INTRODUCTION:Anaplastic lymphoma kinase (ALK) rearrangement located on the short arm of chromosome 2, region 2 and band 3 is frequent in lung cancer patients who respond to targeted therapies with ALK inhibitors Therefore, their identification has become a standard diagnostic test in patients with advanced NSCLS, as such chromosomal alterations may lead to the activation of important signalling pathways involved in cell survival and proliferation. METHODS:To investigate the ALK gene status, we performed FISH and IHC assays in 18 lung adenocarcinoma patients, 12 women and 6 men, aged between 29 and 85 years. Paraffin-embedded samples were analyzed in the Pathology Department of the Hospital Universitario San Ignacio. RESULTS:Results between the two techniques in 5 patients showed discordant patterns, being positive for FISH and negative for IHC. The borderline to define ALK positivity was set at 15%, These results present experimental evidence that the techniques differ in specific situations. CONCLUSIONS:Our findings show that it is advisable to investigate the ALK gene status in patients with suspected lung cancer using both FISH and IHC in combination.

Antecedentes: la Anemia de Fanconi (AF) es una enfermedad heredada, que afecta la reparación del ADN. Clínicamente es heterogénea; mayoritariamente se presentan malformaciones congénitas, aplasia medular temprana y predisposición a cáncer. El defecto genético causa hipersensibilidad a genotóxicos e inestabilidad cromosómica. Esta característica se considera el mejor marcador diagnóstico; sin embargo, llegar a él puede convertirse en un desafío. Objetivo: caracterizar pacientes con AF mediante pruebas citogenéticas en individuos con rasgos clínicos sugestivos de la enfermedad. Métodos: se analizaron 157 individuos con sospecha clínica de AF, 19 con asociación VACTERL, 15 hermanos, y 34 individuos sanos. Se realizó registro de datos clínicos, y prueba citogenética con Diepoxibutano (DEB). Resultados: se identificaron 43 afectados por AF. La relación de índices en células tratadas con DEB del grupo AF vs. No-AF fue significativamente incrementada, 6.7 veces la proporción de células aberrantes, 48 veces el número de roturas por célula, y 6.3 veces el número de roturas por célula aberrante. En AF la edad media de muestreo fue 9.2 años, la proporción de sexos M:F 1.5:1, consanguinidad en 11 casos. Los sistemas hematológico, esquelético, tegumentario, y urinario estuvieron significativamente alterados. Conclusiones: La AF se identificó en 26 % del grupo de sospecha y en 13 % de hermanos sin sospecha previa. La enfermedad hematológica fue el síntoma más recurrente presente en 93 % de los casos, y fue principalmente la primera sospecha de AF y motivo de estudio genético.

Antecedentes: Los trastornos del desarrollo sexual (TDS) incluyen un grupo de entidades clínicas infrecuentes. La baja prevalencia de estas enfermedades y el impacto social que tienen en la comunidad requieren el registro sistemático de la información clínica de los pacientes. Objetivo: caracterizar el espectro clínico de los casos de trastornos del desarrollo sexual diferentes al síndrome de Turner y Klinefelter valorados en el Hospital Universitario San Ignacio. Métodos: por cada caso se diligenció un formulario electrónico diseñado en la herramienta RedCap®, las variables consideradas para el registro se escogieron siguiendo las recomendaciones del Registro Internacional de Desórdenes de Diferenciación sexual (I-DSD). Resultados: se incluyeron en total 28 pacientes, 2 fueron diagnosticados con un tipo de trastorno de los cromosomas sexuales, 17 fueron diagnosticados con un tipo de trastorno del desarrollo sexual 46,XY y 9 con algún tipo de trastorno del desarrollo sexual 46,XX. Diferentes pruebas moleculares fueron solicitadas en el 96,4% de casos, logrando definir un diagnóstico etiológico en 7/28 de los casos. Conclusiones: nuestros hallazgos resaltan la importancia de los estudios citogenéticos como pruebas de primera línea en el enfoque diagnóstico de pacientes con TDS. Este trabajo es el inicio del primer registro de trastornos del desarrollo sexual no solo institucional sino nacional y muy seguramente aportará bases académicas para la construcción y ejecución de futuras investigaciones que permitan generar recomendaciones basadas en la evidencia para mejorar la atención clínica de los individuos afectados con algún tipo de TDS

Objetivo Los trastornos del desarrollo sexual son un grupo de enfermedades congénitas que afectan la formación normal de los genitales. Dentro los mecanismos fisiopatológicos descritos existen factores genéticos causados por alteraciones cromosómicas o en los genes determinantes en la diferenciación sexual. En este trabajo se analizaron alteraciones cromosómicas y en el gen SRY como posible causa del trastorno. Se realizó cariotipo con bandas G o R y FISH para SRY en linfocitos, tejido gonadal y tejido escrotal.   Materiales y métodos La información clínica de los sujetos de investigación se obtuvo de los informes de los médicos tratantes. En 9 (73%) casos el sexo asignado fue masculino y en 3 (27%) casos fue femenino. 8 de los casos (66%) tuvieron cariotipo 46,XY; 2 casos (17%) 46,XX y en 2 casos (17%) se reportaron mosaicos con presencia de idic(Y). Un solo caso de tejido gonadal mostró mosaicismo debido a la presencia de una línea celular tetraploide. El diagnóstico clínico más frecuente fue de genitales ambiguos en 8 casos (67%). Seguido de hipospadias en 5 casos (41,7%).   Conclusiones Los resultados muestran la importancia de aplicar diferentes pruebas citogenéticas en el diagnóstico y la necesidad del seguimiento de los pacientes por un equipo transdisciplinario para abordar estas condiciones clínicas.

Objectives: Etiology of gonadal dysgenesis and ovotesticular syndrome is unknown in a majority of cases. To perform cytogenetic and molecular characterization of a group of patients with ovotesticular syndrome and complete gonadal dysgenesis from peripheral blood and gonadal tissue samples. Materials and methods: A total of 6 patients were included, 3 with diagnosis of 46,XX ovotesticular syndrome, one diagnosed with 46,XY ovotesticular syndrome; one with suspected 46,XX gonadal dysgenesis, and one with 46,XY complete gonadal dysgenesis. Results: All patients were evaluated with karyotype, fluorescent in situ hybridization (FISH) for SRY, multiplex ligation-dependent probe amplification (MLPA) and comparative genomic hybridization (aCGH) on peripheral blood samples. In cases with available gonadal tissue, the levels of genetic expression of SOX3, SRY, and SOX9 were determined through real-time PCR and immunofluorescence. Rearrangements involving SRY gene were ruled out. No deletions/duplications or copy-number variations (CNV) were detected as the etiology for sexual development disorder in any of the patients studied. In a case of 46,XX ovotesticular syndrome, the gonadal karyotype was different from the karyotype in peripheral blood. Aberrant expression of SOX3 and SOX9 in gonadal tissue of a case with 46,XX ovotesticular syndrome was observed. Conclusions: Lower levels of expression of SRY and SOX9 compared to the levels in human cellular lines of embryonic testicle and Sertoli were documented in the gonadal tissue of a case with 46,XY ovotesticular syndrome. Cytogenetic and molecular studies of the gonads as a complement to peripheral blood study have the potential to enrich the understanding of sexual development disorders in patients who are XX or XY in peripheral blood.

BACKGROUND:Analysis of patients with chromosomal abnormalities, including Turner syndrome and Klinefelter syndrome, has highlighted the importance of X-linked gene dosage as a contributing factor for disease susceptibility. Escape from X-inactivation and X-linked imprinting can result in transcriptional differences between normal men and women as well as in patients with sex chromosome abnormalities. OBJECTIVE:To identify differentially expressed genes among patients with Turner (45,X) and Klinefelter (46,XXY) syndrome using bioinformatics analysis. METHODOLOGY:Two gene expression data sets of Turner (45,X) and Klinefelter syndrome (47,XXY) were obtained from the Gene Omnibus Expression (GEO) database of the National Center for Biotechnology Information (NCBI). Statistical analysis was performed using R Bioconductor libraries. Differentially expressed genes (DEGs) were determined using significance analysis of microarray (SAM). The functional annotation of the DEGs was performed with DAVID v6.8 (The Database for Annotation, Visualization, and Integrated Discovery). RESULTS:There are no genes over-expressed simultaneously in both diseases. However, when crossing the list of under-expressed genes for 45,X cells and the list of over-expressed genes for 47,XXY cells, there are 16 common genes: SLC25A6, AKAP17A, ASMTL, KDM5C, KDM6A, ATRX, CSF2RA, DHRSX, CD99, ZBED1, EIF1AX, MVB12B, SMC1A, P2RY8, DOCK7, DDX3X, eight of which are involved in the regulation of gene expression by epigenetic mechanisms, regulation of splicing processes and protein synthesis. CONCLUSION:Of the 16 identified as under-expressed in 45,X cells and over-expressed in 47,XXY cells, 14 are located in X chromosome and 2 in autosomal chromosome; 8 of these genes are involved in the regulation of gene expression: 5 genes are related to epigenetic mechanisms, 2 in regulation of splicing processes, and 1 in the protein synthesis process. Our results are limited by it being the product of a bioinformatic analysis from mRNA isolated from whole blood, this makes necessary further exploration of the relationships between these genes and Turner syndrome and Klinefelter syndrome in the future.

VACTERL association (OMIM 192350) is a heterogeneous clinical condition characterized by congenital structural defects that include at least 3 of the following features: vertebral abnormalities, anal atresia, heart defects, tracheoesophageal fistula, renal malformations, and limb defects. The nonrandom occurrence of these malformations and some familial cases suggest a possible association with genetic factors such as chromosomal alterations, gene mutations, and inherited syndromes such as Fanconi anemia (FA). In this study, the clinical phenotype and its relationship with the presence of chromosomal abnormalities and FA were evaluated in 18 patients with VACTERL association. For this, a G-banded karyotype, array-comparative genomic hybridization, and chromosomal fragility test for FA were performed. All patients (10 female and 8 male) showed a broad clinical spectrum: 13 (72.2%) had vertebral abnormalities, 8 (44.4%) had anal atresia, 14 (77.8%) had heart defects, 8 (44.4%) had esophageal atresia, 10 (55.6%) had renal abnormalities, and 10 (55.6%) had limb defects. Chromosomal abnormalities and FA were ruled out. In 2 cases, the finding of microalterations, namely del(15)(q11.2) and dup(17)(q12), explained the phenotype; in 8 cases, copy number variations were classified as variants of unknown significance and as not yet described in VACTERL. These variants comprise genes related to important cellular functions and embryonic development.

Disorders of sexual development (DSD) are conditions with an atypical chromosomal, gonadal or phenotypic sex, which leads to differences in the development of the urogenital tract and different clinical phenotypes. Some genes have been implicated in the sex development during gonadal and functional differentiation where the maintenance of the somatic sex of the gonad as either male or female is achieved by suppression of the alternate route. The diagnosis of DSD requires a structured approach, involving a multidisciplinary team and different molecular techniques. We discuss the dimorphic genes and the specific pathways involved in gonadal differentiation, as well as new techniques for genetic analysis and their diagnostic value including epigenetic mechanisms, expanding the evidence in the diagnostic approach of individuals with DSD to increase knowledge of the etiology.

ABSTRACT The anti-Müllerian hormone triggers the regression of uterus and fallopian tubes in male embryos; if there are problems in the synthesis or action of this protein, Müllerian structures persist in an otherwise phenotypic male. The most frequent clinical presentation of Persistent Mullerian Duct syndrome is cryptorchidism and inguinal hernia. The few cases reported in adults are incidental findings or inguinal hernias. However, we present an adult male with history of bilateral cryptorchidism with unsuccessful orchidopexy, who presents with a large abdominal mass with the finding of a seminomatous tumor and persistence of Müllerian structures, in whom the variant c.916delC (p.Leu306Cysfs*29) in the AMHR2 gene not previously reported was documented.

Disorders of sex development (DSDs) are congenital conditions in which the external appearance of the individual does not coincide with the chromosomal constitution or the gonadal sex. In other words, there is an ambiguous or intermediate condition between the male and female phenotypes of the anatomical sex. These atypical conditions are manifested in several ways, ranging from genital ambiguity to phenotypes that are so attenuated that they can go unnoticed or appear normal. Currently, there is a lack of understanding of the factors responsible for these outcomes; however, they are likely to be conditioned by genetic, hormonal and environmental factors during prenatal and postnatal development. The present study determined the genetic etiology of DSDs in Colombian patients by conventional cytogenetic analysis, FISH and MLPA (for SF1, DAX1, SOX9, SRY and WNT4). A cohort of 43 patients with clinical phenotypes of sex development disorder was used in the present study. Using this multistep experimental approach, a diagnostic percentage of 25.58% was obtained: 17 patients (39.53%) were classified as having gonadal development disorders, the majority of which were ovotesticular disorders with numerical and/or structural alterations of the sex chromosomes, 9 patients (20.93%) were classified as having testicular DSD with a 46,XY karyotype, and 3 patients (6.98%) as having ovarian DSD with a 46,XX karyotype. The remaining 14 patients (32.56%) were classified as ‘other’ since they could not be grouped into a specific class of gonadal development, corresponding to hypospadias and multiple congenital anomalies. These findings highlight the importance of histological and cytogenetic studies in a gonadal biopsy. In 11/43 cases, the multistep experimental protocol presented in the present study yielded etiological or histological findings that could be used to define the medical management of patients with DSDs. In conclusion, for the etiological diagnosis of DSDs, a broad-spectrum approach that includes endocrinological tests, conventional karyotyping, molecular karyotyping by FISH and, molecular tests is required, in addition to gonadal tissue analyses, to identify genetic alterations.

The objective of this work was to identify 22q11.2 chromosomal deletion in patients with cleft lip and/or cleft palate and suggestive syndromic phenotype in Colombian patients. We studied 49 patients with cleft lip and/or cleft palate, exhibiting additional clinical findings linked to 22q11.2 deletion syndrome. All patients underwent high-resolution G-banded karyotyping, multiplex ligation-dependent probe amplification, and clinical evaluation by a geneticist. Seven patients presented 22q11.2 deletion and 2 patients had other chromosomal abnormalities. In conclusion, this study contributes with new data for genetic etiology in syndromic conditions of oral fissures.

Two sisters phenotypically normal females, presenting with tumor abdominal mass with histopathological findings of teratoma and gonadoblastoma associated to 46,XY male-to-female sex reversal syndrome, secondary to a duplication in DAX-1, possibly inherited of maternal gonadal mosaicism. Copy number variation and functional effects of the duplication were done by MLPA multiplex ligation-dependent probe amplification and real time PCR. DAX-1, also known as dosage sensitive sex reversal gene (DSS), is considered the most likely candidate gene involved in XY gonadal dysgenesis when overexpressed. The excess of DAX-1 gene disturbs testicular development by down regulation of SF-1, WT1, and SOX9. This is the first report of 46,XY sex reversal in two siblings who have a maternally inherited duplication of DAX-1 associated with reduced levels of expression of downstream genes as SOX9–SF1.

The culture of cancer cells is crucial for translational and biomedical research. Nevertheless, in the world, techniques for culturing lung tumor cells have been implemented from samples from invasive procedures. The objective was establish and characterize the culture of primary or metastastic lung cancer cells obtained by percutaneous puncture. Tumor specimens from 6 patients suspected of primary or metastatic lung cancer were obtained by percutaneous puncture guided by chest tomography. Solid tumors were disaggregated mechanically, by stereoscopic visión. Cells were cultured in Base C growth media supplemented with 5% fetal bovine serum in 24-wells cell culture plate. Once a confluent monolayer was obtained, the cells were enzymatically cleaved and passaged to Petri culture plates. These primary cultures were used for their characterization by cytogenetics test and analysis of gene expression of markers diagnostic. Results: Six samples were included in the study, successfully establishing six lung cancer cell cultures that correspond in three cases to NSCLC and the three remaining cell cultures correspond to metastatic lung tumors. Conclusions: Primary culture of human lung tumor cells obtained by percutaneous puncture can be successfully achieved with the method described. These primary cultures of cancer cells showed rearrangements of chromosomes and change in their complement chromosomic typical of tumoral cells. Aditionally, Fluorescence in situ Hybridization analysis showed that three cultures showed amplification for EGFR. Finally the expression profiles of the CK7, Napsin A, TTF-1 and P63 genes allowed in most cases to confirm the tumor phenotype of the samples.

Los desórdenes del desarrollo sexual (DDS) se presentan en 0,76 por cada 4.500 nacimientos. El manejo es complejo y requiere de la habilidad de múltiples especialidades, lo cual tendrá un impacto positivo en el pronóstico y reducción de la discapacidad de estos pacientes. El objetivo del presente trabajo es describir una población manejada por un grupo transdisciplinario de DDS en nuestro medio y establecer las limitantes que enfrentan nuestros pacientes en la atención de sus condiciones. Se describe el seguimiento de los pacientes con DDS valorados por el grupo transdisciplinario de DDS desde 2007. Se tuvo en cuenta el proceso clínico y genético para establecer el diagnóstico. Se hizo una descripción de los casos llevados a cirugía y su evolución postoperatoria desde el punto de vista médico y administrativo. Se valoró a 55 pacientes con DDS, encontrando que la patología más frecuente es la hiperplasia suprarrenal congénita. Se realizó un seguimiento promedio de 17,2 meses desde su ingreso al grupo. El 36% de los casos fueron llevados a cirugía por su condición con una edad promedio de 5 años de edad. La valoración extrainstitucional inicial nunca fue por un grupo multidisciplinario y solo el 72% fue estudiado con cariotipo con análisis de 25 metafases. Ninguno de los casos con mosaicismo fue diagnosticado con los cariotipos con 25 metafases, sino luego de extender el análisis a 100 metafases. El 18% tuvo cambio de género con el que fueron registrados extrainstitucionalmente. Los DDS son patologías muy complejas que requieren del tratamiento integral por múltiples especialidades. Esto se manifiesta con clara reducción en complicaciones, costos y, lo más importante, una mejoría del pronóstico y la discapacidad. En nuestro medio, las limitantes que presentar el sistema de salud para lograr un tratamiento integral transdisciplinario a nuestros pacientes están lejos de ser óptimas. Es importante que los prestadores de la salud tengan conocimiento de los grupos transdisciplinarios para así promover un adecuado tratamiento. Disorders of sex development (DSD) are present in 0.76 per 4,500 births. The management is complex and requires the ability of a multi-disciplinary team, which can have a positive impact on the prognosis. The aim of this article is to describe a population managed by a cross-disciplinary DSD group in our environment, and presenting the limitations faced by our patients in the care of their conditions. Description of the follow-up of patients with DSD by a cross-disciplinary group since 2007. The DSD clinical approach and genetic and diagnostic processes are described. Also a description of cases taken to surgery and their postoperative course was also evaluated from a medical and administrative point of view. The study included 55 patients wIth DSD, with the most common disease being congenital adrenal hyperplasia. The mean follow-up was 17.2 months. Surgery was performed in 36% of cases due to their condition, with a mean age of 5 years at the time of surgery. An initial extra-institutional initial assessment was never made by a multidisciplinary group, and only 72% were studied by karyotype analysis by analysing 25 metaphases. None of the cases were diagnosed as having mosaicism when 25 metaphases were analysed, but were detected after extending the analysis to 100 metaphases. Eighteen percent had gender reasigned. DSD are very complex diseases that require comprehensive treatment by multiple specialties. This is demonstrated by clear reduction in complications, costs and most importantly, an improvement in prognosis and reduction in disability. In our environment, limitations by the health system provides is alarming. A comprehensive treatment by a cross-disciplinary team to these patients is far from optimal. It is important that health care providers are aware of cross-disciplinary groups in order to promote proper treatment.

INTRODUCTION:Mosaic trisomy 8 or "Warkany's Syndrome" is a chromosomopathy with an estimated prevalance of 1:25,000 to 1:50,000, whose clinical presentation has a wide phenotypic variability.CASE DESCRIPTION:Patient aged 14 years old with antecedents of global retardation of development, moderate cognitive deficit and hypothyroidism of possible congenital origin.CLINICAL FINDINGS:Physical examination revealed palpebral ptosis, small corneas and corectopia, hypoplasia of the upper maxilla and prognathism, dental crowding, high-arched palate, anomalies of the extremities such as digitalization of the thumbs, clinodactyly and bilateral shortening of the fifth finger, shortening of the right femur, columnar deviation and linear brown blotches that followed Blaschko's lines. Cerebral nuclear magnetic resonance revealed type 1 Chiari's malformation and ventriculomegaly. Although the karyotype was normal in peripheral blood (46,XY), based on the finding of cutaneous mosaicism the lesions were biopsied and cytogenetic analysis demonstrated mosaic trisomy 8: mos 47,XY,+8[7]/46,XY[93].CLINICAL RELEVANCE:Trisomy 8 is clinically presented as a mosaic, universal cases being unfailingly lethal. In this particular case, cutaneous lesions identified the mosaic in tissue, although the karyotype was normal in peripheral blood. The cutaneous mosaicism represented by brown linear blotches which follow Blaschko's lines is a clinical finding that has not previously been described in Warkany's syndrome.

Resumen es: Introduccion : La trisomia 8 en mosaico o Sindrome de Warkany, es una cromosomopatia con una prevalencia estimada de 1:25,000 a 1:50,000, q...

Introduction: The path of microsatellite instability has mainly been found in cancers of digestive tracts, of which 90% of cases are hereditary cancer patients and 15% are patients with sporadic cancer. That instability produces a phenotype called Microsatellite instability (IMI+) or phenotype by replication mistake (RER+) that leads to the accumulation of mutations in higher rates to normal. Objectives: To identify the presence of IMI+ phenotype in patients analyzed and evaluated its relationship with the differentiation histopathologic tumor, because which together have been associated with a better prognosis and improved response to treatment given to the patient. Methodology: DNA was extracted from blood samples (normal cells) and biopsy of the tumor (tumor cells) of the 23 patients who were included in the study and through the amplification by PCR and subsequent capillary electrophoresis was typified the microsatellite mononucleotidic BAT-26, who was employed by his sensitivity to detect IMI+ phenotype (95%). Finally, we made a statistical correlation between the microsatellite instability phenotype, the presence (IMI+) or the absence (IMI-), with histopathological findings using Fisher’s exact test. Results: In 17% of cases (4 patients) had IMI+: 3 of them with colorectal cancer (CRC) -2 cases possibly with hereditary cancer- and one with gastric cancer (GC). There was no association between phenotype IMI+ with the pathological diagnosis, age, sex and differentiation histopathologic tumor. Conclusion: We found the phenotype IMI + in 17% of cases without association with the degree of differentiation histopathologic tumor, possibly by the reduced number of samples analyzed, making it essential to review the methods of fixation, paraffin and storage tissue because current techniques hinder digestion of proteinase k and PCR.

Introduccion: La via de inestabilidad de microsatelites se ha encontrado sobre todo en canceres de vias digestivas, de los cuales 90% de los casos pertenecen a pacientes con cancer hereditario y 15% con cancer esporadico. De ella se deriva un fenotipo denominado de inestabilidad de microsatelites (IMI+) o fenotipo de error de la replicacion (RER+) que induce a la acumulacion de mutaciones en tasas mas elevadas a las normales. Objetivos: Identificar la presencia del fenotipo IMI+ en los pacientes analizados y evaluar su relacion con la diferenciacion histopatologica del tumor porque en conjunto han sido asociados con un mejor pronostico y una mejor respuesta al tratamiento dado. Metodologia: Se extrajo ADN de las muestras de sangre (celulas normales) y las biopsias de tumor (celulas tumorales) de los 23 pacientes que se pudieron incluir para el estudio y mediante la amplificacion por PCR y posterior electroforesis capilar; se tipifico el microsatelite mononucleotidico BAT-26, empleado por su sensibilidad para descubrir el fenotipo IMI+. Finalmente se hizo una correlacion estadistica segun la presencia (IMI+) o ausencia (IMI-) del fenotipo, con los hallazgos histopatologicos utilizando la prueba exacta de Fisher. Resultados: Del total de pacientes, 4 (17%) presentaron IMI+: 3 de ellos con cancer colorrectal (2 casos posiblemente con cancer hereditario) y uno con cancer gastrico. No se encontro ninguna asociacion entre el fenotipo IMI+ con el diagnostico patologico, la edad, el sexo y la diferenciacion histopatologica del tumor. Conclusion: Se encontro el fenotipo IMI+ en 17% de los casos, sin asociacion con el grado de diferenciacion histopatologica del tumor, posiblemente por el reducido numero de muestras tipificadas, por lo cual es indispensable revisar los metodos de fijacion, parafinacion y almacenamiento de tejidos, pues las tecnicas actuales dificultan la digestion de la proteinaza k y la PCR

OBJECTIVE:Rheumatoid arthritis (RA) is considered a Th1-driven disease. Interleukin 4 (IL-4) binds to its receptor, promoting Th2 differentiation and limiting Th1 responses, but its role in the pathogenesis of RA is conflicting. We analyzed 2 polymorphisms of the IL4 gene and 4 polymorphisms of the IL4RA gene in patients with RA and in a control population, as well as rheumatoid factor (RF) seropositivity, titers of RF, and history of replacement joint surgery among patients with RA.METHODS:The study population consisted of 102 patients with RA and 102 matched healthy controls. Genotyping of IL4 -590, IL4RA +148, +1124, +1218, and +1902 was determined by restriction fragment length polymorphism-polymerase chain reaction (PCR) and sequence-specific primer-PCR. IL4 variable number tandem repeat polymorphism was determined by direct amplification.RESULTS:The IL4 -590TT genotype was significantly more frequent in patients with RA than in controls (p = 0.018, OR 3.34, 95% CI 1.08-11.04). The IL4RA +148A allele was significantly associated with the presence of RF (p = 0.0019, OR 2.55, 95% CI 1.55-4.86) and a history of articular joint replacement (p = 0.024, OR 2.08, 95% CI 1.04-4.18). The IL4RA +1902G allele was more frequently seen in patients with RA and high RF titers (p = 0.00067, OR 4, 95% CI 1.64-9.93).CONCLUSION:Highly complex pathways lead to the development of RA and may not be similar in all patients. Our findings of higher frequency of IL4 and IL4RA genotypes and alleles with RA, presence of RF, RF titers, and history of articular joint replacement support the polygenic expression of RA and the likely role of IL-4 in influencing its initiation and development.