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Neurocognitive Variance and Neurological Underpinnings of the X and Y Chromosomal Variations

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Neurocognitive Variance and Neurological Underpinnings of the X and Y Chromosomal Variations American Journal of Medical Genetics Part C (Seminars in Medical Genetics) ARTICLE Neurocognitive Variance and Neurological Underpinnings of the X and Y Chromosomal Variations 1,2 2 ANDREA GROPMAN * AND CAROLE A. SAMANGO-SPROUSE 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. ß 2013 Wiley Periodicals, Inc. KEY WORDS: aneuploidies; sex chromosome; 47, XXY; 48, XXXY; 49, XXXXY; dyspraxia How to cite this article: Gropman A, Samango-Sprouse CA. 2013. Neurocognitive variance and neurological underpinnings of the X and Y chromosomal variations. Am J Med Genet Part C 9999:1–9. INTRODUCTION functions, but of later neurocognitive making a distinction from 47, development, and early repletion of XXY clinically relevant 48, XXYY, 48, XXXY, and 49, for these patients. XXXXY syndromes are rare sex chro- With each additional X mosome aneuploidies characterized by the presence of two or more extra X chromosome, there are and/or Y chromosomes in males. The increased risks for congenital testosterone may improve cognitive out- presence of one or more additional X comes [Samango-Sprouse et al., 2011, chromosome(s) results in testicular dys- malformations outside of in press]. Prior to cohort studies, 48, genesis with resultant hypergonado- endocrine function, as well as XXYY, 48, XXXY, and 49, XXXXY tropic hypogonadism. The impact of have often been considered ‘‘severe var- early lack of testosterone has been dis- more complex and varied iants’’ of 47, XXY (Klinefelter syndrome) cussed in the setting not only of gonadal neurocognitive variance, thus because of these shared features. Conflict of interest: None. Andrea Gropman, M.D., is an Associate Professor of Neurology and Pediatrics at the George Washington University of the Health Sciences and an attending at the Children’s National Medical Center in Washington, DC. She is the Chief of the division of Neurogenetics and Neurodevelopmental Pediatrics. She is involved in clinical and molecular testing of patients with Neurogenetic conditions and her research is focused on neurological and neurodevelopmental phenotyping of genetic conditions. She also performs research using neuroimaging in children and adults with inborn errors of metabolism. Carole Samango-Sprouse, Ed.D., is an Associate Clinical Professor of Pediatrics at the George Washington University School of Medicine and Health Sciences. She is actively involved in the clinical and developmental care of children with rare neurogenetic disorders. She is the CEO of the Neurodevelopmental Diagnostic Center providing care for children with uncommon neurogenetic disorders from all over the world. She writes extensively about the relationship between brain function, neurodevelopmental profile and neurogenetic disorder. *Correspondence to: Andrea Gropman, M.D., Division of Neurogenetics and Neurodevelopmental Pediatrics, Children’s National Medical Center, 111 Michigan Avenue, Washington, DC 2001. E-mail: [email protected] DOI 10.1002/ajmc.31352 Article first published online in Wiley Online Library (wileyonlinelibrary.com). ß 2013 Wiley Periodicals, Inc. 2 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE However, with longitudinal cohort normal male sperm (Yp). Parent of ori- are present in about 75–100% of boys, studies, the remarkable clinical variabil- gin effects have been described and may impacting their average age of indepen- ity within and among the syndromes has influence the phenotype through im- dent ambulation and quality of gross and been realized. With each additional X printing [Rinaldi et al., 1979]. There fine motor skills development. chromosome, there are increased risks are limited studies that address additional It has been suggested that cognitive for congenital malformations outside of epigenetic factors that may influence abilities decrease by 10–15 IQ points endocrine function, as well as more the clinical presentation of these boys, for each additional X chromosome complex and varied neurocognitive var- and this research is needed to explain [Visootsak et al., 2007]. However, a cog- iance, thus making a distinction from 47, phenotypic variability. nitive profile that emerges in these boys XXY clinically relevant for these includes strengths in visual perceptual patients [Peet et al., 1998; Tartaglia and nonverbal cognitive skills. The DEVELOPMENTAL AND et al., 2008]. weaknesses encompass verbal skills and NEUROCOGNITIVE 47, XXY is the most common of language formulation which has been SPECTRUM IN THE X AND Y the X chromosome aneuploidies in previously well described [Samango- CHROMOSOMAL males with an incidence rate of approxi- Sprouse and Rogol, 2002; Visootsak VARIATIONS mately one in 650 males, making it one et al., 2007; Gropman et al., 2010]. of the most common chromosome Androgens influence neurodevelop- anueploidies [Evans et al., 1982; Coffee ment, brain function, and behavioral 47, XXY et al., 2009] and there is a robust litera- outcomes from as early as 16 weeks ges- ture regarding neurodevelopmental tation, continuing throughout adult- 47, XXY syndrome is the most common profile and brain neuroimaging [Lenroot hood [Knickmeyer and Baron-Cohen, human sex chromosome disorder et al., 2009]. With regard to the more 2006]. Fetal testosterone affects develop- [MacLean et al., 1961]. The cognitive rare X chromosome aneuploidies, 48, ment of the cortex and limbic systems phenotype in 47, XXY includes lan- XXYY syndrome is the most common [Hines et al., 2006; Genazzani et al., guage-based learning disabilities, of these three syndromes and is estimated 2007]. Hormones have an important decreased fine motor skills, and discrep- to occur in 1:18,000–1:40,000 male place in modulating mood, neurocogni- ancies between nonverbal and verbal births [Sørensen et al., 1978], whereas tive capacities, and even the aging pro- cognitive abilities. Delayed speech de- the incidence of 48, XXXY is estimated cess [Collacott et al., 1990; Chura et al., velopment requiring speech therapy to be 1:50,000, and the most rare, 49, 2010; Verri et al., 2010]. Variation in [Ratcliffe, 1982; Leggett et al., 2010] XXXXYoccurs in 1:85,000–1:100,000 brain morphology and linear growth has also been observed in both boys male births [Kleczkowska et al., 1988]. which varies between girls and boys with 47, XXY and boys with 47, XYY. has been attributable to hormonal inter- Previous studies in boys with 47, play. The effect of androgen deficiency XXY or Klinefelter syndrome (KS) GENETIC ETIOLOGY on behavior, neurodevelopment, and have shown language-based learning The majority of cases of 48, XXYY cognition have not been well explored deficits with frontal lobe dysfunction syndrome result from a nondysjunction in boys or men with 47, XXY; however, [Samango-Sprouse, 2001; Simpson event in which there is fertilization of to date, small studies suggest the positive et al., 2003; Giedd et al., 2007] that a normal female oocyte (Xm), with effects of testosterone treatment in adult lead to academic difficulties in school. an aneuploid sperm (XpYpYp) that is males with 47, XXY [Patwardhan et al., produced through nondisjunction 2000; Lanfranco et al., 2004; Steinman events occurring in both meiosis I and et al., 2009]. Androgen deficiency may Previous studies in boys with meiosis II of spermatogenesis. Postzy- be contributing to the complex neuro- 47, XXY or Klinefelter gotic nondisjunction may occur during developmental issues of boys with syndrome (KS) have shown mitosis, (and accounts for 8% of cases 49, XXXXY as well as boys with 47, with 47, XXY and 14% of cases with XXY [Samango-Sprouse et al., 2011, language-based learning 47, XXX), resulting in XmXmYpYp in press]. deficits with frontal lobe [Hassold et al., 2007]. Where parental The earlier literature presented a studies have been performed, the addi- rather dismal picture of the neurocogni- dysfunction that lead to tional X (and Y) chromosome has been tive expectations of boys with 48, academic difficulties in school. shown to be paternal in origin [Rinaldi XXYY, 48, XXXY, and 49, XXXXY et al., 1979; Leal et al., 1994]. syndromes. Across the board, develop- Similarly, 49, XXXXY results from mental delays are common in infancy Decreased motor control and
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