Aspectos citogenéticos y moleculares en los síndromes mielodisplásicos / Cytogenetic and molecular aspects in myelodysplastic syndromes

Introducción: Los síndromes mielodisplásicos constituyen un grupo heterogéneo de alteraciones de la célula progenitora hematopoyética. Estos se caracterizan por presentar una médula ósea hipercelular, una hematopoyesis inefectiva, displasia y citopenia periférica y la posibilidad de evolución a leucemia mieloide aguda. Objetivo: Describir las alteraciones citogenéticas y moleculares más frecuentes de los síndromes mielodisplásicos. Métodos: Se realizó una revisión de la literatura en los idiomas 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 realizó análisis y resumen de la bibliografía. Análisis y síntesis de la información: En los síndromes mielodisplásicos están presentes alteraciones citogenéticas frecuentes como la deleción de los cromosomas 5q, 7q y 20q, la monosomía del cromosoma 7, la trisomía del cromosoma 8 y la presencia de cariotipos complejos, que, unido a mutaciones somáticas en diferentes genes, intervienen en la patogénesis de la enfermedad y su conocimiento permite la estratificación pronóstica de los pacientes. Conclusiones: El diagnóstico a través de los estudios citogenéticos convencionales, la hibridación in situ por fluorescencia y la secuenciación génica permite una mayor comprensión de la biología de la enfermedad, la estratificación del riesgo y la toma de decisiones terapéuticas(AU)

Introduction: Myelodysplastic syndromes constitute a heterogeneous group of alterations of the hematopoietic progenitor cell, characterized by hypercellular bone marrow, ineffective hematopoietic, dysplasia and peripheral cytopenia; and the possibility of progressing to acute myeloid leukemia. Objective: To describe the most frequent cytogenetic and molecular alterations of myelodysplastic syndromes. 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: In myelodysplastic syndromes, frequent cytogenetic alterations are present such as deletion of chromosomes 5q, 7q and 20q, as well as the monosomy of chromosome 7, trisomy of chromosome 8 and the presence of complex karyotypes, which together with somatic mutations in different genes intervene in the pathogenesis of the disease and allow prognostic stratification of patients. Conclusions: Diagnosis through conventional cytogenetic studies, fluorescence in situ hybridization and gene sequencing allow a better understanding of the biology of the disease, risk stratification and therapeutic decision making(AU)

Translocación cromosómica no balanceada t(5; 7)(q22; p15) en un niño con anomalías congénitas: reporte de caso clínico / Unbalanced chromosomal translocation t(5; 7)(q22; p15) in a child with congenital anomalies: clinical case report

Resumen Introducción: La incidencia de las anomalías congénitas es de 0,5% dentro de los cuales el 0,1-0,3% corresponden a anomalías cromosómicas estructurales, entre ellas están las translocaciones no balanceadas en las que hay pérdida o ganancia de información genética que da como resultado manifestaciones fenotípicas con compromiso en la salud de quienes las padecen. Reporte de caso: Se describe un paciente escolar con una translocación no balanceada t(5;7) (q22;p15) de origen paterno y sus repercusiones. Discusión: Cuando existen reordenamientos en el material genético, las manifestaciones clínicas están ligadas a la localización de los puntos de ruptura y como consecuencia a los genes que estén incluidos en estos segmentos, tal como se presentó en nuestro caso índice. Conclusiones: Es importante el estudio de estos pacientes ya que deben permanecer en vigilancia médica por el riesgo de desarrollar patologías relacionadas con alteraciones en los genes implicados en el reordenamiento genético.

Abstract Introduction: The incidence of congenital anomalies is 0,5%, wich 0,1 to 0,3% belong to structural chromosomic anomalies, between these are unbalanced translocations in which there are loss or gain of genetic information that results in phenotypic manifestations with health compromise of whom suffer it. Case report: A scholar patient with an unbalanced translocation t(5;7) (q22;p15) of paternal origin and its repercussions is described. Discussion: When there are rearrangements in genetic material, the clinical manifestations are linked to breakpoints localizations and as consequence to the genes included in this segments, as presented in our index case. Conclusions: The study of these patients is important because they must remain under medical surveillance due the risk of developing pathologies related with gene alterations implicated in the genetic rearrangement.

Clinical feature and pathogenic analysis of a fetus with split hand-foot malformation / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical feature of a fetus with split hand-foot malformation (SHFM) and to explore its etiology.@*METHODS@#Ultrasonographic finding of the fetus and X-ray examination of the abortus were reviewed. Genomic copy number variations (CNVs) of the fetus was analyzed by next-generation sequencing (NGS). Its parents were subjected to chromosomal karyotyping, NGS and fluorescence in situ hybridization (FISH) assays. Real-time fluorescence quantitative PCR was used to measure the expression of genes from the region containing abnormal CNVs.@*RESULTS@#Ultrasonography and X-ray revealed that the right hand and both feet of the fetus were in a V-shape, which was suggestive of SFHM. The results of NGS revealed that the fetus has carried a 0.36 Mb deletion at 7q21.3 region. FISH and NGS analysis of both parents were normal. Real-time fluorescence quantitative PCR confirmed that the fetus carried a single copy of DYNC1I1 gene, while the copy numbers of SEM1, DLX5 and DLX6 genes were normal.@*CONCLUSION@#The 7q21.3 microdeletion probably underlies the SHFM of the fetus, which has a de novo origin.

Genetic analysis of a child with atypical Williams-Beuren syndrome presenting as supravalvular aortic stenosis / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with supravalvular aortic stenosis.@*METHODS@#The child and his parents were subjected to conventional G-banding karyotyping, array comparative genomic hybridization (aCGH) and multiplex ligation-dependent probe amplification (MLPA) analysis.@*RESULTS@#No karyotypic abnormality was detected in the child and his parents. aCGH has identified a de novo 278 kb deletion encompassing the ELN gene in 7q11.23, which overlapped with the critical region of Williams-Beuren syndrome (WBS). MLPA has confirmed above findings.@*CONCLUSION@#The proband was diagnosed with atypical WBS. Deletion of the ELN gene may predispose to supravalvular aortic stenosis in the proband.

Clinical and genetic analysis of a case carrying 7p22.3 deletion, 7p22.3p22.2 duplication and 7q33q36.3 duplication / 中华医学遗传学杂志

OBJECTIVE@#To correlate genotype with clinical phenotype of a child featuring multiple congenital malformations.@*METHODS@#Clinical examination of the patient was carried out. Chromosome microarray analysis (CMA) was employed to detect genomic copy number variations (CNVs), and quantitative PCR (qPCR) was used for verifying the result.@*RESULTS@#The child had congenital heart disease (ventricular septal defect, atrial septal defect, pulmonary arterial hypertension, and tricuspid regurgitation), psychomotor retardation, agenesis of corpus callosum, hypospadias and scoliosis. CMA has detected a 1.8 Mb deletion at 7p22.3, a 1.8 Mb duplication at 7p22.3p22.2 and a 23.5 Mb duplication at 7q33q36.3 in the fetus, all of which were de novo in origin.@*CONCLUSION@#CMA can precisely detect microdeletion/duplications and facilitate the genotype-phenotype correlation analysis.

Prenatal diagnosis for a pregnant woman affected with Williams-Beuren syndrome / 中华医学遗传学杂志

OBJECTIVE@#To carry out genetic diagnosis for a pregnant woman and her fetus.@*METHODS@#Chromosome G-banding and microarray analysis were used to analyze the woman featuring dysmorphism and recognition defect and her fetus featuring developmental retardation.@*RESULTS@#The karyotype of the woman was normal, but chromosome microarray analysis showed that she has carried a 1423 kb deletion at 7q11.23 region. Her fetus has carried a 1530 kb deletion at the same region. Both individuals were diagnosed as Williams-Beuren syndrome.@*CONCLUSION@#Familiarity with its clinical features and proper selection of genetic testing methods are crucial for the diagnosis of Williams-Beuren syndrome.

Considerations for dental treatment of Williams syndrome patients / 대한구강보건학회지

Williams syndrome is a rare congenital disorder with various physical abnormalities and characterized by facial, oral, and dental features. Individuals with Williams syndrome typically have eating disorders in the early childhood, which lead to prolonged night feeding. Prolonged night feeding is a risk factor for rampant dental caries. Williams syndrome is caused by the microdeletion of chromosome 7, resulting in elastin deficiency. Elastin is integral to cardiovascular health. Many patients with Williams syndrome have complex cardiovascular abnormalities that must be considered a part of dental management. Complications related to cardiovascular diseases may induce adverse effects such as dangerously elevated blood pressure. This may occur in patients during stressful dental treatment. In addition, characteristics of auditory hyperalgesia and anxiety disorders among patients with William syndrome, complicate receiving routine dental management. Therefore, dental treatment under sedation or general anesthesia may be preferable for patients with Williams syndrome; in particular, patients who are very uncooperative and/or needs extensive dental treatment. A thorough evaluation of each patient's physical condition is required before making decisions regarding dental treatment. Careful monitoring and preparation for emergencies are very important during and shortly after dental treatment under general anesthesia or sedation. Monitoring is critical until vital signs have stabilized and return to normal. A 28-month-old man diagnosed as having Williams syndrome, visited the Dental Hospital of OO University for the management of rampant dental caries. We reported on the management of this patient who had peripheral pulmonic stenosis, and received dental treatment under general anesthesia. We also reviewed the characteristics of Williams syndrome and discussed considerations for dental treatment under general anesthesia.

Diabetes insipidus como manifestação inicial de leucemia mieloide aguda em paciente com monossomia do cromossomo 7 / Diabetes insipidus as initial manifestation of acute myeloid leukemia in a patient with monosomy of chromosome 7

O diabetes insipidus (DI) central é uma síndrome caracterizada pela incapacidade de concentração urinária devido à deficiência do hormônio antidiurético. O envolvimento do sistema nervoso central é frequente nas leucemias, mas a ocorrência de DI é rara e confere pior prognóstico. A patogênese do DI na leucemia não é totalmente conhecida, mas a infiltração do eixo hipotálamo-hipofisário por células leucêmicas parece ser um fator responsável. O presente relato descreve o caso de um paciente que apresentou DI como primeira manifestação de leucemia mieloide aguda e que evoluiu com dificuldades de ajustes do sódio sérico, da poliúria e da reposição volêmica, necessitando de permanência prolongada em unidade de cuidados intensivos(AU)

Central diabetes insipidus (DI) is a syndrome characterized by the inability to concentrate urine due to a lack of antidiuretic hormone. Involvement of the central nervous system is common in acute leukemia, but the occurrence of DI is rare and determines a worse prognosis. The pathogenesis of DI in leukemia has not been fully understood yet, but infiltration of the hypothalamic-pituitary axis by leukemic cells seems to be involved. This report describes a case of a patient who presented with DI as the first manifestation of acute myeloid leukemia. Difficulties in the management of serum sodium, fluid replacement and polyuria led to prolonged length of stay in an intensive care unit(AU)

Prenatal diagnosis of a rare case of 7q11.23 duplication syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the application of combined techniques for the prenatal diagnosis of a case with 7q11.23 duplication.</p><p><b>METHODS</b>Amniocentesis was performed in the second trimester for a mother with a high risk suggested by serological prenatal screening. G-banded chromosomal analysis was performed on cultured amniocytes and peripheral blood samples from both parents. DNA from amniotic fluid sample was isolated for a BACs-on-Beads (BoBs) assay. To define the range of duplication, copy number variation was determined with single nucleotide polymorphism array (SNP array, Affymetrix CytoScan 750K) and fluorescence in situ hybridization (FISH) analysis.</p><p><b>RESULTS</b>Chromosomal analysis suggested that the fetus and both parents all had a normal karyotype, while a duplication of 7q11.23 was detected by the BoBs assay. SNP array revealed a 1.5 Mb duplication in chromosome 7q11.23, which was confirmed by FISH.</p><p><b>CONCLUSION</b>Combined prenatal BoBs, SNP array and FISH has enabled effective diagnose of a case with 7q11.23 syndrome.</p>

Patient With Delayed Development Resulting From De Novo Duplication of 7q36.1-q36.3 and Deletion of 9p24.3

Patients with a duplication from 7q36 to the terminus or a deletion of 9p24 have been reported, whereas those harboring both mutations have not. Here, we report a patient with simultaneous de novo 7q36.1-q36.3 duplication and 9p24.3 deletion. A 6-year-old boy presented with speech developmental delay, microcephaly, and dysmorphic features, including a long face and small nose. Chromosome and array comparative genomic hybridization analyses revealed 46,XY,dup(7)(q36.1-q36.3) and del(9)(p24.3). The sizes of the duplication and deletion were 9.9 Mb and 1.9 Mb, respectively. The duplication of chromosome 7 contained 68 known genes, of which 3 are related with entries in the Developmental Disorders Genotype-to-Phenotype (DDG2P) database. The deletion of chromosome 9 contained 6 known genes, of which 2 are in the DDG2P database. We investigated the genotype and phenotype in this patient, and reviewed the relevant literatures for possible clinical presentation in these variations.

Do you know this syndrome? Dyspigmentation along the Blaschko lines caused by trisomy 7 mosaicism

Abstract Dyspigmentation along the Blaschko lines is strongly suggestive of a mosaic skin disorder. We report a 9-year-old male patient who presented with swirls and streaks of both hypo and hyperpigmentation involving the entire body. Additionally, he had hypertrichosis, musculoskeletal and minor neurodevelopment abnormalities but no intellectual disability. Cultured fibroblast displayed trisomy 7 mosaicism, which can explain this pigmentary phenotype. Widespread dyspigmentation associated with involvement of other organs should prompt systemic examination to detect additional anomalies and genetic evaluation should be considered, even with normal fetal karyotype.

Síndrome de duplicación 7q11. 23: Primer caso descrito en América Latina / Chromosome 7q11. 23 duplication syndrome: First reported case in Latin America

El síndrome de duplicación 7q11.23 es una patología causada por la duplicación de una región del cromosoma 7 que comprende 26 genes. El primer caso descrito en la literatura fue reportado por Somerville et al., en el año 2005, quienes describieron un paciente con dolicocefalia, frente alta y estrecha, pestanas largas, nariz alta y ancha, filtrum corto, paladar ojival, maloclusión dental, retrognatia y retardo grave en el lenguaje. Presentamos una paciente colombiana con hallazgo de duplicación 7q11.23 mediante técnicas de hibridación genómica comparativa y hallazgos clínicos clásicos. Este es el primer caso comunicado en Colombia y en América Latina.

7q11.23 duplication syndrome is a disease caused by duplication of a region of chromosome 7 comprising 26 genes. The first case described in the literature was reported by Somerville et al. in 2005, who described a patient with dolichocephaly, high and narrow forehead, long eyelashes, high and wide nose, short philtrum, high arched palate, dental malocclusion, retrognathia, and severe language delay. We report the case of a Colombian patient with 7q11.23 duplication by comparative genomic hybridization techniques, and classical clinical findings, this being the first reported case in Colombia and Latin America.

Genotype and phenotype analysis of two patients with Williams syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To perform genetic analysis for two patients with supravalvular aortic stenosis and unusual facial features.</p><p><b>METHODS</b>Cytogenetic and molecular genetic methods including chromosome karyotyping, multiplex ligation-dependent probe amplification (MLPA) and single nucleotide polymorphism array (SNP-array) were performed to detect potential mutation in the patients.</p><p><b>RESULTS</b>No abnormal karyotype was detected in either patient. Deletions in 7q11.23 region (1.36 Mb and 1.73 Mb, respectively) were discovered by SNP-array for the two patients. In both patients, de novo heterozygous deletion of ELN and LIMK1 genes was confirmed by MLPA analysis.</p><p><b>CONCLUSION</b>The genotypes of the two patients were identified by molecular genetic analysis, which has facilitated interpretation of the phenotypes of these patient. According to the deletion mutation, prenatal diagnosis for the family could be performed in the future.</p>

Application of single nucleotide polymorphism-array for the diagnosis of Williams-Beuren syndrome in a case / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To apply single nucleotide polymorphism array (SNP-array) for the diagnosis of Williams-Beuren syndrome (WBS) in a patient.</p><p><b>METHODS</b>Chromosome G-banding and SNP-array were used to analyze a girl featuring mental retardation.</p><p><b>RESULTS</b>The karyotypes of the child and her parents were all normal, but SNP-array showed a 1.9 Mb deletion at 7q11.23 in the patient. The same deletion was not found in her parents.</p><p><b>CONCLUSION</b>The mental retardation and special facies of the girl were probably due to the 7q11.23 microdeletion. SNP-array has an important value for the diagnosis of mental retardation.</p>

Relationship Between Cytogenetic Complexity and Peritumoral Edema in High-Grade Astrocytoma

BACKGROUND: The purpose of the study is to reveal the association of cytogenetic compltyexi and peritumoral edema volume (PTEV) and its prognostic significance in high-grade astrocytoma patients by culturing patient tumor cells. METHODS: Twenty-seven high-grade astrocytoma patients were divided into three groups according to karyotype complexity: normal, non-complex karyotype (NCK), and complex karyotype (CK). Endothelial growth factor receptor (EGFR) amplification was detected by FISH, and its association with chromosome 7 abnormalities was analyzed. Mean PTEV of each group was compared by ANOVA to evaluate the relationship between PTEV and cytogenetic complexity. RESULTS: The PTEV of patients in normal (n=6), NCK (n=8), and CK (n=13) groups were 24.52±17.73, 34.26±35.04, and 86.31±48.7 cm3, respectively (P=0.005). Ten out of 11 patients with EGFR amplification showed abnormalities in chromosome 7. The mean PTEV of EGFR-amplified and non-amplified groups were 80.4±53.7 and 41.3±37.9 cm3, respectively (P=0.035). The average survival of patients with PTEV less than 90 cm3 was 30.52±26.11 months, while in patients with PTEVs over or equal to 90 cm3, it was 10.83±5.53 months (P=0.007). CONCLUSIONS: The results show an association of complex karyotype with the PTEV of high-grade astrocytoma. EGFR amplification plays a significant role in the formation of peritumoral edema, causing PTEV to increase, which is related with survival. This implies that cytogenetic karyotype can be applied as a prognostic factor.

Application of fluorescent in situ hybridization in primary diagnosis of aplastic anemia by morphology / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To investigate the clinical application of fluorescent in situ hybridization (FISH) for the differential diagnosis of myelodysplastic syndromes (MDS) and aplastic anemia (AA).</p><p><b>METHODS</b>A FISH kit capable of detecting the chromosomal abnormalities related to MDS was used to analyze 94 patients who were suspected to have AA by bone marrow morphology.</p><p><b>RESULTS</b>Cytogenetic abnormalities were detected in 11 of the 94 patients, which included trisomy 8 (5 cases), 20q- (1 case) and -Y (1 case). There were 4 cases related to MDS, which included 3 cases of 5q-, in which 1 case carry 20q- at the same time, and 7q- (1 case). No significant difference was found between the MDS and AA groups in terms of age, sex or routine blood examination including absolute neutrophil count, hemoglobin content and platelet count.</p><p><b>CONCLUSION</b>FISH can detect certain cytogenetic abnormalities related to MDS in patients morphologically diagnosed as AA.</p>

Acquired aplastic anemia developing myelodysplastic syndrome/acute myeloid leukemia: clinical analysis of nineteen patients and literatures review / 中华血液学杂志

<p><b>OBJECTIVE</b>To analyze the clinical features of clonal evolution of acquired aplastic anemia (AA) into myelodysplastic syndrome/acute myeloid leukemia (AML) and review of literatures.</p><p><b>METHODS</b>AA developing MDS/AML patients between December 1994 and December 2011 enrolled into this study to analyze their clinical characteristics.</p><p><b>RESULTS</b>During the median follow-up of 49(15-97) months, 19 patients evolved to MDS/AML, of whom 10, 8 and 1 were from VSAA, SAA and NSAA subgroups, respectively. The median G-CSF therapy was 270(29-510) days. There were monosomy 7 in 11(57.9%) of 19 patients with AA evolved to MDS/AML. The median AA evolved to MDS/AML was 33(11-88) months. The median MDS/AML transformation in responders (54.2 months) was significantly longer than of non-responders (25.7 months, P<0.01).</p><p><b>CONCLUSION</b>AA patients could evolved into MDS/AML concomitant with abnormal karotype and worse prognosis.</p>

Diagnosis of a case with Williams-Beuren syndrome by single nucleotide polymorphism array / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To explore the genetic cause for a child with mental retardation, developmental delay and multi-systemic developmental disorders by analyzing the copy number variations (CNVs) and correlating the genotype with the phenotype.</p><p><b>METHODS</b>Routine G-banding was performed to analyze the karyotype of the patient and her parents. In addition, single nucleotide polymorphisms array (SNP-array) was used to determine the CNVs, which was confirmed by fluorescence in situ hybridization (FISH).</p><p><b>RESULTS</b>No karyotypic abnormality was detected upon chromosome analysis. However, SNP-array has identified a de novo hemizygous deletion of 1673 kb on chromosome region 7q11.23, which has been associated with Williams-Beuren syndrome. The microdeletion was confirmed by FISH testing.</p><p><b>CONCLUSION</b>A child with Williams-Beuren syndrome has been diagnosed by SNP-array and FISH. The de novo 7q11.23 microdeletion probably underlies the clinical manifestation of the patient. Compared with routine karyotype analysis, SNP-array is more useful for diagnosing children with multiple congenital anomalies with unclear etiology.</p>

Presentation of Progressive Familial Intrahepatic Cholestasis Type 3 Mimicking Wilson Disease: Molecular Genetic Diagnosis and Response to Treatment / 대한소아소화기영양학회지

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disorder of cholestasis of hepatocellular origin, typically seen in infancy or childhood caused by a defect in the ABCB4 located on chromosome 7. Here we report on an older patient, aged 15, who presented with biochemical testing that led to an initial consideration of a diagnosis of Wilson disease (WD) resulting in a delayed diagnosis of PFIC3. Diagnosis of PFIC3 was later confirmed by molecular studies that identified novel mutations in the ABCB4 gene. Cholestasis due to PFIC3 can cause elevated hepatic copper and increased urine copper excretion that overlap with current diagnostic criteria for WD. Molecular diagnostics are very useful for establishing the diagnosis of PFIC3. Ursodeoxycholic acid ameliorates cholestasis in PFIC3, and may help mediate a reduction in hepatic copper content in response to treatment.