A new look at XXYY syndrome: medical and psychological features. Am J Med Genet 146A(12):1509-1522

Department of Pediatrics, University of Colorado Denver, School of Medicine, Aurora, Colorado, USA.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 06/2008; 146A(12):1509-22. DOI: 10.1002/ajmg.a.32366
Source: PubMed


XXYY syndrome occurs in approximately 1:18,000-1:40,000 males. Although the physical phenotype is similar to 47,XXY (tall stature, hypergonadotropic hypogonadism, and infertility), XXYY is associated with additional medical problems and more significant neurodevelopmental and psychological features. We report on the results of a cross-sectional, multi-center study of 95 males age 1-55 with XXYY syndrome (mean age 14.9 years), describing diagnosis, physical features, medical problems, medications, and psychological features stratified by age groups. The mean age of diagnosis was 7.7 years. Developmental delays and behavioral problems were the most common primary indication for genetic testing (68.4%). Physical and facial features varied with age, although hypertelorism, clinodactyly, pes planus, and dental problems were common across all age groups. Tall stature was present in adolescents and adults, with a mean adult stature of 192.4 cm (SD 7.5; n = 22). Common medical problems included allergies and asthma (>50%), congenital heart defects (19.4%), radioulnar synostosis (17.2%), inguinal hernia and/or cryptorchidism (16.1%), and seizures (15%). Medical features in adulthood included hypogonadism (100%), DVT (18.2%), intention tremor (71%) and type II diabetes (18.2%). Brain MRI (n = 35) showed white matter abnormalities in 45.7% of patients and enlarged ventricles in 22.8%. Neurodevelopmental and psychological difficulties were a significant component of the behavioral phenotype, with developmental delays and learning disabilities universal but variable in severity. Twenty-six percent had full-scale IQs in the range of intellectual disability (MR), and adaptive functioning was significantly impacted with 68% with adaptive composite scores <70. Rates of neurodevelopmental disorders, including ADHD (72.2%), autism spectrum disorders (28.3%), mood disorders (46.8%), and tic disorders (18.9%), were elevated with 55.9% on psychopharmacologic medication overall. Recommendations for evaluation and treatment are summarized.

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Available from: Nicole Tartaglia, Sep 29, 2015
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    • "Males with the Klinefelter syndrome (47,XXY) show socio-emotional difficulties (Geschwind and Boone, 2000; Tartaglia et al., 2010) and show increased levels of autistic and schizotypical traits and are often diagnosed with ASD (Bishop et al., 2011; van Rijn and Swaab, 2011). Also 47,XYY males and 48,XXYY males seem to have an increased rate of autism and 47,XXX females show an increased level of mild communication difficulties (Bishop et al., 2011; Bruining et al., 2009; Geerts et al., 2003; Tartaglia et al., 2008). Females with Turner syndrome (45,X) show an increased rate of autism (Creswell and Skuse, 1999) and problems in social adjustment in this group is common (McCauley et al., 1986). "
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    ABSTRACT: The male predominance of autism spectrum disorders (ASD) is one of the best-known, and at the same time, one of the least understood characteristics of these disorders. In this paper we review genetic, epigenetic, hormonal, and environmental mechanisms underlying this male preponderance. Sex-specific effects of Y-linked genes (including SRY expression leading to testicular development), balanced and skewed X-inactivation, genes that escape X-inactivation, parent-of-origin allelic imprinting, and the hypothetical heterochromatin sink are reviewed. These mechanisms likely contribute to etiology, instead of being simply causative to ASD. Environments, both internal and external, also play important roles in ASD's etiology. Early exposure to androgenic hormones and early maternal immune activation comprise environmental factors affecting sex-specific susceptibility to ASD. The gene-environment interactions underlying ASD, suggested here, implicate early prenatal stress as being especially detrimental to boys with a vulnerable genotype.
    Frontiers in Neuroendocrinology 04/2014; 35(3). DOI:10.1016/j.yfrne.2014.03.006 · 7.04 Impact Factor
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    • "However, with longitudinal cohort studies, the remarkable clinical variability within and among the syndromes has been realized. With each additional X chromosome, there are increased risks for congenital malformations outside of endocrine function, as well as more complex and varied neurocognitive variance , thus making a distinction from 47, XXY clinically relevant for these patients [Peet et al., 1998; Tartaglia et al., 2008]. 47, XXY is the most common of the X chromosome aneuploidies in males with an incidence rate of approximately one in 650 males, making it one of the most common chromosome anueploidies [Evans et al., 1982; Coffee et al., 2009] and there is a robust literature regarding neurodevelopmental profile and brain neuroimaging [Lenroot et al., 2009]. "
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    ABSTRACT: X and Y chromosomal variations including tetrasomy and pentasomy conditions are rare and occur in 1:18,000-1:100,000 male births. The most common sex chromosome aneuploidy is 47, XXY for which there is a rich literature delineating the physical and neurobehavioral phenotype. Although the more complex chromosome aneuploidies 48, XXYY, 48, XXXY, and 49, XXXXY are often compared with 47, XXY (Klinefelter syndrome) because of shared features including tall stature and hypergonadotropic hypogonadism, there is a wider spectrum of physical and cognitive abilities that have recently been delineated. The phenotypic presentation of the boys with more severe aneuploidy shares some characteristics with 47, XXY, but there are also other unique and distinctive features. Previously unappreciated intact nonverbal skills have been demonstrated in association with severe developmental dyspraxia. MRI findings of white matter hyperintensities may underlie cognitive deficits and deserve further study. This report discusses what is known about clinical variability in the XY syndromes collectively evaluated through careful multidisciplinary clinical evaluation including the clinical and neurobehavioral aspects of these conditions. Variability in clinical and cognitive functioning may reflect skewed X inactivation, mosaicism, or epigenetic factors that warrant further investigation. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part C Seminars in Medical Genetics 02/2013; 163(1). DOI:10.1002/ajmg.c.31352 · 3.91 Impact Factor
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    • "More complex male sex chromosome aneuploidies, such as 48,XXYY and 48,XXXY, are less common than KS with prevalences ranging from 1 in 18,000 to 1 in 100,000 or greater [1]. While some phenotypic characteristics of 48,XXYY and 48,XXXY syndromes overlap with KS, the unique and significant differences in physical appearance, cognitive function, social and adaptive skills observed in affected individuals differentiate these aneuploidies from KS [8,9]. "
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    ABSTRACT: 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.
    International Journal of Pediatric Endocrinology 04/2012; 2012(1):8. DOI:10.1186/1687-9856-2012-8
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