Trisomy X Research Articles

Double Aneuploidy (Trisomy 21 and XXX) in a Child with Down Syndrome Phenotype: A Case Report with Review of Literature

Abstract Background: Down syndrome is the most common and extensively studied disorder arising out of human chromosomal aberration. Several aneuploidies are associated with Down syndrome, but double trisomy (48 XXX + 21) is rarely described. Clinical Description: A 3-year-old girl presented with respiratory distress and a chronic history of feeding fatigue and failure to thrive. She had phenotypic features suggestive of Down syndrome and clinical signs of acyanotic heart disease in congestive cardiac failure. Management and Outcome: Echocardiography revealed ventricular septal defect and atrial septal defect. Karyotyping showed double trisomy (trisomy 21 and XXX). Trisomy X was an incidental finding on karyotyping with no clinical features suggestive of XXX syndrome specifically at this age. The patient was managed conservatively with decongestive therapy for congestive heart failure and oral sildenafil for pulmonary hypertension. Additional evaluations were done to identify associated anomalies, and the parents were counseled. Conclusion: Down and XXX syndromes share many clinical signs and symptoms, making karyotyping the only way to make an early diagnosis. A child having a phenotype characteristic of Down syndrome may have an unsuspected double trisomy of X chromosome along with 21 trisomy, which can only be identified by karyotyping.

Triple X syndrome: Psychiatric disorders and impaired social functioning as a risk factor.

Women with triple X syndrome (TXS) have an extra X chromosome. TXS appeared to be associated with psychiatric disorders in biased or underpowered studies. This study aims to describe the prevalence of psychiatric disorders in adults with TXS in a relatively large and less biased group of participants. In this cross-sectional study, data were collected from 34 women with TXS (mean age = 32.9; s.d. = 13.1) and 31 controls (mean age = 34.9; s.d. = 13.7). Psychiatric disorders were assessed using the MINI International Neuropsychiatric Interview (MINI) and the adult behavior checklist (ABCL). Trait and state anxiety were assessed using the State-Trait Anxiety Inventory. In the TXS group, MINI results showed a higher prevalence of major depressive episodes (43.3%), psychotic disorders (29.4%), and suicidality (23.5%). Only 50% of the TXS group earned a normal score for the total syndrome score using the ABCL. In addition, levels of trait anxiety were higher in the TXS group. Only three women in each group received psychotropic medication. Impaired social functioning appeared to represent a major risk factor in TXS as regards psychotic, affective disorders, trait anxiety, and low self-esteem. Women with TXS are vulnerable to developing psychiatric disorders, and women with both TXS and impaired social functioning are even more vulnerable.

Tracking Multifocal Epilepsy With Automated Electric Source Imaging in a Patient With Triple-X Syndrome.

Tracking Multifocal Epilepsy With Automated Electric Source Imaging in a Patient With Triple-X Syndrome.

The comorbidity landscape of 47,XXX syndrome: A nationwide epidemiologic study

PurposeThis study aimed to describe the comorbidity pattern in 47,XXX syndrome. MethodsThis was a registry-based study of hospital diagnoses and prescribed medication in a nationwide cohort of females with 47,XXX (n = 103) and 46,XX/47,XXX (n = 57) in which they were compared with 16,000 age-matched general population female controls. ResultsThe overall occurrence of hospital diagnoses was significantly increased in females with 47,XXX when compared with controls (incidence rate ratio = 2.1, CI = 1.7-2.5), and when divided into 19 organ-specific groups, there was a significantly increased risk in the following 14 groups: infection, blood, endocrine and metabolism, mental, nervous system, eye, ear, respiratory, oral cavity and gastrointestinal, musculoskeletal, perinatal, congenital malformations, external factors, and “other.” The risk of being prescribed any medication was not significantly increased in females with 47,XXX when compared with controls (hazard ratio = 1.2, CI = 0.9-1.4). However, when stratified according to medication groups, a significantly increased risk was detected in 4 of 13 groups. The overall occurrence of hospital diagnoses was also significantly increased when females with 46,XX/47,XXX were compared with controls (incidence risk ratio = 1.3, CI = 1.01-1.8), but generally, in comparison with controls, females with 46,XX/47,XXX were less severely affected than females with 47,XXX. ConclusionThe 47,XXX syndrome is associated with an increased occurrence of a wide variety of diseases. Increased awareness of this may contribute to improve counseling and clinical assessment of these patients.

Dysgerminoma of the ovary in a patient with triple-X syndrome (47, XXX) and Marfanoid habitus features.

Dysgerminoma of the ovary in a patient with triple-X syndrome (47, XXX) and Marfanoid habitus features.

Triple-X syndrome as a cause of primary ovarian insufficiency

Triple-X syndrome as a cause of primary ovarian insufficiency

Autosomal sex-associated co-methylated regions predict biological sex from DNA methylation.

Sex is a modulator of health that has been historically overlooked in biomedical research. Recognizing this knowledge gap, funding agencies now mandate the inclusion of sex as a biological variable with the goal of stimulating efforts to illuminate the molecular underpinnings of sex biases in health and disease. DNA methylation (DNAm) is a strong molecular candidate for mediating such sex biases; however, a robust and well characterized annotation of sex differences in DNAm is yet to emerge. Beginning with a large (n = 3795) dataset of DNAm profiles from normative adult whole blood samples, we identified, validated and characterized autosomal sex-associated co-methylated genomic regions (sCMRs). Strikingly, sCMRs showed consistent sex differences in DNAm over the life course and a subset were also consistent across cell, tissue and cancer types. sCMRs included sites with known sex differences in DNAm and links to health conditions with sex biased effects. The robustness of sCMRs enabled the generation of an autosomal DNAm-based predictor of sex with 96% accuracy. Testing this tool on blood DNAm profiles from individuals with sex chromosome aneuploidies (Klinefelter [47,XXY], Turner [45,X] and 47,XXX syndrome) revealed an intimate relationship between sex chromosomes and sex-biased autosomal DNAm.

Epigenetic and transcriptomic consequences of excess X-chromosome material in 47,XXX syndrome-A comparison with Turner syndrome and 46,XX females.

47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X-chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may ensue from increased or decreased expression from the genes that escape X inactivation, as well as from incomplete X chromosome inactivation in 47,XXX. We aim to study genome-wide DNA-methylation and RNA-expression changes can explain phenotypic traits in 47,XXX syndrome. We compare DNA-methylation and RNA-expression data derived from white blood cells of seven women with 47,XXX syndrome, with data from seven female controls, as well as with seven women with Turner syndrome (45,X). To address these questions, we explored genome-wide DNA-methylation and transcriptome data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven karyotypically normal females (46,XX). Based on promoter methylation, we describe a demethylation of six X-chromosomal genes (AMOT, HTR2C, IL1RAPL2, STAG2, TCEANC, ZNF673), increased methylation for GEMIN8, and four differentially methylated autosomal regions related to four genes (SPEG, MUC4, SP6, and ZNF492). We illustrate how these changes seem compensated at the transcriptome level although several genes show differential exon usage. In conclusion, our results suggest an impact of the supernumerary X chromosome in 47,XXX syndrome on the methylation status of selected genes despite an overall comparable expression profile.

The epidemiology of sex chromosome abnormalities.

Sex chromosome abnormalities (SCAs) are characterized by gain or loss of entire sex chromosomes or parts of sex chromosomes with the best-known syndromes being Turner syndrome, Klinefelter syndrome, 47,XXX syndrome, and 47,XYY syndrome. Since these syndromes were first described more than 60 years ago, several papers have reported on diseases and health related problems, neurocognitive deficits, and social challenges among affected persons. However, the generally increased comorbidity burden with specific comorbidity patterns within and across syndromes as well as early death of affected persons was not recognized until the last couple of decades, where population-based epidemiological studies were undertaken. Moreover, these epidemiological studies provided knowledge of an association between SCAs and a negatively reduced socioeconomic status in terms of education, income, retirement, cohabitation with a partner and parenthood. This review is on the aspects of epidemiology in Turner, Klinefelter, 47,XXX and 47,XYY syndrome.

Behavioral and psychological features in girls and women with triple-X syndrome.

Triple-X syndrome is a common sex chromosome aneuploidy, which appears in 1 out of 1,000 females. The aim of our study was to describe the behavioral features of a large group of girls and women with triple-X in comparison to a control group. A total of 72 subjects with triple-X and 69 subjects of an age-matched control group were included. Psychological and behavioral questionnaires were allocated to three age groups, representing a range of ages from young childhood to adulthood. Regarding the females between 4 and 7 years of age, we found significant differences for social problems, attention problems, and school performance. For the age group 8-17 years, we found larger significant differences for the majority of the scales listed in the child behavior checklist. The most significant differences (p < .001) were from total behavior problems, internalizing problems, and four other scales. Young females with triple-X have significantly lower general self-esteem, especially concerning school and family. In the adults, there were significant differences concerning psychological symptoms and distress, with higher scores in the triple-X subjects. Regardless, their mean scores were still in the normal range. We did not find clinical evidence for more than 50% of the triple-X females in any age group, indicating that approximately half of them do not have behavioral problems, and that more than 60% do not differ in their competence from the control group. However, our findings suggest that triple-X influences mental health and the overall well-being of the individuals across their whole life spans.

Sex differences in psychiatric disorders: what we can learn from sex chromosome aneuploidies.

The study of sexual dimorphism in psychiatric and neurodevelopmental disorders is challenging due to the complex interplay of diverse biological, psychological, and social factors. Males are more susceptible to neurodevelopmental disorders including intellectual disability, autism spectrum disorder, and attention-deficit activity disorder. Conversely, after puberty, females are more prone to major depressive disorder and anxiety disorders compared to males. One major biological factor contributing to sex differences is the sex chromosomes. First, the X and Y chromosomes have unique and specific genetic effects as well as downstream gonadal effects. Second, males have one X chromosome and one Y chromosome, while females have two X chromosomes. Thus, sex chromosome constitution also differs between the sexes. Due to this complexity, determining genetic and downstream biological influences on sexual dimorphism in humans is challenging. Sex chromosome aneuploidies, such as Turner syndrome (X0) and Klinefelter syndrome (XXY), are common genetic conditions in humans. The study of individuals with sex chromosome aneuploidies provides a promising framework for studying sexual dimorphism in neurodevelopmental and psychiatric disorders. Here we will review and contrast four syndromes caused by variation in the number of sex chromosomes: Turner syndrome, Klinefelter syndrome, XYY syndrome, and XXX syndrome. Overall we describe an increased rate of attention-deficit hyperactivity disorder and autism spectrum disorder, along with the increased rates of major depressive disorder and anxiety disorders in one or more of these conditions. In addition to contributing unique insights about sexual dimorphism in neuropsychiatric disorders, awareness of the increased risk of neurodevelopmental and psychiatric disorders in sex chromosome aneuploidies can inform appropriate management of these common genetic disorders.

Generation of integration-free induced pluripotent stem cells (GZHMUi001-A) by reprogramming peripheral blood mononuclear cells from a 47, XXX syndrome patient

47, XXX syndrome is one of several sex-chromosomal aneuploidies, and it has an incidence of approximately 1/1000 in newborn females. Because of heterogeneity in X-inactivation, these patients may exhibit a variety of clinical symptoms. Here, we report the generation of an integration-free human induced pluripotent stem cell line (GZHMUi001-A) by using Sendai virus to reprogram peripheral blood mononuclear cells from a 47, XXX syndrome patient with premature ovarian failure. This 47, XXX iPS cell line has characteristics of pluripotent stem cells and is a useful tool for the investigation of this X chromosome aneuploid disease.

Triple-X syndrome accompanied by Chilaiditi syndrome in preterm infant: a case report

Chilaiditi syndrome is a variant of the rotation of the colon that gives rise to the interposition of the colon between the right diaphragm and the liver intermittently or constantly. Also, Necrotizing enterocolitis is typically seen in premature infants. In this report, we presented a female case report accompanied with a 47,XXX karyotype and Chialiditi syndrome and Necrotizing enterocolitis. This association was not reported in any case study. Our findings suggest that abnormalities of X chromosome may be associated with other anomalies.

Cytogenetic studies of 1232 patients with different sexual development abnormalities from the Sultanate of Oman

The aim of this study was to evaluate cytogenetic findings in Omani patients who had been referred for suspicion of sex chromosome abnormalities that resulted in different clinical disorders. Furthermore, it sought to examine the frequency of chromosomal anomalies in these patients and to compare the obtained results with those reported elsewhere. Cytogenetic analysis was performed on 1232 cases with variant characteristics of sexual development disorders who had been referred to the cytogenetic department, National Genetic Centre, Ministry of Health, from different hospitals in the Sultanate of Oman between 1999 and 2014. The karyotype results demonstrated chromosomal anomalies in 24.2% of the cases, where 67.5% of abnormalities were identified in referral females, whereas only 32.6% were in referral males. Of all sex chromosome anomalies detected, Turner syndrome was the most frequent (38.2%) followed by Klinefelter syndrome (24.9%) and XY phenotypic females (16%). XXX syndrome and XX phenotypic males represented 6.8% and 3.8% of all sex chromosome anomalies, respectively. Cytogenetic analysis of patients referred with various clinical suspicions of chromosomal abnormalities revealed a high rate of chromosomal anomalies. This is the first broad cytogenetic study reporting combined frequencies of sex chromosome anomalies in sex development disorders in Oman.

Karyotyping analysis of 396 newborns with congenital malformations and chromosomal abnormalities and the associated phenotypes

Objective To reveal the chromosome abnormalities and their relationship with the clinical phenotype of neonates with congenital malformation. Methods Karyotype analysis of peripheral blood lymphocytes was performed on 396 newborns with congenital malformation, who were recruited at the Children's Hospital Affiliated to Soochow University from Jan.2006 to May 2012, chromosome karyotypes were prepared with neonatal peripheral lymphocytes by conventional G-banding technique. Results 1.Of 396 newborns, 159(40.2%) cases were detected to have chromosomal abnormalities, including karyotype first reported domestically and internationally in 3 cases.2.Trisomy-21(Down's syndrome), which was the most common abnormal karyotype, was seen in 130 cases, accounting for 81.8%, of whom 119 cases show the standard type, 10 cases accompanied by the Robertsonian translocation involving group D or group G, and 1 case accompanied by sexual chromosomal abnormality: inv(Y)(p11q11), + 21.3.Other common kar-yotype abnormalities were as follows: del(5)(p12-14)(cats cry syndrome) in 4 cases, trisomy-18(Edwards syndrome) in 4 cases, 45, XO(Turner's syndrome) in 4 cases, inv(9)(p11q12-21) in 4 cases, trisomy-X(super female syndrome) in 1 case, rob(13; 14) in 1 case, trisomy-8 in 1 case and del(18)(q22) in 1 case.4.Special faces were seen in 147 cases(92.5%), congenital heart disease in 97 cases(61.0%), low birth weight in 72 cases(45.3%), congenital anal atresia in 13 cases(8.1%), multiple malformations in 11 cases(6.8%), intestinal malformations in 10 cases(6.2%), extrinsic genital abnormalities in 9 cases(5.7%), meow-like cry in 4 cases(2.5%), limb edema in 4 cases(2.5%), fingers and toe abnormalities in 6 cases(3.6%), congenital brain dysplasia in 6 cases(3.6%), webbed neck in 5 cases(3.1%) and cleft lip and palate in 3 cases(1.8%). Conclusions Chromosomal abnormality is an important factor leading to neonatal birth defects, of which special face, congenital heart disease, low birth weight, and multiple malformations are the main clinical manifestations of chromosomal diseases. Key words: Karyotype; Chromosomal abnormalities; Clinical phenotype; Infant, newborn

Poor socio-economic status in 47,XXX – An unexpected effect of an extra X chromosome

One of the most common sex chromosomal abnormalities in females is 47,XXX syndrome, which is characterized by tall stature and reduced IQ, but with a variable phenotype. In order to elaborate on the characteristics of this syndrome, we undertook an investigation in all diagnosed 47,XXX females at risk in Denmark and compared their socio-economic status with an age-matched cohort of the female background population as well as with all Danes diagnosed with Turner syndrome. We focused on cohabitation, motherhoods, income, education, retirement and convictions. Furthermore, we investigated whether some of these parameters influenced the increased mortality identified previously. Thus, socio-economic data were retrieved in 108 47,XXX persons, 10,297 controls, and 831 with Turner syndrome. Comparing the 47,XXX persons with their controls, we identified significantly decreased numbers of first partnership, number of mothers, and number of persons with an education in 47,XXX persons. Significantly more 47,XXX persons retired. In the younger age groups an increased number had income below the median among controls. The increased mortality identified previously was not explained by the reduced number of partnerships or the reduced number of persons with an education. Comparing the 47,XXX persons with Turner syndrome persons, we identified increased number of first partnership, number of mothers, and reduced level of education. We hypothesize that the significantly decreased number of 47,XXX persons becoming mothers could be due to hypogonadism in some. The affected socio-economic status suggests that the presence of an extra X chromosome has more detrimental effects than previously appreciated.

Situs İnversus Totalisli Triple-X Sendromlu Bir Olgu

Triple-X syndrome (47,XXX) is one of the most common aneuploidies. Most 47,XXX patients present with a normal phenotype except a tall stature. In 90% of the cases, additional X chromosome is of maternal origin. Additional X chromosome cannot explain phenotypic findings in triple X syndrome. Situs inversus totalis, resulting from an error during embryonic process, is characterized with complete mirror image transposition of abdominal and thoracic viscera. According to our best knowledge, an association of the triple-X syndrome and situs inversus totalis has not been described in the literature. In this article, we report a 9-month-old female with situs inversus totalis and 47,XXX karyotype.

Chromosomal analysis from blood: 18 year experience of Songklanagarind Hospital

Metaphase chromosome analysis from cultured blood lymphocytes were investigated in 5,866 tests at Songklanagarind Hospital from 1990 through 2007 (18 years). Elaboration of G-bands by trypsin using Giemsa (GTG) was routinely employed with other banding techniques if required. High resolution chromosome banding was performed in suspected cases of structural chromosome abnormality. Successful studies were obtained in 5,665 tests (96.4 %) and 1,680 tests (28.7 %) were found to have chromosomal abnormalities. The failure rate was 3.4 % (201 tests). Fifty duplicated tests were discarded of the 1680 abnormal results, leaving 1,630 cases with abnormal chromosomes. Of 1,630 cases, Down, Edwards, and Patau syndromes were found in 933 (57.2 %), 87 (5.3 %) and 80 (4.9 %) cases, respectively. There were 215 cases with sex chromosome abnormalities (13.2 %), including 188 cases with Turner syndrome, 18 cases with Klinefelter syndrome, 6 cases with XXX syndrome and 3 cases with XYY syndrome. Androgen insensitivity syndrome (female with 46,XY) was found in 23 cases, and structural chromosome abnormalities were found in 222 cases (13.6 %). The remainder (70 cases/4.3 %) was composed of microdeletion, marker chromosome, fragile X syndrome and rare trisomy. To the best of our knowledge, this study is the largest group of chromosome analysis results reported from Thailand. These findings can be available to provide the database for genetic counseling.

Autism in association with Triple X syndrome

Autism in association with Triple X syndrome

Mortality and incidence in women with 47,XXX and variants

47,XXX syndrome is among the most common sex chromosomal disorders; however, apart from screening surveys, epidemiological data are limited. We report data on 136 women diagnosed with 47,XXX or a compatible karyotype in Denmark during 1963-2008. We identified an incidence of 10.7 per 100,000 liveborn girls, which was lower than expected and was stable during the study period. Age at diagnosis ranged from 0 to 73 years, with a diagnostic delay of 18.2 years or more in half the 47,XXX persons. We compared persons with 47,XXX with an age-matched cohort of the female background population (born same year and month), identified in Statistics Denmark (n = 13,400). Mortality was significantly increased in total with a hazard ratio of 2.5 (1.6-3.9), corresponding to a difference in median survival of 7.7 years. When we divided causes of death into 19 chapters according to the International Classification of Diseases, a generally increased mortality was identified in all informative chapters. Furthermore, we identified significantly increased mortality in cardiovascular diseases, in the chapter concerning chromosomal and congenital defects, and in the chapter of unspecified diseases. Better delineation of the clinical phenotype of 47,XXX is needed; available information does not readily explain the increased mortality.