Hemophagocytic syndrome in a patient with Fanconi anemia and VACTERL association / Síndrome hemofagocítica em paciente com anemia de Fanconi e associação VACTERL

INTRODUCTION: Hemophagocytic syndrome results from hyperactivity of histiocytes and lymphocytes, triggered by infections, mainly viral by cytomegalovirus, Epstein-Barr and herpes. Fanconi anemia (FA) is a rare genetic disease with heterogeneous symptoms common to other diseases such as VACTERL, a disease of unknown etiology in which there are several congenital malformations. The concomitance of Fanconi and VACTERL anemia occurs in 5 to 30% of FA patients. REPORT: A 14-month-old male infant was admitted to investigate fever, hepatosplenomegaly, and granulopenia. The patient was diagnosed with hemophagocytic syndrome due to hyperferritinemia, bone marrow hemophagocytosis, transaminase elevation, decreased fibrinogen, and cytomegalovirus (CMV) infection confirmed by serology and PCR. The test with mitomycin C (MMC) showed chromosomal fragility. The patient was diagnosed with a VACTERL/FA association for having a clinic and a test compatible with both FA and VACTERL. CONCLUSION: The VACTERL/FA association is seldom described, but is present in pediatric medical practice. This study presented the main clinical-laboratory aspects and reviewed the main aspects of the concurrence of this pathology.

INTRODUÇÃO: A síndrome hemofagocítica decorre da hiperatividade de histiócitos e linfócitos e é desencadeada por infeções, principalmente virais por citomegalovírus, Epstein-barr e herpes. A anemia de Fanconi (AF) é uma doença genética rara com sintomas heterogêneos em comum a outras doenças como a associação VACTERL, uma doença de etiologia desconhecida na qual existe diversas mal formações congênitas. A concomitância da anemia de Fanconi e VACTERL é descrita em 5 a 30% dos pacientes AF. RELATO: Lactente de 14 meses, sexo masculino, admitido para investigar um quadro de febre, hepatoesplenomegalia e granulopenia. Os exames laboratoriais mostraram a hiperferritemia, elevação da transaminases, medula óssea com hemofagocitose e, sorologia e PCR positivos para citomegalovírus (CMV). O paciente foi diagnosticado com síndrome hemofagocítica por citomegalovírus. Como havia também hipoplasia do polegar esquerdo, presença de hemivértebra, agenesia renal e teste positivo de fragilidades cromossômicas com mitomicina C (MMC), o paciente foi diagnosticado com associação VACTERL/AF. CONCLUSÃO: O citomegalovírus quando infecta pacientes com problemas de imunidade como AF, apresenta risco de desencadear a síndrome hemofagocítica. A associação VACTERL/AF é pouco descrita, mas presente na prática médica da pediatria. Esse estudo descreveu os principais aspectos clínicos-laboratoriais e revisou os aspectos fundamenais descritos sobre a concomitância dessas patologias.

Genetic analysis of an individual with a fragile site at 16q22 / 中华医学遗传学杂志

OBJECTIVE@#To analyze a patient with infertility and a fragile site found at 16q22 by using cytogenetic methods.@*METHODS@#Peripheral blood sample was taken from the patient and subjected to chromosomal karyotyping and single nucleotide polymorphism microarray (SNP-array) analysis.@*RESULTS@#The patient was found to be a mosaicism for a fragile site at 16q22, which has a variable morphology and cannot be induced by folic acid treatment. No abnormality was found by SNP-array analysis.@*CONCLUSION@#A rare fragile site, which can be induced without folic acid treatment, has been identified at 16q22. The strategy of assisted reproduction for such individuals is yet to be explored.

Molecular characterization of X chromosome fragility in idiopathic mental retardation

Background: Fragile X syndrome [FXS] is the most common form of inherited mental retardation. Frequency of fragile X syndrome among male siblings and relatives of mentally retarded patients is relatively high. Cytogenetic diagnosis of FXS is unreliable since it is ineffective for the diagnosis of premutated males or females. Proper molecular diagnosis is a pre-requisite for providing proper counseling advice

Subjects and methods: Sixty-four males with idiopathic mental retardation, ranging in age from 4.2 to 19 years [10.92+/- 4.00] were clinically pre-selected, based on scoring protocol comprising eight features of the syndrome, before molecular testing. A rapid polymerase chain reactionbased screening was applied for detection of expanded FMR1 alleles. Samples that did not yield the normal band lengths were subjected to a second PCR screen. The secondary screen utilizes a chimeric primer demonstrating the presence or absence of an expanded allele

Results: Amplification of FMRI gene by PCR of tested patients revealed that 8 cases [12.5%] have full mutation and 6 cases [9.4%] have premutation. A wide range of Fra X-scoring ranging from 1 to 7 features was detected in examined cases. Significant clinical features included large prominent ears, hyperextensibility of joints and macroorchidism in post pubertal males

Conclusions: A simplified checklist of fragile X should be used for patients with idiopathic MR and those patients above score 3 should be tested for FXS. The diagnostic assay may be used as a screening method for fragile X syndrome being rapid and cost effective compared to other techniques. In addition, screening of all relatives of proven patients should be performed to detect clinically unidentified cases for provision of proper counseling and optimal management of detected cases

Mecanismos de apoptosis en testículos de ratones con rearreglos cromosómaticos robertsonianos / Mechanisms of apoptosis in testes of mice with Robertsonian chromosomal rearrangements

Se han reportado casos de esterilidad masculina en seres humanos portadores de fusiones Robertsonianas. En este trabajo se estudió el deterioro espermatogénico y la participación de las vías apoptóticas en dos modelos animales de ratones machos: híbridos subfértiles (hembras CD1 x machos Milano II) de 5 meses de edad e híbridos infértiles (hembras Graomys griseoflavus x machos Graomys centralis) de 1, 2 y 3 meses de edad, con fusiones Robertsonianas. La presencia de apoptosis se estudió mediante inmunohistoquímica y análisis de Western blots de las moléculas pro-apoptóticas Fas, Fas-L, Bax, citocromo c y caspasa-3, y calbindina D28K como molécula antiapoptótica. La fragmentación del ADN se analizó mediante la técnica de TUNEL. La ultraestructura testicular se visualizó por microscopía electrónica. Los resultados revelaron que la morfología y las asociaciones celulares del epitelio seminífero fueron anormales en los ratones híbridos Robertsonianos, con un mayor deterioro en los híbridos infértiles. Un intenso proceso apoptótico se observó en los túbulos seminíferos del estadio XII en los híbridos subfértiles, principalmente en los espermatocitos en metafase. Estos espermatocitos también mostraron redistribución de Bax y citocromo c. Los ratones híbridos infértiles presentaron mayor mortalidad de células germinales, con arresto de la espermatogénesis en estadios pre-meióticos. La apoptosis de las células germinales se produjo especialmente a nivel de los espermatocitos en paquitene, no llegándose en ningún caso a la espermatogénesis completa. Los espermatocitos de los tres grupos de animales Graomys de 1 mes de edad fueron positivos para todos los marcadores apoptóticos. En los parentales, esta expresión disminuyó a los 2 y 3 meses, mientras que permaneció elevada en los testículos de los híbridos.

Principales factores que producen fragilidad cromosómica transitoria en los pacientes referidos para estudio citogenético / Main factors that produce transitory chromosomic fragility in the patients referred for cytogenetic study

The fragile sites are specific loci that show fractures during karyotyping perform under specific laboratory conditions. Are present in normal individuals and are classified by their population frequency. These sites have been associated with an increase in chromosome fragility, fractures and other chromosomal abnormalities. In recent years, the fragile sites have taken great importance because they represent regions in the genome that are particularly sensitive to replicative stress and are frequently rearrenged in tumor cells. Multiple risk factors endogenous and exogenous have been involved in the increase in chromosome fragility, including microorganisms, drugs, illegal drugs and toxins. The fragile sites have provided insight into understanding of the effects of replicative stress on DNA damage and genomic instability in cancer cells. In this work we aim to summarize the limited information available about the topic, and the clinical significance of fragile sites in vivo in the laboratory.

The Expression of Folate Sensitive Fragile Sites in Patients with Bipolar Disorder

PURPOSE: Genetic factors are known to be important in the etiology of bipolar disorder (BD). The fragile sites (FSs) are a very interesting subject for the study of clinical disorders. The aim of this study was to evaluate fragile sites seen in patients with bipolar disorder and find a correlation between some fragile sites and bipolar disorder. PATIENTS AND METHODS: The frequencies of folate sensitive FSs were compared in short-term whole blood cultures from bipolar patients and from normal individuals. RESULTS: The rate of FS expression in the patients was considerably higher than in the controls (p < 0.001). Several chromosome regions including 1p36, 1q21, 1q32, 3p25, 7q22, 7q32, 11q23, 12q24, 13q32, 14q24, Xp22 and Xq26 were represented considerably more often in the patients than in the controls (p value between 0.001 to 0.036). Among these FSs, the sites 1p36, 1q21, 3p25, 7q22, 7q32, and 14q24 were not observed in other studies. CONCLUSION: These regions can be the most active of hot spots in the genomes of bipolar patients, and may harbor important genes associated with BD.

Fragility in the 14q21q translocation region

Aphidicolin (APC)-induced chromosomal breakage was analyzed for women representing three generations of a single family and carrying a Robertsonian translocation rob(14q21q). Fluorescence in situ hybridization (FISH) analysis confirmed the dicentric constitution of the derived chromosome and indicated the absence of beta-satellite signal at the translocation region. Per-individual analysis of metaphases from APC-treated peripheral blood lymphocyte cultures identified significantly nonrandom chromosomal breakage at the translocation region in all three individuals examined. The APC-inducible fragility at the 14q21q translocation region suggests that this rearrangement was the result of chromosomal mutation at fragile site(s) in the progenitor chromosomes, or that this fragility was the result of the fusion of nonfragile progenitor chromosomes

Chromosomal defects in 34 male homosexuals, half of them with HIV antibodies

Most of the research about viral interactions with human chromosomes was done during the sixties and early seventies and very few was performed after the human immunodeficiency virus (HIV) appearance as an epidemic in the eighties. The objective of this work was to estimate if particular chromosomal changes follow the infection of homosexual males by HIV and to determine if the lifestyle, habits, sexual practices, of our sample of male homosexuals predisposes them to chromosomal abnormalities at a higher rate than the background level of cytogenetic damage the general population has. This was a double blinded case-control study, 17 individuals positive for HIV antibodies (HIV+) detected by enzyme-linked immunosorbent assay (ELISA) and confirmed by western blot (WB) were the cases, and 17 individuals negative for HIV antibodies (HIV-) the controls. These men were a very homogeneous population in terms of age, social status, lifestyles, drug abuse, sexual practices and education. Blood was collected between September 1988 and October 1989. Fresh whole blood was cultured in duplicate for 72 hr. Cell harvest followed conventional methods. Once all cell cultures were gathered, the tubes were picked up at random and air dried chromosome preparations were trypsin-giemsa banded (GTG) after overnight incubation at 60 C degrees. The percentage of gaps and breaks these men had was not different from the reported for the general population, nor were there significant difference among both groups (O.R. = 1.8) in items of amount of chromosomal fragility. The distinction among them was at the level of the specific chromosomal sites where the gaps and breaks located, being sites at 2p21 and at 3p21 four times more frequent among HIV+. These probably represent viral modification sites on chromosomes which are known to look like non-staining gaps which are caused by the virus or viral products. This presumption is supported by an earlier report of repeated breaks at 3p21.1, in fact this was the most common lesion site in this study of chromosomal aberrations of male homosexuals and the authors even considered the probability of "a new type of chromosome marker". Furthermore, years later the CKR5 structural gene was mapped to human chromosome 3p21. This gene codes for the chemokine receptor 5 (CKR5) protein which serves as a secondary receptor on CD4+ T lymphocytes for certain strains of HIV-1. It is possible that this gene was being transcribed in HIV+ men and the cons

Enhancement of bleomycin induced cytoggenetic damage in blood cultures after griseofulvin therapy

Griseofulvin [GF], a naturally occurring food contaminant and a widely prescribed cheap and effective antifungal drug, was tested for its potential mutagenicity using the conventional cytogenetic method to assess the frequency of chromosomal aberrations [CA] in the cultured blood cells of GF treated patients receiving the drug in a dose of 12.5 mg/kg/d. Fourteen patients complaining of Tinea capitis and corporis were divided into two groups according to the duration of therapy [four to six weeks and eight weeks]. Ten healthy control subjects of matched age and sex, who did not receive GF served as blood donors for bleomycin [BLM] tests. It might be considered as a co-mutagen, when there is concomitant exposure of patients receiving GF therapy for a long duration to any radiomimetic agent, as GF amplified their cytogenetic damage. The study recommended the integration of bleomycin test for chromosomal fragility with other cytogenetic assays during the evaluation of the genotoxicity of any chemical agent, as it reflects its possible interaction with any radiomimetic agent

Expresión de sitios frágiles en neoplasias mieloides / Fragile site expression in myeloid leukemias

El objetivo del presente trabajo fue evaluar la expresión de sitios frágiles (SF) en pacientes con leucemia mieloide crónica (LMC) y leucemia mieloblástica aguda (LMA) a fin de establecer si expresan SF constitucionales en los mismos puntos de ruptura de las alteraciones cromosómicas presentes en el tejido neoplásico. Se estudiaron 9 pacientes con LMA, 7 con LMC y 7 individuos sanos. Se determinó el cariotipo en médula ósea y se indujo la expresión de SF con FUDR (10 µg/ml) y BUDR (50 µg/ml) en sangre periférica. El estudio citogenético de médula ósea demostró que todos los casos de LMC presentaron la t(9;22)(q34;q11). En LMA se encontraron 4 individuos con cariotipo normal y los restantes presentaron las siguientes alteraciones clonales: t(3;8)(q11;q13), del (5)(p11), t(3;11)(q21;p15), inv(16)(p13;q22), t(9;22) y del (9q). En los pacientes con LMC no se encontraron SF en las bandas 9q34 ó 22q11, involucradas en el cromosoma Phû. Tampoco se identificaron SF en los puntos de ruptura implicados en AC estructurales de los pacientes con LMA. Estos resultados sugerirían que los SF no estarían involucrados con el origen de los marcadores cromosómicos hallados en estas neoplasias.

Situación y perspectivas de desarrollo de la genetica humana en el Ecuador / Situation and perspective of development of the human genetics in Ecuador

Contiene los res£menes de las exposiciones y documentos del Seminario sobre genética humana sin precedentes realizado en el Ecuador en 1997. Presenta estudios exhaustivos y completos sobre la genética médica y sus fundamentos, as¡ como los principales factores hereditarios que interviene en las malformaci¢n o disfunsiones humanas...

Participacion de los sitios fragiles en cancer / Participation of fragile sites in cancer

La mayor parte de las neoplasias hematológicas y tumores sólidos presentan anomalfas cromosómicas especfficas, numéricas e estructurales, que podrían originarse debido a la existencia de ciertas zonas lábiles en el genoma, denominadas sitios frágiles (SF). Estos sitios se pueden definir como puntos específicos de los cromosomas con mayor susceptibilidad a rupturas y reordenamientos cromosómicos en las células somáticas levando a la activación de oncogenes o a la inactivación de genes supresores de tumor o antioncogenes, iniciando los primeros pasos del proceso oncogénico. En este trabajo se explica la calsificación y los mecanismos de inducción y se discute el significado biológico de estos sitios, principalmente su vinculación con el câncer.

Alteraciones cromosómicas inducidas por el polvo casero de la ciudad de Mexicali, Baja California / Chromosomic alterations induced by domestic dust in the city of Mexicaly, Baja California

El polvo de Mexicali es una mezcla de partículas formada por aluminosilicatos de potasio (98 por ciento) y dióxido de silicio (2 por ciento) que tiene potencial patogénico. El presente estudio se encaminó a evaluar el potencial de este polvo para inducir aberraciones cromosómicas. Se utilizó hierro carbonilo y asbesto crisótilo como controles negativo y positivo, respectivamente. Se emplearon linfocitos humanos de sangre periférica como células blanco provenientes de ocho donadores (hombres de 25-40 años sin antecedentes de cáncer en la familia), tres para la realización de curvas dosis-respuesta y cinco para los ensayos de caracterización de rompimientos cromosómicos. Se encontró que los polvos inducen alteraciones numéricas, independientemente del polvo evaluado, y se observó una tendencia a incrementarse el número de alteraciones numéricas conforme aumentó la dosis. También se observó que a la dosis de 50 µ/mL el polvo de Mexicali indujo un mayor número de aberraciones estructurales (6-15 por ciento), por lo que ésta fue la dosis empleada para la caracterización de las alterciones estructurales por medio del método de bandas GTG. Dentro de los rompimientos que pudieron ser caracterizados se encontraron algunos asociados a sitios frágiles y a bandas en las que se sabe existen protooncogenes o genes supresores de tumor

Estudo da fragilidade cromossomica e cariotípico em pacientes com distúrbio bipolar do tipo I / Chromosomal fragility and karyotypic study in patients with type I bipolar disorder

Estudar a associaçäo de alteraçöes estruturais cromoss"micas particularmente de sítios fr geis, com distúrbio bipolar do tipo I. Planejamento: a) Investigaçäo de sítios fr geis: estudo caso-controle comparando pacientes bipolares com controles normais; b) investigaçäo cariotípica: estudo descritivo. Pacientes/participantes: Vinte e cinco casos com distúrbio bipolar do tipo I diagnosticados de acordo com os critérios do DSM-III-R através do Composite International Diagnostic Interview (CIDI), foram selecionados do programa ambulatorial de distúrbios afetivos da Escola Paulista de Medicina. Para o estudo de sítios fr geis, dez deles foram emparelhados por sexo e idade com dez controles sadios (CIDI negativos para distúrbios psiqui tricos) provenientes do ambulatório geral de otorrinolaringologia da mesma instituiçäo. Intervençäo: An lise citogenètica foi realizada em linfócitos sanguíneos cultivados em: a) meio pobre em folatos para a investigaçäo de sítios fr geis; b) meio padräo para o estudo cariotípico. Aferiçäo: a) Estudo de sítios fr geis: cem mitoses por indivíduo foram analisadas em teste cego ao diagnóstico psiqui trico. Os sítios fr geis foram identificados de acordo com uma frequência mínima de eventos esperada por banda de acordo com uma distribuiçäo de Poisson; b) Estudo cariotípico: 16 mitoses por indivíduo foram analisadas tentando-se identificar possíveis alteraçöes estruturais cromoss"micas cujos pontos de quebra possam sugerir locais de genes associados ao distúrbio bipolar. Resultados: a) Estudos de sítios fr geis: foi encontrada entre os casos maior frequência de lesöes nas seguintes bandas: 1q32, 5q31 e 11q23, sendo 1q32 o único sítio considerado fr gil; b) estudo cariotípico: näo foram evidenciadas alteraçöes estruturais cromoss"micas nem numéricas. Conclusöes: Apesar de que até o momento nenhum componente etiológico aparentemente envolvido em distúrbios neuro-psiqui tricos tenha sido mapeado na regiäo 1q32, estes achados podem levar a futuras investigaçöes de possível ligaçäo entre marcadores genéticos desta regiäo e o distúrbio bipolar

Chromosomal break points in irradiated and ethyl methane sulphonate treated leucocytes of patients with Down syndrome.

Frequencies of chromosomal damage in the peripheral leucocytes of patients with Down syndrome, on exposure to gamma rays (2Gy) or ethyl methane sulphonate (EMS, 1x 10(-4) M), were assessed. Analysis of break points in the chromosomes of irradiated cells revealed a non-random occurrence. Six of the break points observed in EMS-treated cells were found to overlap with those recorded in irradiated cells. Thirteen break points observed were found to correlate with the location of cancer-specific break points and four of these coincided with the bands where oncogenes have been located. Two break points were localised to the same bands as that of known heritable fragile sites.

Induccion de sitios fragiles por agentes quimicos y fisicos / Induction of fragile sites by chemical and physical agents

En la actualidad se acepta que muchas neoplasias humanas están causadas por factores y muchos mutágenos químicos inducen aberraciones cormosómicas (AC), las caules se cree que se origina por roturas en zonas cromosómicas específicas o sitios frágiles (SF). Los SF se estudiaron en cultivos de linfocitos expuestos a diversos inductores químicos, pero todavia no se conoce como influyen los factores ambientales en su expresión. Hasta ahora no hay estudios de SF inducidos con rayos X, ni se conoce la interacción de este agente con los inductores quimicos. Este es el primer trabajo que analiza la expresión de SF inducida por rayos X y por 3 inductores de SF: BUDR, FUDR y anfidicolina. Se identificaron 17 bandas cromosómicas significtivamente afectadas (p<0.oo1), que se definieron como SF. Los SF más frecuentes estaban localizados en las bandas 3p14 y 16q23. Se observó un aumento significativo (p<0.01) de AC y SF en el cultivo expuesto a rayos X y en el tratado con FUDR más radiación, indicando la conveniencia de emplear otro agente radiosensibilizador. Los resultados observados sugerirían que muchos SF pueden ser causados por factores ambientales tales como sustancias químicas o radiación. La alta correlación establecida entre los SF y la ubicación de AC inducidos por radiación, AC en cáncer y oncogenes demostraría la importante interacción entre SF, AC y oncogenes en el proceso neoplásico

Chromosome studies im males affected by Duchenne or Becker muscular dystrophy

Estudamos citogeneticamente 48 pacientes de sexo masculino, casos isolados de distrofia muscular de Duchenne ou Becker. Todos apresentaram cromossomos X normais. Fragilidade da bandfa Xp21 foi investigada em 28 pacientes e somente uma célula apresentou quebra cromossômica nessa regiäo no total de 1400 células analisadas (0.07%). A baixa frequência de quebra exclue Xp21 como um sítio frágil nestes pacientes

Familial fragile secondary constriction on chromosome 2 (2q11) with unusual features and psychomotor retardation.

A child with fragile secondary constriction 2q11 associated with unusual clinical features and psychomotor retardation is described. The pathogenetic significance of this fragile site still remains unclear, and heterogeneity of clinical manifestations is not well understood.