9
AN EXTRA X OR YCHROMOSOME:CONTRASTING THE COGNITIVE AND MOTOR PHENOTYPES IN CHILDHOOD IN BOYS WITH 47,XYY SYNDROME OR 47,XXY KLINEFELTER SYNDROME Judith L. Ross, 1,2 * Martha P.D. Zeger, 1,2 Harvey Kushner, 3 Andrew R. Zinn, 4 and David P. Roeltgen 5 1 Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania 2 Department of Pediatrics, duPont Hospital for Children, Wilmington, Delaware 3 Biomedical Computer Research Institute, Philadelphia, Pennsylvania 4 Department of Internal Medicine, McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 5 Department of Neurology, Georgetown University, Washington, DC Objective: The goal of this study was to contrast the cognitive phe- notypes in boys with 47,XYY (XYY) karyotype and boys with 47,XXY karyotype [Klinefelter syndrome, (KS)], who share an extra copy of the X-Y pseudoautosomal region but differ in their dosage of strictly sex-linked genes. 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 93 boys 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 the controls on tests of general cognitive ability, achievement, language, verbal memory, some aspects of attention, and executive function, and motor function. The boys with XYY on average had more severe and per- vasive language impairment, at both simple and complex levels, and the boys with KS on average had greater motor impairment in gross motor function and coordination, especially in running speed and agility. Conclu- sions: The results from these large XYY and KS cohorts have important neurocognitive and educational implications. From the neurocognitive standpoint, the presenting findings afford an opportunity to gain insights into brain development in boys with XYY and those with KS. From the educational standpoint, it is critical that boys with XYY or KS receive appropriate educational interventions that target their specific learning challenges. 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. Key Words: XXY; Klinefelter syndrome; XYY; sex chromosome T wo sex chromosome aneuploidy disorders, 47,XYY and 47,XXY (Klinfelter syndrome, KS), affect only males. Both disorders are relatively common and are underdiagnosed. In addition, there may be confusion about what distinguishes one from the other. The XYY syndrome affects one in 1,000 males and is characterized by physical 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; Kent et al., 2008]. Testicular function, testosterone levels, and fertil- ity are usually normal [Rudd et al., 1968; Price and van der Molen, 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 chromosome disorder [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 and characteristic cognitive attributes, but, in contrast to XYY, also includes childhood onset testicular failure. The cognitive phenotype in boys with XYY typically includes normal to mildly diminished general intelligence as measured by full-scale intelligence quotient (IQ) [Bender et 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 development and to require speech therapy [Daly, 1969; Valentine, 1979; Ratcliffe, 1982; Bender et al., 1984; Robinson, 1985; Geerts et al., 2003]. Often they have difficulty mastering school 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: [email protected] Received 27 July 2009; Accepted 4 September 2009 Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ddrr.85 DEVELOPMENTAL DISABILITIES RESEARCH REVIEWS 15: 309 – 317 (2009) ' 2009 Wiley -Liss, Inc.

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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Page 1: 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

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

Judith L. Ross,1,2* Martha P.D. Zeger,1,2 Harvey Kushner,3 Andrew R. Zinn,4

and David P. Roeltgen51Department of Pediatrics, Thomas Jefferson University, Philadelphia, Pennsylvania2Department of Pediatrics, duPont Hospital for Children, Wilmington, Delaware

3Biomedical Computer Research Institute, Philadelphia, Pennsylvania4Department of Internal Medicine, McDermott Center for Human Growth and Development,

University of Texas Southwestern Medical Center, Dallas, Texas5Department of Neurology, Georgetown University, Washington, DC

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 4–17 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;15:309–317.

Key Words: XXY; Klinefelter syndrome; XYY; sex chromosome

Two sex chromosome aneuploidy disorders, 47,XYYand 47,XXY (Klinfelter syndrome, KS), affect onlymales. Both disorders are relatively common and are

underdiagnosed. 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

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.

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

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: [email protected] 27 July 2009; Accepted 4 September 2009Published online in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ddrr.85

DEVELOPMENTAL DISABILITIESRESEARCH REVIEWS 15: 309 – 317 (2009)

' 2009Wiley -Liss, Inc.

Page 2: 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

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].

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].

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.

METHODS

SubjectsSubjects were generally referred

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.

Test Procedures

Anthropometric measurementsThe clinical assessment included

conversion of measurements to SDscores using age- and gender-specificnorms of height (by stadiometer),weight [Hamill et al., 1979], and head

circumference [Hall, 1995]. Pubertaldevelopment was assessed according tostandard methods [Marshall and Tanner,1993]. Testicular size was measuredusing standard Prader orchidometerbeads [Hall, 1995].

Cognitive and motor evaluationSubjects were individually admin-

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.

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 individual’s ability to performcomplex mental processing involvingconceptualization and manipulation ofinformation.

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 4–5years) [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 Children’s MemoryScale (CMS) [Cohen, 1997] for StoryRecall and Digit Span [Cohen, 1997],and California Verbal Learning Test-Children’s Version (CVLT-C) [Delis,1994]. We assessed visual-motor andvisual memory with the Rey-Osterrieth

Complex Figure-Copy and Organiza-tion scores [Waber and Holmes, 1985]and the Beery Test of Visual MotorIntegration [Beery, 1997].

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].

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].

Socioeconomic StatusSocioeconomic status (SES) esti-

mate was calculated for children usingthe Hollingshead 2-Factor Index ofSocial Status based on education andoccupation of parents [Hollingshead andRedlich, 1958].

Handedness and LateralizationThe Crovitz Laterality battery was

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 þ 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 <100%[Spreen, 1991; Isaacs et al., 2006].

Testosterone MeasurementTotal testosterone was measured,

generally in the morning, using a com-mercial assay performed by Esoterix En-docrinology (Calabasas Hills, CA).

Genetic Testing

KaryotypeA postnatal G-banded peripheral

blood karyotype was obtained for allsubjects, but not from the male con-trols.

310 Dev Disabil Res Rev � Cognition in Boys with XYY or Klinefelter Syndrome � Ross et al.

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StatisticsResults are presented as the mean

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 Scheffe’stest. 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.

RESULTS

Genetic ResultsKaryotype results were as follows:

21 boys with XYY and 93 boys with47,XXY; no Mosaicism was detected.

DemographicsOur study included 21 boys with

XYY, age 4.3–14.4, 93 boys with KS,age 4.1–17.8 years, and 36 control boys,age 4.5–13.8 (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 <0.0001), consistent with testicular failurein that group and was increased in theXYY boys, compared to controls. Tes-ticular size was increased for age (>1SD) in 11/22 boys with XYY (age4.3–13.6 years), reflecting early pubertaldevelopment in some cases.

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 2–12 years) in12 (two for language issues, three forbehavior issues, and seven for other

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.

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(2–12 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 0.1–2.2 years).

Table 1. Demographics and Auxologic Measurements (Mean 6 SD)

n XXY n XYY n Controls P a

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

aANOVA, comparison of three groups.

Table 2. General Cognitive Ability and Achievement Results (Mean Standard Score 6 SD)

n XXY n XYY n Controls P a

DAS IndexVerbal cluster (VC) SS 92 89 6 14* 17 88 6 18** 35 113 6 14 <0.0001Nonverbal cluster (NVC) SS 92 92 6 15* 18 93 6 21** 36 111 6 16 <0.0001Spatial cluster (SC) SS 75 91 6 15* 16 96 6 16 30 107 6 16 <0.0001General conceptual ability (GCA) SS 90 90 6 14* 17 93 6 18** 35 112 6 15 <0.0001

DAS SubtestsWord definitions SS 76 89 6 14* 17 86 6 15** 30 111 6 14 <0.0001Similarities SS 77 90 6 15* 17 91 6 20** 29 116 6 15 <0.0001Matrices SS 76 93 6 15* 18 92 6 24** 30 110 6 13 <0.0001Sequential and quantitative reasoning SS 77 92 6 15* 17 94 6 20** 30 114 6 18 <0.0001Recall of design SS 75 90 6 16* 16 95 6 20 30 103 6 17 <0.002Pattern construction SS 92 96 6 15* 19 95 6 15** 36 110 6 13 <0.0001

WRAT-3 SubtestReading SS 87 95 6 16* 16 86 6 18** 34 112 6 13 <0.0001Spelling SS 87 90 6 14* 14 91 6 13** 33 107 6 16 <0.0001Arithmetic SS 87 90 6 17* 17 84 6 17** 34 111 6 16 <0.0001

aANOVA, comparison of three groups.*P < 0.05, XXY versus controls, post hoc; **P < 0.05 XYY versus controls, post hoc; ***P < 0.05, XYY versus XXY, post hoc.

Dev Disabil Res Rev � Cognition in Boys with XYY or Klinefelter Syndrome � Ross et al. 311

Page 4: 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

Lateralization and HandednessBased on the Crovitz Handedness

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.

Cognitive ResultsResults from the DAS as well as

measures of language and academicachievement are presented in Table 2.GCA, the DAS indices and subtestsrevealed, on average, higher scores (by>1 SD) in the control group, comparedto the XYY and KS groups (P <0.0001). Performance was similar in theXYY and KS groups for the VC (WordDefinitions and Similarities subtests) andthe Nonverbal cluster (Matrices and Se-quential and Quantitative reasoningsubtests) and was lower than controls(P < 0.0001). For the SC (Recall ofdesign and Pattern construction subt-ests), the KS but not the XYY groupscored lower than the control group.After adjusting for differences in Tannerstage, testicular volume SDS, head cir-cumference SDS, and DAS GCA in theANCOVA, only the XYY group per-formed significantly less well than thecontrols for the VC.

Academic AchievementResults from the WRAT-3rd edi-

tion for reading, spelling, and arithmeticsubtests are shown in Table 2. Meanscores were lower in the XYY and KSgroups versus controls (P < 0.0001).After ANCOVA adjustments for differ-ences in Tanner stage, testicular volumeSDS, head circumference SDS, andDAS GCA, the XYY group but not theKS group performed significantly lesswell than the controls for the WRAT-3Reading test.

LanguageResults from tests of language are

shown in Table 3. One-word receptivevocabulary expression and retrieval, asassessed by ROWPTCT and EOWPVTperformance, was significantly lower inthe XYY and KS groups, compared tothe control group (P < 0.0001). TheXYY group had lower scores than theKS group on the ROWPVT. Rapidnaming from CTOPP Rapid Namingcomposite yielded lower levels of per-formance in the XYY and KS groups,compared to controls. In contrast, per-formance for the Rapid AlternatingNaming composite was similar for thethree groups. Phonetic but not semanticfluency was lower in the XYY and KSgroups, compared to the controls. AfterANCOVA adjustment for differences inTanner stage, testicular volume SDS,

head circumference SDS, and DASGCA, the XYY group performed sig-nificantly less well than both the KSand the control groups for theROWPVT, but not the EOWPVT.There were no differences in theCTOPP for the three groups.

On tests of higher-level language(TLC), the XYY and KS groups per-formed more poorly than controls, spe-cifically in the areas of semantics, syntax,pragmatics and also with expressing andinterpreting intent (P < 0.0001, Table3). The lowest performance in both theXYY and KS groups was in the abilityto formulate propositions in grammati-cally complete sentences using keywords from the context of a givensituation (Oral Expression subtest) andthe ability to recognize and in-terpret alternative meanings of lexicaland structural ambiguities (AmbiguousSentences subtest). After ANCOVAadjustment for differences in Tannerstage, Testicular volume SDS, head cir-cumference SDS, and DAS GCA, theXYY scores were significantly less thancontrol scores for Ambiguous Sentences,Expressing Intent, Interpreting Intentand the Composite.

Verbal MemoryThe results from the tests of

verbal memory are shown in Table 4.Performance for immediate and delayed

Table 3. Language Results (Mean Standard Score 6 SD)

n XXY n XYY n Controls Pa

EOWPVT SS 92 100 6 14*,*** 17 96 6 16*** 36 113 6 13 <0.0001ROWPVT SS 92 101 6 13* 18 90 6 15*** 36 116 6 13 <0.0001CTOPP Composite SSRapid naming composite SS 84 86 6 16* 13 82 6 17*** 33 99 6 16 <0.0002Alternate rapid naming composite SS 72 77 6 18 12 84 6 24 29 86 6 19 0.08

CTOPP SubtestRapid digit naming SS 70 89 6 14* 11 85 6 15*** 28 100 6 16 0.002Rapid letter naming SS 70 88 6 14* 11 87 6 14 28 98 6 13 0.004Rapid color naming SS 86 85 6 15 14 88 6 17 34 90 6 15 0.18Rapid object naming SS 86 79 6 16* 14 84 6 22 34 91 6 16 0.004

D-KEFSPhonetic fluency SS 59 94 6 17* 9 93 6 13*** 25 110 6 18 0.0008Semantic fluency SS 51 101 6 18 9 96 6 25 25 110 6 17 0.09

TLC CompositeExpressing intent SS 78 79 6 12* 14 80 6 14*** 29 101 6 17 <0.0001Interpreting intent SS 78 84 6 13* 13 84 6 19*** 28 103 6 15 <0.0001Total Composite Score SS 77 79 6 12* 14 80 6 17*** 28 102 6 16 <0.0001

TLC SubtestAmbiguous sentences SS 81 83 6 12* 14 83 6 15*** 29 102 6 16 <0.0001Listening comprehension SS 80 90 6 13* 13 90 6 20*** 27 104 6 12 <0.0001Oral expression SS 78 82 6 12* 14 83 6 12*** 29 99 6 17 <0.0001Figurative language SS 78 84 6 13* 14 86 6 15*** 29 103 6 15 <0.0001

aANOVA, comparison of three groups.*P < 0.05, XXY versus controls, post hoc; ***P < 0.05, XYY versus controls, post hoc; ***P < 0.05 XYY versus XXY, post hoc.

312 Dev Disabil Res Rev � Cognition in Boys with XYY or Klinefelter Syndrome � Ross et al.

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memory for short story content (CMSStories subtest) and for Digit Span, for-ward and reverse sequence (CMS Num-bers, and word list learning), was lowerin the XYY and KS groups, comparedto the control group. After ANCOVAadjustment for differences in Tannerstage, testicular volume SDS, head cir-cumference SDS, and DAS GCA, CMSperformance was similar in the threegroups, and Performance on the CVLT-II list recall was lowest in the XYYgroup for Trial 5 recall and for thelearning slope, compared to both theKS and the control groups.

Attention and Executive FunctionOn the Conners’ CPT-II, per-

formance was similar in the threegroups for the tendency to produce anincorrect response as measured byCommission and Perseverative errors(Table 4). The KS but not the XYYgroup had significantly more Omissionerrors, compared to controls. Reactiontime and Variability were increased forboth the XYY and KS groups, com-pared to the controls (P < 0.001). On

tests of executive function (Color-WordInterference Test), scores for inhibitionand switching were lowest in the XYYgroup compared to the KS and thecontrol groups. The three groups didnot differ significantly for Color inter-pretation but did for reading the Words,with both groups performing less wellthan the controls (P 5 0.0003). AfterANCOVA adjustment for differences inTanner stage, testicular volume SDS,head circumference SDS, and DASGCA, performance for Switching waslower in the XYY group only, com-pared to the control group.

Visual-Motor Functionand Visual Memory

Performance on these tests of vis-ual memory and spatial ability showedthe lowest performance on Rey Copyand Immediate and Delayed recall inthe KS group (Table 4). In contrast, or-ganization of the Rey figure copy wassignificantly decreased in both the XYYand KS groups and was lowest in theXYY group, compared to the controlgroup. After ANCOVA adjustment for

differences in Tanner stage, testicularvolume SDS, head circumference SDS,and DAS GCA, performance was simi-lar in the three groups.

Motor SkillsOn the BOT, performance on the

fine motor, gross motor, and the batterycomposites, fine motor integration,bilateral coordination, upper limb speed,visual motor control, and responsespeed was decreased in the KS and theXYY groups (Table 5), compared tothe controls (P < 0.006), indicatingmotor skills deficits. Performancetended to be lowest in the KS groupfor all subtests except Upper LimbCoordination and Visual-Motor Con-trol. Overall, the worst performancewas observed in the KS group on theRunning Speed and Agility subtest,which measures running shuttle speed.Performance on Upper Limb Speed andDexterity and the Strength subtests wasslightly lower in the XYY compared tothe KS group. After ANCOVA adjust-ment for differences in Tanner stage,testicular volume SDS, head circumfer-

Table 4. Verbal Memory, Attention, Visuomotor, and Visual Memory Results(Mean Standard Score 6 SD)

n XXY n XYY n Controls Pa

Verbal memoryCMS StoriesImmediate recall SS 83 90 6 14* 14 87 6 17** 33 103 6 18 0.0002Delayed recall SS 82 90 6 15* 14 87 6 21** 33 102 6 18 0.002Delayed recognition SS 80 93 6 18* 14 89 6 15** 33 104 6 13 0.0007

Digit SpanDigit span forward SS 89 91 6 15* 15 86 6 17** 34 103 6 15 0.0002Digit span backward SS 89 93 6 15* 15 92 6 14 34 102 6 20 0.02

CVLT-IITrial 1-5 list A recall SS 85 89 6 18* 14 82 6 20** 33 103 6 15 <0.0001Trial 5 list A recall SS 85 90 6 17* 14 84 6 21** 33 103 6 13 <0.0001Learning slope SS 86 93 6 16 14 90 6 18 33 100 6 15 0.04

Attention/executive funcionConners CPTOmissions (more errors 5 lower SS) 83 81 6 26* 16 83 6 27 30 99 6 16 0.004Comissions (more errors 5 lower SS) 83 97 6 15 16 99 6 16 30 92 6 16 0.18Reaction time (increased 5 lower SS) 83 87 6 19* 15 85 6 22** 30 105 6 16 <0.0001Variability (increased 5 lower SS) 83 86 6 14* 15 85 6 14** 29 98 6 16 0.001Perseverative errors SS 83 83 6 26 15 85 6 29 29 86 6 29 0.89

DKEFS- Color Word Inference TestColor SS 65 91 6 20 10 87 6 21 26 100 6 18 0.08Word SS 65 89 6 18 10 86 6 19 26 105 6 14 0.0003Inhibition SS 65 92 6 20 10 85 6 17** 26 101 6 12 0.02Switch SS 62 92 6 20 10 78 6 14** 26 102 6 14 0.001

Visuomotor and visual memoryRey-Osterreith figureCopy organization SS 83 89 6 14* 13 85 6 18** 34 100 6 17 0.007Copy accuracy SS 87 75 6 25* 13 85 6 26 32 95 6 17 0.0002Immediate recall SS 82 93 6 14 13 101 6 17 34 99 6 13 0.06Delay recall SS 82 92 6 14 13 100 6 19 34 97 6 13 0.08

Beery test of VMI SS 84 88 6 13* 16 87 6 19 36 97 6 14 0.004

aANOVA, comparison of three groups.*P < 0.05, XXY versus controls, post hoc; **P < 0.05 XYY versus controls, post hoc; ***P < 0.05, XYY versus XXY, post hoc.

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ence SDS, and DAS GCA, the KS butnot the XYY group differed from thecontrol group for Running Speed,Bilateral Coordination, and Strengthsubtests.

For selected tests from the PAN-ESS and the Lafayette Pegboard Test(measure of motor dexterity and coor-dination), performance was similar inthe XYY and the KS groups and wasgenerally slower than the control group.The KS group, on average, was slightlyslower than the XYY group for thePANESS but not the Lafayette Peg-board. After ANCOVA adjustment,there were no major differences in thethree groups for these tasks.

DISCUSSIONThe goal of this study was to

compare and contrast the neuropsycho-logical profile and motor function inboys with the sex chromosome disor-ders, 47,XYY and 47,XXY (KS) versuscontrols. All three populations weresimilar in age (mean age around 9years), SES, handedness, and pubic hairstage. The primary physical phenotypicdifferences were that boys with KS hadbelow average testicular size, whilethose with XYY had above average tes-ticular size. Both aneuploid groups weretaller than controls. Cognitive functionevaluation revealed considerable overlapwith deficits that likely relate to thepresence of an additional sex chromo-some. Both groups performed less well

than controls on tests of general cogni-tive ability, achievement, language,verbal memory, some aspects of atten-tion and executive function, and motorfunction. The XYY boys, on average,had more severe and pervasive languageimpairment, at both simple and com-plex levels. The KS boys, on average,had greater motor impairment in grossmotor function and coordination, espe-cially in running speed and agility,which may be related to testicularfailure.

General CognitionPrevious studies of boys with

XYY and KS concluded that generalintelligence is relatively preserved, butverbal ability is decreased in bothgroups [Welch, 1985; Ratcliffe, 1999;Warwick et al., 1999] [XYY] and [Rat-cliffe et al., 1986; Robinson et al.,1986; Graham et al., 1988; Porter et al.,1988; Walzer et al., 1990; Rovet et al.,1996; Ross et al., 2008] >) [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.

Language and AchievementMost previous studies have

described some features of language thatare impaired in both groups. Delayedspeech, impaired word retrieval, speedof linguistic processing, expressive, andreceptive capabilities and processing ofnarration have been described in boththe XYY and KS groups [Christensenand Nielsen, 1973; Ratcliffe et al.,1982; Walzer, 1985; Welch, 1985;Leonard and Sparrow, 1986]. Althoughthe pattern of impairment is similar inour results, the severity appears to dif-fer. The XYY group appears to have amore severe and pervasive languageimpairment than the KS group that ispresent at varying levels of complexityof oral and written language. We notedgreater impairment in the XYY versusthe KS group particularly for higher-level metalinguistic abilities, as demon-strated by significant difficulty in under-standing figurative language, interpret-ing ambiguities in language, as well asin oral expression and verbal memory.

This language impairment appearsto have important academic implica-tions. The boys with XYY, more thanKS, produced lower achievement inReading and Spelling, compared to thecontrol group. Our findings are similarto previous studies in XYY thatreported school difficulties out of pro-portion to what would be expected onthe basis of IQ. Boys with XYY andboys with KS commonly have difficulty

Table 5. Motor Function Results (Mean Standard Score 6 SD)

n XXY n XYY n Controls Pa

BOT CompositeFine motor composite SS 73 81 6 15* 8 81 6 22** 21 99 6 18 <0.0001Gross motor composite SS 73 80 6 17* 9 82 6 16** 20 106 6 19 <0.0001Battery composite SS 88 80 6 15* 14 81 6 18** 23 103 6 17 <0.0001

BOT SubtestRunning speed and agility SS 92 80 6 18* 18 88 6 15 36 100 6 18 <0.0001Bilateral coordination SS 92 89 6 13* 19 89 6 16** 35 107 6 12 <0.0001

Strength SS 92 88 6 18* 19 89 6 16** 35 106 6 17 <0.0001Upper limb coordination SS 92 88 6 16* 19 82 6 17** 35 99 6 15 0.0004Visual-motor control SS 92 87 6 18* 18 82 6 16** 36 96 6 16 0.006Upper limb speed SS 92 82 6 14* 19 80 6 15** 36 97 6 16 <0.0001

PanessHand alternating-dominant SS 71 81 6 28 14 82 6 19 30 91 6 23 0.20Hand alternating non-dominant SS 71 86 6 21* 14 85 6 19 30 99 6 20 0.009Hand short dominant SS 72 98 6 18* 16 96 6 21** 32 112 6 12 0.0007Hand short non-dominant SS 72 95 6 20* 16 90 6 26** 32 111 6 12 0.0002Foot dominant SS 72 100 6 17* 16 102 6 13 32 113 6 8 0.0009Foot non-dominant SS 72 95 6 18* 16 91 6 23** 32 110 6 12 0.0002

Lafayette PegboardLafayette Pegboard dominant SS 80 76 6 30*,*** 17 53 6 37** 33 96 6 16 <0.0001Lafayette Pegboard non-dominant SS 80 82 6 28 17 64 6 37** 33 96 6 22 0.0008

aANOVA, comparison of three groups.*P < 0.05, XXY versus controls, post hoc; **P < 0.05 XYY versus controls, post hoc; ***P < 0.05, XYY versus XXY, post hoc.

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mastering school curricula and requirespecial education help in reading andwriting [Bender et al., 1984; Netley,1986; Ross et al., 2008].

Attention and Executive FunctionThis study shows that both the

XYY and KS groups had a similardegree of impairment relative to con-trols on attention and executive func-tion tasks, although cognitive flexibility,as exemplified by inhibition and switch-ing, was more impaired in the XYYthan the KS group. Both groups havebeen reported to have increased dis-tractibility [Walzer et al., 1990], and anincreased risk for hyperactivity andattention problems [Money et al., 1974;Theilgaard, 1984; Welch, 1985; Geertset al., 2003] [Ross et al., 2008]. Execu-tive dysfunction has been reported inadults with KS [Geschwind, 2000].

Visual Spatial FunctionPerformance results for visual-spa-

tial and visual-motor function were sig-nificantly lower in the KS but not theXYY group, compared to the controls.This dissociation may reflect testoster-one deficiency in the KS group only.Higher testosterone levels in males maybe related to increased male perform-ance in visual-spatial tasks involvingmental rotation, spatial perception, spa-tial visualization [Arceneaux et al.,1996].

Motor FunctionSimilar to previous observations,

both the XYY and the KS groups hadimpairment of motor function [Salben-blatt et al., 1987; Bender et al., 1993;Ross et al., 2008]. However, the KSgroup appeared to have more pervasivemotor impairment than the XYYgroup. Motor function was examinedusing fine motor and gross motor tasksas well as measures of strength, speedand agility, and coordination. On por-tions of the PANESS, including repeti-tive thumb finger tapping and foottapping, the XYY and KS groups per-formed at or close to levels expected forage, similar to previous results [Salben-blatt et al., 1987; Bender et al., 1993].However, as the tasks became morecomplex (tapping four sequential fingersto thumb), both groups did not per-form as well as controls. The morecomplex tasks require greater utilizationof coordination and attention, whichare impaired in both groups. Bothgroups also performed less well thanexpected for their age on the Strengthand the Upper limb speed and dexterity

subtests. These motor difficulties are notjust of academic interest but have im-portance for these boys because of psy-chosocial implications and the likelyimpaired athletic ability that accompa-nies these particular deficits. Perform-ance by the KS group was lower thanthe XYY group on the test of RunningSpeed and Agility from the BOT,which indexes an array of motor andcognitive skills. This may be due toandrogen deficiency having a negativeimpact in only the KS group and notthe XYY group.

SUMMARY AND CONCLUSIONSIn general, the cognitive pheno-

type in boys with XYY and KS overlapwith some important differences. Bothhave mild generalized cognitive impair-ment, with impaired language verbalmemory, attention, visual-motor, and

motor function. The similarity of cog-nitive findings in these two genetic dis-orders of males may be related to over-lapping gene dosage abnormalities. TheX and Y chromosomes share identicalsequences in the pseudoautosomalregion (PAR1), a 2.6 Mb interval at thetips of Xp and Yp, and genes areequally expressed from the X or YPAR1 [Rappold, 1993; Vaknin et al.,2008]. Specifically, tall stature in both ofthese populations is thought to be dueto increased expression from threeinstead of two copies of the heightdetermining SHOX gene [Rao et al.,1997; Aksglaede et al., 2008].

The differences between cognitivephenotypes in the KS and XYY groupsmay be related to either chromosomalor hormonal causes. The results showthat XYY boys have a more profoundlanguage impairment and the KS boyshave a more profound motor impair-ment. We hypothesize that the moresevere language-based cognitive pheno-type in XYY versus KS is likely to be

genetically determined on the basis ofabnormal dosage of specific Y chromo-some genes, but not abnormal levels oftestosterone because XYY is not associ-ated with testicular failure. The parentalorigin of the extra chromosome maydifferentially impact KS and XYYbecause in KS, the supernumerary Xchromosome may be maternal or pater-nal, whereas in males with XYY, theextra Y chromosome always originatesfrom the father. Hormonal differences(normal testosterone in XYY versus tes-tosterone deficiency in KS) mayaccount for differences in the cognitivephenotype in boys with XYY versusXXY. The testosterone deficiency inKS and the known relationship betweenmuscle function and testosterone mayalso account for some of the motorimpairment in this group.

Another potential factor relatedto the observed difference in the XYYand KS groups relates to their ascertain-ment. In our cohort, most of the boyswith XYY were diagnosed postnatallyon the basis of behavior/developmentalissues, consistent with the observationthat diagnosis of XYY is often delayed[Fryns et al., 1995; Abramsky andChapple, 1997; Geerts et al., 2003]. Incontrast, most of the KS boys in ourcohort were diagnosed prenatally on thebasis of advanced maternal age. Thus,there may be a bias in our cohorttowards greater severity among theXYY boys. However, boys with XYYascertained from screening studies ofmale newborns for sex chromosomeabnormalities also have characteristicspeech, language-based, motor, andbehavior findings [Bender et al., 1984;Salbenblatt et al., 1987; Bender et al.,1993], suggesting that their findings areassociated with the karyotype, inde-pendent of ascertainment.

The results from these large XYYand KS cohorts have important neuro-cognitive and educational implications.From the neurocognitive standpoint,the difficulties present represent an op-portunity to gain insights into brain de-velopment and the interactions of cog-nitive systems in boys with XYY or KS.From the educational standpoint, thedifficulty in complex language process-ing and impaired attention as well asmotor function identified in the XYYand KS populations may be missed.This can be a challenge to educators. Itis critical that boys with XYY and boyswith KS are provided with appropriateeducational interventions that targettheir learning challenges in school.These findings would also be an impor-

The XYY group appearsto have a more severe andpervasive language

impairment than the KSgroup that is present atvarying levels of

complexity of oral andwritten language.

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tant component of counseling cliniciansand families about these disorders. n

ACKNOWLEDGMENTSThe authors thank the families

who participated in these studies.

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