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Background: There is a growing interest in exploring parents' views on the benefits of early diagnosis and awareness of sex chromosome trisomies. However, only a few studies focus specifically on the experience of parents of children with XYY syndrome. The present study aimed to assess, in parents of individuals with XYY, the perceived severity of their children's condition, their level of satisfaction with the disclosure process and their concerns about their children's present and future condition., Methods: A national online sample of 56 Italian parents of children and young adults diagnosed with XYY syndrome participated in the study. They filled out a specifically developed online survey that assessed their children's areas of concern, their experience with the disclosure process and their worries about their children's condition., Results: Seventy per cent of the parents received a prenatal diagnosis, whereas 30% received a postnatal diagnosis. High individual variability was found in the parent report of their child's condition. The most frequent areas of concern were attention regulation, emotion control and behaviour control. Individuals with a postnatal diagnosis showed more severe profiles. Parents were generally dissatisfied with the disclosure process, with no differences between prenatal and postnatal disclosure. However, more than 50% of the parents who received a prenatal disclosure reported that their child's condition was less severe than they had expected. In contrast, only 11% of the parents with postnatal disclosure reported this situation. Parents' concerns were negatively related to global satisfaction with the disclosure process and the correspondence between current and expected conditions but positively associated with the child's severity level., Conclusions: The results suggest that clear and realistic information during the disclosure process to parents is needed in both prenatal and postnatal communication and may alleviate parents' concerns., (© 2024 The Author(s). Child: Care, Health and Development published by John Wiley & Sons Ltd.)

Background: Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome., Method: We gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes., Results: Carriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders. A lower bound of < 25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network., Conclusions: This study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The incidence of 47, XYY syndrome in live-born male infants is 1/1000. Due to its variable clinical symptoms, the diagnosis is easy to miss. The incidence of congenital bilateral absence of the vas deferens (CBAVD) in infertile men is 1-2%. The main cause is the mutation of CFTR and ADGAG2 genes., Case Presentation: The patient was a 33-year-old man who visited a doctor 5 years ago due to infertility. The investigation revealed that the patient's secondary sexual characteristics, testicular, and penis development were normal, and there was no gynecomastia, but the bilateral vas deferens and epididymis were not palpable. Transrectal ultrasound showed that the left seminal vesicle was missing, and the right seminal vesicle was atrophied. No abnormality was observed in Y chromosome microdeletion. Karyotype analysis indicated that the patient was 46, XY/47, XYY mosaic. Genetic testing found heterozygous mutations at two sites of CFTR (c263T > G and c2249C > T)., Conclusions: Herein, we report the rare case of a male patient with clinical manifestations of infertility, chromosome 46, XY/47, XXY mosaic type, simultaneously manifested as the absence of bilateral vas deferens. Two pathogenic heterozygous CFTR gene mutations were found. Given the low genetic risk of the disease, we recommend that patients undergo intracytoplasmic sperm injection (ICSI) for fertility assessment., (© 2022. The Author(s).)

49,XXXXY is the rarest X and Y chromosomal variation and is frequently characterized by expressive and receptive language dysfunction, low muscle tonus, and intellectual deficits. Due to the low incidence of this disorder, comprehensive studies analyzing the specific aspects of the speech and language phenotype in these boys have been uncommon. This is the first in-depth investigation of the speech and language profiles in a large cohort of boys with 49,XXXXY. Based on the clinical judgment of speech and language pathologists, there was an increased incidence (91.8%) of Childhood Apraxia of Speech (CAS), which has not been previously described in this disorder. In preschool boys, some significant differences were demonstrated between boys who received early hormonal treatment (n = 16) and untreated boys (n = 4) on the language scales (p = .047) on the Bayley Scales of Infants and Toddlers, as well as significant differences between treated (n = 13) and untreated boys (n = 8) on the Expressive One Word Picture Vocabulary Test (p = .008). No significant differences between treatment groups were found in school age children, however, treated groups demonstrated less discrepancies between expressive and receptive language. More research and larger samples are needed to determine the extent of the impact of testosterone treatment on boys with 49,XXXXY. This study identifies CAS as a potential explanation for the significant expressive language dysfunction and subsequent behavioral dysfunction. These findings may assist in facilitating more targeted treatment and improved outcomes for boys with 49,XXXXY., (© 2020 Wiley Periodicals LLC.)

An account is given of the introduction of human cytogenetics to the Division of Medical Genetics at Johns Hopkins Hospital, and the first 3 years' work of the chromosome diagnostic laboratory that was established at the time. Research on human sex chromosome disorders, including novel discoveries in the Turner and Klinefelter syndromes, is described together with original observations on chromosome behavior at mitosis. It is written in celebration of the centenary of the birth of Victor McKusick, the acknowledged father of Medical Genetics, who established the Division and had the foresight to ensure that it included the investigation of human chromosomes., (© 2021 The Author. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Objective: The present study aimed to evaluate the efficacy of a non-invasive prenatal test (NIPT) in the detection of the sex chromosome aneuploidies (SCAs) at our prenatal diagnosis centre., Methods: Among a cohort of 34,717 pregnancies, maternal plasma samples from our prenatal diagnosis centre were subject to analysis of SCAs using NIPT detection. Pregnant women with NIPT positive results of SCAs were recommended to undergo an invasive prenatal diagnosis (i.e. karyotyping and fluorescence in situ hybridization) to validate the prediction value of NIPT., Results: From 34,717 clinical pregnancies, 229 (0.66%) pregnancies were identified with SCAs. Of these, 78 (34.1%) cases were positive for 45,X and 151 (65.9%) cases comprised a sex chromosome trisomy. Of the 229 positive NIPT results, 193 (84.3%) cases had accepted an invasive diagnosis involving karyotyping analysis of the amniotic fluid, which confirmed 67 cases (34.7%) as true positive, as well as 126 cases (65.3%) as false positive. The positive predictive values were 23.07%, 50%, 36% and 27.27% respectively. The remaining 36 (15.7%) cases declined a prenatal diagnosis. The termination rates of 45,X, 47,XXY, 47,XXX and 47,XYY were 20.5%,46%,12.9% and 11.5% respectively., Conclusions: NIPT demonstrated a lower accuracy in predicting monosomy X than sex chromosome trisomies. After invasive testing, the fetal chromosome with 45,X and 47,XXY were terminated more often than those with 47,XXX, 47,XYY. Because NIPT is a screening test, false positive/negative cases exist, and pre- and post-test counselling is essential for informing patients about the benefits and limitations of the test. Confirmatory testing of abnormal results is recommended prenatally or after birth, and the importance of confirmatory testing and benefits of early diagnosis should be addressed., (© 2021 John Wiley & Sons, Ltd.)

As human life expectancy increases substantially and aging is the primary risk factor for most chronic diseases, there is an urgent need for advancing the development of post-genomic era biomarkers that can be used for disease prediction and early detection (DPED). Mosaic loss of Y chromosome (LOY) is the state of nullisomy Y in sub-groups of somatic cells acquired from different post-zygotic development stages and onwards throughout the lifespan. Multiple large-cohort based epidemiology studies have found that LOY in blood cells is a significant risk factor for future mortality and various diseases in males. Many features intrinsic to LOY analysis may be leveraged to enhance its use as a non-invasive, sensitive, reliable, high throughput-biomarker for DPED. Here, we review the emerging literatures in LOY studies and highlight ten strengths for using LOY as a novel biomarker for genomics-driven DPED diagnostics. Meanwhile, the current limitations in this area are also discussed. We conclude by identifying some important knowledge gaps regarding the consequences of malsegregation of the Y chromosome and propose further steps that are required before clinical implementation of LOY. Taken together, we think that LOY has substantial potential as a biomarker for DPED, despite some hurdles that still need to be addressed before its integration into healthcare becomes acceptable., (Copyright © 2021. Published by Elsevier B.V.)

Background: Equal dosage of X-linked genes between males and females is maintained by the X-inactivation of the second X chromosome in females through epigenetic mechanisms. Boys with aneuploidy of the X chromosome exhibit a host of symptoms such as low fertility, musculoskeletal anomalies, and cognitive and behavioral deficits that are presumed to be caused by the abnormal dosage of these genes. The objective of this pilot study is to assess the relationship between CpG methylation, an epigenetic modification, at several genes on the X chromosome and behavioral dysfunction in boys with supernumerary X chromosomes., Results: Two parental questionnaires, the Behavior Rating Inventory of Executive Function (BRIEF) and Child Behavior Checklist (CBCL), were analyzed, and they showed expected differences in both internal and external behaviors between neurotypical (46,XY) boys and boys with 49,XXXXY. There were several CpGs in AR and MAOA of boys with 49,XXXXY whose methylation levels were skewed from levels predicted from having one active (Xa) and three inactive (Xi) X chromosomes. Further, methylation levels of multiple CpGs in MAOA showed nominally significant association with externalizing behavior on the CBCL, and the methylation level of one CpG in AR showed nominally significant association with the BRIEF Regulation Index., Conclusions: Boys with 49,XXXXY displayed higher levels of CpG methylation at regulatory intronic regions in X-linked genes encoding the androgen receptor (AR) and monoamine oxidase A (MAOA), compared to that in boys with 47,XXY and neurotypical boys. Our pilot study results suggest a link between CpG methylation levels and behavior in boys with 49,XXXXY.

Purpose : To describe a family with presumed SOX2 gonadosomatic mosaicism diagnosed upon ophthalmic examination of the proband's mother. Methods : The family underwent comprehensive ophthalmic and physical examination. Variant detection was performed using trio exome analysis on peripheral leukocyte DNA from blood and saliva samples. Variant segregation analysis was performed using a custom panel NGS sequencing. An identified variant in the SOX2 gene was confirmed in the proband by Sanger sequencing. Results : We report an individual with bilateral microphthalmia, developmental delay, hearing loss, and dysmorphic features. Her mother was found to have asymptomatic forme fruste uveal coloboma affecting her anterior segment. Her father, aunt, and sisters were unaffected. Trio exome sequence analysis showed an apparent de novo heterozygous deletion in the proband, NM&#95;003106.3:c.70&#95;89del, NP&#95;003097.1:p.(Asn24Argfs*65), classified as pathogenic. Testing of the other family members' peripheral blood and saliva was negative for this variant. The iris transillumination abnormalities in the proband's mother supports a gonadosomatic mosaicism scenario. Conclusions : The results from this family underscore the importance of performing detailed evaluations of the parents of apparently sporadically affected individuals with heritable ophthalmic disorders. The identification of mildly affected individuals could substantially alter recurrence risks.

Background: Noninvasive prenatal testing (NIPT) has been widely used to screen for fetal aneuploidies, including fetal sex chromosome aneuploidies (SCAs). However, there is less information on the performance of NIPT in detecting SCAs., Methods: A cohort of 47,800 pregnancies was recruited to review the high-risk NIPT results for SCAs. Cell-free fetal DNA (cffDNA) was extracted and sequenced. All NIPT high-risk cases were recommended to undergo invasive prenatal diagnosis for karyotyping analysis and chromosome microarray analysis (CMA)., Results: A total of 238 high-risk cases were detected by NIPT, including 137 cases of 45,X, 27 cases of 47,XXX, and 74 cases of 47,XYY/47,XXY. Prenatal diagnosis, including karyotyping analysis and CMA, was available in 170 cases. The positive predictive value (PPV) was 30.00% for 45,X, 70.58% for 47,XXX, and 81.13% for 47,XYY/47,XXY. In addition, 13 cases of sex chromosome mosaicism and 9 cases of sex chromosome CNVs were incidentally found in this study., Conclusion: Our study showed that NIPT was reliable for screening SCAs based on a large sample, and it performed better in predicting sex chromosome trisomies than monosomy X. Our study will provide an important reference for clinical genetic counseling and further processing of the results.

Background: The present study aimed to determine the accuracy (Z-value) of non-invasive prenatal testing (NIPT) results for sex chromosome aneuploidy (SCA) in routine clinical practice., Methods: Among a cohort of 12505 pregnant females, maternal plasma samples collected from our hospital were utilized for SCA analysis by NIPT detection. The positive samples were validated through an invasive procedure and karyotyping analysis. The predictive value from positive samples in sex chromosomes was compared to analyze the accuracy of the Z-value., Results: There were 65 females with sex chromosome abnormalities within 12,505 pregnant females in the NIPT detection, which was validated by karyotype analysis of amniotic fluid puncture through sequencing, as well as bioinformatics analysis, with 18 true-positive samples. The true-positive results with 45,X, 47,XXY, 47,XXX and 47,XYY karyotypes predicted by NIPT were 14.29%, 50.00%, 66.67% and 71.43%, respectively. Among sex chromosome cases, the findings indicated that positive NIPT results with Z ≥ 9 show a higher accuracy., Conclusions: The findings of the present study demonstrate that the positive predictive value of NIPT for sex chromosome abnormalities is distinctive. The positive predictive value was highest for 47,XYY and lowest for 45,X. Additionally, the Z-value results are considered to be correlated with the accuracy of NIPT, although further studies need to be made., (© 2020 John Wiley & Sons, Ltd.)

This cross-sectional study examined the neurodevelopment of a large, prenatally diagnosed population of boys with 47,XXY; investigated the potentially positive effects of early hormonal therapy (EHT) on language, cognition, and motor in this population; and identified novel at risk biomarkers associated with 47,XXY. Two-hundred and seventy two evaluations were collected from 148 prenatally diagnosed boys with 47,XXY between 0 and 36 months and separated into one of three groups, depending on visit age: Y1 (0-12 months; n = 100), Y2 (13-24 months; n = 90), and Y3 (25-36 months; n = 82). Those who received EHT (administered by 12 months) were further separated (Y1, n = 37; Y2, n = 34; Y3, n = 30). Neurodevelopmental evaluations consisted of Preschool Language Scales, Early Language Milestone Scale, and Bayley Scales of Infant and Toddler Development and evaluated the effect of EHT on auditory comprehension, expressive communication, receptive language, cognition, and motor. EHT was found to be associated with a positive effect within the first year of life in these domains, as well as in the second and third year of life. Additionally, three novel at-risk biomarkers were identified in this cohort: feeding difficulties in infancy, positional torticollis, and the need for orthotics. The positive effects of EHT observed in language, cognition, and motor at variable stages within the first 3 years of life provide additional evidence into the possible efficacy of early biological treatment for boys with 47,XXY to address the neurodevelopmental dysfunction., (© 2020 Wiley Periodicals, Inc.)

Background: Follow-up cytogenetic analysis has been recommended for cases with positive noninvasive prenatal screening (NIPS) results. This study of five cases with numerical and structural sex chromosomal abnormalities (SCA) and a review of large case series of NIPS provided guidance to improve prenatal diagnosis for SCA., Methods: Following positive NIPS results for SCA, karyotype analysis, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH), and locus-specific quantitative PCR were performed on cultured amniocytes, chorionic villi cells, and stimulated lymphocytes. Review of large case series was performed to evaluate the NIPS positive rate, follow-up rate of cytogenetic analysis, positive predictive value (PPV) for major types of SCA, and relative frequencies of subtypes of major SCA., Results: Of the five cases with positive NIPS for SCA, case 1 showed a mosaic pattern of monosomy X and isodicentric Y; case 2 showed a mosaic pattern of monosomy X confined to the placenta; cases 3 and 4 had an isochromosome of Xq, and case 5 showed a derivative chromosome 14 from a Yq/14p translocation of maternal origin. Review of literature showed that mean positive rate of NIPS for SCA was 0.61%, follow-up rate of cytogenetics analysis was 76%, and mean PPV for SCA was 48%. Mosaic patterns and structural rearrangements involving sex chromosomes were estimated in 3%-20% and 3% of SCA cases, respectively., Conclusion: These five cases further demonstrated the necessity to pursue follow-up cytogenetic analysis to characterize mosaic patterns and structural abnormalities involving sex chromosomes and their value for prenatal genetic counseling. A workflow showing the performance of current NIPS and cytogenetic analysis for SCA was summarized. These results could facilitate an evidence-based approach to guide prenatal diagnosis of SCA., (© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Sex chromosome trisomies (SCT), including Klinefelter syndrome/XXY, Trisomy X, and XYY syndrome, occur in 1 of every 500 births. The past decades of research have resulted in a broadening of known associated medical comorbidities as well as advances in psychological research. This review summarizes what is known about early neurodevelopmental, behavioral, and medical manifestations in young children with SCT. We focus on recent research and unanswered questions related to the risk for neurodevelopmental disorders that commonly present in the first years of life and discuss the medical and endocrine manifestations of SCT at this young age. The increasing rate of prenatal SCT diagnoses provides the opportunity to address gaps in the existing literature in a new birth cohort, leading to development of the eXtraordinarY Babies Study. This study aims to better describe and compare the natural history of SCT conditions, identify predictors of positive and negative outcomes in SCT, evaluate developmental and autism screening measures commonly used in primary care practices for the SCT population, and build a rich data set linked to a bank of biological samples for future study. Results from this study and ongoing international research efforts will inform evidence-based care and improve health and neurodevelopmental outcomes., (© 2020 Wiley Periodicals, Inc.)

Children with SCT have an increased risk of suboptimal neurodevelopment. Previous studies have shown an elevated risk for neurobehavioral problems in individuals with SCT. However, not much is known about neurobehavioral problems in very young children; knowledge that could help with early identification of children at risk for suboptimal development, and that could help establish targets for early intervention. This study addressed the question of what the behavioral profile of children with SCT aged 1-5 years looks like. In total, 182 children aged 1-5 years participated in this study (N SCT =87, N nonclinical controls = 95). Recruitment and assessment took place in the Netherlands and the United States. The SCT group was recruited through prospective follow-up (50%), information seeking parents (31%), and clinical referral (18%). Behavioral profiles were assessed with the child behavior checklist and the ages-and-stages social-emotional questionnaire. Levels of parent-rated problem behavior were higher in children with SCT. Difficulties with overall social-emotional functioning were already present in 1-year-olds, and elevated scores were persistent across the full age range. Affective and pervasive developmental behaviors were seen in late toddlerhood and prominent at preschool age. Anxiety, attention deficit, and oppositional defiant behaviors were seen in preschool-aged children. Within this cross-sectional study, the developmental trajectory of affective, pervasive developmental, and oppositional defiant behaviors seemed to be different for SCT children than nonclinical controls. Collectively, these results demonstrate the importance of behavioral screening for behavioral problems in routine clinical care for children with SCT from a young age. Social-emotional problems may require special attention, as these problems seem most prominent, showing increased risk across the full age range, and with these problems occurring regardless of the timing of diagnosis, and across all three SCT karyotypes., (© 2020 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals, Inc.)

Subjects with 47XYY often have normal amounts of gonadotropin-releasing hormone. In these subjects the association between 47XYY and 5-alpha reductase deficiency is rare. The common clinical manifestation of 5-alpha reductase deficiency is male pseudohermaphrodism, rarely it has been revealed by micropenis. Testosterone enanthate does not give good results in patients with 5-alpha reductase deficiency; dihydrotestosterone (DHT) has proven effectiveness in these cases. We report the case of a 17-year old patient, referred to our Hospital with micropenis. The patient didn't respond to two enanthate testosterone therapies. Assessment showed normal testosterone levels, amounts of gonadotropin-releasing hormone at the upper limit of normal, low DHT, elevated testosterone/DHT ratio>20, karyotype 47 XYY. This study highlights that 5-alpha reductase deficiency in these subjects raises the issue of simple coincidence or effective link., Competing Interests: Les auteurs ne déclarent aucun conflit d'intérêts., (© Nestor Ghislain Andzouana Mbamognoua et al.)

Sex chromosome aneuploidies (SCAs) are the most commonly occurring aneuploidies in children with a collective prevalence rate of 1 in 500 live births. Prior research has documented SCAs are associated with an increased risk for early expressive language and gross motor delays, learning disorders, ADHD, autism spectrum disorder, anxiety, and executive function problems. Although SCAs have been historically underdiagnosed in young children, recent advances in noninvasive prenatal testing have resulted in an increasing nationwide cohort of infants with confirmed diagnoses. Consequently, early childhood support systems must prepare for an influx of children with known risks for associated developmental delays and potential school problems. This national survey aimed to update our understanding of current early childhood intervention services for young children with SCA in the United States and to describe parent perspectives and priorities. Descriptive statistics, chi-square tests, and logistic regression models controlling for parent education revealed a majority of respondents reported receiving public early childhood intervention services with speech therapy as the most common service. There were significant differences in early childhood intervention services by timing of diagnosis (prenatal vs. postnatal), number of sex chromosomes (trisomy vs. tetra/pentasomy), and geographic location. Parents described interventions as desirable and effective yet also difficult to obtain due to issues with the SCA phenotype, lack of provider knowledge, and challenges navigating the intervention systems. Results support the need for enhanced provider training in SCAs, policy change for early childhood intervention qualification criteria for SCA conditions, and collaboration between medical and early childhood settings., (© 2020 Wiley Periodicals, Inc.)

Background: Intellectual disability (ID) affects 1-3% of the Western population and is heterogeneous in origin. Mutations in X-linked genes represent 5-10% of ID in males. Fragile X syndrome, due to the silencing of the FMR1 gene, is the most common form of ID, with a prevalence of around 1:5000 males. Females are usually non- or mildly affected carriers, and in a few rare cases, the only gender affected. Array comparative genome hybridization (aCGH) and next-generation sequencing (NGS) have dramatically changed the nature of human genome analysis leading to the identification of new X-linked intellectual disability syndromes and disease-causing genes., Sources of Data: Original papers, reviews, guidelines and experiences of the diagnostic laboratories., Areas of Agreement: Family history and clinical examination still are essential to choose the appropriate diagnostic tests, including, a disease-specific genetic test, aCGH or FMR1 molecular analysis. If negative, NGS approaches like well-defined gene panels, whole exome, or even whole genome sequencing, are increasingly being used, improving diagnostics and leading to the identification of novel disease mechanisms., Areas of Controversy: The main challenge in the era of NGS is filtering and interpretation of the data generated by the analysis of a single individual. In X-linked cases, assessing pathogenicity is particularly challenging, even more when the variant is found to be inherited from a healthy carrier mother or when a heterozygous X-linked mutation is found in an impaired female., Growing Points: At present, variant interpretation remains a challenging task, especially in X-linked disorders. We review the main difficulties and propose a comprehensive overview that might aid in variant interpretation. Establishing a genetic diagnosis facilitates counseling and allows better delineation of clinical phenotypes., Areas Timely for Developing Research: To improve variant interpretation, there is need to refine in silico predictions with specific criteria for each gene, and to develop cost-effective functional tools, which can be easily transferred to diagnostics., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We report the case history of a 32-year-old man with no phenotypical abnormalities who presented with infertility. Semen analysis revealed azoospermia and testicular biopsy confirmed Sertoli cell-only (SCO) syndrome. Karyotyping revealed 47,XYY and pituitary hyperplasia was found on MRI pituitary. In our patient, 47,XYY karyotype is likely to have given rise to SCO syndrome that in turn resulted in pituitary hyperplasia. The patient was evaluated by various members of the multidisciplinary team including the pituitary surgeon, endocrinologist and andrologist. The patient's partner successfully delivered a healthy baby via in vitro fertilisation with donor sperm. This triad of diagnoses (SCO syndrome, 47,XYY karyotype and pituitary hyperplasia) has not been reported previously. SCO syndrome should be considered in the presence of azoospermia, elevated follicle-stimulating hormone, low inhibin-B and normal testosterone levels. Our case report also highlights the importance of excluding genetic causes of infertility even when the patient has no phenotypical abnormalities., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the attitudes of parents of children with a sex chromosome aneuploidy (SCA) regarding the impact of an early diagnosis and noninvasive prenatal testing (NIPT)., Method: A survey consisting of multiple choice and long response formatted questions was completed by parents of children with SCA(s)., Results: Fifty-five participants responded to the survey. A total of 88.1% of participants who received an early diagnosis expressed that it had a positive impact on their child's life. Of the 23 participants who utilized NIPT, 95.7% believed it was a decisive factor in their life because they could research the disorders prior to the birth of their child (35.3%), pinpoint valuable resources and interventions (38.2%), and determine possible risk factors of neurodevelopmental delays to be considered after delivery (20.6%)., Conclusion: This study documented parental perspectives on the impact of an early SCA diagnosis and attitudes towards NIPT use for identifying those at risk for SCAs. These informative and insightful results provide personal experiences that health care providers may want to consider when providing prenatal counseling on NIPT for expectant mothers. As this analysis is the first of its kind, ascertainment is limited, and future research should aim to expand these findings by investigating the different factors influencing attitudes towards NIPT., (© 2019 John Wiley & Sons, Ltd.)

Objective: To explore the impact of maternal sex chromosome aneuploidies (SCAs) and copy number variation (CNV) on false-positive results of non-invasive prenatal screening (NIPS) for predicting foetal SCAs., Methods: In total, 22 844 pregnant women were recruited to undergo NIPS. Pregnant women with high-risk of SCAs underwent prenatal diagnosis and maternal copy number variation sequencing (CNV-seq)., Results: Among 117 women with high-risk of SCAs, 72 accepted prenatal diagnosis, 86 accepted maternal CNV-seq, and 21 had maternal sex chromosome abnormalities. The abnormality rate was significantly higher than women at low-risk of SCAs (24.42% vs 3.51%). Using a novel parameter cffDNA (ChrX)/cffDNA, when the ratio was greater than 2, all foetuses had normal karyotype, and 75.0% (6/8) had abnormal maternal chromosome X. If the ratio was less than or equal to 2, only 10% (4/40) of the mothers had chromosome X CNV alterations, while 33.3% (13/40) of their foetuses had sex chromosomes CNV abnormalities., Conclusions: Approximately 25% of pregnant women with SCAs predicted by NIPS had sex chromosome abnormalities as determined by CNV-seq. The ratio of cffDNA (ChrX)/cffDNA can tentatively distinguish the maternal or foetal origin of abnormal cell-free DNA. In a reanalysis of previous NIPS data, false-positive results caused by maternal CNV might be elucidated., (© 2019 John Wiley & Sons, Ltd.)

Objective: To explore the clinical characteristics and prognosis of the 48,XXYY syndrome and gain a deeper insight into this condition., Methods: This retrospective study included 4 cases of 48,XXYY syndrome confirmed between 2011 and 2018. We analyzed the general information, clinical manifestations, laboratory results, imaging features and outcomes of assisted reproductive technology (ART) of the patients and reviewed the relevant literature., Results: The 4 patients with 48,XXYY syndrome were characterized by low literacy, soft texture and small volume of the testis, high levels of FSH and LH, and low level of serum T. Two of them were diagnosed with ejaculatory dysfunction and aspermia, and the other 2 with normal ejaculatory function but azoospermia. Biochemical analysis of seminal plasma indicated normal quantifications of both fructose and neutral α glucosidase. ART with donor sperm was performed for all the 4 cases and 3 of them got full-term babies., Conclusions: The 48,XXYY syndrome is often complicated by hypergonadotropic hypogonadism, with the clinical manifestations of aspermia or non-obstructive azoospermia. ART with donor sperm can be employed to help the patient with 48,XXYY syndrome get their non-biological offspring.

Objective: To describe (a) the observed cognitive, emotional, and behavioral phenotype in a cohort of male children with 47,XYY syndrome and (b) stress levels in their parents., Methods: We conducted a cross-sectional observational study of 11 boys diagnosed with 47,XYY syndrome and compared them with 11 age-matched boys with normal karyotype (46,XY). The participants performed standardized assessments of cognitive function, emotional state, and behavioral features; the parents completed a questionnaire evaluating parental stress. All data were analyzed using parametric and nonparametric statistical methods., Results: All of the boys exhibited a normal cognitive profile. However, emotional-behavioral profiling revealed that internalizing and externalizing problems were more prevalent in the 47,XYY group. In addition, the stress levels of the parents of the 47,XYY group were reportedly higher than those of the parents of the 46,XY group. We also found that the time of the diagnosis had an effect on the mothers' stress levels; that is, postnatal fetal 47,XYY diagnosis was associated with higher maternal stress, whereas prenatal fetal 47,XYY diagnosis was not., Conclusions: Generally, 47,XYY syndrome is associated with certain cognitive, emotional, and behavioral features. High stress levels have been reported by the mothers of 47,XYY boys who had been diagnosed postnatally because of unexpected developmental delay and/or learning difficulties. The present study highlights the need to better define the neuropsychiatric phenotype of 47,XYY children; namely, the effect of the chromosomal abnormality on their cognitive function and emotional-behavioral (internalizing and externalizing) features. This study could improve prenatal counseling and pediatric surveillance.

This study supports training in genetic counseling for obstetricians and adoption of a multidisciplinary approach in the counseling process following prenatal diagnosis of sex chromosome aneuploidy.

Background: XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data., Methods: We evaluated a single-center cohort of 64 individuals with XYY aged 5-25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis., Results: Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features., Conclusions: By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology., Trial Registrations: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls."

Background: The 47,XYY syndrome could result in fertility problems. However, seldom studies reported comprehensive researches on the embryonic development and pregnancy outcomes of these patients. This study aimed to evaluate the clinical outcomes of nonmosaic 47,XYY patients performed with fluorescent in situ hybridization (FISH) and preimplantation genetic diagnosis (PGD) treatment., Methods: This was a retrospective study. Between January 2012 and May 2017, 51 infertile males with nonmosaic 47,XYY syndrome underwent FISH-PGD were included in the study. According to sex chromosomal FISH results, embryos were classified as normal signal, no nuclei fixed, no signal in fixed nuclei, suspensive signal, and abnormal signal groups, respectively. The incidence of each group, the fixation rate, and hybridization rate were calculated. Embryonic development and pregnancy outcomes were also analyzed. The measurement data were analyzed with Student's t-test. The comparison of categorical data was analyzed with the Chi-square test and Fisher's exact test when expected cell count was <5., Results: The 53 PGD cycles with 433 embryos were analyzed. The fixation rate was 89.6%, while the hybridization rate was 96.4%. There were 283 embryos with two sex chromosomal signals with clear diagnosis (65.4%). The numbers of no nuclei fixed, no signal in fixed nuclei, suspensive signal, and abnormal signal groups were 45 (10.4%), 14 (3.2%), 24 (5.5%), and 67 (15.5%), respectively. Embryos with abnormal signals were abandoned. The number of good-quality embryos was 210 (57.4%), including implanted embryos on day 4/day 5 and cryopreserved. The rates of good-quality embryos in the no nuclei fixed (22.2%), no signal in fixed nuclei (28.6%), and suspensive signal groups (33.3%) were comparable (P > 0.05), and were significantly lower than the normal signal group (66.4%, P < 0.001). The clinical pregnancy rates of fresh and frozen embryos transferred cycles were 70.6% and 85.7%, respectively., Conclusions: Among embryos with a clear diagnosis of sex chromosome, about one-fifth showed abnormal signals. Embryos with two sex chromosomal signals are more likely to develop into good-quality ones. The application of the PGD by FISH may help to improve the clinical outcome s., Competing Interests: There are no conflicts of interest

The dicentric Y chromosome is the most common cytogenetically visible structural abnormality of Y chromosome. The sites of break and fusion of dicentric Y are variable, but break and fusion at Yq12 (proximal to the pseudoautosomal region 2/PAR 2) is very rare. Dicentric Y chromosome is unstable during cell division and likely to generate chromosomal mosaicism. Here, we report a case of infertile male with nonmosaic 46,XY where chromosome Y was dicentric with break and fusion at Yq12 (proximal to PAR 2). Clinical presentation of the case was nonobstructive azoospermia due to early maturation arrest at the primary spermatocyte stage. Various molecular techniques such as FISH, STS-PCR and DNA microarray were carried out to characterise genetic defect leading to testicular maturation arrest in the patient. The break and fusion was found at Yq12 (proximal to PAR 2) and resulted in near total duplication of Y chromosome (excluding PAR 2). The reason for maturation arrest seems due to CNVs of PARs (gain in PAR 1 and loss of PAR 2) and azoospermia factors (gain)., (© 2017 Blackwell Verlag GmbH.)

Objectives: To assess the accuracy of non-invasive prenatal testing (NIPT) for sex chromosome aneuploidy (SCA) in routine clinical practice and to review counselling and sonographic issues arising in SCA cases., Methods: Three specialist Australian obstetric ultrasound and prenatal diagnosis practices offering NIPT after 10 weeks' gestation participated in this study. NIPT was reported for chromosomes 21, 18, 13, X, and Y., Results: NIPT screening was performed in 5,267 singleton pregnancies. The odds of being affected given a positive screening result (OAPR) was lowest for SCAs, most notably for monosomy X (20%). Fewer women underwent invasive prenatal testing when counselled regarding a high risk for SCA (65.5%) compared with those who had a high risk for another aneuploidy (85%). The positive screening rate of NIPT including SCA was 2.3%, but 1.2% if only the autosomal trisomies were included in the panel., Conclusion: The addition of SCA testing to NIPT doubles the positive screening rate. The OAPR for SCAs (most notably for monosomy X) is reduced compared with the autosomal trisomies. Clinicians need a more extensive discussion with women prior to the inclusion of the X and Y chromosomes in the NIPT panel, given the complexity in counselling regarding further management and the additional anxiety that these abnormal results may cause. A benefit of sex chromosome analysis is an improvement in antenatal diagnosis of some disorders of sexual development., (© 2017 S. Karger AG, Basel.)

Objective: To study patient choice regarding testing for sex chromosome aneuploidy (SCA) and the performance of cell-free DNA (cfDNA) screening for SCA., Methods: Patient choice regarding screening for SCA and factors influencing this choice were evaluated in a single center. In a subsequent two-center study, cases that screened positive for SCA were analyzed to determine the positive predictive value (PPV) for each SCA., Results: In all, 1,957 (61.9%) of the 3,162 patients undergoing cfDNA testing opted for SCA screening. Regression analysis demonstrated that independent predictors of a patient's decision for SCA were earlier gestational age, spontaneous conception, and cfDNA chosen as a primary method of screening. A total of 161 cases screened positive for SCA and follow-up data were available for 118 (73.3%). Forty-six of the 61 cases of 45,X were false-positive results and 15 were concordant with the fetal karyotype (PPV = 24.6%). Seventeen of the 22 cases of 47,XXX were false positive and 5 concordant (PPV = 22.7%). Eleven of the 30 cases of 47,XXY were false positive and 19 concordant (PPV = 63.3%). All 5 cases of 47,XYY were correctly identified, thus yielding a PPV of 100%., Conclusion: More than half of the patients undergoing cfDNA aneuploidy screening also opted for SCA testing, but they were less likely to do so in the presence of an increased risk of trisomy. SCAs involving the X chromosome had a lower PPV than those involving the Y chromosome., (© 2017 S. Karger AG, Basel.)

Purpose: To present a case of a patient with XXXXY syndrome, anomalous optic nerves, and dural ectasia in conjunction with macular detachment., Methods: Case report., Results: A 3-year-old boy with XXXXY chromosomal abnormality presented with bilateral maculopathy. On evaluation, he was found to have anomalous optic disks with serous detachment of the left eye. Magnetic resonance imaging of the brain revealed bilateral optic nerve dural ectasia without evidence of elevated intracranial pressure., Conclusion: XXXXY syndrome, like the related condition of Klinefelter syndrome, can manifest with ocular abnormalities. In the present case, the dural ectasia may have facilitated access of cerebrospinal fluid through anomalous optic nerves, resulting in neurosensory detachment.

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.

Objective To explore the feasibility of high-throughput massively parallel genomic DNA sequencing technology for the noninvasive prenatal detection of fetal sex chromosome aneuploidies (SCAs). Methods The study enrolled pregnant women who were prepared to undergo noninvasive prenatal testing (NIPT) in the second trimester. Cell-free fetal DNA (cffDNA) was extracted from the mother's peripheral venous blood and a high-throughput sequencing procedure was undertaken. Patients identified as having pregnancies associated with SCAs were offered prenatal fetal chromosomal karyotyping. Results The study enrolled 10 275 pregnant women who were prepared to undergo NIPT. Of these, 57 pregnant women (0.55%) showed fetal SCA, including 27 with Turner syndrome (45,X), eight with Triple X syndrome (47,XXX), 12 with Klinefelter syndrome (47,XXY) and three with 47,XYY. Thirty-three pregnant women agreed to undergo fetal karyotyping and 18 had results consistent with NIPT, while 15 patients received a normal karyotype result. The overall positive predictive value of NIPT for detecting SCAs was 54.54% (18/33) and for detecting Turner syndrome (45,X) was 29.41% (5/17). Conclusion NIPT can be used to identify fetal SCAs by analysing cffDNA using massively parallel genomic sequencing, although the accuracy needs to be improved particularly for Turner syndrome (45,X).

Segmental aneusomies are usually associated with clinical consequences, but an increasing number of nonpathogenic cytogenetically visible as well as large cryptic chromosomal imbalances have been reported. Here, we report a 3.6-Mb Xq21.33 microduplication detected prenatally on a female fetus which was inherited from a phenotypically normal mother and grandfather. It is assumed that male patients harboring Xq or Xp duplication present with syndromic intellectual disability because of functional disomy of the corresponding genes. Female carriers are generally asymptomatic because of preferential inactivation of the abnormal X. In the present case, the 3.6-Mb-duplicated segment encompasses only 2 genes, DIAPH2 and RPL4A. Since the asymptomatic grandfather carries the duplication, we hypothesize that these genes are not dosage sensitive and/or involved in cognitive function. Our observation further illustrates that large copy number variants can be associated with a normal phenotype, especially where gene density is low. Reporting rare cases of large genomic imbalances without a phenotypic effect can be very helpful, especially for genetic counseling in the prenatal setting., (© 2017 S. Karger AG, Basel.)

Known genetic alterations play a major role in perturbing male reproductive health. We sought to retrospectively validate the European Association of Urology (EAU) guidelines for karyotype analysis (KA) in a homogenous cohort of 1168 White European men presenting for primary couple's infertility (noninterracial infertile couples only) and to develop a novel nomogram capable of predicting karyotype alterations. Overall, 742 (63.5%) patients would have deserved KA according to the EAU guidelines. Of those, 48 (6.9% of the assessable patients according to EAU guidelines) displayed any kind of alteration at KA. Conversely, hypothetically relying on the EAU criteria, 12 (20%) out of 60 patients with karyotype abnormalities would not have been candidates for the same genetic assessment. Overall, 694 (62.6%) patients would have been candidates for genetic workup despite having a normal karyotype. As a whole, the EAU guideline sensitivity, specificity, and discrimination were 80%, 37%, and 59%, respectively. We developed a novel nomogram, with a 2% probability cut-off, which allows for a more careful detection of KA alterations., Patient Summary: The application of the European Association of Urology guidelines for karyotype analysis does not ensure an adequate diagnostic process. In this regard, we propose a novel diagnostic tool to improve detection of alterations at karyotype analysis., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To explore the genetic cause for a boy featuring mainly with mental retardation., Methods: G-banding karyotyping and fluorescence in situ hybridization (FISH) were carried out for the child and his parents. The child was also analyzed with chromosome microarray (CMA). Suspected microdeletion was validated with quantitative PCR., Results: The proband was found to have a 47,XYY karyotype by both chromosome and FISH analyses, while both of his parents had a normal karyotype. CMA suggested that the proband had one copy of X chromosome and two copies of Y chromosome. In addition, CMA has also detected deletion of the KYNU gene (mapped at 2q22.2), which could be pathogenic. The result was confirmed by qPCR., Conclusion: For its high resolution, CMA can be used to identify potential microdeletion/duplications among children with chromosome aneuploidy and unusual phenotypes.

Objective: Sex chromosome aneuploidies are frequently detected fortuitously in a prenatal diagnosis. Most cases of 47, XXX and 47, XYY syndromes are diagnosed in this context, and parents are thus faced with an unexpected situation. The objective of the present study was to characterize a French cohort of prenatally diagnosed cases of 47, XXX and 47, XYY and to evaluate the termination of pregnancy (TOP) rate before and after France's implementation of multidisciplinary centres for prenatal diagnosis in 1997., Methods: This retrospective study identified respectively 291 and 175 cases of prenatally diagnosed 47, XXX and 47, XYY between 1976 and 2012. For each case, the indication, maternal age, karyotype and outcome were recorded., Results: Most diagnoses of the two conditions were fortuitous. The occurrence of 47, XXX was associated with advanced maternal age. The overall TOP rate was higher for 47, XXX (22.9%) than for 47, XYY (14.6%), although this difference was not statistically significant. However, the TOP rates fell significantly after 1997 (from 41.1% to 11.8% for 47, XXX and from 25.8% to 6.7% for 47, XYY)., Conclusion: The TOP rates after prenatal diagnoses of 47, XXX and 47, XYY fell significantly after 1997, following France's implementation of multidisciplinary centres for prenatal diagnosis. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)

We report 13 new individuals with duplications in Xp11.22-p11.23. The index family has one male and two female members in three generations with mild-severe intellectual disability (ID), speech delay, dysmorphic features, early puberty, constipation, and/or hand and foot abnormalities. Affected individuals were found to have two small duplications in Xp11.22 at nucleotide position (hg19) 50,112,063-50,456,458 bp (distal) and 53,160,114-53,713,154 bp (proximal). Collectively, these two regions include 14 RefSeq genes, prompting collection of a larger cohort of patients, in an attempt to delineate critical genes associated with the observed phenotype. In total, we have collected data on nine individuals with duplications overlapping the distal duplication region containing SHROOM4 and DGKK and eight individuals overlapping the proximal region including HUWE1. Duplications of HUWE1 have been previously associated with non-syndromic ID. Our data, with previously published reports, suggest that duplications involving SHROOM4 and DGKK may represent a new syndromic X-linked ID critical region associated with mild to severe ID, speech delay +/- dysarthria, attention deficit disorder, precocious puberty, constipation, and motor delay. We frequently observed foot abnormalities, 5th finger clinodactyly, tapering fingers, constipation, and exercise intolerance in patients with duplications of these two genes. Regarding duplications including the proximal region, our observations agree with previous studies, which have found associations with intellectual disability. In addition, expressive language delay, failure to thrive, motor delay, and 5th finger clinodactyly were also frequently observed in patients with the proximal duplication., (© 2015 Wiley Periodicals, Inc.)

Chromosome 47, XYY syndrome is usually diagnosed late. Some of the clinical characteristics of XYY syndrome may be perceptible in dental care. The slow development of cognitive and motor activities and tall stature is common in XYY patients. The aim of this article was to relate the oral, physical, and behavioral aspects of a 6-year-old patient with the chromosome 47, XYY syndrome, diagnosed by means of karyotyping. The patient presented motor difficulty, which led to a fall and traumatism in the anterior region. In the radiography, agenesia of the permanent maxillary lateral incisors, presence of taurodontism in the primary molars, and macrodontia of the maxillary central incisors and permanent molars could be observed. Once the diagnosis was made, it was possible to understand his difficulty at school, and make available appropriate monitoring by a suitable multidisciplinary team to stimulate, control, and minimize the day-to-day difficulties found by patients with this syndrome.

Study Question: How does a national prenatal screening program for Down syndrome (DS) perform in detecting sex chromosome abnormalities (SCAs)-Turner syndrome (TS), Klinefelter syndrome, 47,XXX and 47,XYY syndromes., Summary Answer: The SCA detection rate resulting from DS screening was below 50% for all four groups of SCAs., What Is Known Already: The detection rates of SCAs are higher in countries with DS screening. TS is associated with greater nuchal translucency (NT) and lower pregnancy-associated plasma protein-A (PAPP-A). However, specific detection rates of SCAs using prenatal DS screening have not been determined. No clear trend in PAPP-A, free beta human chorionic gonadotropin (β-hCG) and NT has been found in the remaining SCAs. Several lines of inquiry suggest that it would be advantageous for individuals with SCA to be detected early in life, leading to prevention or treatment of accompanying conditions. There is limited information about pre- and perinatal status that distinguishes SCA embryogenesis from normal fetal development., Study Design, Size, Duration: A register-based case-control study from the Danish Central Cytogenetic Register (DCCR), cross-linked with the Danish Fetal Medicine Database (DFMD), was performed from 2008 to 2012. Groups of SCAs were compared with DS and then matched with non-SCA controls to assess differences between these groups in prenatal markers and birth outcomes., Participants/materials, Setting, Methods: We included cases with prenatal and post-natal SCA karyotypes (n = 213), DS (n = 802) and 168 056 controls. We screened 275 037 individuals examined prenatally. We retrieved information regarding maternal age, NT, β-hCG and PAPP-A, as well as details regarding maternal and newborn characteristics., Main Results and the Role of Chance: The DS screening procedure detected 87 per 100 000 TS (42% of expected), 19 per 100 000 Klinefelter syndrome (13% of expected), 16 per 100 000 47,XXX (16% of cases) and 5 per 100 000 47,XYY (5% of expected) SCAs, with an overall detection rate of 27%. Compared with controls, all four SCA groups showed significantly higher NT and lower PAPP-A compared with controls (all P < 0.01) and similar to DS. The legal abortion rate was high for all four syndromes (47,XXX: 24%; 47,XYY: 29%; Klinefelter syndrome: 48%, TS: 84%). For SCA fetuses carried to term, only TS fetuses had consistently lower birthweights and placenta weights than non-SCA controls (both P = 0.0001). A few SCA cases localized in DCCR could not be found in DFMD (n = 16)., Limitations, Reason for Caution: Controls were matched on sex of the fetus of cases, meaning that all electively aborted fetuses (before week 12) were excluded, possibly reducing the diversity in the control group. We were not able to localize all diagnosed cases of SCA and DS in DFMD. Although these cases were present in DCCR, we were not able to account for the discrepancy. In addition, we suspect that several SCA children have not been diagnosed yet and future post-natal diagnosis of these cases would reduce the diagnostic yield reported here even further., Wider Implications of the Findings: The prenatal detection rate is below 50% for all SCAs. The approach used for detecting DS cannot be extended to also include SCAs. In addition, all SCAs have low PAPP-A and increased NT, thus probably reflecting an abnormal embryogenesis. Growth retardation of TS fetuses is if anything more pronounced than previously reported, both when evaluating fetus and placenta., Study Funding/competing Interests: This study received support from Aarhus University and the Novo Nordisk Foundation. The authors have no competing interests that may be relevant to the study., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Cell-free DNA (cfDNA) testing is increasingly being used to screen pregnant women for fetal aneuploidies. This technology may also identify fetal sex and can be used to screen for sex chromosome aneuploidies (SCAs). Physicians offering this screening will need to be prepared to offer comprehensive prenatal counseling about these disorders to an increasing number of patients. The purpose of this article is to consider the source of information to use for counseling, factors in parental decision-making, and the performance characteristics of cfDNA testing in screening for SCAs. Discordance between ultrasound examination and cfDNA results regarding fetal sex is also discussed., (© 2015 John Wiley & Sons, Ltd.)

Unlabelled: The aim of the study was to assess whether commercial kit QF-PCR can be used as the only method for rapic prenatal dia gnosis of chromosomes 13, 18, 21, X and Y aneuploidies, omitting cell culture and complete cyt6genetik analysis of fetal chromosomes., Material and Methods: DNA from amniocytes (94 cases) and trophoblast cells (6 cases) was analyzed witt QF-PCR according to the manufacturer's protocol. The obtained products were separated using ABI 310 Genetic Analyzer and the resulting data were analyzed using GeneMarker software., Results: The results of QF-PCR were obtained in 95 out of 100 cases (95%). Abnormalities were found in 28 casea (29.5%). All these results were confirmed in subsequent cytogenetic analysis. Normal results were obtained in 62 patients (70.5%). However in that group, we found three chromosomal aberrations other than those analyzed b3 QF-PCR. Additionally two abnormal and three normal karyotypes were found in patients with inconclusive QF-POF results., Conclusions: QF-PCR is a fast and reliable tool for chromosomal aneuploidy analysis and can be used as the only method without a full analysis of the karyotype, but only in cases of suspected fetal 13, 18, 21 trisomy or numerica aberrations of X chromosome. In other cases, fetal karyotype analysis from cells obtained after cell culture should be offered to the patient.

Objective: The aim of this study is to explore women's opinions about the use of noninvasive prenatal testing (NIPT) to assess the risk of sex chromosome aneuploidies and microdeletion syndromes., Methods: Focus groups were conducted with women who were currently pregnant or had recently delivered. Qualitative analysis using interpretive description was used to generate study findings., Results: Thirty-one women (mean age 32.4 years) participated in the focus groups. Participants were unfamiliar with sex chromosome aneuploidies but expressed support for the use of NIPT to detect these conditions. Participants were uncertain about the utility and actionability of receiving information about microdeletion syndromes with variable or unknown phenotypic expression. Participants voiced their desire to be informed of all conditions assessed by NIPT prior to testing. They considered clinicians to be the key provider of such information, although stated that patients have a responsibility to be knowledgeable prior to testing in order to support informed decision making., Conclusions: The use of NIPT to identify sex chromosome aneuploidies and microdeletion syndromes will introduce new challenges for clinicians to ensure pregnant women have the information and resources to make informed choices about NIPT when used for these conditions., (© 2015 John Wiley & Sons, Ltd.)

47, XXY occurs in up to 1 in 650 male births and is associated with androgen deficiency, neurodevelopmental delays, and atypical social-behaviors. Previously, we showed that young boys with 47, XXY who received early hormonal therapy (EHT) had significantly improved neurodevelopment. The objective of this follow-up study was to examine the effects of EHT on social behavior in boys with 47, XXY. The study consisted of boys prenatally diagnosed with 47, XXY who were referred for evaluations. Twenty-nine boys received three injections of 25 mg testosterone enanthate and 57 controls did not receive EHT. Behavioral functioning was assessed using the Behavior Rating Inventory of Executive Function, Social Responsiveness Scale, 2nd Ed., and the Child Behavior Checklist for Ages 6-18. The hypothesis that EHT may affect behavior was formulated prior to data collection. Questionnaire data was prospectively obtained and analyzed to test for significance between two groups. Significant differences were identified between group's scores over time in Social Communication (P=0.007), Social Cognition (P=0.006), and Total T-score (P=0.001) on the SRS-2; Initiation (P=0.05) on the BRIEF; and Externalizing Problems (P=0.024), Affective Problems (P=0.05), and Aggressive Behaviors (P=0.031) on the CBCL. This is the third study revealing positive effects of EHT on boys with XXY. There was a significant improvements associated with the 47, XXY genotype in boys who received EHT. Research is underway on the neurobiological mechanisms, and later developmental effects of EHT., (© 2015 Wiley Periodicals, Inc.)

In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic., (© 2015 Wiley Periodicals, Inc.)