis (P=0.039). Gain of chromosome 12 was associated with adverse event-free survival (P=0.009) in patients with localised disease. These results indicate that in addition to a 22q12 rearrangement confirmation in Ewing tumours it is important to assess the copy number of 1q and 16q to identify patients with a higher probability of adverse outcome.
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Neoplasias Óseas/genética , Aberraciones Cromosómicas , Mapeo Cromosómico , Sarcoma de Ewing/genética , Adulto , Factores de Edad , Anciano , Neoplasias Óseas/mortalidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Sarcoma de Ewing/mortalidad , Caracteres Sexuales , Tasa de SupervivenciaRESUMEN
Acute lymphoblastic leukemia (ALL) of childhood has been cytogenetically well characterized, and approximately 25% of cases will have a high-hyperdiploid (51-68) chromosome complement. In a 5 year period a consecutive series of 152 presentation ALL's were karyotyped. In all cases a result was obtained and 138 (91%) had a detectable abnormal clone of which 44 (29%) were high-hyperdiploid. Within the high-hyperdiploidy group karyotypic cell to cell variation was observed in many cases. To provide further evidence of this phenomenon a dual-color fluorescence in-situ hybridization (FISH) experiment was performed on stored fixed suspension from 14 ALL's with such a karyotype. In each case 4-6 probes were investigated, employing probes to centromeres of chromosomes X, 4, 6, 8, and 10 and a locus specific probe to chromosome 21q22. It was found that the FISH produced results that were generally in good agreement with the G-banding findings and supported the notion of karyotypic cell to cell variation. FISH further showed that most of cases would have two extra copies of chromosome 21 in the majority of leukemic cells and a single extra copy in the minority. A further finding was that fewer cells contained extra copies of chromosomes 6, 8 and 10 than was expected based on the comparison of the signal number of the other probes investigated. In contrast chromosomes X, 4, and 21 seldom displayed this feature. We have demonstrated that karyotypic instability as defined by karyotypic cell to cell variation is a feature of the high-hyperdiploid subgroup in childhood ALL. It is questioned whether the underlying defect resulting in the observed karyotypic instability of this subgroup is one of the primary causative events in the formation of the leukemia.
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Análisis Citogenético/métodos , Poliploidía , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Niño , Bandeo Cromosómico , Análisis Citogenético/normas , Humanos , Hibridación Fluorescente in Situ/métodos , Hibridación Fluorescente in Situ/normas , CariotipificaciónRESUMEN
Spectral karyotyping (SKY) is a novel technique based on the simultaneous hybridization of 24 fluorescently labeled chromosome painting probes. It provides a valuable addition to the investigation of many tumors that can be difficult to define by conventional banding techniques. One such tumor is neuroblastoma, which is often characterized by poor chromosome morphology and complex karyotypes. Ten primary neuroblastoma tumor samples initially analyzed by G-banding were analyzed by SKY. In 8/10 tumors, we were able to obtain additional cytogenetic information. This included the identification of complex rearrangements and material of previously unknown origin. Structurally rearranged chromosomes can be identified even in highly condensed metaphase chromosomes. Following the SKY results, the G-banding findings were reevaluated, and the combination of the two techniques resulted in a more accurate karyotype. This combination allows identification not only of material gained and lost, but also of breakpoints and chromosomal associations. The use of SKY is therefore a powerful tool in the genetic characterization of neuroblastoma and can contribute to a better understanding of the molecular events associated with this tumor.
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Aberraciones Cromosómicas/genética , Cariotipificación , Neuroblastoma/genética , Niño , Preescolar , Trastornos de los Cromosomas , Pintura Cromosómica , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Cariotipificación/métodos , Masculino , Células Tumorales CultivadasRESUMEN
We present six cases of childhood acute lymphoblastic leukemia (ALL) in which an acquired loss of the X chromosome was detected. The cases derive from a consecutive series of 178 childhood ALL, consisting of 80 girls and 98 boys. In five cases the presence of the TEL-AML1, t(12;21), fusion product was detected by FISH. The single negative case had an unusual t(1;19)(p13;q13). In addition, this was the only case that did not have a cytogenetically visible rearrangement involving one of the chromosome regions 6q, 9p, or 12p. The six cases showed the typical presentation features of an ALL of FAB type L1, a common ALL immunophenotype with myeloid marker co-expression, and a median presenting age of 7 years. We, therefore, conclude that loss of chromosome X may be a secondary event in older girls with TEL-AML1-positive ALL.
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Deleción Cromosómica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Cromosoma X , Adolescente , Niño , Preescolar , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 21 , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Proteínas de Fusión Oncogénica/genética , Translocación GenéticaRESUMEN
A predisposition to tumor development is currently associated with some, but not all, constitutional chromosomal abnormalities. In a series of 578 children, in which conventional cytogenetic investigation was performed on material from various benign and malignant tumors, four boys and one girl were also found to have constitutional balanced chromosomal rearrangements. The figure of 5 in 578 is notable because the reported incidence of balanced rearrangements in newborns is approximately 1 in 450. Thereby suggesting that some, if not all, children with balanced constitutional chromosomal rearrangements have an increased predisposition for neoplasms developing.
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Aberraciones Cromosómicas , Cromosomas Humanos/ultraestructura , Neoplasias/genética , Anomalías Múltiples/genética , Adolescente , Aneuploidia , Niño , Preescolar , Trastornos de los Cromosomas/complicaciones , Trastornos de los Cromosomas/epidemiología , Trastornos de los Cromosomas/genética , Femenino , Genes Supresores de Tumor , Predisposición Genética a la Enfermedad , Humanos , Lactante , Cariotipificación , Neoplasias Renales/genética , Leucemia/epidemiología , Leucemia/genética , Linfoma/epidemiología , Linfoma/genética , Masculino , Neoplasias/epidemiología , Nefroma Mesoblástico/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudios Retrospectivos , Rabdomiosarcoma Embrionario/genética , Riesgo , Translocación Genética , Tumor de Wilms/genética , Xantogranuloma Juvenil/genéticaRESUMEN
We present a premature newborn of 32 wk of gestation with a congenital malignant extrarenal rhabdoid tumor (MERT) on the right shoulder with generalized metastases. Standard histologic, immunohistochemical, molecular and cytogenetic methods were used in the evaluation of diagnostic material. Biopsy of a skin lesion showed the histologic features of a malignant rhabdoid tumor. Cytogenetic analysis of the tumor cells revealed an inv(11)(p13p15) and additionally, an increased expression of myf-3 (myogenic determination factor, MyoD1) and PAX3 was detected. These results suggest an origin of the neoplasm derived from a pluripotent cell with the potential of myogenic differentiation. Tumor suppressor genes located on chromosome 11p13 and 11p15 may play an important role for malignant rhabdoid tumor development and progression.
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Cromosomas Humanos Par 11 , Recien Nacido Prematuro , Proteína MioD/genética , Tumor Rabdoide/genética , Adulto , Inversión Cromosómica , Femenino , Edad Gestacional , Humanos , Inmunohistoquímica , Recién Nacido , Microscopía Electrónica , Mucina-1/análisis , Metástasis de la Neoplasia , Fosfopiruvato Hidratasa/análisis , Embarazo , Tumor Rabdoide/diagnóstico por imagen , Tumor Rabdoide/patología , Hombro , Ultrasonografía Prenatal , Vimentina/análisisAsunto(s)
Neoplasias Encefálicas/diagnóstico , Tumor Rabdoide/diagnóstico , Actinas/inmunología , Anticuerpos/inmunología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Preescolar , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 22/genética , Citogenética , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Mucina-1/inmunología , Músculo Liso/inmunología , Mioglobina/inmunología , Tumor Rabdoide/genética , Tumor Rabdoide/patología , Translocación Genética/genética , Vimentina/inmunologíaRESUMEN
Few human monoblastic cell lines have been characterized to date. We have established the SigM5 cell line from a patient with acute monoblastic leukaemia (FAB M5a). Original leukaemic cells had a karyotype of 47,XY,+8, whereas the cell line showed a stemline clone of 81,XX,Y,Y,1,4,6,7,+8,+8,9,10,10,11,13,16,19[cp], with a minor sideline also present. Cytochemical staining was strongly positive with alpha-naphthylbutyrate acetate esterase, particulate positive with Sudan black and weakly positive for myeloperoxidase. Cells were positive for CD13, CD15, CD18, CD23, CD33, CD38, CD45, CD68 and myeloperoxidase. CD14 expression was 3-15%. SigM5 constitutively secreted interleukin (IL)-2, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, ferritin, lysozyme, N-elastase and neopterin upon stimulation with interferon (IFN)-gamma. Cells expressed the proinflammatory mediator macrophage migration inhibitory factor (MIF). All NADPH oxidase subunits were constitutively present, but nitroblue tetrazolium reduction was only detectable upon activation with IFN-gamma. SigM5 monoblasts were sensitive to arsenic trioxide (As2O3) previously not described to induce apoptosis in monoblastic cells. Differing considerably in morphology, immunophenotype and sensitivity to arsenics from the widely used cell lines U937, HL-60 and THP-1, SigM5 is a new monoblastic cell line useful for studying leukaemogenesis, monocyte differentiation and tumour cell susceptibility to arsenic compounds.
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Antineoplásicos/farmacología , Arsenicales/farmacología , Técnicas de Cultivo de Célula/métodos , Leucemia Monocítica Aguda/patología , Leucocitos Mononucleares/patología , Óxidos/farmacología , Apoptosis/efectos de los fármacos , Trióxido de Arsénico , Diferenciación Celular , Línea Celular/inmunología , Línea Celular/patología , Cromosomas Humanos Par 8 , Humanos , Cariotipificación , Leucemia Monocítica Aguda/genética , Microscopía Electrónica , PoliploidíaRESUMEN
A novel human cell line was established from a primary botryoid rhabdomyosarcoma. Reverse transcription polymerase chain reaction investigations of this cell line, called RUCH-2, demonstrated expression of the regulatory factors PAX3, Myf3 and Myf5. After 3.5 months in culture, cells underwent a crisis after which Myf3 and Myf5 could no longer be detected, whereas PAX3 expression remained constant over the entire period. Karyotype analysis revealed breakpoints in regions similar to previously described alterations in primary rhabdomyosarcoma tumour samples. Interestingly, cells progressed to a metastatic phenotype, as observed by enhanced invasiveness in vitro and tumour growth in nude mice in vivo. On the molecular level, microarray analysis before and after progression identified extensive changes in the composition of the extracellular matrix. As expected, down-regulation of tissue inhibitors of metalloproteinases and up-regulation of matrix metalloproteinases were observed. Extensive down-regulation of several death receptors of the tumour necrosis factor family suggests that these cells might have an altered response to appropriate apoptotic stimuli. The RUCH-2 cell line represents a cellular model to study multistep tumorigenesis in human rhabdomyosarcoma, allowing molecular comparison of tumorigenic versus metastatic cancer cells.
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Transformación Celular Neoplásica , Regulación Neoplásica de la Expresión Génica , Rabdomiosarcoma/genética , Factores de Transcripción/genética , Animales , Apoptosis , Progresión de la Enfermedad , Regulación hacia Abajo , Femenino , Humanos , Lactante , Ratones , Biología Molecular , Invasividad Neoplásica , Metástasis de la Neoplasia , Rabdomiosarcoma/patología , Rabdomiosarcoma/fisiopatología , Células Tumorales CultivadasRESUMEN
BACKGROUND: Pleomorphic adenoma (PA) arising in the external auditory canal (EAC) is a very rare neoplasm, thought to be derived from ceruminous glands. CASE: A 43-year-old male presented with a slowly growing mass in the right EAC. Clinical and radiologic examinations showed a well-circumscribed tumor limited to the EAC, without a connection to the parotid gland. Fine needle aspiration cytology (FNAC) revealed the typical cytologic findings of PA. The diagnosis was confirmed by histologic examination. CONCLUSION: This case illustrates that together with clinical and radiologic findings, primary PA of the EAC can confidently be diagnosed by FNAC.
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Adenoma Pleomórfico/patología , Biopsia con Aguja , Conducto Auditivo Externo , Neoplasias del Oído/patología , Neoplasias de las Glándulas Salivales/patología , Adulto , Conducto Auditivo Externo/patología , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
BACKGROUND: Gain of genetic material from chromosome arm 17q (gain of segment 17q21-qter) is the most frequent cytogenetic abnormality of neuroblastoma cells. This gain has been associated with advanced disease, patients who are > or =1 year old, deletion of chromosome arm 1p, and amplification of the N-myc oncogene, all of which predict an adverse outcome. We investigated these associations and evaluated the prognostic importance of the status of chromosome 17. METHODS: We compiled molecular cytogenetic analyses of chromosome 17 in primary neuroblastomas in 313 patients at six European centers. Clinical and survival information were collected, along with data on 1p, N-myc, and ploidy. RESULTS: Unbalanced gain of segment 17q21-qter was found in 53.7 percent of the tumors, whereas the chromosome was normal in 46.3 percent. The gain of 17q was characteristic of advanced tumors and of tumors in children > or =1 year of age and was strongly associated with the deletion of 1p and amplification of N-myc. No tumor showed amplification of N-myc in the absence of either deletion of 1p or gain of 17q. Gain of 17q was a significant predictive factor for adverse outcome in univariate analysis. Among the patients with this abnormality, overall survival at five years was 30.6 percent (95 percent confidence interval, 21 to 40 percent), as compared with 86.0 percent (95 percent confidence interval, 78 to 91 percent) among those with normal 17q status. in multivariate analysis, gain of 17q was the most powerful prognostic factor, followed by the presence of stage 4 disease and deletion of 1p (hazard ratios, 3.4, 2.3, and 1.9, respectively). CONCLUSIONS: Gain of chromosome segment 17q21-qter is an important prognostic factor in children with neuroblastoma.
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Cromosomas Humanos Par 17 , Neuroblastoma/genética , Translocación Genética , Análisis de Varianza , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Amplificación de Genes , Genes myc/genética , Humanos , Lactante , Análisis Multivariante , Estadificación de Neoplasias , Neuroblastoma/mortalidad , Neuroblastoma/patología , Pronóstico , Análisis de Regresión , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Unbalanced translocations generating trisomy of 1q are common in Wilms tumor (WT). We present eight unbalanced 1q translocations from seven tumors and a review of the literature. An unbalanced translocation that results in a der(16)t(1q;16q) chromosome represents more than half of the published +1q generating translocations in WT. This translocation is also common to many other tumor types. Four of the tumors presented here contained this chromosome and,in two cases, it was the primary acquired cytogenetic abnormality within the tumor. The other four translocations involved 9q31, 9q34, 17p1?, and 21p11 as the partner to 1q. The chromosome 17 and 21 translocations occurred within the same tumor as apparently independent events. In contrast with the 16q translocations, these other translocations were secondary cytogenetic events, thereby indicating a role in tumor progression rather than initiation. Probes mapping to 1q12 and 1q21 were employed for fluorescence in situ hybridization and it was demonstrated that different 1q breakpoints are possible. In this series, the majority of breakpoints either mapped to 1q12 or were centromeric to this region.
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Cromosomas Humanos Par 1 , Translocación Genética , Trisomía , Tumor de Wilms/genética , Humanos , Hibridación Fluorescente in Situ , CariotipificaciónRESUMEN
PURPOSE: The clinical implications of many cytogenetic abnormalities in acute myeloid leukemia (AML) are now well established. However, questions about the significance of rarer abnormalities still exist, particularly in childhood disease. PATIENTS AND METHODS: We report a case of a 9 1/2-year-old girl who had AML of the FAB M2 subtype. A diagnostic bone marrow aspirate and subsequent bone marrow aspirates were investigated using conventional cytogenetic methods. RESULTS: Cytogenetic analysis of the diagnostic bone marrow aspirate showed a t(1;20)(p15;q11.2) translocation as the sole acquired abnormality. After one course of chemotherapy, the patient achieved hematopoietic and cytogenetic remission which has been sustained for 1 year after presentation. CONCLUSION: This report demonstrates that rare non-random cytogenetic abnormalities are still to be described in AML, and that care should be taken when ascribing clinical significance to cytogenetic findings in childhood disease based on those of older patients.
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Cromosomas Humanos Par 11 , Cromosomas Humanos Par 20 , Leucemia Mieloide Aguda/genética , Translocación Genética , Niño , Femenino , HumanosRESUMEN
We present the cytogenetic investigations of five histiocytic tumour lesions from children. In four cases there was a confirmed diagnosis of Langerhans cell histiocytosis (LCH) and one case of histiocytosis that did not fulfil all the criteria for true LCH. All five cases showed cytogenetic abnormalities, including the first report of an abnormal clone in LCH. The clone showed a t(7;12)(q11.2;p13) translocation and was detected in only a small percentage of cells. This case and a further three also contained non-clonal abnormalities and an increase in chromosome breakage. The fifth case, the only one in which no acquired abnormalities were seen, had a constitutional paracentric inversion of chromosome 13q.