An extra X or Y chromosome: Contrasting the cognitive and motor phenotypes in childhood in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome

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<ul><li><p>AN EXTRA X OR Y CHROMOSOME: CONTRASTINGTHE COGNITIVE AND MOTOR PHENOTYPES INCHILDHOOD IN BOYS WITH 47,XYY SYNDROME</p><p>OR 47,XXY KLINEFELTER SYNDROME</p><p>Judith L. Ross,1,2* Martha P.D. Zeger,1,2 Harvey Kushner,3 Andrew R. Zinn,4</p><p>and David P. Roeltgen51Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania2Department of Pediatrics, duPont Hospital for Children, Wilmington, Delaware</p><p>3Biomedical Computer Research Institute, Philadelphia, Pennsylvania4Department of Internal Medicine, McDermott Center for Human Growth and Development,</p><p>University of Texas Southwestern Medical Center, Dallas, Texas5Department of Neurology, Georgetown University, Washington, DC</p><p>Objective: The goal of this study was to contrast the cognitive phe-notypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXYkaryotype [Klinefelter syndrome, (KS)], who share an extra copy of the X-Ypseudoautosomal region but differ in their dosage of strictly sex-linkedgenes. Methods: Neuropsychological evaluation of general cognitive abil-ity, language, memory, attention, visual-spatial abilities, visual-motor skills,and motor function. Results: Study cohort: 21 boys with 47,XYY and 93boys with 47,XXY (KS), age 417 years, and 36 age-matched control boys.Both the XYY and KS groups performed less well, on average, than thecontrols on tests of general cognitive ability, achievement, language,verbal memory, some aspects of attention, and executive function, andmotor function. The boys with XYY on average had more severe and per-vasive language impairment, at both simple and complex levels, and theboys with KS on average had greater motor impairment in gross motorfunction and coordination, especially in running speed and agility. Conclu-sions: The results from these large XYY and KS cohorts have importantneurocognitive and educational implications. From the neurocognitivestandpoint, the presenting findings afford an opportunity to gain insightsinto brain development in boys with XYY and those with KS. From theeducational standpoint, it is critical that boys with XYY or KS receiveappropriate educational interventions that target their specific learningchallenges. These findings also provide important information for counsel-ing clinicians and families about these disorders. ' 2009 Wiley-Liss, Inc.Dev Disabil Res Rev 2009;15:309317.</p><p>Key Words: XXY; Klinefelter syndrome; XYY; sex chromosome</p><p>Two sex chromosome aneuploidy disorders, 47,XYYand 47,XXY (Klinfelter syndrome, KS), affect onlymales. Both disorders are relatively common and areunderdiagnosed. In addition, there may be confusion aboutwhat distinguishes one from the other. The XYY syndromeaffects one in 1,000 males and is characterized by physical</p><p>findings such as tall stature as well as neurological, cognitive,and behavioral phenotypes [Welch, 1985; Robinson et al.,1990; Ratcliffe et al., 1982, 1992; Aksglaede et al., 2008; Kentet al., 2008]. Testicular function, testosterone levels, and fertil-ity are usually normal [Rudd et al., 1968; Price and van derMolen, 1970; Baghdassarian et al., 1975; Benezech, 1985;Welch, 1985; Ratcliffe et al., 1994; Geerts et al., 2003; Aks-glaede et al., 2008]. KS, the most common sex chromosomedisorder [MacLean, 1961; Robinson et al., 1990; Rovet et al.,1995], occurs in 1 in 426 to 1 in 1,000 males [Bojesen et al.,2003]. Like XYY, the KS phenotype includes tall stature andcharacteristic cognitive attributes, but, in contrast to XYY, alsoincludes childhood onset testicular failure.</p><p>The cognitive phenotype in boys with XYY typicallyincludes normal to mildly diminished general intelligence asmeasured by full-scale intelligence quotient (IQ) [Benderet al., 1984; Evans et al., 1986; Netley, 1986; Robinson,1985], with Verbal IQ impaired more than Performance IQ[Christensen and Nielsen, 1973; Ratcliffe et al., 1982; Welch,1985]. These boys tend to have delayed speech developmentand to require speech therapy [Daly, 1969; Valentine, 1979;Ratcliffe, 1982; Bender et al., 1984; Robinson, 1985; Geertset al., 2003]. Often they have difficulty mastering school</p><p>Grant sponsor: NIH; Grant number: RO1NS050597 (J.L.R.).*Correspondence to: Judith L. Ross, MD, Department of Pediatrics, Division of En-docrinology, Thomas Jefferson University, 1025 Walnut Street, Suite 726, Philadel-phia, PA 19107. E-mail: judith.ross@mail.tju.eduReceived 27 July 2009; Accepted 4 September 2009Published online in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ddrr.85</p><p>DEVELOPMENTAL DISABILITIESRESEARCH REVIEWS 15: 309 317 (2009)</p><p>' 2009Wiley -Liss, Inc.</p></li><li><p>curricula and need educational supportservices in reading and writing [Benderet al., 1984; Netley, 1986]. Increasedrisk for hyperactivity and attentionproblems has also been reported [Ruudet al., 2005]. Boys with XYY also havedelayed motor milestones and impairedfine and gross motor function, coordi-nation, and tone [Ratcliffe et al., 1982;Bender et al., 1984; Robinson et al.,1985; Ratcliffe, 1999; Geerts et al.,2003].</p><p>The cognitive phenotype in boyswith KS is similar, with depressed verbalIQ relative to performance IQ in both inchildren and adults [Graham et al., 1988;Walzer et al., 1990; Rovet et al., 1995].This may be accompanied by moderateto severe problems with reading, spelling,writing, and arithmetic [Nielsen et al.,1981; Stewart et al., 1986]. Languageand speech impairments are evident insome form at all ages. Attention issuesrelated more to omission than commis-sion errors have also been described inchildhood in KS [Ross et al., 2008].</p><p>Thus, there appears to be someoverlap in the cognitive phenotypes inthese two disorders, especially in thearea of language dysfunction. However,in the absence of a systematic compari-son of these two groups, the similaritiesas well as the differences are not welldefined. The goal of this study was tocompare and contrast the cognitive phe-notypes in boys with XYY, boys withXXY, and age-matched control boys.</p><p>METHODS</p><p>SubjectsSubjects were generally referred</p><p>to the pediatric endocrine clinic atThomas Jefferson University or wereself-referred. All were diagnosed withXYY or XXY (KS) by karyotype. Thestudy was approved by the HumanStudies Committee at Thomas JeffersonUniversity and UT Southwestern Medi-cal School. All subjects and their parentsgave informed consent and assent. Theclinical evaluation was performed atThomas Jefferson University and thekaryotyping was performed by the clini-cal cytogenetics laboratory at UTSouthwestern Medical School.</p><p>Test Procedures</p><p>Anthropometric measurementsThe clinical assessment included</p><p>conversion of measurements to SDscores using age- and gender-specificnorms of height (by stadiometer),weight [Hamill et al., 1979], and head</p><p>circumference [Hall, 1995]. Pubertaldevelopment was assessed according tostandard methods [Marshall and Tanner,1993]. Testicular size was measuredusing standard Prader orchidometerbeads [Hall, 1995].</p><p>Cognitive and motor evaluationSubjects were individually admin-</p><p>istered a battery of neuropsychologicaltests specifically designed to assess mem-ory, attention, executive function, vis-ual-spatial abilities, visual-motor skills,and language. The evaluation wasadministered by trained and experiencedpsychometricians under the supervisionof a licensed neuropsychologist. Rawscores were converted to standard scores(mean of 100, standard deviation of 15),based on the test-specific norms or ourown population of age-matched controlchildren.</p><p>We chose the Differential AbilityScales (DAS) [Elliott, 1983], to assessgeneral cognitive ability in childrenbetween age 4 years and 17 years, 11months. The DAS cognitive batteryincludes three composite scores: theverbal cluster (VC) score measuressemantic knowledge, verbal expression,and verbal comprehension, the spatialcluster (SC) score measures nonverbalspatial cognitive ability, and the nonver-bal reasoning cluster score measuresnonverbal aspects of fluid reasoning.Performance on subtests was combinedto yield a general conceptual ability(GCA) score, which is a general indexof an individuals ability to performcomplex mental processing involvingconceptualization and manipulation ofinformation.</p><p>Academic achievement wasassessed with the Reading, Spelling, andArithmetic subtests from the WideRange Achievement Test-3 (WRAT3)[Wilkerson, 1993]. The tasks used toassess attention/executive functionincluded Conners Continuous Per-formance Test (CPT-II) [Connors,1995], Connors Kiddie CPT (age 45years) [Connors, 1995], and the Delis-Kaplin Executive Function System (D-KEFS) Color-Word Interference Test[Delis, 2001]. These tasks measure proc-essing speed, sustained attention,response inhibition, and inhibitory con-trol. We examined aspects of verbalmemory using the Childrens MemoryScale (CMS) [Cohen, 1997] for StoryRecall and Digit Span [Cohen, 1997],and California Verbal Learning Test-Childrens Version (CVLT-C) [Delis,1994]. We assessed visual-motor andvisual memory with the Rey-Osterrieth</p><p>Complex Figure-Copy and Organiza-tion scores [Waber and Holmes, 1985]and the Beery Test of Visual MotorIntegration [Beery, 1997].</p><p>Language ability was evaluated atthe level of single words with the Ex-pressive One-Word Vocabulary Test(EOWPVT) [Williams, 1997] and theReceptive One-Word Vocabulary Test(ROWPVT) [Brownell, 2000]. Phono-logical processing was assessed with theComprehensive Test of PhonologicalProcessing (CTOPP) [Rashotte, 1999],and fluency with the D-KEFS subtest,which tapped both phonemic andsemantic fluency [Korkman, 1998]. Weevaluated more complex levels of lan-guage processing with the Test of Lan-guage Competence-Expanded Edition[Wiig, 1989].</p><p>The tasks used to assess fine andgross motor skills included the LafayettePegboard [Klove, 1963], the Bruininks-Oseretsky Test of Motor Proficiency(BOT) [Bruininks, 1978] and Physicaland Neurological Evaluation for SoftSigns (PANESS) [Close, 1976].</p><p>Socioeconomic StatusSocioeconomic status (SES) esti-</p><p>mate was calculated for children usingthe Hollingshead 2-Factor Index ofSocial Status based on education andoccupation of parents [Hollingshead andRedlich, 1958].</p><p>Handedness and LateralizationThe Crovitz Laterality battery was</p><p>administered to document hand prefer-ences [Crovitz and Ziner, 1962]. Chil-dren were asked to demonstrate whichhand they use for eight activities (righthand 5 RH and left hand 5 LH). Alaterality quotient was calculated usingthe following formula: [(RH 2 LH)/(RH LH) 3 100]. Right-handednesswas defined as a score of 100% (per-formance of eight of eight tasks withthe RH). Non right-hand dominancewas characterized as a score </p></li><li><p>StatisticsResults are presented as the mean</p><p>6 SD of standard scores. Statisticalcomparisons performed includedANOVA comparing the three karyo-type groups for demographic, auxologicand cognitive measurements and ananalysis of covariance (ANCOVA) com-paring the three karotype groups,adjusting for pubic hair Tanner stage,head circumference SDS, testicular vol-ume SDS, lateralization index, andGCA from the DAS. The six pairwisecomparisons among the three karyotypegroups were performed using Scheffestest. P-values less than 0.05 were con-sidered to be statistically significant.Nominal P-values are reported andwere not adjusted for multiple compari-sons.</p><p>RESULTS</p><p>Genetic ResultsKaryotype results were as follows:</p><p>21 boys with XYY and 93 boys with47,XXY; no Mosaicism was detected.</p><p>DemographicsOur study included 21 boys with</p><p>XYY, age 4.314.4, 93 boys with KS,age 4.117.8 years, and 36 control boys,age 4.513.8 (Table 1). The groupswere well matched for age, SES, race,handedness, and for pubic hair Tannerstage development. Most participantswere Caucasian. The boys with XYYand XXY were, on average, taller thanthe control boys but had similar weightSDS. Testicular volume SDS was thelowest in the boys with KS (P 1SD) in 11/22 boys with XYY (age4.313.6 years), reflecting early pubertaldevelopment in some cases.</p><p>Diagnosis of XYY was made ininfancy in eight boys [six for prenatalscreening (advanced maternal age), onefor hypotonia, and one for other rea-sons], in childhood (age 212 years) in12 (two for language issues, three forbehavior issues, and seven for other</p><p>developmental reasons), and after age12 years in one boy (behavioral reasons).Of the 21 boys, 20 had received speechand/or reading therapy and 18 receivedoccupational and/or physical therapy bythe time of the evaluation. No boys withXYY were diagnosed with testicular fail-ure or had received testosterone treat-ment by the time of the evaluation.</p><p>Diagnosis of KS was made ininfancy in 61 boys [51 for prenatalscreening (advanced maternal age), onefor hypotonia, one for small genitalia,and eight for other reasons], in childhood(212 years) in 24 boys (seven for lan-guage issues, five for behavior issues, onefor tall stature, and 11 for other reasons),and after age 12 in 8 (two for languageissues and six for puberty issues). Of the93 boys, 83 had received special educa-tion services in school by the time of theevaluation: 75 received speech and/orreading therapy and 61 received occupa-tional and/or physical therapy. Twenty-one boys with KS had received testoster-one treatment by the time of the evalua-tion (duration of 0.12.2 years).</p><p>Table 1. Demographics and Auxologic Measurements (Mean 6 SD)</p><p>n XXY n XYY n Controls P a</p><p>Age 93 9.4 6 3.4 21 9.4 6 2.8 36 9.5 6 2.6 0.99SES 93 51 6 10 21 52 6 10 36 54 6 8 0.32Height SDS 93 0.9 6 1.2 21 0.9 6 1.1 36 0.1 6 1.0 0.001Weight SDS 93 0.6 6 1.2 21 0.6 6 1.2 36 0.4 6 1.2 0.65Head Circ SDS 93 0.4 6 1.6 21 1.2 6 2.3 36 0.9 6 1.4 0.08Tanner stage-pubic hair 93 1.6 6 1.1 20 1.3 6 0.9 34 1.3 6 0.8 0.18Testicular volume SDS (mean of 2) 92 21.3 6 1.5 20 2.7 6 4.1 34 1.0 6 2.6 0.0001Testosterone 87 55 6 111 21 47 6 92 Not done 0.66Race (%Caucasian) 93 85% 21 95% 36 78% 0.16</p><p>aANOVA, comparison of three groups.</p><p>Table 2. General Cognitive Ability and Achievement Results (Mean Standard Score 6 SD)</p><p>n XXY n XYY n Controls P a</p><p>DAS IndexVerbal cluster (VC) SS 92 89 6 14* 17 88 6 18** 35 113 6 14 </p></li><li><p>Lateralization and HandednessBased on the Crovitz Handedness</p><p>Questionnaire, 63% (12/19) of theXYY group, 73% (68/93) of the KSgroup, and 72% (26/36) controls werecompletely right-handed (lateralityindex of 100%). The occurrence of nonright-handedness did not differ amongthe groups.</p><p>Cognitive ResultsResults from the DAS as well as</p><p>measures of language and academicachievement are presented in Table 2.GCA, the DAS indices and subtestsrevealed, on average, higher scores (by&gt;1 SD) in the control group, comparedto the XYY and KS groups (P ) [KS]. In thisstudy, scores on the DAS GCA suggestthat general cognitive ability is mildlydiminished in both groups, comparedto controls. This general cognitive pro-file reflects not just decreased verbal,but also decreased nonverbal abilities inboth groups and diminished spatial abil-ity in the KS group. Importantly, afteradjusting for GCA differences betweenthe groups, the DAS VC in the XYYgroup still differed significantly from thecontrol group.</p><p>Language and Achieve...</p></li></ul>