RESUMEN
BACKGROUND: The differential diagnosis of vaginal blood loss in childhood is broad, and includes irritation of the mucous membranes, trauma, tumours, foreign bodies and sexual abuse. Physical and additional examination is often initially difficult; however, prompt detection of a rhabdomyosarcoma, a soft-tissue tumour principally diagnosed in childhood, is vitally important. CASE DESCRIPTION: A 3-year-old girl with a history of vaginal blood loss and an introital mass was referred to the gynaecologist. Treatment with oestriol and triamcinolone cream did not lead to healing. Pathological examination of a biopsy taken under general anaesthetic indicated an embryonic rhabdomyosarcoma. Chemotherapy, surgical resection and brachytherapy lead to persistent remission of the tumour. CONCLUSION: Because rhabdomyosarcoma is rare and can present atypically, diagnosis can be delayed. Early recognition is, however, essential and this condition should be placed high in the differential diagnosis by vaginal blood loss or vaginal abnormality in childhood.
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Rabdomiosarcoma/diagnóstico , Hemorragia Uterina/diagnóstico , Biopsia , Braquiterapia , Preescolar , Femenino , Humanos , Rabdomiosarcoma/terapia , Hemorragia Uterina/etiologíaRESUMEN
PURPOSE: Head and neck rhabdomyosarcoma (HNRMS) survivors are at increased risk of developing pituitary dysfunction as an adverse event of radiotherapy. Our aim was to investigate the frequency and risk factors for pituitary dysfunction in these survivors. Secondly, we aimed to compare the prevalence of pituitary dysfunction between survivors treated with external beam radiation therapy (EBRT) and survivors treated with the ablative surgery, moulage technique after loading brachytherapy, and surgical reconstruction (AMORE) procedure. METHODS: Eighty HNRMS survivors treated in London (EBRT based) and Amsterdam (AMORE based: AMORE if feasible, otherwise EBRT) in the period 1990-2010 and alive ≥ 2 years post-treatment were evaluated. Survivors were evaluated in multidisciplinary late-effects clinics, with measurement of linear growth, determination of thyroid function, and growth hormone parameters. Additional data, such as baseline characteristics, anthropometrics, pubertal stage, and the results of additional laboratory investigations, were retrieved from patient charts. RESULTS: Pituitary dysfunction was diagnosed in 24 in 80 (30%) survivors, after a median follow-up time of 11 years. Median time to develop pituitary dysfunction after HNRMS diagnosis was 3.0 years. Risk factors were EBRT-based therapy (odds ratio [OR] 2.06; 95% confidence interval [CI] 1.79-2.46), parameningeal tumour site (OR 1.83; 95% CI 1.60-2.17) and embryonal RMS histology (OR 1.49; 95% CI 1.19-1.90). CONCLUSIONS: Radiotherapy used for the treatment of HNRMS confers a significant risk of the development of pituitary dysfunction. AMORE-based treatment in children with HNRMS resulted in less pituitary dysfunction than treatment with conventional EBRT. Our findings underscore the importance of routine early endocrine follow-up in this specific population.
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Braquiterapia/efectos adversos , Irradiación Craneana/efectos adversos , Neoplasias de Cabeza y Cuello/radioterapia , Enfermedades de la Hipófisis/epidemiología , Traumatismos por Radiación/epidemiología , Rabdomiosarcoma/radioterapia , Sobrevivientes , Adolescente , Desarrollo del Adolescente , Adulto , Factores de Edad , Niño , Desarrollo Infantil , Preescolar , Estudios Transversales , Femenino , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Incidencia , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Modelos Logísticos , Londres/epidemiología , Masculino , Análisis Multivariante , Países Bajos/epidemiología , Oportunidad Relativa , Enfermedades de la Hipófisis/diagnóstico , Pruebas de Función Hipofisaria , Prevalencia , Traumatismos por Radiación/diagnóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Rabdomiosarcoma/cirugía , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
The human FCGR2/3 locus, containing five highly homologous genes encoding the major IgG receptors, shows extensive copy number variation (CNV) associated with susceptibility to autoimmune diseases. Having genotyped >4000 individuals, we show that all CNV at this locus can be explained by nonallelic homologous recombination (NAHR) of the two paralogous repeats that constitute the majority of the locus, and describe four distinct CNV regions (CNRs) with a highly variable prevalence in the population. Apart from CNV, NAHR events also created several hitherto unidentified chimeric FCGR2 genes. These include an FCGR2A/2C chimeric gene that causes a decreased expression of FcγRIIa on phagocytes, resulting in a decreased production of reactive oxygen species in response to immune complexes, compared with wild-type FCGR2A. Conversely, FCGR2C/2A chimeric genes were identified to lead to an increased expression of FCGR2C. Finally, a rare FCGR2B null-variant allele was found, in which a polymorphic stop codon of FCGR2C is introduced into one FCGR2B gene, resulting in a 50% reduction in protein expression. Our study on CNRs and the chimeric genes is essential for the correct interpretation of association studies on FCGR genes as a determinant for disease susceptibility, and may explain some as yet unidentified extreme phenotypes of immune-mediated disease.
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Receptores de IgG/genética , Alelos , Variaciones en el Número de Copia de ADN/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Recombinación Homóloga , Humanos , Proteínas Mutantes Quiméricas/genética , Proteínas Mutantes Quiméricas/metabolismo , Polimorfismo de Nucleótido SimpleRESUMEN
Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case-control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3-CCR2-CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5-Delta32 was observed with an allele frequency of 10.7% in the control population compared to 6.5% in the KD patients (P = 0.04). Two haplotypes of the CCR3-CCR2-CCR5 gene-cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene-cluster CCR3-CCR2-CCR5 was observed.
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Síndrome Mucocutáneo Linfonodular/genética , Polimorfismo de Nucleótido Simple , Receptores de Quimiocina/genética , Estudios de Casos y Controles , Cromosomas Humanos Par 3/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Haplotipos , Humanos , Receptores CCR2 , Receptores CCR3 , Receptores CCR5/genéticaRESUMEN
OBJECTIVE: To investigate whether common genetic variants in the vascular endothelial growth factor (VEGF) gene are associated with Kawasaki disease (KD) and the subsequent development of coronary artery lesions. METHODS: Common genetic variants in the VEGF gene were analyzed in an association study in a Dutch cohort of 170 KD patients and 300 healthy Dutch Caucasian controls. Genotyping was done with 5'-nuclease TaqMan assays and 3'-hybridization-triggered fluorescence minor groove binder Eclipse assays. RESULTS: An association with susceptibility to KD was observed with 2 of the 6 single-nucleotide polymorphisms analyzed in VEGF: -2594 A>C (rs699947) and the 236 bp 3' of STP C>T (rs3025039). Also for an 18-bp deletion in the promoter of VEGF a significant difference in the genotype and allele frequencies was observed between the KD patients and the controls. The haplotype CGCC (based on rs699947, rs2010963, rs25648, and rs3025039) was significantly associated with the development of KD (hap score 3.8; P = 0.0002). VEGF plasma levels were significantly higher in patients with the early phase of KD than in the healthy controls, and there was a trend toward higher VEGF plasma levels in KD patients with the -2594 CC and 236 bp 3' of STP CC genotypes. CONCLUSION: Our results suggest that polymorphisms of the VEGF gene may play a role in the pathogenesis of KD.
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Haplotipos , Síndrome Mucocutáneo Linfonodular/genética , Factores de Crecimiento Endotelial Vascular/genética , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Polimorfismo GenéticoRESUMEN
Prospective studies in children with B-precursor acute lymphoblastic leukaemia (ALL) have shown that polymerase chain reaction (PCR)-based detection of minimal residual disease (MRD) using immunoglobin (Ig) and T-cell receptor (TCR) gene rearrangements as targets can be used to identify patients with a high relapse risk. The disadvantage of this approach is that for each patient preferably two different targets have to be identified. The t(12;21)(p13;q22) with the TEL-AML1 fusion gene is present in approximately 25% of children with B-precursor ALL. In these patients, sensitive reverse transcription (RT)-PCR analysis of the TEL-AML1 fusion transcript might be a more simple and less laborious alternative approach. However, it is unknown how stable the mRNA is and whether the number of transcripts per leukaemic cell remains constant during follow-up. We investigated whether the MRD results obtained using RT-PCR of TEL-AML1 transcripts correlated with the clinically validated genomic PCR for Ig and TCR gene rearrangements. Therefore, we used real-time quantitative (RQ)-PCR analysis for both types of targets and assessed the MRD levels in 36 follow-up bone marrow samples (obtained during the first 1.5 years after diagnosis) from 13 patients with B-precursor ALL. In 34/36 bone marrow samples the Ig/TCR RQ-PCR and TEL-AML1 RQ-PCR revealed equal levels of MRD and these results had a strong correlation (P < 0.0001, R2 = 0.84). Therefore, we conclude that the TEL-AML1 RQ-PCR can, in principle, replace Ig/TCR RQ-PCR in B-precursor ALL with t(12;21).
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Neoplasia Residual/diagnóstico , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , ARN Mensajero/análisis , Niño , Sistemas de Computación , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Estudios de Seguimiento , Reordenamiento Génico de Linfocito T , Genes de Inmunoglobulinas , Humanos , Modelos Lineales , Sensibilidad y EspecificidadRESUMEN
Large-scale clinical studies on detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) have shown that quantification of MRD levels is needed for reliable MRD-based risk group classification. Recently, we have shown that 'real-time' quantitative PCR (RQ-PCR) can be applied for this purpose using patient-specific immunoglobulin (Ig) and T cell receptor (TCR) gene rearrangements as PCR targets with TaqMan probes at the position of the junctional region and two germline primers. Now, we tested an alternative approach on 35 immunoglobulin heavy chain (IGH) gene rearrangements, by designing three germline JH TaqMan probes to be used in combination with one of six corresponding germline JH primers and one allele specific oligonucleotide (ASO) primer complementary to the junctional region. In nine cases in which both approaches were compared, at least similar (n = 4) or slightly higher (n= 5) maximal sensitivities were obtained using an ASO primer. The ASO primer approach reached maximal sensitivities of at least 10(-4) in 33 out of 35 IGH rearrangements. The reproducible range for accurate quantification spanned four to five orders of magnitude in 31 out of 35 cases. In 13 out of 35 rearrangements the stringency of PCR conditions had to be increased to remove or diminish background signals; this only concerned the frequently occurring JH4, JH5 and JH6 gene rearrangements. After optimization of the conditions (mainly by increasing the annealing temperature), only occasional aspecific amplification signals were observed at high threshold cycle (CT) values above 42 cycles and at least six cycles above the CT value of the detection limit. Hence, these rare aspecific signals could be easily discriminated from specific signals. We conclude that the here presented set of three germline JH Taq-Man probes and six corresponding germline JH primers can be used to develop patient-specific RQ-PCR assays, which allow accurate and sensitive MRD analysis in almost all IGH gene rearrangements. These results will facilitate standardized RQ-PCR analysis for MRD detection in large clinical studies.