Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study.

Orphanet J Rare Dis. 2019 Jan 14;14(1):16. doi: 10.1186/s13023-018-0976-2.

Changes in the cohort composition of turner syndrome and severe non-diagnosis of Klinefelter, 47,XXX and 47,XYY syndrome: a nationwide cohort study.

Berglund A1,2, Viuff MH3,4, Skakkebæk A3,5, Chang S6,7, Stochholm K3,8, Gravholt CH3,4.

Author information デンマーク


Abstract

BACKGROUND:

Knowledge on the prevalence of sex chromosome abnormalities (SCAs) is limited, and delayed diagnosis or non-diagnosis of SCAs are a continuous concern. We aimed to investigate change over time in incidence, prevalence and age at diagnosis among Turner syndrome (TS), Klinefelter syndrome (KS), Triple X syndrome (Triple X) and Double Y syndrome (Double Y).

METHODS:

This study is a nationwide cohort study in a public health care system. The Danish Cytogenetic Central Registry (DCCR) holds information on all karyotypes performed in Denmark since 1961. We identified all individuals in the DCCR with a relevant SCA during 1961-2014; TS: n = 1156; KS: n = 1235; Triple X: n = 197; and Double Y: n = 287. From Statistics Denmark, which holds an extensive collection of data on the Danish population, complete data concerning dates of death and migrations in and out of Denmark were retrieved for all individuals.

RESULTS:

The prevalence among newborns was as follows: TS: 59 per 100,000 females; KS: 57 per 100,000 males; Triple X: 11 per 100,000 females; and Double Y: 18 per 100,000 males. Compared with the expected number among newborns, all TS, 38% of KS, 13% of Triple X, and 18% of Double Y did eventually receive a diagnosis. The incidence of TS with other karyotypes than 45,X (P < 0.0001), KS (P = 0.02), and Double Y (P = 0.03) increased during the study period whereas the incidence of 45,X TS decreased (P = 0.0006). The incidence of Triple X was stable (P = 0.22).

CONCLUSIONS:

The prevalence of TS is higher than previously identified, and the karyotypic composition of the TS population is changing. Non-diagnosis is extensive among KS, Triple X and Double Y, whereas all TS seem to become diagnosed. The diagnostic activity has increased among TS with other karyotypes than 45,X as well as among KS and Double Y.


KEYWORDS:

Age at diagnosis; Double Y syndrome; Incidence; Klinefelter syndrome; Prevalence; Triple X syndrome; Turner syndrome

Delivering the Diagnosis of Sex Chromosome Aneuploidy: Experiences and Preferences of Parents and Individuals.

Clin Pediatr (Phila). 2018 Dec 5:9922818817310. doi: 10.1177/0009922818817310. [Epub ahead of print]

Delivering the Diagnosis of Sex Chromosome Aneuploidy: Experiences and Preferences of Parents and Individuals.

Jaramillo C1, Nyquist C1, Riggan KA1, Egginton J1, Phelan S1, Allyse M1.

Author information
1 Mayo Clinic, Rochester, MN, USA.

Abstract

Increased prenatal diagnoses of sex chromosome aneuploidies (SCAs) amid limited knowledge of their prognoses heighten the need to understand how families contend with the implications of an SCA. To explore the experiences of parents and individuals who received a genetic diagnosis of an SCA (excluding Turner syndrome), we conducted semistructured qualitative telephone interviews with 43 participants affected by these conditions. Parents (n = 35) and individuals (n = 8) expressed almost unanimous interest in more optimistic portrayals of their condition from their providers, even when the prognosis is uncertain. While some participants reported success in receiving accurate information from their provider and identifying supportive resources, numerous families received outdated or misleading information about their condition and lacked direction in accessing follow-up care and support. Parents desire greater coordination of their child's medical care and access to care that approaches an SCA holistically. Opportunities remain to improve the diagnosis and care of individuals with SCAs.


KEYWORDS:
Jacob’s syndrome; Klinefelter syndrome; pediatric diagnosis; prenatal diagnosis; trisomy X

Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study

Genetics and genomics Research

Criminality in men with Klinefelter's syndrome and XYY syndrome: a cohort study

Kirstine Stochholm1, Anders Bojesen2, Anne Skakkebæk Jensen1, Svend Juul3, Claus Højbjerg Gravholt1

デンマーク

Abstract

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.

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

Neuropsychopharmacology. 2018 Jul 16. doi: 10.1038/s41386-018-0153-2. [Epub ahead of print]

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

Green T1,2, Flash S3, Reiss AL3,4,5.



Author information

1Center for Interdisciplinary Brain Sciences Research, Stanford University, Stanford, CA, 94305, USA. tgreen2@stanford.edu.
2Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA. tgreen2@stanford.edu.
3Center for Interdisciplinary Brain Sciences Research, Stanford University, Stanford, CA, 94305, USA.
4Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA.
5Department of Radiology, Stanford University, Stanford, CA, 94305, USA.

Abstract

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

Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis.

Wellcome Open Res. 2018 Feb 12;3:10. doi: 10.12688/wellcomeopenres.13828.2. eCollection 2018.

Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis.

Newbury DF1, Simpson NH2, Thompson PA2, Bishop DVM2.

Author information
1 Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, Oxfordshire, OX3 0BP, UK.
2 Department of Experimental Psychology, University of Oxford, Oxford, Oxfordshire, OX1 3UD, UK.


Abstract

Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. Group averages, however, obscure a wide range of outcomes.

Hypothesis: The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. Neuroligin-4 genes are expressed from X and Y chromosomes; they play an important role in synaptic development and have been implicated in neurodevelopment. We predict that the impact of an additional sex chromosome on neurodevelopment will be correlated with common autosomal variants involved in related synaptic functions. We describe here an analysis plan for testing this hypothesis using existing data. The analysis of genotype-phenotype associations will be conducted after this plan is published and peer-reviewed

Methods: Neurodevelopmental data and DNA are available for 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Children from a twin study using the same phenotype measures will form two comparison groups (Ns = 184 and 186). Three indicators of a neurodevelopment disorder phenotype will be used: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Autosomal genes were identified by literature search on the basis of prior association with (a) speech/language/reading phenotypes and (b) synaptic function. Preselected regions of two genes scoring high on both criteria, CNTNAP2 and NRXN1, will be tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. We predict the association with one or both genes will be detectable in children with SCTs and stronger than in the comparison samples.

KEYWORDS:

Language disorder; autism; genetics; neurexin; neuroligin; sex chromosome trisom

Sex chromosome aneuploidies and copy-number variants: a further explanation for neurodevelopmental prognosis variability?

Sex chromosome aneuploidies and copy-number variants: a further explanation for neurodevelopmental prognosis variability?

Eur J Hum Genet. 2017 Aug;25(8):930-934

Authors: Le Gall J, Nizon M, Pichon O, Andrieux J, Audebert-Bellanger S, Baron S, Beneteau C, Bilan F, Boute O, Busa T, Cormier-Daire V, Ferec C, Fradin M, Gilbert-Dussardier B, Jaillard S, Jønch A, Martin-Coignard D, Mercier S, Moutton S, Rooryck C, Schaefer E, Vincent M, Sanlaville D, Le Caignec C, Jacquemont S, David A, Isidor B

Abstract

Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter's syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder.

Autism Spectrum Disorder in Males with Sex Chromosome Aneuploidy: XXY/Klinefelter Syndrome, XYY, and XXYY.

Autism Spectrum Disorder in Males with Sex Chromosome Aneuploidy: XXY/Klinefelter Syndrome, XYY, and XXYY.

J Dev Behav Pediatr. 2017 Apr;38(3):197-207

Authors: Tartaglia NR, Wilson R, Miller JS, Rafalko J, Cordeiro L, Davis S, Hessl D, Ross J

Abstract

OBJECTIVE: Neurodevelopmental concerns in males with sex chromosome aneuploidy (SCA) (XXY/Klinefelter syndrome, XYY, XXYY) include symptoms seen in autism spectrum disorder (ASD), such as language impairments and social difficulties. We aimed to: (1) evaluate ASD characteristics in research cohorts of SCA males under DSM-IV compared to DSM-5 criteria, and (2) analyze factors associated with ASD diagnoses in SCA.

METHODS: Evaluation of participants with XXY/KS (n=20), XYY (n=57) and XXYY (n=21) included medical history, cognitive/adaptive testing, Social Communication Questionnaire, Social Responsiveness Scale, Autism Diagnostic Observation Schedule, Autism Diagnostic Interview-Revised, and DSM ASD criteria. Clinical impressions of ASD diagnostic category using the ADOS and DSM-IV criteria were compared to ADOS-2 and DSM-5 criteria. T-tests compared cognitive, adaptive, SES and prenatal vs. postnatal diagnoses between ASD and no ASD groups.

RESULTS: ASD rates in these research cohorts were 10% in XXY/KS, 38% in XYY, and 52% in XXYY using ADOS-2/DSM-5, and were not statistically different compared to DSM-IV criteria. In XYY and XXYY, the ASD group had lower verbal IQ and adaptive functioning compared to those without ASD. Many children without ASD still showed some social difficulties.

CONCLUSION: ASD rates in males with SCA are higher than reported for the general population. Males with Y chromosome aneuploidy (XYY and XXYY) were 4.8 times more likely to have a diagnosis of ASD than the XXY/KS group, and 20 times more likely than males in the general population (1 in 42 males, CDC 2010). ASD should be considered when evaluating social difficulties in SCA. Studies of SCA and Y-chromosome genes may provide insight into male predominance in idiopathic ASD.