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1.  Autism, language and communication in children with sex chromosome trisomies 
Archives of disease in childhood  2010;96(10):954-959.
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.
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).
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.
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.
PMCID: PMC3182523  PMID: 20656736
2.  Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin–neurexin hypothesis 
To compare the phenotype in Klinefelter syndrome (KS) with (i) specific language impairment (SLI) and (ii) XXX and XYY trisomies.
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.
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.
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.
PMCID: PMC3107947  PMID: 21418292
Autism; Klinefelter syndrome; Language impairment; Neurexin; Neuroligin; Sex chromosome trisomy
3.  The Sex Chromosome Trisomy mouse model of XXY and XYY: metabolism and motor performance 
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.
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.
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.
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.
PMCID: PMC3751353  PMID: 23926958
Klinefelter; Sex chromosome trisomy; XXY; XYY; Mouse; X chromosome; Y chromosome; Body weight; Obesity
4.  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.
PMCID: PMC3025783  PMID: 20736977
sex chromosome trisomies; prenatal diagnosis; termination of pregnancy
5.  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
6.  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 
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.
Neuropsychological evaluation of general cognitive ability, language, memory, attention, visual-spatial abilities, visual-motor skills, and motor function.
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.
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.
PMCID: PMC2876236  PMID: 20014371
XYY; XXY; Klinefelter syndrome; sex chromosome
7.  Attention-Deficit Hyperactivity Disorder Symptoms in Children and Adolescents with Sex Chromosome Aneuploidy: XXY, XXX, XYY, and XXYY 
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.
Evaluation included medical and developmental history, cognitive and adaptive functioning assessment, and parent and teacher ADHD questionnaires containing DSM-IV criteria.
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).
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.
PMCID: PMC3348431  PMID: 22333574
attention-deficit hyperactivity disorder (ADHD); XXY; Klinefelter syndrome; XYY; XXYY; sex chromosome aneuploidy
8.  Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study 
BMJ Open  2012;2(1):e000650.
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.
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’).
Denmark 1978–2006.
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).
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.
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.
PMCID: PMC3289987  PMID: 22357573
9.  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.
PMCID: PMC2996824  PMID: 20014372
sex chromosome; aneuploidy; neuroimaging; brain; development
10.  Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: a systematic review and meta-analysis of prospective clinical trials 
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.
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.
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)).
AlloSCT has significant RFS and OS benefit for intermediate- and for poor-risk AML, but not for good-risk AML in CR1.
PMCID: PMC3163846  PMID: 19509382
acute myeloid leukemia; allogeneic transplantation; meta-analysis
11.  Behavioral and Social Phenotypes in Boys With 47,XYY Syndrome or 47,XXY Klinefelter Syndrome 
Pediatrics  2012;129(4):769-778.
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.
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.
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.
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.
PMCID: PMC3356148  PMID: 22412026
XXY; XYY; Klinefelter syndrome; autism; ADHD
12.  Dermatoglyphic findings in 54 triple-X females and a review of some general principles applying to the soles in sex chromosome aneuploidy. 
Journal of Medical Genetics  1975;12(2):185-192.
The dermatoglyphic findings from 54 females with XXX sex chromosomes are reported. Sole prints were available for study in 33 cases. Compared with female controls, an excess of radial loops and arches and a reduced mean for total finger ridge-count were the main peculiarities on the fingers. On the palms, the absence of pattern in areas I and II, and wider ridges in the a-b interval were characteristics observed. Prevous findings by other authors with respect to: (1) zygodactylous tendency in the palms, (2) tendency for the ridge width to increase with the number of sex chromosomes, and (3) greater effect of an extra X chromosome in pattern size reduction but lesser influence on ridge width than an additional Y chromosome, were confirmed. On the soles, pattern intensity was above the control average. There was a significant deficit of proximal loops in area III but excess of proximal V together with triradius H. Triradius p" and zygodactylous z' were also significantly reduced in frequency. General findings with respect to the soles of patients with X,XXX,XXY, and XYY sex chromosomal abnormalities are also reviewed. Discrepancies are apparent and further studies are needed. Finally, a dictionary (Appendices 1 and 2) is provided which gives the frequencies of the complete pattern configurations on the palms and soles of XXX females.
PMCID: PMC1013263  PMID: 1142381
13.  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.
PMCID: PMC2883963  PMID: 20459843
14.  Effects of sex chromosome aneuploidy on male sexual behavior 
Genes, brain, and behavior  2008;7(6):609-617.
Incidence of sex chromosome aneuploidy in men is as high as 1:500. The predominant conditions are an additional Y chromosome (47,XYY) or an additional X chromosome (47,XXY). Behavioral studies using animal models of these conditions are rare. To assess the role of sex chromosome aneuploidy on sexual behavior, we used mice with a spontaneous mutation on the Y chromosome in which the testis-determining gene Sry is deleted (referred to as Y−) and insertion of a Sry transgene on an autosome. Dams were aneuploid (XXY−) and the sires had an inserted Sry transgene (XYSry). Litters contained six male genotypes, XY, XYY−, XXSry, XXY−Sry, XYSry and XYY−Sry. In order to eliminate possible differences in levels of testosterone, all of the subjects were castrated and received testosterone implants prior to tests for male sex behavior. Mice with an additional copy of the Y− chromosome (XYY−) had shorter latencies to intromit and achieve ejaculations than XY males. In a comparison of the four genotypes bearing the Sry transgene, males with two copies of the X chromosome (XXSry and XXY−Sry) had longer latencies to mount and thrust than males with only one copy of the X chromosome (XYSry and XYY−Sry) and decreased frequencies of mounts and intromissions as compared with XYSry males. The results implicate novel roles for sex chromosome genes in sexual behaviors.
PMCID: PMC2563427  PMID: 18363850
Klinefelter syndrome; libido; male sex behavior; sex chromosome aneuploidy
15.  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
16.  Which Neurodevelopmental Disorders Get Researched and Why? 
PLoS ONE  2010;5(11):e15112.
There are substantial differences in the amount of research concerned with different disorders. This paper considers why.
Bibliographic searches were conducted to identify publications (1985–2009) concerned with 35 neurodevelopmental disorders: Developmental dyslexia, Developmental dyscalculia, Developmental coordination disorder, Speech sound disorder, Specific language impairment, Attention deficit hyperactivity disorder, Autistic spectrum disorder, Tourette syndrome, Intellectual disability, Angelman syndrome, Cerebral palsy, Cornelia de Lange syndrome, Cri du chat syndrome, Down syndrome, Duchenne muscular dystrophy, Fetal alcohol syndrome, Fragile X syndrome, Galactosaemia, Klinefelter syndrome, Lesch-Nyhan syndrome, Lowe syndrome, Marfan syndrome, Neurofibromatosis type 1, Noonan syndrome, Phenylketonuria, Prader-Willi syndrome, Rett syndrome, Rubinstein-Taybi syndrome, Trisomy 18, Tuberous sclerosis, Turner syndrome, Velocardiofacial syndrome, Williams syndrome, XXX and XYY. A publication index reflecting N publications relative to prevalence was derived.
The publication index was higher for rare than common conditions. However, this was partly explained by the tendency for rare disorders to be more severe.
Although research activity is predictable from severity and prevalence, there are exceptions. Low rates of research, and relatively low levels of NIH funding, characterise conditions that are the domain of a single discipline with limited research resources. Growth in research is not explained by severity, and was exceptionally steep for autism and ADHD.
PMCID: PMC2994844  PMID: 21152085
17.  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.
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.
PMCID: PMC2775902  PMID: 19572154
Pediatric SCT; Parental stress; Adaptation; Review
18.  Noninvasive Fetal Trisomy (NIFTY) test: an advanced noninvasive prenatal diagnosis methodology for fetal autosomal and sex chromosomal aneuploidies 
BMC Medical Genomics  2012;5:57.
Conventional prenatal screening tests, such as maternal serum tests and ultrasound scan, have limited resolution and accuracy.
We developed an advanced noninvasive prenatal diagnosis method based on massively parallel sequencing. The Noninvasive Fetal Trisomy (NIFTY) test, combines an optimized Student’s t-test with a locally weighted polynomial regression and binary hypotheses. We applied the NIFTY test to 903 pregnancies and compared the diagnostic results with those of full karyotyping.
16 of 16 trisomy 21, 12 of 12 trisomy 18, two of two trisomy 13, three of four 45, X, one of one XYY and two of two XXY abnormalities were correctly identified. But one false positive case of trisomy 18 and one false negative case of 45, X were observed. The test performed with 100% sensitivity and 99.9% specificity for autosomal aneuploidies and 85.7% sensitivity and 99.9% specificity for sex chromosomal aneuploidies. Compared with three previously reported z-score approaches with/without GC-bias removal and with internal control, the NIFTY test was more accurate and robust for the detection of both autosomal and sex chromosomal aneuploidies in fetuses.
Our study demonstrates a powerful and reliable methodology for noninvasive prenatal diagnosis.
PMCID: PMC3544640  PMID: 23198897
Noninvasive Fetal Trisomy (NIFTY) test; Massively parallel sequencing; Autosomal aneuploidies; Sex chromosomal aneuploidies
19.  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.
PMCID: PMC3328784  PMID: 22502852
Klinefelter syndrome (KS); autism; social deficits; social skills; XXY; XYY; XXYY
20.  Chromosome studies in a neonatal population 
The results of chromosome studies on 6809 consecutive newborn infants are presented. One hundred and one (1.48%) were heterozygous for a marker chromosome, the significance of which is not at present clear. Twenty-two infants (0.32%) had a major chromosome abnormality. Only six of these infants (0.09%) had a clinically recognizable abnormal phenotype (Down's syndrome). The occult chromosome abnormalities included five sex chromosome abnormalities (one 47,XYY; two 47,XXY; two 47,XXX) and 11 balanced translocations. Seven of these were t(DqDq) and four were reciprocal translocations. The results of the present survey are combined with four other similar neonatal surveys in which a total of 23,328 newborns have been screened. Of these, 117 (0.5%; range 0.65-0.32%) had major chromosome abnormalities. The majority of these (72.7%) would not have been detected at birth without chromosome studies, an important fact in the context of prenatal diagnosis of chromosome disease and the early ascertainment of high-risk families.
PMCID: PMC1940521  PMID: 4259580
21.  Molecular diagnostic testing for Klinefelter syndrome and other male sex chromosome aneuploidies 
Male sex chromosome aneuploidies are underdiagnosed despite concomitant physical and behavioral manifestations.
To develop a non-invasive, rapid and high-throughput molecular diagnostic assay for detection of male sex chromosome aneuploidies, including 47,XXY (Klinefelter), 47,XYY, 48,XXYY and 48,XXXY syndromes.
The assay utilizes three XYM and four XA markers to interrogate Y:X and X:autosome ratios, respectively. The seven markers were PCR amplified using genomic DNA isolated from a cohort of 323 males with aneuploid (n = 117) and 46,XY (n = 206) karyotypes. The resulting PCR products were subjected to Pyrosequencing, a quantitative DNA sequencing method.
Receiver operator characteristic (ROC) curves were used to establish thresholds for the discrimination of aneuploid from normal samples. The XYM markers permitted the identification of 47,XXY, 48,XXXY and 47,XYY syndromes with 100% sensitivity and specificity in both purified DNA and buccal swab samples. The 48,XXYY karyotype was delineated by XA marker data from 46,XY; an X allele threshold of 43% also permitted detection of 48,XXYY with 100% sensitivity and specificity. Analysis of X chromosome-specific biallelic SNPs demonstrated that 43 of 45 individuals (96%) with 48,XXYY karyotype had two distinct X chromosomes, while 2 (4%) had a duplicate X, providing evidence that 48,XXYY may result from nondisjunction during early mitotic divisions of a 46,XY embryo.
Quantitative Pyrosequencing, with high-throughput potential, can detect male sex chromosome aneuploidies with 100% sensitivity.
PMCID: PMC3411476  PMID: 22524164
Pyrosequencing; Sex chromosome aneuploidy; Klinefelter (47,XXY) syndrome; 47,XYY syndrome; 48,XXYY syndrome; 48,XXXY syndrome; Male infertility
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.
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.
A cross-sectional nationwide questionnaire study.
All physicians working in Sweden in 2008.
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.
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’.
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.
PMCID: PMC3293140  PMID: 22382120
23.  SNP-based non-invasive prenatal testing detects sex chromosome aneuploidies with high accuracy 
Prenatal diagnosis  2013;33(7):643-649.
To develop a single nucleotide polymorphism- and informatics-based non-invasive prenatal test that detects sex chromosome aneuploidies early in pregnancy.
Fifteen aneuploid samples, including thirteen 45,X, two 47,XXY, and one 47,XYY, along with 185 euploid controls, were analyzed. Cell-free DNA was isolated from maternal plasma, amplified in a single multiplex PCR assay that targeted 19,488 polymorphic loci covering chromosomes 13, 18, 21, X, and Y, and sequenced. Sequencing results were analyzed using a Bayesian-based maximum likelihood statistical method to determine copy number of interrogated chromosomes, calculating sample-specific accuracies.
Of the samples that passed a stringent quality control metric (93%), the algorithm correctly identified copy number at all five chromosomes in all 187 samples, for 934/935 correct calls as early as 9.4 weeks of gestation. We detected 45,X with 91.7% sensitivity (CI: 61.5-99.8%) and 100% specificity (CI: 97.9-100%), and 47,XXY and 47,XYY. The average calculated accuracy was 99.78%.
This method non-invasively detected 45,X, 47,XXY, and 47,XYY fetuses from cfDNA isolated from maternal plasma with high calculated accuracies, and thus offers a non-invasive method with the potential to function as a routine screen allowing for early prenatal detection of rarely diagnosed yet commonly occurring sex aneuploidies.
PMCID: PMC3764608  PMID: 23712453
24.  Chromosomal Abnormalities and Their Relation to Disease 
When human chromosome anomalies were first described in 1959, it appeared that specific abnormalities might be correlated with specific syndromes. Mongolism and the D and E syndromes are examples of specific syndromes associated with the presence of an extra autosome. Klinefelter's syndrome may be associated with a variety of different sex chromosome anomalies including XXY, XXYY, XXXY and XXXXY. The lastnamed variant is the only one that frequently presents features distinguishing it from the others. An XO sex chromosome complex is found in many women with gonadal dysgenesis. However, a variety of mosaicisms have been described in association with this condition, including XO/XX, XO/XXX, XO/XX/XXX, XO/XY and XO/XYY. Extra X chromosomes in phenotypical females do not seem to impair fertility or be consistently associated with congenital anomalies. Two families are described in which chromosome anomalies were found, but the association with defects was irregular. In one family the abnormality involved one of the number 16 chromosomes and in the other it involved one of the small acrocentric chromosomes.
PMCID: PMC1921148  PMID: 14018845
25.  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.
PMCID: PMC2897903  PMID: 20302959
leukemia; hematopoietic stem cell transplantation; long-term outcome

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