MIC accident: lesson may guide for evaluation of genotoxic potential of the industrial chemicals for prevention of industrial accidents.

Most of the individual and/or amalgamated compounds present in the atmospheric air are not known for their toxicologic potential and impact on human health. The toxicologic strength of methyl isocyanate (MIC) gas was unknown till its accidental leakage that instantly claimed thousands of lives. Cytogenetic study showed increased chromosome aberrations (CA) and sister chromatid exchanges (SCEs) and delayed cell replication index (RI) in a multicentre genetic screening program on gas victims immediate post-disaster. A surveillance study after 30 years displayed reduction in CA compared to the initial status in survivors of the severely and moderately exposed strata. Altogether, cytogenetic damage was significantly predominant in the severely exposed population. Stable and replicable aberrations and chromatid exchanges were detected in both studies, which collectively indicate genetic instability. The variation in individual cytogenetic spectrum from similar exposure status could be the result of inter-individual response to the external factors over 30 years post-disaster. The spectrum of CA detected after 30 years might be the cumulative effect of occupational, environmental and life-style factors at a background of one episode of acute MIC exposure. Had MIC's toxicologic potential was known before, fatality and health effects could have been averted. In vitro assessment of toxicity of tin showed a positive correlation with dose and age of exposure, which was aggravated by smoking. Age has shown a significant effect on CA in the general population. The present report recommends evaluation of toxicity prior to use, and reduction of pollution at source for a maintaining a sustainable environmental context.

Therapeutics for mitochondrial dysfunction-linked diseases in Down syndrome.

Genome-wide deregulation contributes to mitochondrial dysfunction and impairment in oxidative phosphorylation (OXPHOS) mechanism resulting in oxidative stress, increased production of reactive oxygen species (ROS) and cell death in individuals with Down syndrome (DS). The cells, which require more energy, such as muscles, brain and heart are greatly affected. Impairment in mitochondrial network has a direct link with patho-mechanism at cellular and systemic levels at the backdrop of generalized metabolic perturbations in individuals with DS. Myriads of clinico-phenotypic features, including intellectual disability, early aging and neurodegeneration, and Alzheimer disease (AD)-related dementia are inevitable in DS-population where mitochondrial dysfunctions play the central role. Collectively, the mitochondrial abnormalities and altered energy metabolism perturbs several signaling pathways, particularly related to neurogenesis, which are directly associated with cognitive development and early onset of AD in individuals with DS. Therefore, therapeutic challenges for amelioration of the mitochondrial defects were perceived to improve the quality of life of the DS population. A number of pharmacologically active natural compounds such as polyphenols, antioxidants and flavonoids have shown convincing outcome for reversal of the dysfunctional mitochondrial network and oxidative metabolism, and improvement in intellectual skill in mouse models of DS and humans with DS.

Spectrum of stable and unstable rearrangements in lymphocytic chromosomes investigated in Bhopal population 30 years post MIC disaster amid co-exposure to lifestyle, living, and occupational hazards.

Immediate assessment of genetic damage in methyl isocyanate (MIC) gas-exposed population in small and heterogeneous samples using diversified study designs and solid-stained metaphases could not depict the actual genetic impact of MIC on accidentally exposed individuals. The outcome of the then large multi-center genetic screening program was not available to the public and scientific community. Also, the routine and regular epidemiological health survey does not capture the genetic and long-term effect of MIC. Therefore, genetic screening was carried out 30 years post disaster during 2015-2017 with a view to screen the present status of chromosomal consequences in lymphocytic cells. Participants were recruited from moderate (34) and severely (78) exposed and unexposed (35) cohorts with their informed consent. Analysis of ~100 mitotic cells and karyotyping of at least 10-15 and all abnormal metaphases detected structural and numerical alterations, including stable and replicable ones. Clonal abnormalities were detected with monosomal and complex karyotypes, trisomy 8, del5q/20q, loss of Y, etc. Among all, X-chromosome was frequently involved in numerical alterations. Structural aberrations appeared higher in the then exposed populations, though abnormalities cannot be linked directly to MIC exposure 30 years post disaster. Collectively, all rearrangements were markedly higher in the severely exposed population. Altogether, the detected abnormalities appeared random and indicated genomic instability, suggesting follow-up at shorter intervals for the individuals detected with clonal aberrations. G-banding has facilitated recognition of chromosomal involvement and their breakpoints and classification of structural rearrangements. The present data has been derived from the 30-year post-disaster genetic screening.

Effects of tyrosine kinase inhibitors for controlling Ph+ clone and additional clonal abnormalities in a chronic myeloid leukemia.

Purpose: The chronic myeloid leukemia (CML) is characterized by the presence of t(9;22)(q34;q11) that results in chimerization of BCR and ABL genes on the rearranged chromosome 22 or Philadelphia chromosome (Ph). Imatinib has been established as the first line of therapy for CML; in case of Imatinib failure or resistance, other second or third generation tyrosine kinase inhibitors (TKIs) are considered. However, acquisition of additional clonal abnormalities (ACAs) interferes in management of CML. We described a complex scenario of cytogenetic remission, relapse, response to TKIs and behavior of ACAs in a case of CML. Materials and Methods: Conventional G-banding and FISH cytogenetics, and quantitative PCR studies were conducted in the bone marrow for diagnosis and follow up (FU) of the changes of BCR-ABL gene and ACAs at different time intervals. Results: Ph- chromosome disappeared within 6 months of Imatinib therapy, and re-appeared within a year. Subsequent change of TKI to dasatinib eliminated the Ph+ clone, but established an ACA with trisomy 8 (+8). Further change to Nilotinib, eliminated +8 clone, but re-emergence of Ph+ clone occurred with an ACA with monosomy 7 (-7). Reinstate of Dasatinib eliminated Ph+ and -7 clones, but with gradual reappearance of Ph+ and +8 clones. The patient discontinued FU, though participated in a long term examination. Conclusion: The complexity of ACAs and Ph+ clones needs frequent monitoring with changes of TKI and technologies.

Triplication of HSA21 on alterations in structure and function of mitochondria.

Triplication of genes encoded in human chromosome 21 (HSA21) is responsible for the phenotypes of Down syndrome (DS). The dosage-imbalance of the nuclear genes and the extra-nuclear mitochondrial DNA (mtDNA) jointly contributes to patho-mechanisms in DS. The mitochondrial organelles are the power house of cells for generation of ATP and maintaining cellular calcium and redox homeostasis, and cellular energy-metabolism processes. Each cell contains hundreds to thousands of mitochondria depending on their energy consumption. The dynamic structure of mitochondria is maintained with continuous fission and fusion events, and thus, content of mtDNA and its genetic composition are widely variable among cells. Cells of brain and heart tissues of DS patients and DS-mouse models have demonstrated elevated number but reduced amount of mtDNA due to higher fission process. This mechanism perturbs the oxidative phosphorylation (OXPHOS) and generates more free radicals such as reactive oxygen species (ROS), suggesting contribution of mtDNA in proliferation and protection of cells from endogenous toxic environment and external stressors. Gene-dosage in DS population collectively contributes to mitochondrial dysfunction by lowering energy production and respiratory capacity via the impaired OXPHOS, and damaged redox homeostasis and mitochondrial dynamics in all types of cells in DS. The context is highly complex and affects the functioning of all organs. The effect in brain and heart tissues promotes myriads of neurodegenerative diseases and cardiac complexities in individuals with DS. Crosstalk between trisomic nuclear and mitochondrial genome has been crucial for identification of potential therapeutic targets.

Age-related disease burden in Indian population.

OBJECTIVES: Aging is not just a consequence of wear-and-tear, but it is the inappropriate regenerative mechanism of the stem cells. Aging is directly proportional to increase in health-problems involving all organs and physiological systems - more of non-communicable types. On the other hand, medical advancement and awareness about health-care are increasing the life expectancy, which could outnumber the young generation or the mainstream of work-force gradually. Hence, understanding of disease-prevalence is essential with a view to making necessary medical, environmental and economic arrangements and offering holistic care to the older population. STUDY DESIGN: Records of medical consultancies of outpatient departments (OPD) were retrieved from the hospital database and considered for understanding the disease-prevalence in the geriatric population. METHODS: Over 47000 subjects of 60 years and above were categorized into eight age-groups and analyzed for age-related disease-prevalence in both males and females. RESULTS: Approximately 25% were affected with cardiovascular system followed by 20% with general complication of cold/cough/fever and GI-disorientation. A uniform damage was observed in systems such as gastro-/neuro-/nephro-/ophthalmic and urology in both genders. Males were more prone to cardiac, nephorologic and urologic problems whereas females were more affected with musculo-skeletal problems than men. In general, men were more affected with geriatric diseases. CONCLUSION: Cardiovascular disorder after 60 years onwards could be related to stress for transition from 'income-to-no-income' state and lack of financial and other preparedness. Significant osteoarthritis problem in females is undoubtedly associated with ageing of ovaries. An intensive medical intervention following hospital-admission and outcome will guide for building age-friendly, long-stay and isolated accommodation, which could be considered for low- and middle-income countries as a model for handling geriatric disease burden.

Exposure index of methyl isocyanate (MIC) gas disaster and a comprehensive spectrum of cytogenetic analysis after 30 years.

Severity of clinical expression and high mortality could not facilitate establishing exposure index/association following MIC disaster in Bhopal. Mortality-based exposure stratification was critiqued by the International Medical Commission on Bhopal (IMCB). IMCB stratified exposure considering distance as surrogate at 2 km intervals after 10 years. The first follow-up cytogenetic screening of the pre-screened survivors after 30 years has demonstrated chromosome abnormalities (CA). Exposure stratification was attempted considering cytogenetic screening conducted during 1986-1988. Elevation of CA appeared proportional to exposure status and authenticated the initial mortality-based stratification. The one-on-one comparison of the previous and present cytogenetics has described the individual response to MIC exposure over 30 years. Chi-square test has been carried out for checking the cytogenetic changes at the individual level statistically, which revealed that differences of chromosomal aberrations collected immediately post-disaster and 30 years later are nonsignificant. The prominence of interindividual variation was noticed in general. The impact of overall exposure was higher in males. Constitutional abnormalities in 8.5% of the study population, including translocation, inversion, deletion, fragile sites, etc., necessitate screening of blood-linked members. The incidence of acrocentric association was prominent in the study population. Normal karyotype in children born to severely exposed parents with congenital anomalies indicates necessity of molecular karyotyping and/or screening of mutations. The study highlights follow-up of the health of the index cases at shorter (3-6 months) intervals. This comprehensive spectrum of cytogenetic report highlights immediate post-disaster chromosomal aberrations, the changes that occurred over 30 years in conjunction with other environmental factors at the individual level, constitutive genomic aberrations, polymorphic variations, and chromosomal patterns in congenitally malformed children of the survivors, which collectively indicate the possibility of acquisition/persistence of stable aberrations in MIC-exposed lymphocytes through interaction with environmental/biological confounders.

Effect of age at exposure on chromosome abnormalities in MIC-exposed Bhopal population detected 30 years post-disaster.

Follow-up cytogenetic study was carried out on 145 individuals from areas stratified by Indian Council of Medical Research, for evaluation of the effect of age-at-exposure and its interaction with exposure status on chromosomal aberrations (CA) in blood-lymphocytes. CA was presented as abnormal cell (Abc), aberrations (Abn) and number of aberration/abnormal cell (Abn/Abc), and correlated with age-at-exposure (childhood: <1-10 years; young: 11-26 years; adult: >27 years). Age related increase in abnormalities (Abc, Abn, Abn/Abc) was observed in all exposure strata, except moderately exposed adult-group, which has exhibited lower Abn/Abc than similarly exposed childhood and young age-groups. Elevation of CA was also related to exposure status. Abn/Abc frequency was significantly higher in the severely exposed young and adult groups compared to the controls of the same age. Two-way ANOVA revealed significant abnormalities between the exposed groups; however, interaction of age and exposure was not statistically significant. Significant difference in group-means of Abc and Abn was also observed between adult and childhood in Tukey HSD test. Altogether, a significant interaction of age and MIC-exposure on CA could not be established due to inter-individual variation and lack of baseline information on CA. Significantly higher Abn was observed in people consuming tobacco; however, interaction of lifestyle with additional environmental/occupational exposures during last 30 years against a background exposure to MIC remained un-elucidated. Nevertheless, the study was important for demonstration of the correlation of the current status of CA in circulating lymphocytes with age and exposure status of the MIC-exposed survivors.

Spectrum of health condition in methyl isocyanate (MIC)-exposed survivors measured after 30 years of disaster.

Health effects of methyl isocyanate (MIC) exposure were mostly reported on the one-time acute exposure in Bhopal population. Epidemiological survey conducted by the Indian apex body of health research has been reported as Technical Reports, which were lacking in peer review by the expert epidemiologic scientists. The present pilot survey was aimed to measure the health effects 30 years post disaster in MIC-exposed survivors. Questionnaire-based survey has captured every health complaint in 168 individuals and grouped as systemic functions for interpreting the long-term effects of MIC. Key health parameters, including reproductive outcome and respiratory/orthopedic/general morbidity, were prevalent among the severely exposed population compared to control and moderately exposed groups. The collective incidence of diabetes, hypertension, and cancer also was prevalent in the severely exposed group. Ophthalmic morbidity was almost similar in the three groups, rather with higher incidence in the control group, though not statistically significant. Among all health parameters, reproductive, ophthalmic, and respiratory effects were prevalent over others. Although the incidence of health problems has been declined among the survivors, long-term effect is apparent as scars of one-time acute exposure might trigger sequel of long-term effects. Additionally, acquisition of genetic rearrangements, survival of T cell sub-populations, variable latency of chemical effect on DNA nucleosides, nutritional status, occupational exposure, living environment, lifestyle, and overall gene-environment interaction might perturb individual immunity and favor onset of long-term illness in a scenario of background exposure to MIC. However, the exercise should be continued on a larger sample size for drawing a conclusive result on long-term MIC effect on survivors' health.

Impact of chromosome alterations, genetic mutations and clonal hematopoiesis of indeterminate potential (CHIP) on the classification and risk stratification of MDS.

The advent of technological development has undoubtedly advanced biological and molecular inputs for better understanding the heterogeneous hematopoietic pre-malignant disorder of the stem cells known as myelodysplastic syndromes (MDS). Chromosomal rearrangements, including del(3q/5q/7q/11q/12p/20q), loss of 5/7/Y, trisomy 8/19, i(17q), etc. frequently detected in MDS with variable frequencies and combinations, are the integral components of the 5-tier risk-stratification and WHO-2016 classification. Observations on mutations in genes involved in RNA-splicing, DNA methylation, chromatin modification, transcription factor, signal transduction/kinases, RAS pathway, cohesin complex, DNA repair and other pathways have given insights in independent effects and biological interaction of co-occurrence on disease-phenotype and treatment outcome. However, recent concepts of clonal hematopoiesis of indeterminate potential (CHIP) and idiopathic cytopenia of undetermined significance (ICUS) have urged a re-definition of mutational events in non-clonal cytopenia and non-MDS healthy elderly but with a higher risk of overt leukemia. Considering gene mutations, chromosomal alterations, CHIP, ICUS and their significance in classification and risk-scoring certainly presents a comprehensive picture of disease-phenotype towards better understanding of MDS-pathogenesis, its evolution to AML and its response to therapeutic agents. The present review summarizes chromosomal and gene mutations, co-existence of mutational complexity, and WHO-2016 classification and risk-stratifications of MDS to facilitate a better understanding of its pathogenesis.

Cytogenetic changes in the Bhopal population exposed to methyl isocyanate (MIC) in 1984: Then and 30 years later.

Following the 1984 Bhopal methyl isocyanate (MIC) gas disaster, genetic alterations were sporadically reported on small cohorts. However, the outcome of the multi-center cytogenetic screening conducted at that time remains unknown and no follow-up studies on the long-term effects of MIC exposure have been published. The present work examines genetic changes in the exposed population,with the aim of identifying any long-term effects of MIC. G-Banded metaphases were studied in lymphocytes of 130 individuals. Chromosomal aberrations (CA) were broadly grouped as abnormal cells (Abc), aberrations (Abn), and aberration/abnormal cell (Abn/Abc). From the previous multi-center screening, 946 records were retrieved, from which CA, sister chromatid exchanges (SCE), and cell-cycle kinetics (RI) were computed. In our analysis of the previous study, Abc and Abn were higher in the moderately and severely exposed groups than in the unexposed population. Abc appeared uniform in all groups of the present study, although Abn and Abn/Abc were higher in the exposed groups. Aberrations were now significantly higher in the unexposed and moderately exposed groups than in the previous screening. Although Abn and Abc now appeared lower in severely exposed subjects, the Abn/Abc ratio was higher, perhaps due to more rearrangements and damage in a smaller number of Abc. This result may be attributed to differences between the methods used in the studies, then and now. Elevated SCEs and reduced RI were seen in the severely exposed population shortly after exposure, and stable/clonal rearrangements were seen 30 y later. Follow-up of index cases and their progenies is needed.

Complexity of chromosomal rearrangements in Down syndrome leukemia.

Reports on imbalanced HSA21 gene expression and chromosomal rearrangements on leukemogenesis, drug sensitivity, and treatment outcome of leukemia in Down syndrome (DS) are limited. DS has been recognized as one of the most common leukemia-predisposing syndromes with unique clinical features, significant differences in treatment outcome and treatment-related toxicity profiles. Acute myeloid leukemia (AML), especially acute megakaryocytic leukemia, is reported with high cure rates presenting 80%-100% event-free survivals (EFSs); however, acute lymphoid leukemia indicates a worse prognosis in DS patients compared to non-DS children. Complex rearrangements are responsible for poor-to-very poor prognosis in all cases, irrespective of genetic predisposition or type of hematopoietic subunits affected. We report a 2-year-old female DS diagnosed with acute erythroleukemia (French-American-British: AML-M6) with highly complex chromosomal rearrangements in the bone marrow with 39 chromosomes. Parental consanguinity and genetic predisposition might be responsible for origin of multiple clones. Genetic instability and heterogeneity of complex clonal developments might cause poor prognosis. The case is a rare one with acute erythroleukemia in DS patient where too many rearrangements had masked identification of three 21s.

Small-molecule Inhibitors of Epigenetic Mutations as Compelling Drugtargets for Myelodysplastic Syndromes.

BACKGROUND: Involvement of mutations in epigenetic mechanism in the development of heterogeneous MDS and its evolution to AML has been understood with at least one mutation and median of 2-3 mutations of the landscapes of driver mutations in ~40 genes described in >90% MDS patients. Exclusivity and cooperating effects of mutations have directed therapeutic implementation with hypomethylating agents and identified a number of first-in-class small molecules as inhibitors of mutational expression. Preclinical and clinical trials have already been initiated for some synthetic and natural products and established proof-of-concept for mitigation of mutagenic effects. OBJECTIVE: The present review article entails the mutational signatures in DNA-methylation and hydroxymethylation, histone acetylation and Deacetylation, polycomb repressor complex (PRC2), and small molecule inhibitors of these mutational expressions. METHOD: Information has been collected from the recently published literature available mainly through Google search in Medline and PubMed database. Special emphasis was paid on the literature available during 2009-2016. RESULT: The up-to-date information accumulated on signature-mutations and their inhibitors has to integrate the function of clonal hematopoiesis of indeterminate potential (CHIP) and mutational complexities for re-defining MDS-genesis. Nevertheless, molecular understanding of MDS heterogeneity and its transformation to AML is expanding at fast pace with expanding knowledge on abundant non-coding RNAs (ncRNAs), which forms the basis of targeted drug-tailoring, and will further develop personalized medicines based on individual genetic blue-prints. CONCLUSION: Mutation-specific targeted epigenetic drugs, which have already sensitized drug-makers and regulators, may promise attestation of 'del5q and lenalidomide'-like specific drugs for every mutational signature independently or in combination with standard therapeutic elements used for MDS-management, and that will add to understand their antagonistic/synergistic effects.

Mutations of myelodysplastic syndromes (MDS): An update.

The plethora of knowledge gained on myelodysplastic syndromes (MDS), a heterogeneous pre-malignant disorder of hematopoietic stem cells, through sequencing of several pathway genes has unveiled molecular pathogenesis and its progression to AML. Evolution of phenotypic classification and risk-stratification based on peripheral cytopenias and blast count has moved to five-tier risk-groups solely concerning chromosomal aberrations. Increased frequency of complex abnormalities, which is associated with genetic instability, defines the subgroup of worst prognosis in MDS. However, the independent effect of monosomal karyotype remains controversial. Recent discoveries on mutations in RNA-splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1, U2AF2); DNA methylation (TET2, DNMT3A, IDH1/2); chromatin modification (ASXL1, EZH2); transcription factor (TP53, RUNX1); signal transduction/kinases (FLT3, JAK2); RAS pathway (KRAS, NRAS, CBL, NF1, PTPN11); cohesin complex (STAG2, CTCF, SMC1A, RAD21); DNA repair (ATM, BRCC3, DLRE1C, FANCL); and other pathway genes have given insights into the independent effects and interaction of co-occurrence of mutations on disease-phenotype. RNA-splicing and DNA methylation mutations appeared to occur early and are reported as 'founder' mutations in over 50% MDS patients. TET2 mutation, through altered DNA methylation, has been found to have independent prognostic response to hypomethylating agents. Moreover, presence of DNMT3A, TET2 and ASXL1 mutations in normal elderly individuals forms the basis of understanding that accumulation of somatic mutations may not cause direct disease-development; however, cooperation with other mutations in the genes that are frequently mutated in myeloid and other hematopoietic cancers might result in clonal expansion through self-renewal and/or proliferation of hematopoietic stem cells. Identification of small molecules as inhibitors of epigenetic mutations has opened avenues for tailoring targeted drug development. The recommendations of a Clinical Advisory Committee is being considered by WHO for a revised classification of risk-groups of MDS, which is likely to be published in mid 2016, based on the new developments and discoveries of gene mutations.

Spectrum of complex chromosomal aberrations in a myelodysplastic syndrome and a brief review.

Myelodysplastic syndrome (MDS) is a heterogeneous premalignant condition characterized by cytopenia, ineffective hematopoiesis, dysplastic marrow, and risk of progression to acute myeloid leukemia. Cytogenetic abnormalities, including del(3q/5q/7q/11q/12p/20q), monosomy 5/7, trisomy 8/19, i(17q), and -Y, are the indicators of diagnosis and risk stratification. The present case with bicytopenia detected with highly complex chromosome rearrangements with variability in numerical and structural combinations. Chromosome analysis was carried out following unstimulated marrow culture and G-banding. In addition to known MDS-aberrations, der(9p), der(12) dic(12;?19), +15, -18, and ring and marker chromosomes were recorded having, at least, nine abnormal chromosomes/cell. To our knowledge, this is the first case with all MDS-aberrations in one single individual. The case has been discussed in relevance to current MDS research. In the present case, i(17q)/-17, der(12p), del(5q26), del(7q36), and del(20q11) indicate possible alterations in TP53, ETV6, IDH2, EZH2, and SRSF2 genes, which are responsible for pathomechanism, genetic instability, clonal evolution, and advancement of disease condition.

Clinical expression of an inherited unbalanced translocation in chromosome 6.

Unbalanced chromosomal rearrangements are not common; however, they have a significant clinical expression. The parental balanced translocation produces unbalanced chromosome, which is transmitted to next generation through fertilization of gametes carrying the derivative chromosome. The carriers of balanced rearrangements mostly do not have recognizable phenotypic expression. We report a family comprising of healthy and non-consanguineous young parents and their preemie newborn severely affected with congenital anomalies and systemic disorders. Conventional Gbanding analysis of somatic chromosomes identified a balanced translocation, t(6;10)(p23;q24), in mother and an unbalanced rearrangement, der(6)t(6:10)(p23;q24)mat, in the child. The child has inherited a derivative chromosome 6 with partial deletion of 6(p23-pter) and partial trisomy 10(q24-qter), which has resulted in fusion of genes of two different chromosomes. The prominent phenotypic features of del(6p), including high forehead, flat nasal bridge, agenesis of left ear, atrial septal defect (ASD), craniosynostosis, and growth retardation, are overlapping with specific Axenfeld-Reiger-, Larsen-, and Ritscher-Sinzel/3-C syndromes, however, lacking in ocular anomalies, skeletal laxity, or cerebellar malformation. Therefore, this paper rules out the isolated effect of del(6p23) or trisomy 10(q24) on distinct previously reported syndromes and proposes the combined effect of unbalanced chromosomal alteration.

Conventional and fluorescence in situ hybridization analysis of three-way complex BCR-ABL rearrangement in a chronic myeloid leukemia patient.

Chromosomal analysis was carried out in bone marrow sample of an 11-year-old girl suspected of myeloproliferative disorder. Conventional G-banding study detected a complex three-way translocation involving 7, 9 and 22, which has resulted in the formation of a variant Philadelphia chromosome causing rearrangement of abl and bcr genes in 87% cells. Fluorescence in situ hybridization (FISH) confirmed the fusion of bcr-abl oncogene. Thus the bone marrow karyotype was observed as 46,XX (13%)/46,XX,t(7;9;22)(q11;q34;q11) (87%). Hyperdiploidy was present in two cells. In this study, both conventional cytogenetic and FISH diagnosis proved to be significant to identify the variant nature of the Philadelphia chromosome and hyperdiploid condition for introduction of a suitable treatment regimen and estimation of life expectancy of the young girl.

X chromosomal abnormalities in Indian adolescent girls.

In girls of adolescent age, primary amenorrhea is a major problem and it is often suspected as Turner syndrome (TS), with complete or partial absence of one of the two X chromosomes. The girls who are unable to menstruate are primarily investigated by the gynecologists with the help of a physical examination, sonogram of the pelvis, endocrinologic tests, and ultimately cytogenetic analysis. Chromosomal analyses have been carried out in 280 such cases that were referred from different parts of the country. The standard protocol for peripheral blood lymphocyte culture was followed for metaphase chromosome preparation and conventional analysis of G-banded chromosomes. A total of 29% cases were found to have some chromosomal abnormality, including TS and testicular feminization syndrome involving sex chromosomes. Amongst those with sex chromosomal anomaly, 34% had evidence of a 46,XY karyotype in phenotypic females and 51% had pure line 45,X or mosaic with normal XX or other aberrations in X. The classification of the TS group further showed the spectrum of variant TS in Indian adolescent girls who suffered from absence or delayed menarche to correspond well with the Belgian, Danish, or Russian population. However, it has been reported that only 1% of the pure line 45,X conception is viable, indicating the necessity of mosaicism with X or Y chromosome. It has been understood that conventional banding analysis is absolutely necessary for segregating the variant nature of TS. In addition, molecular genetic or molecular cytogenetic investigations can determine the nature of mosaicism. The present study further indicated the involvement of autosomes in causing improper sexual development in girls of adolescent age.