Técnicas de citogenética para el estudio de las leucemias / Cytogenetic techniques for the study of leukemias

Introducción: La leucemia se define como un proceso clonal de células hematopoyéticas, que se origina cuando las células sanguíneas que se producen en la médula ósea, cambian y se multiplican sin control. Esta se caracteriza por su heterogeneidad genética y se explica a través de mecanismos causados por alteraciones cromosómicas utilizados en la práctica clínica diaria como biomarcadores útiles para el diagnóstico, el pronóstico o la predicción de respuesta al tratamiento. Objetivo: Describir las técnicas de citogenética convencional y molecular para el diagnóstico y seguimiento de las leucemias. Métodos: Se realizó una revisión de la literatura en inglés y español, a través del sitio web PubMed y el motor de búsqueda Google Académico, de artículos publicados en los últimos cinco años. Se hizo un análisis y resumen de la bibliografía revisada. Análisis y síntesis de la información: En el transcurso de los años la citogenética ha proporcionado información crucial para el diagnóstico y el pronóstico de las neoplasias hematológicas. Tanto las técnicas de citogenética convencional y molecular, como la hibridación in situ fluorescente, la hibridación in situ fluorescente multicolor, el cariotipo espectral, la hibridación genómica comparada y los microarreglos, participan en el reconocimiento de alteraciones cromosómicas y de genes, así como de interacciones involucradas en el proceso de oncogénesis. Conclusiones: Las técnicas de citogenética contribuyen al diagnóstico, a la estratificación pronóstica y a la aplicación del tratamiento según el tipo o subtipo de leucemia(AU)

Introduction: Leukemia is defined as a clonal process of hematopoietic cells, which occurs when blood cells that are produced in the bone marrow change and multiply uncontrollably. This is characterized by its genetic heterogeneity and is explained through mechanisms caused by chromosomal alterations that are used in daily clinical practice as useful biomarkers for diagnosis, prognosis or prediction of response to treatment. Objective: To describe the conventional and molecular cytogenetic techniques used for the diagnosis and monitoring of leukemias. Methods: A review of the literature in English and in Spanish was carried out, in the PubMed website and using the search engine Google, for articles published in the last five years. We performed analysis and summary of the reviewed bibliography. Analysis and synthesis of information: Cytogenetics over the years has provided crucial information for the diagnosis and prognosis of hematologic malignancies. Both conventional and molecular cytogenetic techniques such as fluorescent in situ hybridization, multicolor fluorescent in situ hybridization, spectral karyotype, comparative genomic hybridization and microarrays, participate in the recognition of chromosomal and gene alterations, as well as interactions involved in the oncogenesis process. Conclusions: These cytogenetic techniques contribute to the diagnosis, prognostic stratification and application of treatment according to the type or subtype of leukemia(AU)

Caracterización molecular de pacientes con cáncer colorrectal / Molecular characterization of colorectal cancer patients

Introducción. El cáncer colorrectal tiene una alta incidencia en la población mundial. Diversas vías moleculares están involucradas en su desarrollo, entre ellas, la inestabilidad cromosómica, la inestabilidad microsatelital y la epigenética. Objetivo. Hacer la caracterización molecular de 44 individuos con cáncer colorrectal esporádico. Materiales y métodos. El análisis de mutaciones en los genes APC, KRAS, TP53 y BRAF se hizo mediante secuenciación de Sanger; la inestabilidad microsatelital se determinó mediante electroforesis capilar utilizando cinco marcadores de repetición corta en tándem (Short Tandem Repeat) y el estado de metilación del promotor del gen MLH1 se hizo con la técnica MS-PCR (Methylation-Specific PCR). Resultados. La frecuencia de mutación de los genes APC, KRAS y TP53 fue del 18,1, 25 y 4,5 %, respectivamente; las mutaciones detectadas se localizaron con mayor frecuencia en el colon derecho. La frecuencia de inestabilidad microsatelital fue del 27,2 % y el 73,1 % en los tumores con metilación en el gen MHL1, y el 91,6 % de los tumores con inestabilidad microsatelital presentaba metilación en el gen MLH1. En el grupo de tumores con estabilidad microsatelital, las mutaciones en los genes APC, KRAS y TP53 fueron más frecuentes que en el grupo de tumores con inestabilidad microsatelital. La metilación del gen MLH1 fue la alteración más predominante. Conclusiones. En los pacientes con cáncer colorrectal evaluados se demostró la presencia de alteraciones moleculares en las diferentes vías genéticas, las cuales son comunes en su carcinogénesis. Los pacientes presentaron un perfil de mutaciones diferente al de otras poblaciones. Los hallazgos obtenidos en este estudio confirman la heterogeneidad molecular descrita en el desarrollo del cáncer colorrectal.

Introduction: Colorectal cancer has a high incidence in the world population. Different molecular pathways, such as chromosomal instability, microsatellite instability, and epigenetics are involved in its development. Objective: To perform molecular characterization in 44 individuals with sporadic colorectal cancer. Materials and methods: We conducted mutation analyses of the APC, KRAS, TP53 y BRAF genes using Sanger sequencing techniques; microsatellite instability was determined by capillary electrophoresis with five STR genetic markers while the methylation status of the MHL1 promotor gene was analyzed using methylation-specific PCR. Results: APC, KRAS, and TP53 genes mutation frequency was 18.1%, 25%, and 4.5%, respectively; the somatic mutations detected were located more frequently in the right colon. The frequency of microsatellite instability was 27.2% and 73.1% of the tumors had the MHL1 gene methylated while 91.6% of microsatellite instability-positive tumors had the methylated MLH1 gene. The mutation profile of microsatellite stability tumors APC, KRAS, and TP53 genes was more frequent than in the microsatellite instability-positive tumors. The methylation of the MLH1 gene was the most predominant molecular alteration. Conclusions: We identified molecular alterations in different genetic pathways of the colorectal cancer patients evaluated, which are common in the carcinogenesis of this cancer. These patients showed a different mutational profile compared to other populations. Our findings confirm the molecular heterogeneity described in the development of colorectal cancer.

Síndrome de Cornelia de Lange: análise de uma série de 33 pacientes em um centro de referência / Cornelia de Lange syndrome: analysis of a series of 33 patients in an excellence center

Introdução: A Síndrome de Cornelia de Lange (CdLS) (OMIM: 122470) é uma doença genética rara com quadro clínico e fenótipo variáveis, compreendendo um grupo de doenças denominado coesinopatias. Entre suas principais características: deficiência intelectual (DI), baixa estatura, doença do refluxo gastroesofágico (DRGE), hipertricose, dismorfismos faciais e anomalias em membros superiores. O diagnóstico pode ser dificultado nos quadros atenuados. O objetivo do estudo foi determinar os principais achados clínicos e moleculares em uma série de pacientes com o diagnóstico clínico de CdLS.Métodos: Foram avaliados 33 pacientes com diagnóstico clínico e/ou molecular de CdLS (18 sexo feminino e 15 masculino) com idades entre 1 mês e 43 anos. Aplicou-se um escore clínico visando a categorização dos pacientes baseado em Kline et al. (2018). Esta ferramenta utiliza sinais clínicos para determinar as formas clássicas (n: 23), não clássicas (n: 6) e os casos que, apesar de não se enquadrarem nestas categoriais, também deveriam ser testados molecularmente para a síndrome (n: 4).Resultados: Atraso do desenvolvimento/DI, distúrbios de comportamento, déficit de crescimento e DRGE foram as comorbidades mais prevalentes. Entre as dismorfias: sinofris, micrognatia, narinas antevertidas e comissura labial desviada para baixo. Os achados moleculares nos pacientes submetidos ao sequenciamento completo do exoma revelaram 6 variantes em NIPBL (46%), 2 variantes em SMC1A (15%), 1 variante em SMC3, 1 variante em HDAC8, 1 variante em AHDC1 e 2 resultados negativos.Conclusões: Os dados obtidos revelaram uma grande heterogeneidade de apresentação da síndrome. A utilização de escores clínicos podem auxiliar no diagnóstico de CdLS.

Introduction: Cornelia de Lange syndrome (CdLS) (OMIM: 122470) is a rare genetic disease with variable clinical presentation and phenotype, part of a group of disorders termed cohesinopathies. Intellectual disability, growth retardation, gastroesophageal reflux disease, hypertrichosis, facial dysmorphisms, and anomalies of the upper limbs are the most common clinical characteristics. Diagnosis may be difficult, especially in attenuated presentations. The aim of this study was to determine the main clinical and molecular findings in a series of patients with clinical diagnosis of CdLS.Methods: Thirty-three patients with typical clinical and/or molecular diagnosis of CdLS (18 female and 15 male) aged between 1 month and 43 years were evaluated. A clinical score was applied to categorize patients. This tool uses clinical signs to determine the classic (n: 23) and nonclassic (n: 6) forms, in addition to a category to suggest which cases should be molecularly tested for the syndrome (n: 4).Results: Developmental delay/intellectual disability, behavioral disorders, growth retardation, and gastroesophageal reflux disease were the most prevalent comorbidities. Dysmorphic features included synophrys micrognathia, anteverted nostrils, and labial commissure turning downwards. Molecular findings in those who underwent whole exome sequencing revealed 6 variants in NIPBL (46%), 2 variants in SMC1A (15%), 1 variant in SMC3, 1 variant in HDAC8, 1 variant in AHDC1, and 2 negative results.Conclusions: The data revealed a great heterogeneity in the presentation of the syndrome. The use of clinical scores can help in the diagnosis of CdLS.

Brain Tumor Heterogeneity

Tumor heterogeneity is the concept that different tumor cells provide distinct biomorphological lesions, gene expressions, proliferation, microenvironment and graduated capacity of metastatic lesions. Brain tumor heterogeneity has been recently discussed about the interesting interaction of chronic inflammation, microenvironment, epigenetics and glioma steam cells. Brain tumors remain a challenge with regards to medication and disease, due to the lack of treatment options and unsatisfactory results. These results might be the result of the brain tumor heterogeneity and its multiple resistance mechanisms to chemo and radiotherapy.

External Apical Root Resorption and IL-1A, IL-1RN Gene Polymorphisms: A Systematic Review and Meta-Analysis of Prospective Studies

ABSTRACT Objective: To reconnoiter the IL-1A (-889) and IL-1RN (+2018) gene polymorphisms and their association with EARR. Material and Methods: The Science Direct, PubMed and Scopus databases were comprehensively searched by two independent reviewers. In addition, the bibliographies of all relevant publications and textbooks were searched manually. A meta-analysis was performed using data available up to May 9, 2020. Results: A total of 13 and 9 publications were selected for the systematic review and meta-analysis, respectively for both IL-1A and IL-1RN genes. Odds ratio (OR) was used to evaluate the association of the gene polymorphism and the risk of EARR. The risk of EARR was estimated using the overall OR from the published studies. No association was found for IL-1A gene for the risk of EARR. However, the dominant and co-dominant models of IL-1RN gene polymorphism were associated with the risk of EARR. Conclusion: More studies are warranted to determine the relationship between IL-1A and IL-1RN gene polymorphisms and EARR for a clearer understanding of their interactions.

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma / 医学前沿

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Intra-tumor genetic heterogeneity in Wilms tumor samples

SUMMARY Childhood renal tumors account for ~7% of all childhood cancers, and most cases are embryonic Wilms' tumors (WT). Children with WT are usually treated by either COG or SIOP. The later treats the children using preoperative chemotherapy, but both have around 90% of overall survival in five years. WT is a genetically heterogeneous group with a low prevalence of known somatic alterations. Only around 30% of the cases present mutation in known genes, and there is a relatively high degree of intra-tumor genetic heterogeneity (ITGH). Besides potentially having an impact on the clinical outcome of patients, ITGH may interfere with the search for molecular markers that are prospectively being tested by COG and SIOP. In this review, we present the proposal of the current UMBRELLA SIOP Study 2017/Brazilian Renal Tumor Group that requires the multi-sampling collection of each tumor to better evaluate possible molecular markers, as well as to understand WT biology

RESUMO Os tumores renais pediátricos correspondem a aproximadamente 7% de todos os tumores infantis, sendo o mais frequente o tumor de Wilms (TW). Crianças com TW são geralmente tratadas seguindo dois distintos protocolos terapêuticos (COG ou SIOP), sendo que no último, os pacientes recebem tratamento quimioterápico pré-operatório. Ambos apresentam sobrevida global em cinco anos em torno de 90%. TW é geneticamente heterogêneo, apresentando baixa prevalência de alterações somáticas conhecidas, com cerca de 30% dos casos apresentando mutações em genes conhecidos e um alto grau de heterogeneidade genética intratumoral (HGIT). Além de potencialmente ter um impacto sobre o desfecho clínico dos pacientes, a HGIT pode interferir na busca de marcadores moleculares que estão sendo testados prospectivamente pelos grupos COG e Siop. Nesta revisão, apresentamos a proposta do atual estudo Umbrella Siop 2017/Grupo de Tumores Renais Brasileiros (GTRB), que orienta a coleta de três diferentes regiões do tumor para melhor avaliar possíveis marcadores moleculares, bem como para compreender a biologia do TW.

Use of testicular tone and echogenicity in identifying boars with low sperm quality / Uso de tônus e ecogenicidade testiculares na identificação de reprodutores suínos com baixa qualidade espermática

This study aimed to evaluate the use of some testicular traits to identify boars with low sperm morphological quality. The consistency (scores from 1 to 5), tone with tonometry (mm), parenchyma echogenicity and heterogeneity with ultrasound (pixel) were assessed in 402 mature boars (18.5 months on average). Sperm abnormality thresholds (≤ 25% of total sperm abnormalities, ≤ 5% of heads, acrosome, neck or midpiece defects, ≤ 10% tail defects, and 15% cytoplasmic droplets) were used to classify boars as approved or disapproved. Three classes of testicular traits were formed (extremely low and high values, approximately 15% each, were kept in separated classes). When the traits were individually evaluated, fewer boars were approved if the echogenicity or heterogeneity were high, or if the tone was rigid. When evaluated in combination, the interaction between heterogeneity and tone, and between heterogeneity and echogenicity were significant. The high heterogeneity combined with soft tone or with hypo-echogenicity resulted in lower approval of boars. Tonometry and ultrasonography have a moderate potential to be included in breeding soundness examination of boars. When combined, they provide more reliable information about the impact of testicular parenchymal alterations on morphology of sperm cells.(AU)

O estudo objetivou avaliar o uso de características testiculares para identificar reprodutores com baixa qualidade de morfologia espermática. A consistência (escore de 1 a 5), o tônus por tonometria (mm), a ecogenicidade e a heterogeneidade do parênquima testicular por ultrassonografia (pixel) foram avaliados em 402 machos suínos maduros (18,5 meses, em média). Limiares máximos de anormalidades espermáticas (≤ 25% de defeitos totais, ≤ 5% de defeitos de cabeça, acrossoma, colo e peça intermediária, ≤ 10% de defeitos de cauda e 15% de gota citoplasmática) foram utilizados para classificar os machos como aprovados ou reprovados. Três classes de características testiculares foram formadas (valores extremamente baixos e altos, aproximadamente 15% em cada, foram mantidos em classes separadas). Quando as características testiculares foram avaliadas individualmente, menos machos foram aprovados se a ecogenicidade ou a heterogeneidade foram altas, ou se o tônus era rígido. Quando avaliadas em combinação, a interação entre heterogeneidade e tônus e a interação entre heterogeneidade e ecogenicidade foram significativas. A alta heterogeneidade combinada com testículos flácidos ou com testículos hipoecogênicos resultou em menor aprovação de cachaços. A tonometria e a ultrassonografia possuem potencial moderado para serem incluídas no exame andrológico de cachaços. Quando combinadas, as técnicas fornecem uma informação mais consistente do impacto das alterações do parênquima testicular na morfologia das células espermáticas.(AU)

Use of denosumab in osteogenesis imperfecta: A case report / Uso de denosumab en osteogénesis imperfecta: informe de un caso

ABSTRACT Osteogenesis imperfecta (01) is an inherited disorder of phenotypically heterogeneous affec tions of the connective tissue. Until now, no definitive treatment for OI has been found. Certain drugs used in osteoporosis are used in these patients such as intravenous bisphosphonates in order to improve bone density. However, in recent years the use of denosumab, an anti-resorptive monoclonal antibody has shown positive results in bone mineral loss. There are no studies that directly compare the use of bisphosphonates and denosumab in OI. The following article presents a case of a 9-year-old patient with diagnosis of OI and a past medical history of epilepsy and cerebral palsy that was treated with bisphosphonates and denosumab.

RESUMEN La osteogénesis imperfecta (OI) es un trastorno hereditario del tejido conectivo fenotípicamente heterogéneo. Hasta ahora no se ha encontrado ningún tratamiento definitivo para la OI. Se aplican ciertos fármacos utilizados en la osteoporosis en estos pacientes como los bisfosfonatos intravenosos para mejorar la densidad ósea. Sin embargo, en los últimos arios el uso de denosumab, un anticuerpo monoclonal anti-resorción ha demostrado resultados positivos en la pérdida mineral ósea. No hay estudios que comparen directamente el uso de bisfosfonatos y denosumab en la OI. El artículo presenta un caso de OI infantil en una paciente de 9 años con antecedentes de epilepsia y parálisis cerebral, que fue tratada con bisfosfonatos y denosumab.

Intraspecific food resource partitioning in Brazilian silverside Atherinella brasiliensis (Atheriniformes: Atherinopsidae) in a tropical estuary, Brazil

We investigated the intraspecific partitioning of food resources of the Brazilian silverside Atherinella brasiliensis in a tropical estuary. A total of 1,099 stomachs were analyzed, and the diet consisted mainly of Gastropoda, Ceratopogonidae larvae, Decapoda larvae, Calanoida, Cyclopoida, Hymenoptera and Brachyura. Ordination of the mean volumetric percentage contribution of preys indicated differences in the dietary compositions between sites and size classes. By SIMPER analysis, we detected high dissimilarity between size classes, suggesting ontogenetic niche shifts: the diet of the early juveniles was based in zooplankton, whereas adults consumed mainly benthic macroinvertebrates. These shifts were related to changes in feeding structures and foraging abilities that show a strong relationship with body size, and showed functional trade-offs in swimming capacity, and feeding strategies used to capture prey. Differences in the diet between size classes and habitat selection by Brazilian silverside are likely strategies to avoid intraspecific competition, clearly related to the abundance and accessibility of resources along the estuarine habitats.(AU)

Nós investigamos a partição intraespecífica de recursos alimentares do peixe-rei Atherinella brasiliensis em um estuário tropical. Um total de 1.099 estômagos foi analisado, e a dieta foi constituída principalmente de Gastropoda, Larva de Ceratopogonidae, Larva de Decapoda, Calanoida, Cyclopoida, Hymenoptera e Brachyura. A análise de ordenação da contribuição do volume das presas indicou diferenças na composição da dieta entre locais e classes de tamanho. Pela análise do SIMPER, nós detectamos alta dissimilaridade entre as classes de tamanho, sugerindo mudanças ontogenéticas: a dieta dos indivíduos menores foi baseada em zooplâncton, enquanto os maiores indivíduos consumiram principalmente macroinvertebrados bentônicos. Essas variações foram relacionadas com mudanças nas estruturas para captura do alimento e na habilidade de forrageamento que evidenciaram uma forte relação com o tamanho do corpo, e mostraram trade-offs funcionais na capacidade de natação e no modo de captura das presas. Diferenças na dieta entre as classes e a seleção de habitat pelo peixe-rei são estratégias para evitar a competição intraespecífica, claramente relacionada com a abundância e a acessibilidade dos recursos alimentares ao longo dos habitats estuarinos.(AU)

PTEN loss in Gleason grade 7 prostate tumors exhibits intratumoral heterogeneity and is associated with unfavorable pathological features

Background: PTEN loss is observed in 20­30% of prostate cancers and is associated with a poor outcome, but clinical details of the impact of this biomarker are unclear for intermediate grade tumors. Methods: We investigated 43 radical prostatectomy-derived grade 7 prostate tumors from the Clinics Hospital of Ribeirão Preto. Tissue microarray (TMA) blocks were constructed and PTEN copy number status was determined for all patients through fluorescence in situ hybridization (FISH). To determine the presence of PTEN protein loss in our study cohort, we performed immunohistochemistry (IHC) in TMA sections. We then developed an automated algorithm in HALO™ to identify regions of PTEN protein loss in whole prostate scanned sections from ten patients with known PTEN deletion status by FISH. Clinical analyses were conducted to determine the associations between PTEN loss and patient outcome. All statistical analyses were conducted in R v3.4.3 with P-values below 0.05 being considered statistically significant. Results: In this study of 43 grade 7 tumors, we found PTEN deletions by FISH in 18.9% of tumors, and PTEN protein loss by IHC in 16.3% of tumors. Both techniques were highly concordant and complementary. Clinical analysis demonstrated that PTEN deletion by FISH was significantly associated with positive margin invasion (P = 0.04) and Gleason score upgrade (P = 0.001). Digital image analysis of ten representative tumors demonstrated distinct intratumoral heterogeneity for PTEN protein loss in four tumors. Conclusions: This study shows that PTEN loss in Gleason grade 7 tumors can be heterogeneous and that a systematic analysis of this biomarker using a combination of FISH, IHC, and digital imaging may identify patients with a greater risk of poor outcome (AU)

Waist circumference percentiles of black South African children aged 10 - 14 years from different study sites

Background. Waist circumference (WC) is a useful predictor of cardiometabolic risk in children. Published data on WC percentiles of children from African countries are limited.Objectives. To describe age- and sex-specific Wpercentiles in black South African (SA) children from different study sites, and compare these percentiles with median WCpercentiles of African-American (AA) children.Methods. Secondary data on WC for 10 - 14-year-old black SA children (N=4 954; 2 406 boys and 2 548 girls) were extracted from the data sets of six studies. Smoothed WC percentile curves for boys and girls were constructed using the LMS method. The 50th percentile for age- and sex-specific WC measurements was compared across study sites and with AA counterparts.Results. Girls had higher WC values than boys from the 50th to 95th percentiles at all ages. The 50th WC percentiles of all groups of SA children combined were lower than those of AA children. When SA groups were considered separately, Western Cape children had median WC values similar to AA children, while rural Limpopo children had the lowest WC values. The 95th percentiles for Western Cape girls exceeded the adult cutoff point for metabolic syndrome (WC ≥80 cm) from age 11years.Conclusions. The differences in WC values for 10 - 14-year-old children across the six study sites highlight the need for nationally representative data to develop age-, sex- and ethnic-specific WC percentiles for black SA children. The results raise concerns about high WC among Western Cape girls

Heterogeneity of cell therapy products

Cellular therapy has become a billion-dollar industry and is set to become one of the therapeutic pillars of healthcare in the 21st century. Adult stem cells, which include haematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal/stem cells (MSCs), is one of the major cell types currently under investigation for use in cell therapy. This review focuses on HSPCs and MSCs and discusses their heterogeneous nature and the problems faced in expanding these cells to therapeutic numbers for use in clinical applications

Assessment of the Clinical Heterogeneity of Kawasaki Disease Using Genetic Variants of BLK and FCGR2A

BACKGROUND AND OBJECTIVES: Patients with Kawasaki disease (KD) are clinically heterogeneous because its diagnosis is based solely on clinical observation and there are no definitive biomarkers. We dissected the clinical heterogeneity of KD patients using the KD-associated genetic variants. METHODS: We performed a genetic association analysis in several KD subgroups categorized by clinical characteristics using the KD-associated variants of the B lymphoid tyrosine kinase (BLK; rs6993775) and Fc gamma receptor II a (FCGR2A; rs1801274) in a large number of case (n=1,011) and control (n=4,533) samples. RESULTS: BLK and FCGR2A were very significantly associated with KD in Korean KD patients (odds ratio [OR],1.48; p=4.63×10⁻¹¹ for BLK, and OR, 1.26; p=1.42×10⁻⁴ for FCGR2A). However, in KD subgroup analysis, we found that neither BLK nor FCGR2A were associated with either incomplete Kawasaki disease (iKD) type patients or those older than 5 years of age (p>0.2), suggesting that patients with iKD or those older than 5 years of age are a unique subgroup of KD. In genetic association analysis after excluding iKD patients and those older than 5 years old, we found that BLK was associated with all KD subgroups, whereas FCGR2A was specifically associated with male KD patients younger than 1 year of age (OR, 2.22; p=2.35×10⁻⁵). CONCLUSIONS: KD is a clinically and genetically heterogeneous disease. These findings will provide new insights into the clinical and genetic heterogeneity of KD.

New Insight to the Pathogenetic Mechanism of Kawasaki Disease (KD): the Relationship between Clinical Diversity and Genetic Heterogeneity

No abstract available.

Correlation between genetic heterogeneity and variability for response to growth hormone in Noonan syndrome / 소아과

No abstract available.

Sospecha diagnóstica de síndrome de Ehlers Danlos tipo vascular: reporte de un caso y revisión de literatura / Suspected vascular ehlers danlos syndrome: case report

Ehlers Danlos Syndrome comprises a heterogeneous group of genetic disorders of the connective tissue, due to defects in collagen or its modifying enzymes. We report a 21 years old male presenting with translucent skin revealing the subcutaneous venous pattern. He had a thin face, large-appearing eyes, thin lips, thin nose, joint hypermotility and history of hip dysplasia. A vascular Ehlers Danlos Syndrome was suspected. However, the genetic study to confirm the diagnosis was not done.

Síndrome de Lynch: aspectos genéticos, clínicos y diagnósticos / Lynch syndrome: genetic, clinical and diagnostic aspects

Esta revisión tiene como objetivo dar a conocer los aspectos genéticos, clínicos y diagnósticos del síndrome de Lynch, además de brindar la información más relevante acerca de la asesoría genética en estos pacientes y las recomendaciones actuales para su seguimiento.

This review aims to present the genetic, clinical and diagnostic aspects of Lynch syndrome, as well as providing the most relevant information about genetic counseling in these patients and the current recommendations for their surveillance.

Integrated diagnostic approach of pediatric neuromuscular disorders

Clinical and genetic heterogeneity in association with overlapping spectrum is characteristic in pediatric neuromuscular disorders, which makes confirmative diagnosis difficult and time consuming. Considering evolution of molecular genetic diagnosis and resultant upcoming genetically modifiable therapeutic options, rapid and cost-effective genetic testing should be applied in conjunction with existing diagnostic methods of clinical examinations, laboratory tests, electrophysiologic studies and pathologic studies. Earlier correct diagnosis would enable better clinical management for these patients in addition to new genetic drug options and genetic counseling.

Genetic Alterations among Korean Melanoma Patients Showing Tumor Heterogeneity: A Comparison between Primary Tumors and Corresponding Metastatic Lesions / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Melanoma is a highly heterogeneous neoplasm, composed of subpopulations of tumor cells with distinct molecular and biological phenotypes and genotypes. In this study, to determine the genetic heterogeneity between primary and metastatic melanoma in Korean melanoma patients, we evaluated several well-known genetic alterations of melanoma. In addition, to elucidate the clinical relevance of each genetic alteration and heterogeneity between primary and metastatic lesions, clinical features and patient outcome were collected. MATERIALS AND METHODS: In addition to clinical data, BRAF, NRAS, GNAQ/11 mutation and KIT amplification data was acquired from an archived primary Korean melanoma cohort (KMC) of 188 patients. Among these patients, 43 patients were included for investigation of tumor heterogeneity between primary melanoma and its corresponding metastatic lesions. RESULTS: Overall incidence of genetic aberrations of the primary melanomas in KMC was 17.6% of BRAF V600, 12.6% of NRAS mutation, and 28.6% of KIT amplification. GNAQ/11 mutation was seen in 66.6% of the uveal melanoma patients. Patients with BRAF mutation were associated with advanced stage and correlated to poor prognosis (p < 0.01). Among 43 patients, 55.8% showed heterogeneity between primary and metastatic lesion. The frequency of BRAF mutation and KIT amplification significantly increased in the metastatic lesions compared to primary melanomas. GNAQ/11 mutation showed 100% homogeneity in uveal melanoma patients. CONCLUSION: Our data demonstrated heterogeneity between primary melanomas and corresponding metastatic lesions for BRAF, NRAS mutation and KIT amplification. However, GNAQ/11 mutation was genetically homogeneous between primary and metastatic melanoma lesions in uveal melanoma.