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1.  The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance 
Background
Klinefelter syndrome (KS), caused by XXY karyotype, is characterized by low testosterone, infertility, cognitive deficits, and increased prevalence of health problems including obesity and diabetes. It has been difficult to separate direct genetic effects from hormonal effects in human studies or in mouse models of KS because low testosterone levels are confounded with sex chromosome complement.
Methods
In this study, we present the Sex Chromosome Trisomy (SCT) mouse model that produces XXY, XYY, XY, and XX mice in the same litters, each genotype with either testes or ovaries. The independence of sex chromosome complement and gonadal type allows for improved recognition of sex chromosome effects that are not dependent on levels of gonadal hormones. All mice were gonadectomized and treated with testosterone for 3 weeks. Body weight, body composition, and motor function were measured.
Results
Before hormonal manipulation, XXY mice of both sexes had significantly greater body weight and relative fat mass compared to XY mice. After gonadectomy and testosterone replacement, XXY mice (both sexes) still had significantly greater body weight and relative fat mass, but less relative lean mass compared to XY mice. Liver, gonadal fat pad, and inguinal fat pad weights were also higher in XXY mice, independent of gonadal sex. In several of these measures, XX mice also differed from XY mice, and gonadal males and females differed significantly on almost every metabolic measure. The sex chromosome effects (except for testis size) were also seen in gonadally female mice before and after ovariectomy and testosterone treatment, indicating that they do not reflect group differences in levels of testicular secretions. XYY mice were similar to XY mice on body weight and metabolic variables but performed worse on motor tasks compared to other groups.
Conclusions
We find that the new SCT mouse model for XXY and XYY recapitulates features found in humans with these aneuploidies. We illustrate that this model has significant promise for unveiling the role of genetic effects compared to hormonal effects in these syndromes, because many phenotypes are different in XXY vs. XY gonadal female mice which have never been exposed to testicular secretions.
doi:10.1186/2042-6410-4-15
PMCID: PMC3751353  PMID: 23926958
Klinefelter; Sex chromosome trisomy; XXY; XYY; Mouse; X chromosome; Y chromosome; Body weight; Obesity
2.  Attention-Deficit Hyperactivity Disorder Symptoms in Children and Adolescents with Sex Chromosome Aneuploidy: XXY, XXX, XYY, and XXYY 
Objective
Attentional problems, hyperactivity, and impulsivity have been described as behavioral features associated with sex chromosome aneuploidy (SCA). In this study, the authors compare attention-deficit hyperactivity disorder (ADHD) symptoms in 167 participants aged 6 to 20 years with 4 types of SCA (XXY n = 56, XYY n = 33, XXX n = 25, and XXYY n = 53). They also evaluate factors associated with ADHD symptomatology (cognitive and adaptive scores, prenatal vs postnatal ascertainment) and describe the clinical response to psychopharmacologic medications in a subset of patients treated for ADHD.
Methods
Evaluation included medical and developmental history, cognitive and adaptive functioning assessment, and parent and teacher ADHD questionnaires containing DSM-IV criteria.
Results
In the total study group, 58% (96/167) met DSM-IV criteria for ADHD on parent-report questionnaires (36% in XXY, 52% in XXX, 76% in XYY, and 72% in XXYY). The Inattentive subtype was most common in XXY and XXX, whereas the XYY and XXYY groups were more likely to also have hyperactive/impulsive symptoms. There were no significant differences in Verbal, Performance, or Full Scale IQ between children with symptom scores in the ADHD range compared with those below the ADHD range. However, adaptive functioning scores were significantly lower in the group whose scores in the ADHD range were compared with those of the group who did not meet ADHD DSMIV criteria. Those with a prenatal diagnosis of XXY were less likely to meet criteria for ADHD compared with the postnatally diagnosed group. Psychopharmacologic treatment with stimulants was effective in 78.6% (66/84).
Conclusions
Children and adolescents with SCA are at increased risk for ADHD symptoms. Recommendations for ADHD evaluation and treatment in consideration of other aspects of the SCA medical and behavioral phenotype are provided.
doi:10.1097/DBP.0b013e31824501c8
PMCID: PMC3348431  PMID: 22333574
attention-deficit hyperactivity disorder (ADHD); XXY; Klinefelter syndrome; XYY; XXYY; sex chromosome aneuploidy
3.  Autism, language and communication in children with sex chromosome trisomies 
Archives of disease in childhood  2010;96(10):954-959.
Purpose
Sex chromosome trisomies (SCTs) are found on amniocentesis in 2.3–3.7 per 1000 same-sex births, yet there is a limited database on which to base a prognosis. Autism has been described in postnatally diagnosed cases of Klinefelter syndrome (XXY karyotype), but the prevalence in non-referred samples, and in other trisomies, is unclear. The authors recruited the largest sample including all three SCTs to be reported to date, including children identified on prenatal screening, to clarify this issue.
Design
Parents of children with a SCT were recruited either via prenatal screening or via a parental support group, to give a sample of 58 XXX, 19 XXY and 58 XYY cases. Parents were interviewed using the Vineland Adaptive Behavior Scales and completed questionnaires about the communicative development of children with SCTs and their siblings (42 brothers and 26 sisters).
Results
Rates of language and communication problems were high in all three trisomies. Diagnoses of autism spectrum disorder (ASD) were found in 2/19 cases of XXY (11%) and 11/58 XYY (19%). After excluding those with an ASD diagnosis, communicative profiles indicative of mild autistic features were common, although there was wide individual variation.
Conclusions
Autistic features have not previously been remarked upon in studies of non-referred samples with SCTs, yet the rate is substantially above population levels in this sample, even when attention is restricted to early-identified cases. The authors hypothesise that X-linked and Y-linked neuroligins may play a significant role in the aetiology of communication impairments and ASD.
doi:10.1136/adc.2009.179747
PMCID: PMC3182523  PMID: 20656736
4.  An extra X or Y chromosome: contrasting the cognitive and motor phenotypes in childhood in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome 
Objective
The goal of this study was to contrast the cognitive phenotypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXY karyotype (Klinefelter syndrome, KS), who share an extra copy of the X-Y pseudoautosomal region but differ in their dosage of strictly sex-linked genes.
Methods
Neuropsychological evaluation of general cognitive ability, language, memory, attention, visual-spatial abilities, visual-motor skills, and motor function.
Results
Study cohort: 21 boys with 47,XYY and 93 boys with 47,XXY (KS), ages 4-17 years, and 36 age-matched control boys. Both the XYY and KS groups performed less well, on average, than the controls on tests of general cognitive ability, achievement, language, verbal memory, some aspects of attention and executive function, and motor function. The boys with XYY on average had more severe and pervasive language impairment, at both simple and complex levels, and the boys with KS on average had greater motor impairment in gross motor function and coordination, especially in running speed and agility.
Conclusions
The results from these large XYY and KS cohorts have important neurocognitive and educational implications. From the neurocognitive standpoint, the presenting findings afford an opportunity to gain insights into brain development in boys with XYY and those with KS. From the educational standpoint, it is critical that boys with XYY or KS receive appropriate educational interventions that target their specific learning challenges. These findings also provide important information for counseling clinicians and families about these disorders.
doi:10.1002/ddrr.85
PMCID: PMC2876236  PMID: 20014371
XYY; XXY; Klinefelter syndrome; sex chromosome
5.  Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin–neurexin hypothesis 
Aim
To compare the phenotype in Klinefelter syndrome (KS) with (i) specific language impairment (SLI) and (ii) XXX and XYY trisomies.
Methods
Phenotypes of KS, XXX and XYY were based on data from a systematic review of neurodevelopmental outcomes plus a recent parent survey. Phenotype of SLI was based on a published survey of children attending a special school.
Results
There are close similarities between the KS phenotype and SLI. Furthermore, a minority of children with KS have features of autistic spectrum disorder. Similar language and communication problems are seen in the other two sex chromosome trisomies (SCTs), XXX and XYY.
Conclusion
We propose the neurexin–neuroligin hypothesis, based on the observation that neuroligin genes, which occur on both X and Y chromosomes, are involved in the same synaptic networks as neurexin genes with common variants that affect risk for SLI and autism. According to our hypothesis, the effect of a triple dose of neuroligin gene product will be particularly detrimental when it occurs in conjunction with specific variants of neurexin genes on other chromosomes. This speculative proposal demonstrates the potential of illuminating the aetiology of common neurodevelopmental disorders by studying children with SCTs.
doi:10.1111/j.1651-2227.2011.02150.x
PMCID: PMC3107947  PMID: 21418292
Autism; Klinefelter syndrome; Language impairment; Neurexin; Neuroligin; Sex chromosome trisomy
6.  Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study 
BMJ Open  2012;2(1):e000650.
Objective
To investigate the criminal pattern in men between 15 and 70 years of age diagnosed with 47,XXY (Klinefelter's syndrome (KS)) or 47,XYY compared to the general population.
Design
Register-based cohort study comparing the incidence of convictions among men with KS and with 47,XYY with age- and calendar-matched samples of the general population. Crime was classified into eight types (sexual abuse, homicide, burglary, violence, traffic, drug-related, arson and ‘others’).
Setting
Denmark 1978–2006.
Participants
All men diagnosed with KS (N=934) or 47,XYY (N=161) at risk and their age- and calendar-time-matched controls (N=88 979 and 15 356, respectively).
Results
The incidence of convictions was increased in men with KS (omitting traffic offenses) compared to controls with a HR of 1.40 (95% CI 1.23 to 1.59, p<0.001), with significant increases in sexual abuse, burglary, arson and ‘others’, but with a decreased risk of traffic and drug-related offenses. The incidence of convictions was significantly increased among men with 47,XYY compared to controls with a HR of 1.42 (95% CI 1.14 to 1.77, p<0.005) in all crime types, except drug-related crimes and traffic. Adjusting for socioeconomic variables (education, fatherhood, retirement and cohabitation) reduced the total HR for both KS and 47,XYY to levels similar to controls, while some specific crime types (sexual abuse, arson, etc) remained increased.
Conclusion
The overall risk of conviction (excluding traffic offenses) was moderately increased in men with 47,XYY or KS; however, it was similar to controls when adjusting for socioeconomic parameters. Convictions for sexual abuse, burglary, arson and ‘others’ were significantly increased. The increased risk of convictions may be partly or fully explained by the poor socioeconomic conditions related to the chromosome aberrations.
Article summary
Article focus
To investigate crime rates of men with an extra sex chromosome (47,XXY and 47,XYY). Based on previous small studies, we hypothesised that an increased crime rate would be present in men with an extra sex chromosome and investigated this in a nationwide registry study.
Key messages
Using a nationwide approach, we show that men diagnosed with KS (47,XXY) and 47,XYY are more frequently convicted for sexual abuse, burglary, arson and other reasons. Traffic offenses are seen less frequently in both groups.
Whether early diagnosis and improved clinical care can lead to a decrease in convictions is not clear.
The increased crime rate may be partly or fully mediated by poor socioeconomic conditions.
Strengths and limitations of this study
The study clearly delineates a pattern of increased crime rates among men diagnosed with an extra sex chromosome. The strength of the present study is the large number of men with sex chromosomes and the large control group and the merging of several registries.
The limitations are that we were not able to control for concomitant medicinal use, especially testosterone use in KS, nor to include clinical data.
doi:10.1136/bmjopen-2011-000650
PMCID: PMC3289987  PMID: 22357573
7.  Social Deficits in Male Children and Adolescents with Sex Chromosome Aneuploidy: A Comparison of XXY, XYY, and XXYY syndromes 
We compare social skills in three groups of males with sex chromosome aneuploidies (SCAs) using the Social Responsiveness Scale (SRS). Participants included males with XXY (N=102, M=10.08 years), XYY (N=40, M=9.93 years), and XXYY (N=32, M=11.57 years). XXY had lower (better) SRS scores compared to XYY and XXYY. Scores were not significantly different between XYY and XXYY. In all groups, there were significantly more with SRS scores in the severe range compared to the SRS normative sample. All groups scored lowest (better) on Social Motivation. Relationships between SRS scores and demographic and clinical variables were examined. Results describe the social skills in males with SCA, and suggest that an additional Y chromosome may contribute to increased risk of autistic behaviors.
doi:10.1016/j.ridd.2012.02.013
PMCID: PMC3328784  PMID: 22502852
Klinefelter syndrome (KS); autism; social deficits; social skills; XXY; XYY; XXYY
8.  Social Function in Multiple X and Y Chromosome Disorders: XXY, XYY, XXYY, XXXY 
Klinefelter syndrome (47,XXY) was initially described in the context of its endocrinologic and physical features; however, subsequent studies have revealed specific impairments in verbal skills and social functioning. Males with sex chromosomal aneuploidies are known to have variability in their developmental profile with the majority presenting with expressive language deficits. As a consequence of language delays, they have an increased likelihood of language-based learning disabilities and social-emotional problems that may persist through adulthood. Studies on males with 47,XXY have revealed unique behavioral and social profiles with possible vulnerability to autistic traits. The prevalence of males with more than one extra sex chromosome (e.g., 48,XXYY and 48,XXXY) and an additional Y (e.g., 47,XYY) is less common, but it is important to understand their social functioning as it provides insight into treatment implications.
doi:10.1002/ddrr.76
PMCID: PMC3909519  PMID: 20014367
Sex chromosomal aneuploidies; Klinefelter syndrome; 47,XXY; 48,XXYY; 48,XXXY; 47,XYY
9.  Clinical and gonadal features and early surgical management of 45,X/46,XY and 45,X/47,XYY chromosomal mosaicism presenting with genital anomalies 
Journal of Pediatric Urology  2013;9(2):139-144.
Objective
The 45,X/46,XY and 45,X/47,XYY group of patients includes some of those previously diagnosed with ‘mixed gonadal dysgenesis’. Our aim was to establish the clinical and gonadal spectrum, and early surgical management, of patients with chromosomal mosaicism presenting with genital anomalies.
Patients and methods
We performed a retrospective review of patients with 45,X/46,XY or 45,X/47,XYY mosaicism presenting with genital ambiguity between 1988 and 2009. At least one gonadal biopsy or gonadectomy specimen was available for each patient. Gonadal histology was re-evaluated by a paediatric pathologist.
Results
Of 31 patients with 45,X/46,XY (n = 28) or 45,X/47,XYY (n = 3) mosaicism and genital anomalies, 19 (61%) were raised male. Histology of 46 gonads was available from patients who had undergone a gonadectomy or gonadal biopsy, at a median age of 9.5 months. 18 gonads were palpable at presentation, including 5 (28%) histologically unremarkable testes, 2 streak gonads, and 1 dysgenetic gonad with distinct areas of testicular and ovarian stroma but no oocytes. All intra-abdominal gonads were found to be dysgenetic testes (of which 2 were noted to have pre-malignant changes) or streaks, apart from 1 histologically unremarkable testis. 15 (48%) patients had other anomalies, most commonly cardiac and renal; 4 (13%) had a Turner phenotype.
Conclusion
The anatomy and gonadal histology of 45,X/46,XY and 45,X/47,XYY individuals with genital ambiguity do not conform to a set pattern, and hence management of each patient should be individualized according to detailed anatomical and histological assessment.
doi:10.1016/j.jpurol.2011.12.012
PMCID: PMC3625110  PMID: 22281282
45,X/46,XY; 45,X/47,XYY; Mixed gonadal dysgenesis; Chromosomal mosaicism; Ambiguous genitalia; Disorder of sex development; Streak gonad; Dysgenetic gonad
10.  Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy 
This study aims to assess prevalence and pregnancy outcome for sex chromosome trisomies (SCTs) diagnosed prenatally or in the first year of life. Data held by the European Surveillance of Congenital Anomalies (EUROCAT) database on SCT cases delivered 2000–2005 from 19 population-based registries in 11 European countries covering 2.5 million births were analysed. Cases included were livebirths diagnosed to 1 year of age, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly (TOPFA). In all, 465 cases of SCT were diagnosed between 2000 and 2005, a prevalence of 1.88 per 10,000 births (95% CI 1.71–2.06). Prevalence of XXX, XXY and XYY were 0.54 (95% CI 0.46–0.64), 1.04 (95% CI 0.92–1.17) and 0.30 (95% CI 0.24–0.38), respectively. In all, 415 (89%) were prenatally diagnosed and 151 (36%) of these resulted in TOPFA. There was wide country variation in prevalence (0.19–5.36 per 1000), proportion prenatally diagnosed (50–100%) and proportion of prenatally diagnosed resulting in TOPFA (13–67%). Prevalence of prenatally diagnosed cases was higher in countries with high prenatal detection rates of Down syndrome. The EUROCAT prevalence rate for SCTs diagnosed prenatally or up to 1 year of age represents 12% of the prevalence expected from cytogenetic studies of newborn babies, as the majority of cases are never diagnosed or are diagnosed later in life. There is a wide variation between European countries in prevalence, prenatal detection and TOPFA proportions, related to differences in screening policies as well as organizational and cultural factors.
doi:10.1038/ejhg.2010.148
PMCID: PMC3025783  PMID: 20736977
sex chromosome trisomies; prenatal diagnosis; termination of pregnancy
11.  Behavioral and Social Phenotypes in Boys With 47,XYY Syndrome or 47,XXY Klinefelter Syndrome 
Pediatrics  2012;129(4):769-778.
OBJECTIVE:
To contrast the behavioral and social phenotypes including a screen for autistic behaviors in boys with 47,XYY syndrome (XYY) or 47,XXY Klinefelter syndrome (KS) and controls and investigate the effect of prenatal diagnosis on the phenotype.
METHODS:
Patients included 26 boys with 47,XYY, 82 boys with KS, and 50 control boys (ages 4–15 years). Participants and parents completed a physical examination, behavioral questionnaires, and intellectual assessments.
RESULTS:
Most boys with XYY or KS had Child Behavior Checklist parental ratings within the normal range. On the Child Behavior Checklist, mean problem behaviors t scores were higher in the XYY versus KS groups for the Problem Behavior, Externalizing, Withdrawn, Thought Problems, and Attention Problems subscales. On the Conners’ Parent Rating Scale–Revised, the XYY versus KS group had increased frequency of hyperactive/impulsive symptoms (P < .006). In addition, 50% and 12% of the XYY and KS groups, respectively, had scores >15 for autism screening from the Social Communication Questionnaire. For the boys with KS, prenatal diagnosis was associated with fewer problem behaviors.
CONCLUSIONS:
A subset of the XYY and KS groups had behavioral difficulties that were more severe in the XYY group. These findings could guide clinical practice and inform patients and parents. Boys diagnosed with XYY or KS should receive a comprehensive psychoeducational evaluation and be screened for learning disabilities, attention-deficit/hyperactivity disorder, and autism spectrum disorders.
doi:10.1542/peds.2011-0719
PMCID: PMC3356148  PMID: 22412026
XXY; XYY; Klinefelter syndrome; autism; ADHD
12.  Early manifestations in a cohort of children prenatally diagnosed with 47,XYY. Role of multidisciplinary counseling for parental guidance and prevention of aggressive behavior 
Background
An increasing number of foetuses are recognized as having double Y because of the widespread use of prenatal screening using chorionic villus sampling and amniocentesis. 47, XYY karyotype occurs in about one out of 1,000 newborn males, but it is not often detected unless it is diagnosed during prenatal testing. Despite the fact that unbiased follow-up studies demonstrate largely normal post-natal development of young men with 47, XYY, there is a scarcity of controlled studies about the neurological, cognitive and behavioural phenotype which remains the main reason for anxiety and anticipatory negative attitudes of parents. Furthermore, prejudices still exist among professionals and the general population concerning the relationship between this sex chromosome aneuploidy and aggressive and antisocial behaviours.
Methods
We report on the clinical follow-up of children diagnosed prenatally with a 47,XYY karyotype, whose parents received multidisciplinary counselling and support at time of diagnosis. The specific focus of our study is on auxology, facial features, developmental milestones, behaviour, detection of aggressiveness as well as the evaluation of parental attitudes toward prenatal counselling. Clinical evaluations including auxological measurements and dysmorphological descriptions were as conducted on 13 boys aged 9 month -7 years. The Child Behavior Check List test specific for age and a 15 item questionnaire were administered to both parents. An update of ongoing problems was carried out by means of a telephone interview two years later.
Results
Our results show that, from birth, weight, height and head circumference were above average values while some facial features such mild hypertelorism are overrepresented when compared to parents' facial features. Language delay was detected in 8 out of 11 children older than 20 months. Parental attitudes were found to be favourable toward prenatal diagnoses of sexual chromosome aneuploidies.
Conclusions
Our data, although limited, is similar to other observational studies, and serves to alert clinicians about opportunities to delineate new and appropriate educational interventions that target the specific learning challenges of XYY boys. Our experience better defines the early manifestation of XYY and should aid those involved in prenatal counselling and paediatric surveillance.
doi:10.1186/1824-7288-38-52
PMCID: PMC3523010  PMID: 23034220
13.  Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: a systematic review and meta-analysis of prospective clinical trials 
Context
The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (alloSCT) for poor-risk but not for good-risk AML. AlloSCT, autologous transplant and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML. We undertook a systematic review and meta-analysis of prospective trials evaluating alloSCT versus non-alloSCT therapies for AML-CR1.
Objective
To quantify relapse-free survival (RFS) and overall survival (OS) benefit of alloSCT for AML in CR1. In subgroup analyses, RFS and OS benefit of alloSCT was determined for good-, intermediate- and poor-risk AML.
Methods
Combining the search terms: ‘allogeneic’; ‘acut*’ and ‘leukem*/leukaem*/leucem*/leucaem*/aml’; ‘myelo*’ or ‘nonlympho*’, we searched the PubMed, Embase and Cochrane Registry of Controlled Trials databases in March 2009. 1712 articles were accessed.
Study Selection
Prospective trials assigning adult AML-CR1 patients to alloSCT versus non-alloSCT treatment(s) based on donor availability, and reporting RFS and/or OS outcomes on intent-to-treat, donor versus no-donor basis were identified.
Data Extraction
Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (HR) (with 95% CI) were determined.
Data Synthesis
24 trials and 6,007 patients were analyzed. Inter-study heterogeneity was not significant. Fixed effects meta-analysis was performed. HR of relapse or death with alloSCT for AML-CR1 was 0.80 (0.74–0.86). Significant RFS benefit of alloSCT was documented for poor-risk (HR 0.69 (0.57–0.84)) and intermediate-risk AML (HR 0.76 (0.68–0.85)); but not for good-risk AML (HR 1.06 (0.80–1.42)). HR of death with alloSCT for AML-CR1 was 0.90 (0.82–0.97). Significant OS benefit of alloSCT was documented for poor-risk (HR 0.73 (0.59–0.90)) and intermediate-risk AML (HR 0.83 (0.74–0.93)); but not for good-risk AML (HR 1.07 (0.83–1.38)).
Conclusion
AlloSCT has significant RFS and OS benefit for intermediate- and for poor-risk AML, but not for good-risk AML in CR1.
doi:10.1001/jama.2009.813
PMCID: PMC3163846  PMID: 19509382
acute myeloid leukemia; allogeneic transplantation; meta-analysis
14.  Volumetric magnetic resonance imaging study of the brain in subjects with sex chromosome aneuploidies 
OBJECTIVES—Cognitive impairment has been reported in people with sex chromosome aneuploides (SCAs) and it has been proposed that the presence of an extra sex chromosome may have an adverse effect on neurodevelopment. This study examines the hypothesis with structural MRI of the brain.
METHODS—Thirty two subjects with SCA (XXX (n=12), XYY (n=10), and XXY (n=10)) from a birth cohort study were matched groupwise for age, parental social class, and height with normal controls (13female, 26 male). Brain MRI , measurements of IQ, and a structured psychiatric interview were performed.
RESULTS—The XXX females and XXY males had significantly smaller whole brain volumes than controls of the same phenotypic sex (p=0.003 and p⩽0.05 respectively). The XXY group also had bilaterally enlarged lateral ventricles (p⩽0.05). No significant differences were found between the XYY group and controls. IQ scores in all SCA groups were lower than in the control groups.
CONCLUSIONS—The main result of reduced brain volumes in XXX and XXY subjects, but not in XYY subjects, indicates that the presence of a supernumerary X chromosome has a demonstrable effect on brain development.


PMCID: PMC1736357  PMID: 10209175
15.  A review of trisomy X (47,XXX) 
Trisomy X is a sex chromosome anomaly with a variable phenotype caused by the presence of an extra X chromosome in females (47,XXX instead of 46,XX). It is the most common female chromosomal abnormality, occurring in approximately 1 in 1,000 female births. As some individuals are only mildly affected or asymptomatic, it is estimated that only 10% of individuals with trisomy X are actually diagnosed. The most common physical features include tall stature, epicanthal folds, hypotonia and clinodactyly. Seizures, renal and genitourinary abnormalities, and premature ovarian failure (POF) can also be associated findings. Children with trisomy X have higher rates of motor and speech delays, with an increased risk of cognitive deficits and learning disabilities in the school-age years. Psychological features including attention deficits, mood disorders (anxiety and depression), and other psychological disorders are also more common than in the general population. Trisomy X most commonly occurs as a result of nondisjunction during meiosis, although postzygotic nondisjunction occurs in approximately 20% of cases. The risk of trisomy X increases with advanced maternal age. The phenotype in trisomy X is hypothesized to result from overexpression of genes that escape X-inactivation, but genotype-phenotype relationships remain to be defined. Diagnosis during the prenatal period by amniocentesis or chorionic villi sampling is common. Indications for postnatal diagnoses most commonly include developmental delays or hypotonia, learning disabilities, emotional or behavioral difficulties, or POF. Differential diagnosis prior to definitive karyotype results includes fragile X, tetrasomy X, pentasomy X, and Turner syndrome mosaicism. Genetic counseling is recommended. Patients diagnosed in the prenatal period should be followed closely for developmental delays so that early intervention therapies can be implemented as needed. School-age children and adolescents benefit from a psychological evaluation with an emphasis on identifying and developing an intervention plan for problems in cognitive/academic skills, language, and/or social-emotional development. Adolescents and adult women presenting with late menarche, menstrual irregularities, or fertility problems should be evaluated for POF. Patients should be referred to support organizations to receive individual and family support. The prognosis is variable, depending on the severity of the manifestations and on the quality and timing of treatment.
doi:10.1186/1750-1172-5-8
PMCID: PMC2883963  PMID: 20459843
16.  Is microcephaly a so-far unrecognized feature of XYY syndrome?☆ 
Meta Gene  2014;2:160-163.
Highlights
•47,XYY syndrome is a frequent sex chromosome aneuploidy.•Overview of characteristic symptoms of 47,XXY•First report of 47,XYY and microcephaly in a preterm child•Brief differential diagnosis of microcephaly
doi:10.1016/j.mgene.2013.10.013
PMCID: PMC4287790  PMID: 25606399
47,XYY syndrome; Microcephaly; Mental retardation; Delayed speech development; Hyperactivity; Impulsiveness; array CGH, array comparative genomic hybridization; HAWIK-IV, Hamburg-Wechsler Intelligence test for Children; NCBI, National Center for Biotechnology Information; OFC, occipitofrontal head circumference; OMIM, Online Mendilian Inheritance in Man
17.  Clinical outcomes of a novel combination of lenalidomide and rituximab followed by stem cell transplantation for relapsed/refractory aggressive B-cell non-hodgkin lymphoma 
Oncotarget  2014;5(17):7368-7380.
We retrospectively compared outcomes of patients with relapsed/refractory non-Hodgkin lymphoma (NHL) who underwent stem cell transplantation (SCT) with stable disease or better following a novel combination of lenalidomide and rituximab (LR) treatment and did not undergo SCT in a phase I/II clinical trial. We retrospectively compared outcomes of patients who underwent SCT with that of patients who had stable disease or better following LR treatment and did not undergo SCT. Twenty-two patients enrolled in LR clinical trial and undergone SCT were identified, 13 with mantle cell lymphoma (MCL) and nine with large B-cell lymphoma (LBCL). All patients who underwent SCT achieved complete response. In the MCL subset, there were no significant differences between SCT and non-SCT groups except that non-SCT patients were older and had a higher mantle-cell international prognostic index score. There was no difference between SCT-group and non-SCT-group in response duration (P=0.3), progression-free survival (PFS) (P=0.304) and overall survival (OS) (P=0.87). In LBCL subgroup, there were no significant differences between two groups except that non-SCT group had a higher international prognostic index score. Patients with LBCL who underwent SCT had significantly longer response duration (P=0.001), PFS (P=0.000), and OS (P=0.003) than the non-SCT group. The novel therapeutic combination offers a bridge to SCT in patients with relapsed/refractory aggressive B-cell NHL.
PMCID: PMC4202129  PMID: 25228589
Clinical outcomes; Lenalidomide; Relapsed lymphoma; Rituximab; Stem cell transplantation
18.  Parental stress before, during, and after pediatric stem cell transplantation: a review article 
Supportive Care in Cancer  2009;17(12):1435-1443.
Goals of work
Pediatric stem cell transplantation (SCT) is a stressful treatment for children with relapsed or high-risk malignancies, immune deficiencies and certain blood diseases. Parents of children undergoing SCT can experience ongoing stress related to the SCT period. The aim of this article was to present a literature review of articles on parental distress and adaptation before, during, and after SCT and to identify risk and protective factors.
Materials and methods
The review was conducted systematically by using PubMed, Web of Science, PsychInfo, and Picarta databases. Eighteen articles met our inclusion criteria: publishing date between January 1, 1990 and January 1, 2009; studies concerning parents of children undergoing SCT; studies examining the psychological adjustment and/or stress reactions of parents as primary outcomes and studies available in English.
Main results
Highest levels of parental stress are reported in the period preceding SCT and during the acute phase. Stress levels decrease steadily after discharge in most parents. However, in a subgroup of parents, stress levels still remain elevated post-SCT. Parents most at risk in the longer term display highest levels of stress during the acute phase of the SCT.
Conclusions
Psychosocial assessment before SCT, during the acute phase and in the longer term, is necessary to identify parents in need for support and follow-up care.
doi:10.1007/s00520-009-0685-4
PMCID: PMC2775902  PMID: 19572154
Pediatric SCT; Parental stress; Adaptation; Review
19.  Ring chromosome 13 syndrome characterized by high resolution array based comparative genomic hybridization in patient with 47, XYY syndrome: a case report 
Introduction
The co-occurrence of ring chromosome 13 syndrome and 47, XYY syndrome in the same individual is rare. To the best of our knowledge, this is the first report of the co-existence of this kind of chromosome aberrations. At present, the deletion 13q syndrome is divided into three groups based on the deletion's location relative to chromosomal band 13q32. Group 1 (proximal to q32) and group 2 (including q32) have shown distinctive phenotypes including mental retardation and growth deficiency. Group 3 (q33-34 deletion) is defined by the presence of mental retardation but there is usually an absence of major malformations.
Case presentation
We describe a 10-month-old Chinese Han boy presenting with severe mental retardation, profound congenital bilateral hearing loss with a terminal 13q33.2 deletion and multiple malformations. Routine chromosome analysis disclosed a de novo complex karyotype 47, XYY, r(13)(p11q34). Further investigation by high resolution array-based comparative genomic hybridization delineated an 8.5 Mb terminal deletion on the long arm of chromosome 13(13q33.2→q34).
Conclusion
The co-occurrence of double syndromes in the same individual is rare and its clinical presentation is variable depending on the predominating abnormality or a combination of the effect of both. Hearing impairment is suggested as another new clinical feature to 13qter deletion. This case report will contribute to more accurate genetic counselling and provide further insight to the syndrome.
doi:10.1186/1752-1947-5-99
PMCID: PMC3063811  PMID: 21396087
20.  Diagnosis and mortality in 47,XYY persons: a registry study 
Background
Sex chromosomal abnormalities are relatively common, yet many aspects of these syndromes remain unexplored. For instance epidemiological data in 47,XYY persons are still limited.
Methods
Using a national Danish registry, we identified 208 persons with 47,XYY or a compatible karyotype, whereof 36 were deceased; all were diagnosed from 1968 to 2008. For further analyses, we identified age matched controls from the male background population (n = 20,078) in Statistics Denmark. We report nationwide prevalence data, data regarding age at diagnosis, as well as total and cause specific mortality data in these persons.
Results
The average prevalence was 14.2 47,XYY persons per 100,000, which is reduced compared to the expected 98 per 100,000. Their median age at diagnosis was 17.1 years. We found a significantly decreased lifespan from 77.9 years (controls) to 67.5 years (47,XYY persons). Total mortality was significantly increased compared to controls, with a hazard ratio of 3.6 (2.6-5.1). Dividing the causes of deaths according to the International Classification of Diseases, we identified an increased hazard ratio in all informative chapters, with a significantly increased ratio in cancer, pulmonary, neurological and unspecified diseases, and trauma.
Conclusion
We here present national epidemiological data regarding 47,XYY syndrome, including prevalence and mortality data, showing a significantly delay to diagnosis, reduced life expectancy and an increased total and cause specific mortality.
doi:10.1186/1750-1172-5-15
PMCID: PMC2889887  PMID: 20509956
21.  The placenta findings from an XYY abortus: a case report 
Introduction
The placenta morphology from an XYY pregnancy abortus has not been reported in the medical literature. This case report consists of the first detailed documentation. The reported case is also highly unusual because the mother had two prior pregnancies with fetuses being confirmed to have Zellweger syndrome and one prior molar pregnancy.
Case presentation
A 43-year-old Caucasian woman presented for induction of labor secondary to diagnosis of XYY chromosomes by chorionic villus sample.
Conclusions
This is the first detailed observation of placenta morphology in an XYY abortus. Although not highly specific, the observation is very unique and should prompt further investigation of karyotyping of the fetus or infant because an XYY individual may be viable and grow to adulthood. The association of an XYY abortus and prior pregnancies with Zellweger syndrome and one prior molar pregnancy is also highly notable.
doi:10.1186/1752-1947-7-228
PMCID: PMC4015697  PMID: 24083480
22.  Physicians who experience sickness certification as a work environmental problem: where do they work and what specific problems do they have? A nationwide survey in Sweden 
BMJ Open  2012;2(2):e000704.
Objectives
In a recent study, 11% of the Swedish physicians below 65 years dealing with sickness certification tasks (SCT) experienced SCT to a great extent as a work environment problem (WEP). This study aimed at exploring which SCT problems those physicians experienced and if these problems varied between general practitioners (GPs), psychiatrists, orthopaedists and physicians working at other types of clinics.
Design
A cross-sectional nationwide questionnaire study.
Setting
All physicians working in Sweden in 2008.
Participants
The 1554 physicians <65 years old, working in a clinical setting, having SCT and stating SCT to a great extent being a WEP.
Outcome measures
Frequency of possibly problematic situations or lack of time, reasons for sickness certifying unnecessarily long, experience of difficulties in contacts with sickness insurance offices, and severity of experienced problems.
Results
In all, 79% of this group of physicians experienced SCT as problematic at least once weekly, significantly higher proportion among GPs (p<0.001) and psychiatrists (p=0.005). A majority (at most 68.3%) experienced lack of time daily, when handling SCT, the proportion being significantly higher among orthopaedists (p=0.003, 0.007 and 0.011 on three respective items about lack of time). Among psychiatrists, a significantly higher proportion (p<0.001) stated wanting a patient coordinator. Also, GPs agreed to a higher extent (p<0.001) to finding 14 different SCT tasks as ‘very problematic’.
Conclusions
The main problem among physicians who experience SCT to a great extent as a WEP was lack of time related to SCT. The proportion of physicians experiencing problems varied in many aspects significantly between the different work clinics; however, GPs were among the highest in most types of problems. The results indicate that measures for improving physicians' sickness certification practices should be focused on organisational as well as professional level and that the needs in these aspects differ between specialties.
Article summary
Article focus
A study of the minority of physicians who state sickness certification tasks to a great extent being a work environment problem.
What problems do these physicians experience in relation to sickness certification?
Do the experienced problems vary with type of work clinic/specialty?
Key messages
A vast majority of these physicians experienced daily lack of time when handling sickness certification tasks.
About half of these physicians found it very problematic to assess level of work incapacity, to manage the two roles as the patient's physician and as a medical expert, and to provide the Social Insurance Office with more extensive sickness certificates.
Measures for improving physicians' sickness certification practices should be focused on organisational as well as professional levels and might need to differ between specialties.
Strengths and limitations of this study
The study was based on a questionnaire sent to all 37 000 physicians in a whole country, and the response rate (61%) could be regarded as relatively high.
Only one question about work environment was included.
doi:10.1136/bmjopen-2011-000704
PMCID: PMC3293140  PMID: 22382120
23.  Favorable Outcomes in Patients Surviving 5 or More Years after Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies 
Allogeneic hematopoietic stem cell transplantation (SCT) is a curative treatment for some hematological malignancies. As the overall number of survivors continues to increase, studies systematically examining outcomes in long-term survivors are needed. We studied the clinical and quality of life outcomes in SCT recipients surviving five or more years from SCT. Since 1993, 262 patients with hematological malignancies received a T cell depleted myeloablative SCT from an HLA-identical sibling at a single center. Ninety-two survived beyond 5 years from SCT (median follow-up 9.4 years, range 5.1-15.3). Median age at transplantation was 35 years (range 10 - 56). Twenty-two (24%) received a bone marrow transplant, and 70 (76%) received a peripheral blood SCT. Of the 92 survivors, 60 completed quality of life measures. The main outcomes examined were chronic graft-versus-host-disease (cGVHD), disease relapse, survival, health-related quality of life (HRQL) (Functional Assessment of Cancer Therapy-General), physical and mental health (SF-36) and symptom experience (Rotterdam Symptom Checklist). Seventy-five (82%) of 92 survivors no longer required systemic immunosuppressive treatment (IST). Four (4.3%) relapsed with leukemia at a median of 8.5 years (range 6.2 -14.0) after SCT. Four (4.3%) died between 7.4 and 13.4 years post SCT (1 relapse, 1 lung cancer, 1 pneumonia, 1 brain hemorrhage). Most survivors beyond 5 years had an excellent performance status with no difference in physical and mental health and higher HRQL scores (p =0.02) compared with population norms. Although physical and psychological symptom distress was low, those with higher symptom distress experienced inferior HRQL. These results show that five or more years after T cell depleted SCT for hematological malignancy most individuals survive disease free with an excellent performance status, preserved physical and psychological health, and excellent HRQL.
doi:10.1016/j.bbmt.2010.03.005
PMCID: PMC2897903  PMID: 20302959
leukemia; hematopoietic stem cell transplantation; long-term outcome
24.  Autologous stem-cell transplantation in refractory autoimmune diseases after in vivo immunoablation and ex vivo depletion of mononuclear cells 
Arthritis Research  2000;2(4):327-336.
Autoimmune diseases that are resistant to conventional treatment cause severe morbidity and even mortality. In the present study we demonstrate that complete remissions can be achieved in refractory polychondritis and systemic lupus erythematosus (SLE), even at advanced stage, with the use of autologous stem-cell transplantation (SCT). Remissions persisted after reconstitution of the immune system. In the treatment of advanced systemic sclerosis (SSc), stable disease may be achieved with autologous SCT.
Introduction:
Patients with persistently active autoimmune diseases are considered to be candidates for autologous SCT. We performed a phase 1/2 study in a limited number of patients who were refractory to conventional immunosuppressive treatment. Following a period of uncontrolled disease activity for at least 6 months, autologous SCT was performed, after in vivo immunoablation and ex vivo depletion of mononuclear cells.
Aims:
To investigate feasibility, toxicity and efficacy of the treatment, and the incidence of emergent infections.
Methods:
Seven patients (aged between 23 and 48 years) were included in the single-centre trial: one had relapsing polychondritis, three had treatment-refractory SLE and three patients had SSc. Stem-cell mobilization was achieved by treatment with moderate-dose cyclophosphamide (2 g/m2; in terms of myelotoxic side effects or myelosuppression) and granulocyte colony-stimulating factor (G-CSF). CD34- cells of the leukapheresis products were removed by high-gradient magnetic cell sorting. After stem-cell collection, immunoablation was performed with high-dose cyclophosphamide (200 mg/kg body weight) and antithymocyte globulin (ATG; 90 mg/kg body weight). Autologous SCT was followed by reconstitution of the immune system, which was monitored by six-parameter flow cytometry and standard serology. The trial fulfilled the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT) guidelines for blood and bone marrow stem-cell transplants in autoimmune disease.
Results:
Among the seven patients studied, the patient with relapsing polychondritis and the patients with SLE were successfully treated and remained in complete remission during a follow up of 10-21 months. Remission persisted despite reconstitution of the immune system, resulting in high numbers of effector-/memory-type T-helper lymphocytes and increasing populations in the naïve T-cell compartment. Before autologous SCT, one of the patients with SLE had a long-lasting secondary antiphospholipid syndrome, with high anticardiolipin antibodies and thromboembolic events. After autologous SCT the antiphospholipid antibodies became negative, and no thrombosis occurred during follow up. Two of the patients with SSc were unaffected by treatment with autologous SCT for 6 or 13 months. The other patient with SSc died 2 days after autologous SCT because of cardiac failure.
During stem-cell mobilization with G-CSF, flares of autoimmune disease were seen in the patient with polychondritis and in one patient with SLE. The strategy utilized for depletion of CD34- cells led to a reduction by 4.5-5 log of contaminating CD3+ cells in the transplant. T-cell add-back was required in the patient with polychondritis and in one patient with SLE to provide a dose of 1×104 CD3+ cells/kg body weight for the transplant.
Discussion:
In vivo immunoablation in combination with autologous SCT after ex vivo depletion of CD34- cells can block the autoimmune process in relapsing polychondritis or SLE without incidence of severe infections. The remissions were achieved in patients with advanced disease that was refractory to previous intensive immunosuppressive therapy. The present results do not indicate that large-scale contamination of the stem-cell transplant with autoreactive cells after selection for CD34+cells occurred. After the preparative regimen, the application of G-CSF was avoided, because induction of flares of the autoimmune disease were noticed during the mobilization of stem cells. In SSc patients, distinct remissions were not observable after autologous SCT; the serological and clinical status did not improve. Follow-up periods of more than 12 months may be required to identify successful treatment with autologous SCT in SSc patients. Among the various autoimmune diseases the efficacy of autologous SCT appears to be dependent on the underlying pathophysiology. The results of the present phase 1/2 study suggest that patients with advanced stage SSc should not be treated with autologous SCT, until the reasons for the lack of response and the possible mortality due to cardiac complications are identified. The observation of flares of autoimmune disease after application of G-CSF emphasizes the need for critical evaluation of the role of G-CSF in immunoablative regimens.
PMCID: PMC17815  PMID: 11056673
autologous stem-cell transplantation; polychondritis; refractory autoimmune disease; systemic lupus erythematosus; systemic sclerosis
25.  Effects of Sex Chromosome Aneuploidies on Brain Development: Evidence From Neuroimaging Studies 
Variation in the number of sex chromosomes is a relatively common genetic condition, affecting as many as 1/400 individuals. The sex chromosome aneuploidies (SCAs) are associated with characteristic behavioral and cognitive phenotypes, although the degree to which specific individuals are affected can fall within a wide range. Understanding the effects of different dosages of sex chromosome genes on brain development may help to understand the basis for functional differences in affected individuals. It may also be informative regarding how sex chromosomes contribute to typical sexual differentiation. Studies of 47,XXY males make up the bulk of the current literature of neuroimaging studies in individuals with supernumerary sex chromosomes, with a few small studies or case reports of the other SCAs. Findings in 47,XXY males typically include decreased gray and white matter volumes, with most pronounced effects in the frontal and temporal lobes. Functional studies have shown evidence of decreased lateralization. Although the hypogonadism typically found in 47,XXY males may contribute to the decreased brain volume, the observation that 47,XXX females also show decreased brain volume in the presence of normal pubertal maturation suggests a possible direct dosage effect of X chromosome genes. Additional X chromosomes, such as in 49,XXXXY males, are associated with more markedly decreased brain volume and increased incidence of white matter hyperintensities. The limited data regarding effects of having two Y chromosomes (47,XYY) do not find significant differences in brain volume, although there are some reports of increased head size.
doi:10.1002/ddrr.86
PMCID: PMC2996824  PMID: 20014372
sex chromosome; aneuploidy; neuroimaging; brain; development

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