Behavior and Emotional Disturbance inPrader-Willi Syndrome

Stewart L. Einfeld,1* Arabella Smith,2 Seeta Durvasula,3 Tony Florio,1 and Bruce J. Tonge4

1School of Psychiatry, University of New South Wales, Kensington, Australia2New Children’s Hospital, Westmead, New South Wales, Australia3Centre for Developmental Disability Studies, Ryde, New South Wales, Australia4Centre for Developmental Psychiatry, Monash University, Clayton, Victoria, Australia

To determine if persons with the Prader-Willi syndrome (PWS) have increased psy-chopathology when compared withmatched controls, and whether there is aspecific behavior phenotype in PWS, the be-havior of 46 persons with PWS was com-pared with that of control individuals de-rived from a community sample (N = 454) ofpersons with mental retardation (MR). Be-haviors were studied using the Develop-mental Behaviour Checklist, an instrumentof established validity in the evaluation ofbehavioral disturbance in individuals withMR. PWS subjects were found to be more be-haviorally disturbed than controls overall,and especially in antisocial behavior. In ad-dition, some individual behaviors weremore common in PWS subjects than con-trols. When these behaviors are consideredtogether with findings from other studiesusing acceptably rigorous methods, a con-sensus behavior phenotype for PWS can beformulated. This will provide a valid foun-dation for studies of the mechanism of ge-netic pathogenesis of behavior in PWS. Am.J. Med. Genet. 82:123–127, 1999.© 1999 Wiley-Liss, Inc.

KEY WORDS: Prader-Willi syndrome; be-havior problems; Develop-mental Behaviour Checklist

INTRODUCTION

The study of the behavior of individuals with Prader-Willi syndrome (PWS) is of interest for several reasons.

Previous reports have suggested that behavioral prob-lems are a serious additional handicap in this condi-tion. If a specific behavioral phenotype were associatedwith PWS, this could contribute to the diagnosis. Suchstudy may allow behavior—for example, hyperpha-gia—to be correlated with specific gene locations andfunctions. If this last possibility were realised, it mayhave a significance far beyond PWS itself. In this case,we might learn about pathogenic mechanisms in obe-sity or eating disorders in the general population.

However, for this potential to be realised, postulatedbehavior-genotype associations must be validated byrigorous methodology. Einfeld and Hall [1994] de-scribed examples of putative behavior phenotypes thatwere not verified in later studies. Such unsupportedclaims can lead to fruitless research studies, inappro-priate use of clinical and laboratory resources, unnec-essary anxiety on the part of caregivers, and stigmati-sation of the affected individuals. These authors ar-gued that accurate behavior-genotype associationscould only be determined by data derived from studiesthat met the following criteria:

1. Evidence obtained of an association from a case-control study.

2. Chance ruled out with tests of statistical signifi-cance and corrections for multiple comparisons.

3. Where no association is found, the possibility ofType 2 error is considered.

4. Confounding variables are measured or controlled.5. Ascertainment bias is reduced with attention to se-

lection and participation.6. Measurement error is reduced and evaluated by us-

ing measures of known reliability and validity.

In addition, it might be added that replication of re-sults from several studies is required before a behaviorphenotype can be determined reliably. None of the re-ports and studies of behavior disturbances in PWS hasmet all these criteria. Some of the earlier studies werepurely descriptive in nature, with little use of stan-dardised methods for assessing behavior [Bray et al,1983; Greenswag, 1987; Hall and Smith, 1972; Turnerand Ruvalcaba, 1981; Zellweger and Schneider, 1968].Other studies have used validated measures of behav-ior but not all of these have been standardised for per-

Contract grant sponsor: Apex Foundation for Research in Men-tal Retardation, Australia.

*Correspondence to: Stewart L. Einfeld, Area Mental Health, 2Short St., Kogarah, NSW, Australia. E-mail: s.einfeld@unsw.edu.au

Received 20 April 1998; Accepted 23 June 1998

American Journal of Medical Genetics 82:123–127 (1999)

© 1999 Wiley-Liss, Inc.

sons with mental retardation (MR). For example, Curfset al. [1991] and Dykens et al. [1992] used the ChildBehavior Checklist (CBCL), which is standardised forthe normal population but not for people with MR[Achenbach and Edelbrock, 1983]. However, this in-strument may well be useful in those PWS subjectswith normal or near normal intellectual level. In manystudies there was no description of the criteria used forthe diagnosis of PWS [e.g., Laurance et al, 1981; Thorn-ton and Dawson, 1990; Turner and Ruvalcaba, 1981;Whitman and Accardo, 1987]. Other authors cited theclinical characteristics on which they made a diagnosis,but these were not standardised criteria [Bray et al,1983; Hall and Smith, 1972].

Many studies were uncontrolled [e.g., Bray et al.,1983; Greenswag, 1987] or drew controls from the gen-eral population [e.g., Whitman and Accardo, 1987]rather than from those with MR. As psychopathology isknown to be more common in persons with MR in gen-eral [Corbett, 1979], an MR population sample pro-vides a more rigorous control group. The use of subjectsdrawn purely from institutions [Thornton and Dawson,1990; Turner and Ruvalcaba, 1981] may produce anascertainment bias selecting those with more severebehavior pathology.

More recent studies have had sufficient rigour tosuggest a valid general picture of behavior in PWS.Overall behavior disturbance is found to be higher thanMR controls [Curfs et al., 1991], with higher scores fortantrums or rages, irritability and agitation, and re-petitive speech in the PWS group [Clarke, 1996; Clarkeet al., 1996] and high rates of obsessive behaviors, skin-picking, and impulsivity [Dykens, 1995; Dykens andKasari, 1997]. However, a range of uncertainties re-mains. Behaviors identified in some studies but notothers include lying, arguing [Dykens and Kasari,1997], and repetitive speech [Clarke et al, 1996], whileTaylor and Caldwell [1983] found less stereotyped be-havior. There is no consensus on the influence of age onbehavior disturbance, though two reports suggest IQlevel is not associated with severity of behavior distur-bance [Dykens and Cassidy 1995; Curfs et al., 1991].

In a study of 59 PWS patients Wenger et al. [1987]compared those with and without the 15q cytogeneticdeletion. The study showed no significant differences interms of physical characteristics or in the effects of abehavior modification programme. However, Curfs etal. [1995] found PWS girls without 15q11-q13 deletionto have less physical activity.

AIMS

This study aimed to explore the psychopathology ofPWS using methods intended to address some of theidentified methodological limitations, to determinewhether this would confirm or contradict emerging be-havior phenotype findings. These methods were tospecify the criteria for diagnosis of PWS; to use a vali-dated instrument to document behaviors; to use a suf-ficiently large sample size to minimise statistical er-rors; and to compare behaviors of PWS individualswith a representative epidemiological sample of young

people with intellectual disability, while taking ac-count of some potential confounders.

The study aimed to determine whether PWS subjectswere different from controls in (a) overall behavior dis-turbance, (b) syndromes or dimensions of disturbance,(c) individual symptoms or behaviors. Further, thestudy sought to determine the extent to which suchitem differences could discriminate PWS subjects fromcontrols.

METHODSubjects

Parents and caregivers of 75 children with a putativediagnosis of PWS were invited to participate by meansof a letter describing the purpose of the study. Theywere identified through a register of the Department ofGenetics at the Royal Alexandra Hospital for Childrenin Sydney, Australia.

There were 55 replies, representing a participationrate of 73%. These subjects were then assessed accord-ing to the Holm criteria [Holm et al., 1993]. The Holmsystem provides a quantitative measure of PWS symp-toms. Eight traits are considered major (scored 1 point)and 11 minor (scored 0.5). A total score of 8 indicates‘‘typical’’ PWS. There are three behavior items withinthe 19 of the Holm Scale. These can contribute a maxi-mum of two out of the minimum necessary eight points.

According to these criteria 46 of these 55 subjectswere classified as having the classical PWS phenotype.These 46 are the subjects of this study. Of those onwhom DNA data were available, 12 had the deletion,six had uniparental disomy, and four had neither de-letion or disomy.

Control Subjects

Control subjects were derived from a multicentre epi-demiological prevalence study of individuals with MR.Full details of the methods and results of this study areprovided in Einfeld and Tonge [1996a, 1996b]. Parentsor primary caregivers of 454 children and adolescentsparticipated. The study is considered to provide an ac-curate representation of those with moderate, severe,and profound MR. However, the sample is less repre-sentative of those with mild MR. As found in otherstudies of mild MR, those most likely to be identifiedare those who come in contact with services [Kirman,1986]. Such a group may have a bias towards thosewith behavior problems.

Instrument

The Developmental Behaviour Checklist (DBC) [Ein-feld and Tonge, 1994, 1995] was used to measure be-havioral and emotional disturbance. The DBC is a 96-item checklist designed to assess a broad range of be-havioral and emotional disturbances in children andadolescents with intellectual disability. The PrimaryCarer Version (DBC-P) is completed by persons closelyresponsible for the care of the developmentally dis-abled child, usually the parents. The DBC is an instru-ment of established reliability and validity that hasbeen used in a number of studies of behavior pheno-types. Details of its psychometric properties are pro-

124 Einfeld et al.

vided in Einfeld and Tonge [1994, 1995]. It measurespsychopathology at three levels: severity of overall be-havior disturbance (total behavior problem score); dis-turbance in six particular dimensions of psychopathol-ogy (six subscale scores derived from factor analysis);and level of disturbance of particular individual behav-iors (96 items or symptoms).

Measurement of Intellectual Level

Presence of mild, moderate, or severe mental retar-dation was determined based on results of standard IQassessments performed in developmental assessmentclinics or by school psychologists. The tests most com-monly used were the Wechsler Intelligence Scale forChildren–Revised (WISC-R), and the Stanford-Binet.

DATA ANALYSIS

Subjects and controls were compared on the total be-havior problem score, subscale scores, and individualitems of the DBC. Simultaneous multiple regressionwas used to determine the significance of the groupdifferences. Seven separate analyses were conductedusing each of total behavior problem and subscalescores as dependent variables. In each of these sevenanalyses group (PWS versus control), age, sex, and IQrange (1 4 profound, 2 4 severe, 3 4 moderate, 4 4mild, 5 4 borderline, 6 4 normal range) were used asthe independent variables.

The effect of the simultaneous multiple regressionprocedure is to remove the differences between thePWS groups and controls that might have resultedfrom differences in age, sex, or IQ range between thegroups. This means that remaining differences are at-tributable to PWS or control status [Cohen, 1977; Ta-bachnick and Fidell, 1989].

The individual items were examined in two sets. Thefirst set consisted of 11 items identified in at least onereport in the literature to be a trait in PWS. The secondset was the remaining items of the DBC. The Bonfer-roni correction to the probability level regarded as sig-nificant was thus different for the two groups, being.05/11 (.005) for the first set and .05/85 (.0005) for thesecond set. For these items the mean score for the twogroups was compared again using multiple regression,which adjusted for the effects of differences in age, sex,and IQ. The results of these analyses are presented inTables II and III. The possibility of Type 2 error wasalso considered. The sample size, expressed as a geo-metric mean, was 165. This is sufficiently large to havean adequate chance of detecting medium and large ef-fects [Cohen, 1977].

RESULTS

A comparison of characteristics of PWS subjects andcontrols is given in Table I. The PWS subjects wereolder and had less severe MR. As described above,these differences were controlled for in the data analy-ses. The study group appears representative of PWSsubjects in terms of IQ range [Borghgraef et al., 1990;Clarke and Boer, 1995; Dykens et al., 1992; Green-swag, 1987]. That is, the IQ range in PWS is most

typically in the mild MR group, with a range from mod-erate MR to normal IQ

The PWS group had higher levels of overall psycho-pathology than controls and were also significantlymore ‘‘antisocial’’ than controls as measured by thatsubscale (Table I). Items on the antisocial subscale in-clude lies, steals, hides, and lights fires. Scores on otherscales namely the disruptive, self-absorbed, communi-cation disturbance, anxiety, and social relating’’ subs-cales were higher for PWS, but not significantly so.

Table II shows the behaviors predicted from the lit-erature to be common in PWS. Of these, five are foot-noted as being scored significantly higher in PWS sub-jects than for controls. Prevalence figures (combiningscores of 1 and 2) for the items are also shown. Otherbehaviors with significant differences are shown inTable III.

The above results were adjusted for the main poten-tial confounders of age, sex, and level of MR. Within thePWS group disturbance is greatest in those who areolder (p 4 .014) and have more severe MR (p 4 .009).Other potential confounders such as place of residenceand psychosocial status were not considered in thisstudy, but we have no particular reason to think thatthese factors would vary significantly between the sub-jects and controls.

Given that the DBC is not normed for those withborderline and normal IQ, it is possible that the behav-ior patterns identified in this study might only apply tothose with MR. To test this, two evaluations were car-ried out. First, we asked whether the PWS subjectswith borderline and normal IQ had different behaviorfrom the PWS subjects with MR. There was no signifi-cant difference in mean PWS Behavior Scale scores be-tween these two groups (f 4 1.331, p 4 0.225).

Second, we examined the items of the PWS BehaviorScale, that is, those items on the DBC found to dis-criminate PWS subjects from controls, and selectedthose items from the CBCL that appeared to measuresimilar behaviors. CBCL equivalents were identifiedfor 11 of the 16 items of the PWS Behavior Scale. APWS Behavior Scale score was then calculated for the13 normal/borderline IQ subjects by adding their meanscores on the CBCL items. This was then compared

TABLE I. Characteristics of Prader-Willi Syndrome (PWS)Subjects and Controls, Overall Behavioral and

Emotional Disturbance, and Significantly DifferentDimension of Psychopathology*

PWS Control

N 46 454Mean age (yrs) 17.7 12Male 50% 58%Severe MR 0% 31%Moderate MR 4% 39%Mild MR 67% 30%Borderline/normal IQ range 28% 0%Mean total behaviour problem

score (regression coefficient,significance)

51.7 42.3 (f 4 7.9,p < .005)

Mean antisocial subscale score(regression coefficient,significance)

3.3 1.1 (f 4 20.6,p < .000)

*MR 4 mental retardation.

Behavior and Emotional Disturbance in Prader-Willi Syndrome 125

with the score for the same items for the Achenbachnonreferred boys and girls age 4–18.

For the 2402 CBCL nonreferred boys and girls aged4–18 years the average score on the sum of the itemsabove was 1.72. For the 13 borderline/normal IQ PWSsubjects the average score on the sum of similar itemswas 9.93, with a standard deviation of 4.7. The differ-ence is highly significant (z 4 6.47, p < .0001). Thus,the borderline/normal IQ PWS subjects are signifi-cantly more disturbed on the discriminating behavioralcharacteristics of PWS than similar IQ controls.

These two tests suggest that the identified behaviorphenotype of PWS holds true across the IQ range, in-cluding those of borderline/normal IQ.

DISCUSSION

There are some potential limitations to this study.Thirty percent of the controls were in the mild MRrange and ascertainment of this group may well bebiased towards those with greater behavior distur-bance. Therefore, the true difference in the behaviordisturbance between the two groups may be evengreater than that found in this study. The possibility ofascertainment bias of subjects also needs to be consid-ered. The subjects were drawn from a large geneticclinic. This is less likely to introduce a bias towardsthose with higher levels of behavior problems than ifthey were drawn from a psychiatric clinic or purelyfrom a support organisation.

The Holm criteria, accepted as a standard for clinicaldiagnosis, were used to validate the diagnosis of PWS.However, validation of the diagnosis now includes ge-netic testing. As more is learned about genetic sub-types [Smith et al., 1995], changes of diagnostic criteriamay result. This may result in changes to diagnosticcriteria. We attempted to determine whether thoseidentified in this sample as having a DNA subtypecould be distinguished in terms of their behavior. Therewere no differences, but there was insufficient power inthe study to detect these.

Previous studies have noted that PWS patients havea higher level of psychopathology than do normal con-trols [Curfs et al, 1991; Whitman and Accardo, 1987].This study has shown that this excess of psychopathol-ogy in PWS subjects is even greater than the excessseen in people with intellectual disability due to othercauses. This is significant, given that the level of be-havioral disturbance is high among people with intel-lectual disability in general. This study and that ofDykens [1995] found that obsessive-compulsive symp-toms were elevated in PWS subjects. It is possible thatthe findings represent preoccupations rather Diagnos-tic and Statistical Manual of Mental Disorders (DSM-IV) obsessive-compulsive disorder. Clarke and Boer[1995] , using the Aberrant Behavior Checklist, whichis standardised for people with intellectual disability,found that the levels of irritability and agitation wereparticularly elevated in PWS subjects. These behaviors

TABLE III. Other Behaviors With Significant Differences

BehaviorPrevalence in Prader-Willi

syndrome (%)Prevalence incontrols (%)

Significance(P-value)

Stubborn, disobedient, or uncooperative 85 61 .000Cries easily for no reason or over small upsets 77 43 .000Shy 13 40 (−).000Underreacts to pain 65 36 .000Moves slowly, underactive, does little, e.g., only sits and watches others 80 31 .000Smells, tastes, or licks objects 39 24 .000Tells lies 74 22 .000Sleeps too much 54 16 .000Steals 59 12 .000Upset and distressed over small changes in routine or environment 72 45 .000

TABLE II. Behaviors Predicted to be Associated With Pradel-Willi Syndrome (PWS)

BehaviorPrevalence in PWS

(per cent)Prevalence in controls

(per cent)

Significance (P value)from f-test, controlledfor age, sex, and IQ

Severe temper tantrums, e.g., stamps feet, slams doors 83 26 .000a

Gets obsessed with an idea or activity 72 43 .000a

Scratches or picks his/her skin 89 27 .000a

Eats nonfood items, e.g., dirt, grass, soap 17 14 .000a

Gorges food. Will do anything to get food; e.g., takes foodout of garbage bins or steals food 72 14 .000a

Mood changes rapidly for no apparent reason 63 44 .057Kicks, hits others 41 41 .748Abusive, swears at others 52 30 .625Impulsive, acts before thinking 59 52 .248Tense, anxious, worried 46 35 .522Thoughts are unconnected. Different ideas are jumbled

together, etc. 35 28 .794

aScored significantly higher in PWS subjects than for controls.

126 Einfeld et al.

are similar to those that load on the disruptive subscaleof the DBC used in our study. While this was elevatedin our PWS subjects, it was not significantly so. PWSsubjects had significantly increased scores in the anti-social scale. It may help parents and caregivers toknow that antisocial behaviors are syndrome-relatedrather than solely related to their upbringing, as thesebehaviors cause great stress to families and caregivers.

Behaviors identified as occurring at a significantlyhigher rate in the PWS subjects than in controls inboth this study and those with more rigorous designmay be grouped into those of externalising, internalis-ing, and somatoform types, the externalising symp-toms being irritability, tantrums or rages, lying, dis-obedient or uncooperative, and impulsivity. The inter-nalising behaviors are agitation, crying for no reason orover small upsets, distress over small changes in rou-tine, and obsessed or preoccupied with an idea or ac-tivity. The somatoform symptoms are underreaction topain, underactivity, scratching or picking his/her skin,eating nonfood items, and gorging food.

CONCLUSION

This study confirms that PWS subjects have a highlevel of psychopathology and that this excess persistswhen corrected for age, sex, and IQ. It is suggested thatthe externalising, internalising, and somatoform be-haviors listed above are the most valid current descrip-tion of the behavior phenotype of PWS. Study of furthersubjects with DNA analysis will be needed to deter-mine whether there are any significant differences inbehavior between genetic subtypes. This will allow fur-ther understanding of the relationship between DNAand behavior.

ACKNOWLEDGMENTS

We wish to acknowledge the professionalism andsensitivity shown by Irene Laptev in contacting subjectfamilies. We would also like to thank participatingfamilies and the executive of the PWS Association ofAustralia. David Dossetor assisted with the grant ap-plication. Lea Einfeld and Darryl Taylor assisted withediting.

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