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Behavioral Profiles in Phelan-McDermidSyndrome: Focus on Mental HealthSteven R. Shaw a , Amira Rahman a & Akanksha Sharma aa Educational and Counseling Psychology, McGill University ,Montreal, Quebec, CanadaPublished online: 07 Mar 2011.

To cite this article: Steven R. Shaw , Amira Rahman & Akanksha Sharma (2011) Behavioral Profilesin Phelan-McDermid Syndrome: Focus on Mental Health, Journal of Mental Health Research inIntellectual Disabilities, 4:1, 1-18, DOI: 10.1080/19315864.2011.554615

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Journal of Mental Health Researchin Intellectual Disabilities, 4:1–18, 2011Copyright © Taylor & Francis Group, LLCISSN: 1931-5864 print/1931-5872 onlineDOI: 10.1080/19315864.2011.554615

Behavioral Profiles in Phelan-McDermidSyndrome: Focus on Mental Health

STEVEN R. SHAW, AMIRA RAHMAN, ANDAKANKSHA SHARMA

Educational and Counseling PsychologyMcGill University, Montreal, Quebec, Canada

Phelan-McDermid syndrome (PMS) is a multiple congenitalanomalies and intellectual disabilities syndrome associated witha deletion of chromosome 22 terminal band 13.3. The dele-tion is associated with severe intellectual disabilities, absent ordelayed speech, behavior problems, and autism. The objective ofthis study was to provide a detailed assessment and analysis ofproblematic behaviors in this population. Semistructured parentinterviews, checklists, and record reviews were conducted for35 families with children with PMS. Parents participated incompleting the Vineland Adaptive Behavior Scales-II, Reiss Scalesfor Children’s Dual Diagnosis (Reiss), and the Parent Form ofthe Children’s Interview for Psychiatric Symptoms (P-ChIPS).Children with PMS showed adaptive behaviors more than 3standard deviations below the mean. Maladaptive behaviorswere present in nearly all children. Moreover, the P-ChIPS andinterview results showed evidence of unstable mood, depressivesymptoms, and overactivity. The Reiss showed high scores forpsychosis, autism, depression, and attention deficit. Childrenwith PMS have high levels of maladaptive behaviors as wellas evidence of mood, attention, autistic, and psychotic issuesreported by parents. Although PMS previously has been associatedwith autism, there are confounds between autism and mentalissues in this rare population. Implications for understanding the

Address correspondence to Steven R. Shaw, McGill University, Educational andCounseling Psychology, 3700 McTavish, Montreal, Quebec H3A 1Y2, Canada. E-mail: steven.shaw@mcgill.ca

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nature of autism and mental health disorders in children arediscussed.

KEYWORDS Phelan-McDermid syndrome, 22q13 deletion syn-drome, autism, early onset schizophrenia, dual diagnosis, behav-ioral phenotypes

Phelan-McDermid syndrome (PMS), also known as 22q13 deletion syn-drome, is caused by a deletion at the terminal band of 22q13.3 (Phelanet al., 1992). This deletion is associated with moderate to severe intel-lectual disabilities, absent or delayed speech, hypotonia, dolichocephaly,large hands, dysplastic toenails, ptosis, developmental regression, autism,and severe behavior problems (Havens, Visootsak, Phelan, & Graham, 2004;Manning et al., 2004; Phelan et al., 2001; Phelan et al.„ 1992; Wilson et al.,2003). There is much research that implicates SHANK3, a scaffolding andregulatory protein in the postsynaptic density that affects glutamate recep-tion, as a major factor in the neurological symptoms associated with PMS(Havens et al., 2004; Luciani et al., 2003; Manning et al., 2004).

Although the prevalence of PMS is unknown, confirmed numbers ofcases have grown dramatically over the past 15 years and there are nowapproximately 420 known cases (Luciani et al., 2003). Despite this increasein diagnosis, clinical diagnosis of PMS is often overlooked because there is nosingular dysmorphology (Phelan et al., 2001). Like several recently identifiedmicrodeletion syndromes there is likely a large, but unknown, number ofpersons diagnosed with idiopathic severe intellectual disabilities who have22q13, yet large-scale studies of this nature have not been conducted (Phelanet al., 2001). Many affected persons present with no apparent dysmorphicfeatures or associated medical features, whereas others have severely dys-morphic features and have significant medical issues (Havens et al., 2004).Reported physical features associated with PMS include almond-shaped eyes,large ears, large hands, bulbous nasal tip, broad first toe, sandal gap toe,and wide nasal bridge (Phelan et al., 2001; Phelan et al., 1992). Commonlyreported medical issues include acid reflux, seizures, lack of perspiration,strabismus, and abnormalities of the spine (Havens et al., 2004; Phelan etal., 1992). These presenting symptoms overlap with other well-known devel-opmental disabilities. Many children diagnosed with PMS previously carrieddiagnoses of Angelman syndrome, FG syndrome, velocardiofacial syndrome,and tricho-rhino-phelangeal syndrome (Phelan, 2008). Most children diag-nosed with PMS also have had normal routine karyotypes (Havens et al.,2004). PMS is diagnosed via fluorescent in situ hybridization (FISH).

Given that the majority of known persons affected by PMS are under5 years of age, little is known about the behavioral phenotype throughoutthe life span. However, there have been published reports of maladaptive

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Phelan-McDermid Syndrome 3

behaviors increasing with age (Phillippe et al., 2008; Sovner, Stone, & Fox,1996). These reports include behaviors such as aggression, chewing behav-iors, attention disorders, developmental regression, and autistic behaviors(Phillippe et al., 2008; Wilson et al., 2008). Nevertheless, there is not awell-defined behavioral phenotype specific to PMS, which includes adap-tive behavior strengths (i.e., motor skills), problematic and maladaptivebehaviors, and behaviors that may be pathognomic for dual diagnoses (i.e.,intellectual disabilities and mental health problems; Einfeld, 2005). However,there is some evidence supporting common neurobehavioral features of PMS(Luciani et al., 2003; Phelan, 2008).

NEUROBEHAVIORAL FEATURES

Persons with intellectual disabilities have a higher probability of experi-encing mental health problems than typically developing peers (Bresch,2006; Einfeld & Tonge, 1996). Yet, making effective diagnosis of personswith such dual diagnoses is challenging (Fletcher, Loschen, Stavrakaki, &Kingston, 2007; Tsakanikos, Bouras, Costello, & Holt, 2007). Behaviors suchas screaming, assaulting others, withdrawing from social situations, hallu-cinating, engaging in suicidal and other self-injurious behaviors, damagingproperty, and others are common in persons with intellectual disabilities(Einfeld & Tonge, 1996; Sovner et al., 1996). In some cases, these behaviorsmay be learned responses to the environment (Koskentausta, Iivanainen, &Almqvist, 2007). However, the relationship between these behaviors and for-mal psychiatric disorders is not well defined (Fletcher et al., 2007; Tsakanikoset al., 2007). Nonetheless, there is continued need to understand adap-tive and maladaptive behaviors in children with chromosomal disorders(Koskentausta et al., 2007).

Linkage studies have focused on the terminal band of the 22nd chromo-some to identify susceptibility genes for schizophrenia and bipolar disorder(Badner & Gershon, 2002; Condra, Neibergs, Wei, & Brennan, 2007; Fujiiet al., 2006; Lachman et al., 2006; Lewis et al., 2003; Pramparo et al., 2008;Severinsen, Bjarkam et al., 2006). Specifically, there are at least four lociwithin 22q13 that influence susceptibility to schizophrenia and/or affectivedisorders via linkage studies. One of these loci includes the G protein-coupled receptor 24 (GPR24), which is located between markers D22S279and D22S276 on 22q13.2 (Condra et al., 2007; Severinsen, Bjarkam et al.,2006). Another region of interest is the PICK1 gene located on 22q13 andassociated with schizophrenia (Fujii et al., 2006). Recently, Sult4A1 and BZRPand other genes close to the microsatellite region D22S526 are associatedwith the schizophrenia spectrum of behavior and bipolar disorders (Condraet al., 2007; Severinsen, Als et al., 2006; Severinsen, Bjarkam et al., 2006;Pramparo et al., 2008). Moreover, there are meta-analyses indicating linkage

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with genes located at 22q11, 22q12, and 22q13 with schizophrenia andbipolar disorder (Lewis et al., 2003). Although several loci on 22q13 areassociated with schizophrenia, no studies to date have suggested that PMSis associated with schizophrenia.

AUTISTIC BEHAVIORS

Multiple studies have linked PMS with autism spectrum disorders (ASD;MacLean, Teshima, Szatmari, & Nowaczyk, 2000; Moessner et al., 2007).Originally, the association was based on case studies and anecdotal reports(Assumpcao, 1998; DeMas et al., 2002). There is also evidence based onthe Childhood Autism Rating Scale linking autistic-like behaviors and PMSin descriptive studies (Phelan et al., 2001). Subsequently, there have beendetailed studies elaborating on the link between PMS and ASD.

In a study that provided evidence of a link between PMS and ASD,82 persons diagnosed with ASD (69 with an International Classificationof Diseases, 10th edition, diagnosis of autism and 13 with a diagnosis of“atypical autism”) were tested for terminal deletions in the 22q13.3 region(Nair-Miranda et al., 2004). All regions were intact for at least 20 metaphases.In addition, two individuals with ring chromosome 22 participated in assess-ment using the Autism Diagnostic Observation Schedule (ADOS) and AutismDiagnostic Interview–Revised (ADI-R). Although both participants weredescribed by caregivers, educators, and physicians as having autistic charac-teristics, neither met the diagnostic criteria for ASD on the ADOS or ADI-R.

Durand and colleagues (2006) conducted an extensive study of the rela-tionship between PMS deletion syndrome and ASD. The sample consisted of227 persons with ASD diagnosed through clinical evaluation, which includedthe ADOS and the ADI-R. The study also included a comparison group of270 nonaffected persons. The ages of participants was not reported. Threefamilies (five affected children) with ASD were identified as having 22q13deletions. There were no cases where 22q13 deletions were found in com-parison group samples. Reasonable hypotheses are that there are specializedpostsynaptic proteins that affect the development of language and socialcommunication, and persons with PMS have severely affected postsynapticdensities due the impairment of SHANK3 (Bourgeron & Durand, 2008).

SUMMARY

Phelan-McDermid is a rare microdeletion syndrome caused by a deletionin the terminal band of the 22nd chromosome. Intellectual disabilities andexpressive language disorders are the most common features. However,

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Phelan-McDermid Syndrome 5

severe behavior problems are frequently reported by parents and clinicians.Although never formally associated with PMS, several loci on the terminalband of the 22nd chromosome are considered susceptibility genes for bipolardisorder and/or schizophrenia. Moreover, there is a compelling case that ASDand PMS are associated. The purpose of this study was to describe adaptiveand maladaptive behaviors in children with PMS and to consider whetherthere is evidence of identifiable mental health issues in this population.

METHODS

Participants

Thirty-five families participated in the study. All families had one child diag-nosed with PMS via FISH analysis. For this study, children with translocationsor ring chromosomes were excluded, leaving a sample of children with sim-ple 22q13 deletion. This sample was in contrast to cases of ring chromosome22 and unbalanced translocations involving the terminal band of the 22ndchromosome that previously have been described in the literature.

The median age of the affected participants was 7 years 8 months. One41-year-old participant skewed the distribution of ages. Other participantsranged from 28 months to 13 years of age. Although this participant wasincluded in the study, median scores were used during analysis to accountfor the skewed distribution. The median age at the time of the diagnosiswas 4 years 1 month. Participants included 29 from the United States, 3from Canada, and 1 each from Australia, England, and Ireland. Eleven ofthe participants had been previously diagnosed with ASD using the ADOSand ADI-R. The other 24 participants did not meet criteria for a diagnosis ofautism on the ADOS and ADI-R.

Families were recruited with assistance from the 22q13 DeletionFoundation. Information concerning this study was placed on their websiteand the 22q13 Deletion Foundation’s parent listserv. Most participants (n =23) were families attending the biennial 22q13 deletion syndrome supportgroup meeting in Greenville, SC. Other parents (n = 12) were interviewedvia telephone and used ground mail for completion of behavioral checklists.Informed consent was obtained during the interview. Some participants hadmissing information during the interview and a follow-up telephone callwas used to collect the remaining information. The Research Ethics Board atMcGill University approved this study.

Procedures

Parents were interviewed by licensed psychologists or graduate studentsin psychology trained in the interviewing, administration, and scoring ofthe instruments used. The interview included the Children’s Interview for

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Psychiatric Symptoms (ChIPS; Weller, Weller, Fristad, Rooney, & Schecter,2000, for participants 6 to 17 years of age) or interviews based on theDiagnostic and Statistical Manual, Fourth Edition–Text Revision (DSM-IV-TR; for participants younger than 6 or older than 17 years of age), familyhistory, medications and previous diagnoses, and qualitative descriptions ofbehaviors. The average duration of the interviews was 95 min. Behavioralchecklists were also completed by parents. In addition, parents also suppliedcopies of genetic, pediatric, educational, and psychological reports.

Instruments

The Parent Form of the Children’s Interview for Psychiatric Symptoms (P-ChIPS) is a structured diagnostic interview for children ages 6 to 18 years(Weller et al., 2000). Items are based on the DSM-IV-TR criteria for AxisI as well as questions concerning environmental stressors such as illness,household changes, and family disruptions. The P-ChIPS covers 20 Axis Idiagnoses. There is strong evidence of validity and reliability for the P-ChIPS.

For parents of children younger than 6 years or older than 18, asemistructured interview based on DSM-IV-TR criteria for Axis I diagnoseswas administered. Specifically, parents were asked detailed questions relatedto depressive disorders, psychotic disorders, and anxiety disorders.

The Vineland Adaptive Behavior Scales-II (VABS-II) Parent/CaregiverRating Form was used to assess personal and social skills needed for every-day living (Sparrow, Cicchetti, & Balla, 2005). The VABS-II is a measure forassessing intellectual disabilities, developmental delays, ASD, and develop-mental disabilities. The VABS-II assesses communication, daily living skills,socialization, motor skills, and maladaptive behaviors. The VABS-II manualreports adequate reliability and validity.

The Reiss Scales for Children’s Dual Diagnosis (Reiss & Valenti-Hein,1990) is a 60-item checklist completed by caregivers. The purpose is toassist in making dual diagnoses. The Reiss Scales are divided into 10Psychometric Scales. These scales are as follows: Anger/Self-Control, AnxietyDisorder, Attention Deficit, Autism/Pervasive Developmental Disorder,Conduct Disorder, Depression, Poor Self-Esteem, Psychosis, SomatoformBehavior, and Withdrawn/Isolated. Ten other items of clinical importanceare crying spells, enuresis/encopresis, hallucinations, involuntary move-ments, lies, obese, pica, sets fires, sexual problems, and verbally abusivebehaviors. The Reiss is psychometrically sound with high internal consis-tency, Cronbach’s alpha of 0.91 to 0.92, good factor content validity, andfactor loadings of 0.42 to 0.83 (Havercamp & Reiss, 1997; Reiss & Valenti-Hein, 1990, 1994). All 60 items have explanations and provide an example ofthe behavior of focus. Each item has a 3-point scale: 0 (no problem), 1 (someproblem), or 2 (major problem). The Reiss Scales have been used widely in

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Phelan-McDermid Syndrome 7

studies of dual diagnosis of children (Clark & Wilson, 2003; Havercamp &Reiss, 1997; Reiss & Valenti-Hein, 1994).

RESULTS

Thirty-five families participated in the interviews and completed the check-lists. Twenty-one of the children with PMS were female and 14 male. Thirtyof the 35 children with PMS were White (non-Hispanic), 2 Hispanic, 2 Asian,and 1 Black.

Vineland Adaptive Behavior Scales-II

Based on results from previous psychological assessments and individual-ized educational plans from schools, all 35 children with PMS had intellectualabilities in the severe to profound intellectually disabled range of function-ing. No child was reported to have an intelligence test score greater than 40.However, 13 of the 35 had the notation of “not testable” or equivalent underthe heading of intelligence testing results in previous psychological reports.Given restricted range of ability and limitations of most intelligence tests atthis level of intellectual ability, the VABS-II was used to describe specificstrengths and weaknesses in adaptive functioning.

Children with PMS demonstrated low to very low adaptive behavioracross domains (i.e., averaging more than three standard deviations belowthe mean; see Table 1). Standard scores tend to decrease with age on theVABS-II for this population. Four of the youngest participants (mean age =57 months) had the highest Adaptive Behavior Composites (mean standardscore = 64). A multivariate analysis of variance does not indicate significantdifferences among the domain scores (F [3, 109] = 2.183, ns).

Subdomains on the VABS-II indicate consistently low or very low adap-tive functioning across domains (see Table 2). A multivariate analysis ofvariance shows significant differences among the adaptive subdomain scores(F [10, 310] = 4.728, p < .001, η2 = 0.12). Bonferroni post hoc analysis

TABLE 1 Results From Vineland Adaptive Behavior Scale–II Domain Scores

Domain scores M SD

Communication 48 13.73Daily living skills 49.09 15.03Socialization 54.32 14.88Motor skills 57.28 9.66Adaptive behavior composite 49.58 11.91

Note. Population mean = 100, standard deviation = 15.

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TABLE 2 Results From Vineland Adaptive Behavior Scale–IISubdomain Scores

Subdomains M SD

Written language 7.7 3.22Expressive language 4.59 2.89Receptive language 6.52 2.17Community skills 6.34 3.31Domestic skills 7.5 3.18Personal skills 5.53 2.98Coping skills 8.38 2.78Play and leisure time 5.72 2.79Interpersonal relationships 6.53 2.58Fine motor 7.17 2.53Gross motor 8.06 2.15Externalizing behaviors 16.14 2.47Internalizing behaviors 18.30 2.23Maladaptive behavior index 18.66 1.42

Note. Population mean = 15, standard deviation = 3.

indicates significant differences between Gross Motor and ExpressiveLanguage (t = 5.44, p < .001), Gross Motor and Personal Skills (t = 3.44, p< .0006), and Gross Motor and Interpersonal Skills (t = 2.23, p < .15).

Mean scores on the Maladaptive Domain are elevated (i.e., moresevere maladaptive behaviors than the normative sample). The maladaptivesubdomains show significant elevations in both internalizing and externaliz-ing behaviors. Although not a detailed analysis of behaviors, the VABS-IIprovides a standardized method of indicating significantly maladaptiveinternalizing and externalizing behaviors.

P-ChIPS and Interviews

All previous literature describing the behavior issues for children with PMShave focused on externalizing problems (e.g., aggression; Luciani et al.,2003; Wilson et al., 2003). However, many of the participants had previousAxis I diagnoses made by primary care pediatricians, neurologists, psychi-atrists, and psychologists. Two participants had the diagnosis of bipolardisorder, 1 unipolar major depressive episode, 11 ASD, and 12 attention-deficit/hyperactivity disorder (ADHD). Moreover, the association of theterminal band of the 22nd chromosome with schizophrenia and bipolardisorder made further elaboration of these behavioral features worthwhile(Sovner et al., 1996). Therefore, a clinical diagnostic interview was adminis-tered to parents in order to assess parent perceptions of many internalizingissues and psychotic behaviors in addition to externalizing behaviors.

All parents endorsed a variety of problematic behaviors (see Table 3).Inattentiveness, impulsiveness, and rapid shifts of mood are all frequently

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Phelan-McDermid Syndrome 9

TABLE 3 ChIPS and Additional Interview Data on ADHD, Psychotic, and Bipolar Behaviors

Item % of responses endorsing

Appears distracted 22.4Runs away 14.6Acts impulsively 32.4Does not seem to listen when spoken to directly 42.2Flat affect 29.4Inappropriate affect 42.8Responds to imaginary sights or sounds 25.0Maintains a rigid posture 29.4Appears to be in a stupor, as if intoxicated 33.3Random and inappropriate speech 47.2Refuses to respond to directions 45.7Appears confused 41.1Unable to make simple decisions 13.8Makes facial grimaces 22.2Posturing (voluntarily assuming bizarre postures) 25.7Appears frightened for no apparent reason 14.2Laughs or appears angry for no apparent reason 45.7Sniffs or smells novel objects 0Needs little sleep 32.3Becomes obsessed with certain objects 42.8Easily distractible 41.6Has extra high energy levels 45.7Has rapid shifts in mood for no apparent reason 45.7Is irritable or aggressive 45.7Appears euphoric or too happy for no reason 33.3Has periods of extreme sadness for no apparent reason 19.4Has periods of noticeable weight loss or weight gain 8.3Has periods of extreme fatigue or loss of energy 22.2Suddenly shows no pleasure in things formerly very interested in 8.3Appears to be moving in slow motion 5.8Shows increased levels of risky or dangerous behaviors 25.0Is moody 30.5Has demonstrated a loss of previously demonstrated skills 32.2

Note. ChIPS = Children’s Interview for Psychiatric Symptoms; ADHD = attention-deficit/hyperactivitydisorder.

endorsed items. Certainly, some of the frequently endorsed behaviors arejust as likely to be characteristics of severe to profound intellectual disabil-ities or ASD as mental health issues (e.g., “Does not seem to listen whenspoken to directly,” “Random and inappropriate speech,” “Appears con-fused,” and “Refusing to respond to directions”). However, some frequentlyendorsed items are more consistent with psychotic disorders than with intel-lectual disabilities, mood disorders or autism. These items include “Reactsto imaginary sights and sounds” (25%); “Maintains a rigid posture” (27.7%);“Appears to be in a stupor, as if intoxicated” (33.3%); “Posturing (voluntar-ily assuming bizarre postures)” (25%); and “Laughs or appears angry for noapparent reason” (45.2%).

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When considered separately the 11 participants diagnosed with ASDpresent with a different set of maladaptive behaviors from their non-ASDpeers. There are significant differences between ASD diagnosed and non-ASD diagnosed participants on seven different questions. These questionsare as follows: Reacts to imaginary stimuli; Appears to be in a stupor,as if intoxicated; Maintains a rigid posture; Posturing (voluntarily assum-ing bizarre postures); Refusing to respond; Becomes obsessed with certainobjects; and Needs little sleep. There were no significant differences for theremaining questions asked.

Reiss Scales for Children’s Dual Diagnosis

The mean subtotal for the Psychometric Scales was 35.08 and the meansubtotal for Other Significant Behaviors was 5.42. This yields a mean totalscore, a measure of severity, of 39.50. Overall, this elevated score indicatesa high likelihood of dual diagnosis in the sample of persons with PMS (seeTables 4 and 5).

The means of several scales were above the cutoff score (i.e., twostandard deviations from the mean) indicating possible dual diagnosis (i.e.,Withdrawal, Somatization, Depression, Autism/Pervasive, Attention Deficit,Anxiety, Anger/Self-control; Reiss&Valenti-Hein, 1990). Thehighest threepsy-chometric scales were Psychosis, Autism/Pervasive Developmental Disorders,and Depression. However, when the sample was split by median age (7.8years), the results changed. Although the Depression Scale stayed the same,there is a clear interaction by age for the Autism/Pervasive and Psychosis.The younger participants were reported to have no difference between theAutism/Pervasive Scale than Psychosis Scale (t = 1.52, ns), whereas the olderparticipants were reported to have far higher scores on the Psychosis Scalethan the Autism/Pervasive Scale (t = 10.78, p < .001; see Figure 1).

TABLE 4 Results From Reiss Scales for Children’s Dual Diagnosis

Scales M SD Cutoff score

Withdrawn 3.78 0.67 6.0Somatoform 2.34 0.74 5.0Psychosis 7.00 1.17 5.0Poor self-esteem 1.56 0.67 6.0Depression 5.28 1.28 5.0Conduct disorder 1.36 0.55 5.0Autism 4.14 2.04 5.0Attention Deficit 6.08 1.72 6.0Anxiety disorder 3.48 1.04 5.0Anger/Self-control 2.64 0.96 6.0

Note. Scales range from 0 to 10. Scales in bold italics are above the cutofffor clinical significance.

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Phelan-McDermid Syndrome 11

TABLE 5 Other Significant Behaviors From the ReissScales for Children’s Dual Diagnosis

Significant Behaviors M SD

Crying spells 0.88 0.12Enuresis/Encopresis 1.14 0.16Hallucinations 1.68 0.46Involuntary movements 0.74 0.18Lies 0.24 0.16Obese 0.44 0.21Pica 0.68 0.24Sets fires 0.00 0.00Sexual problems 0.00 0.00Verbally abusive 0.24 0.08

Note. Scores range from 0 (no problem) to 2 (major problem).The cutoff score for all behaviors is 1.5. The scale in bold italicsis above the cutoff for clinical significance.

0 2 4 6 8 10

Withdrawn

Somatoform

Psychosis

Poor Self-Esteem

Depression

Conduct Disorder

Autism

Attention Deficit

Anxiety Disorder

Anger/Self-Control

> 7.8 Years

< 7.8 Years

FIGURE 1 Mean scores for Reiss Scales—Psychometric Scales for persons with Phelan-McDermid syndrome split by median age. There are significant differences between groups(p < .05) on Autism and Psychosis Scales.

An item in the “Other Significant Behavior” category concerning halluci-nations is not a part of the Psychosis Scale. This item was the most endorseditem of the 10 in this category. Moreover, there is a significant differencebetween younger and older children on this item (M = 0.78 for < 7.8 yearsand M = 1.58 for > 7.8 years = 1.58, t = 4.22, p < .01), mirroring the resultsof the Psychosis Scale.

In addition, when the sample was divided between those previouslydiagnosed with ASD (median age = 9.1) and those not diagnosed (medianage = 7.1), the behaviors generally fall into a pattern widely reported onthe Reiss for persons with ASD. The two groups were similar on most

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12 S. R. Shaw et al.

0 2 4 6 8 10

Withdrawn

Somatoform

Psychosis

Poor Self-Esteem

Depression

Conduct Disorder

Autism

Attention Deficit

Anxiety Disorder

Anger/Self-Control

ASD No ASD

FIGURE 2 Mean scores for Reiss Scales—Psychometric Scales for persons with Phelan-McDermid syndrome diagnosed with autism spectrum disorder (ASD) and those withoutASD. There are significant differences between groups on Autism and Psychosis Scales.

scales. However, the elevation in psychosis showed differences betweenASD and non-ASD groups (t = 2.87, p = .004). The elevation in autismshowed differences between ASD and non-ASD groups (t = 2.05, p = .026).An additional psychometric category, self-esteem, also showed significantdifferences between ASD and non-ASD groups (t = −1.63, p = 0.5). Inaddition, 8 of the 11 diagnosed with ASD also were reported to have signsof hallucinations as seen in Figure 2.

DISCUSSION

Although previous studies have described maladaptive behaviors for per-sons with PMS, there has not been a detailed analysis of these behaviors(Havens et al., 2004; Phelan et al., 2001; Phelan et al., 1992; Wilson et al.,2003). Moreover, most studies of maladaptive behaviors have included per-sons with ring chromosome 22 rather than simple deletions (Phelan, 2008;Phillippe et al., 2008; Wilson et al., 2008). The present study providesdetailed parent-report information on the adaptive skills and maladaptivebehaviors of children with PMS due to deletion of the terminal band of22q13.3.

The VABS-II confirmed previous studies (Phelan et al., 2001), demon-strating that persons with PMS are consistently in the moderate to severerange of intellectual disabilities. In the present sample, there were no excep-tions to this finding. There were relative strengths in Fine and Gross MotorSkills, Coping Skills, and Interpersonal Relationships. Language and Daily

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Phelan-McDermid Syndrome 13

Living Skills were consistently weak. Yet, the Maladaptive Behavior Scaleprovided evidence of internalizing and externalizing behavior problems.

To develop a behavior phenotype of PMS, a fine-grained analysisof specific reported behaviors is required. Three scales from the Reisswere consistently elevated—Psychosis, Depression, and Attention Deficit.Specific behaviors associated these three diagnoses on the P-ChIPS/DSM-IV-TR checklists did not create a clear pattern or an obvious behavioralphenotype as no specific behavior was endorsed by more than 50% of par-ents. Logically, the Autism Scale was elevated for participants previouslydiagnosed with ASD, and there are significant differences on the AutismScale between ASD-diagnosed and non-ASD-diagnosed participants.

Attention, impulse control, and other behaviors consistent with ADHDare commonly observed in children with intellectual disabilities and are notspecific to PMS. Diagnosing ADHD is challenging given the criteria stating“an additional diagnosis of ADHD should be made only if the symptomsof inattention or hyperactivity are excessive for the child’s mental age”(American Psychiatric Association, 2000, p. 91). Nonetheless, the problems ofattention, impulse control, and overactivity are present in a large percentageof children with PMS.

Bipolar disorder, depression, and psychosis are much more difficult tointerpret for persons with PMS. In typically developing populations, thesethree disorders tend to have an adolescent or early adult onset; yet forPMS, behaviors consistent with these three disorders were present in chil-dren as young as 6 years of age. Moreover, the formal criteria for all threedisorders require the ability to verbalize feelings, fears, delusions, grandios-ity, and other factors. All children with PMS in this sample had limited orno speech.

Many of the behaviors consistent with bipolar disorder, depressive dis-order, and psychosis were reported by parents and are unusual for childrenwith other causes of intellectual disabilities. There is a significant age mediansplit differences that may provide evidence of developmental differences inexpression of behaviors. This result may be because older children are morelikely to demonstrate psychotic symptoms than young children. Longitudinalanalyses of these data are required to test this hypothesis. It is also possiblethat the behaviors presented for ASD and early onset psychotic disorders aresimilar, but parents perceive the behaviors of younger children as consistentwith autism and behaviors of older children and adolescents as consistentwith mental health issues such as psychosis. Although differentiation ofautism and mental health issues remains a clinical and research challenge forchildren with severe intellectual disabilities and language impairments, thereis circumstantial evidence from linkage studies and the current study thatchildren with PMS are susceptible to psychotic behaviors, bipolar disorder,and depression (Lewis et al., 2003).

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14 S. R. Shaw et al.

Functional Limitations

There are several limitations of this study. All data were collected throughparent checklists and interviews. Therefore, this study reflects parent obser-vations and perceptions of their children’s behavior. Direct assessment ofaffected persons may provide different results. In addition, a large numberof the participants consisted of families attending the 22q13 support groupmeeting (24 of 35). These families are likely to have higher socioeconomicstatus than affected families who were not in attendance. Another limitationis that the ChIPS has an age limitation and there are 9 children younger than6 years, thus making the ChIPS inappropriate. A less structured interview ofDSM-IV-TR diagnostic symptoms was used in these cases.

Analysis of the Reiss Scale does not eliminate many of the issues con-cerning mental health diagnoses for children who do not use oral commu-nication and have severe intellectual disabilities; nor does the differentiationbetween Autism/Pervasive and Psychosis Scales appear to be sufficient. Forexample, two items on the Psychosis Scale are “Communication problems”and “Blank stares.” Both behaviors are common in ASD. “Unusual vocal-ization” and “Self-stimulation” are items on the Autism/Pervasive Scale andare quite common in schizophrenic populations (Veenstra-VanderWeele &Cook, 2004). Although factor analysis clearly differentiates the two scalesin validation studies, there remain some clinical questions. In addition,“Hallucinations” was an item that is not scored as part of the PsychosisScale. However, this item was the most endorsed of the 10 items on the“Other Significant Behavior” scale, especially in the cases of children witha diagnosis of autism. High scores for the Psychosis Scale of the Reiss forchildren diagnosed with ASD have been noted in the literature (Reiss &Valenti-Hein, 1994). However, there may be evidence for bipolar disorder,psychosis, and depression being an issue in children with PMS and perhapsother children with intellectual disabilities (Lee, Moss, Friedlander, Donnelly,& Honer, 2003).

Future Directions and Clinical Implications

Genetic associations with autism and early onset schizophrenia are com-monly reported (Bakken, Friis, Lovoll, Smeby, & Martinsen, 2007; Bishop,Richler, & Lord, 2006; Lee et al., 2003; Werry, 1996). In addition, link-age studies show several loci at 22q13 that are susceptibility genes forschizophrenia and bipolar disorder. However, the distinction between autismand schizophrenia in a sample of children with severe intellectual disabilitiesis not completely clear. Future studies would involve detailed clinical inves-tigations of ASD and schizophrenia. In addition, persons with PMS havea range of deletion sizes. Examining the behavioral differences between

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Phelan-McDermid Syndrome 15

persons whose deletions include loci associated with schizophrenia andbipolar disorder and persons with the same loci intact could provide usefulinformation about the nature and cause of schizophrenia and bipolar disor-der. Moreover, following children with PMS into adolescence and adulthoodwould allow study of the developmental progression of adaptive, mal-adaptive, autistic-like symptoms, and symptoms associated with psychosis,bipolar disorders, and depression.

The link between autism and PMS, specifically SHANK3, is plausible(Bourgeron & Durand, 2008). However, children with PMS also have signif-icant maladaptive behaviors that are also associated with psychosis, bipolardisorder, and depression. Moreover, there are locations on the 22q13.3that are associated with bipolar disorder and schizophrenia through link-age studies (Condra et al., 2007; Fujii et al., 2006; Lachman et al., 2006).One alternative possibility is that children with PMS may be demonstrat-ing psychotic, prodromal psychotic, or bipolar disorders and are beingdiagnosed as ASD. The nature of the relationships among autism, psychi-atric disorders, and intellectual disabilities requires further study and clinicalconsideration.

REFERENCES

American Psychiatric Association. (2000). Diagnostic and statistical manual ofmental disorders, 4th edition–Text revision. Washington, DC: Author.

Assumpcao, F. B. (1998). Brief report: A case of chromosome 22 alteration associatedwith autistic syndrome. Journal of Autism and Developmental Disorders, 28,253–256.

Badner, J. A., & Gershon, E. S. (2002). Meta-analysis of whole-genome linkage scansof bipolar disorder and schizophrenia. Molecular Psychiatry, 7 , 405–411.

Bakken, T. L., Friis, S., Lovoll, S., Smeby, N., & Martinsen, H. (2007). Behavioraldisorganization as an indicator of psychosis in adults with intellectual disabilityand autism. Mental Health Aspects of Developmental Disabilities, 10, 37–47.

Bishop, S., Richler, J., & Lord, C. (2006). Association between restricted and repet-itive behaviours and nonverbal IQ in children with autism spectrum disorders(ASDs). Child Neuropsychology, 12, 247–267.

Bourgeron, T., & Durand, C. M. (2008). Genetic, neurobiological and clinical find-ings related to SHANK3 mutations and 22q13 chromosomal rearrangements inautism spectrum disorders. European Psychiatric Review, 1, 58–61.

Bresch, D. (2006). Problems and questions in the dual diagnosis of schizophre-nia and intellectual disability: A reply. Mental Health Aspects of DevelopmentalDisabilities, 9, 103.

Clark, D., & Wilson, G. N. (2003). Behavioral assessment of children with Downsyndrome using the Reiss Psychopathology scale. American Journal of MedicalGenetics A, 118, 210–216.

Dow

nloa

ded

by [

Mem

oria

l Uni

vers

ity o

f N

ewfo

undl

and]

at 1

4:52

02

Dec

embe

r 20

14

16 S. R. Shaw et al.

Condra, J. A., Neibergs, H., Wei, W., & Brennan, M. D. (2007). Evidence for twoschizophrenia susceptibility genes on chromosome 22q13. Psychiatric Genetics,15, 292–298.

DeMas, P., Chassaing, N., Chaix, Y., Vincent, M.-C., Julia, S., Bourrouillou, G., . . .Bieth, E. (2002). Molecular characterisation of a ring chromosome 22 in apatient with severe language delay: A contribution to the refinement of thesubtelomeric 22q deletion syndrome. Journal of Medical Genetics, 39, e17.

Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P.,Fauchereau, F., . . . Bourgeron, T. (2006). Mutations in the gene encodingthe synaptic scaffolding protein SHANK3 are associated with autism spectrumdisorder. Nature Genetics, 39, 25–27.

Einfeld, S. L. (2005). Behaviour problems in children with genetic disorders causingintellectual disability. Educational Psychology, 25, 341–346.

Einfeld, S. L., & Tonge, B. J. (1996). Population prevalence of psychopathology inchildren and adolescents with intellectual disability: Rationale and methods.Journal of Intellectual Disabilities Research, 40, 91–98.

Fletcher, R., Loschen, E., Stavrakaki, C., & Kingston, M. F. (Eds.). (2007). Diagnosticmanual—Intellectual disability (DM-ID): A clinical guide for diagnosis ofmental disorders in persons with intellectual disability. Kingston, NY: NADDPress.

Fujii, K., Maeda, K., Hikida, T., Mustafa, A. K., Balkissoon, R., Xia, J., . . . Sawa, A.(2006). Serine racemase binds to PICK1: Potential relevance to schizophrenia.Molecular Psychiatry, 11, 150–157.

Havens, J. M., Visootsak, J., Phelan, M. C., & Graham, J. M. (2004). 22q13 dele-tion syndrome: An update and review for the primary pediatrician. ClinicalPediatrics, 43, 43–53.

Havercamp, S. M., & Reiss, S. (1997). The Reiss Screen for Maladaptive Behavior:Confirmatory factor analysis. Behavior Research and Therapy, 35, 967–971.

Koskentausta, T., Iivanainen, M., & Almqvist, F. (2007). Risk factors for psychi-atric disturbance in children with intellectual disability. Journal of IntellectDisabilities Research, 51, 43–53.

Lachman, H. M., Stopkova, P., Papolos, D. F., Pedrosa, E., Margolis, B., Aghalar,M. R., & Saito, T. (2006). Analysis of synapsin III-196 promoter mutation inschizophrenia and bipolar disorder. Neuropsychobiology, 53, 57–62.

Lee, P., Moss, S., Friedlander, R., Donnelly, T., & Honer, W. (2003). Early-onsetschizophrenia in children with mental retardation: Diagnostic reliability andstability of clinical features. Journal of the American Academy of Child andAdolescent Psychiatry, 42, 162–169.

Lewis, C. M., Levinson, D. F., Wise, L. H., DeLisi, R., Straub, I., Hovatta, N., . . .Helgason, T. (2003). Genome scan meta-analysis of schizophrenia and bipolardisorder, part II: Schizophrenia. American Journal of Human Genetics A, 73,34–48.

Luciani, J. J., DeMas, P., Depetris, D., Mignon-Ravix, A., Bottani, A., Prieur, M., . . .Mattei, M. G. (2003). Telometric 22q13 deletions resulting from rings, simpledeletions, and translocations: Cytogenetic, molecular, and clinical analysis of 32new observations. Journal of Medical Genetics, 40, 690–696.

Dow

nloa

ded

by [

Mem

oria

l Uni

vers

ity o

f N

ewfo

undl

and]

at 1

4:52

02

Dec

embe

r 20

14

Phelan-McDermid Syndrome 17

MacLean, J. E., Teshima, I. E., Szatmari, P., & Nowaczyk, M. J. (2000). Ring chromo-some 22 and autism: Report and review. American Journal of Medical Genetics,90, 382–385.

Manning, M. A., Cassidy, S. B., Clericuzio, C., Cherry, A. M., Schwartz, S., Hudgins, L.,. . . Hoyme, H. E. (2004). Terminal 22q deletion syndrome: A newly recognizedcause of speech and language disability in the autism spectrum. Pediatrics, 114,451–457.

Moessner, R., Marshall, C., Sutcliff, J., Skaug, J., Pinto, D., Vincent, J., . . . Scherer,S. W. (2007). Contribution of SHANK3 mutations to autism spectrum disorder.American Journal of Human Genetics, 81, 1289–1297.

Nair-Miranda, K., Murch, A., Petterson, B., Hill, W., Nikolova-Hill, A., Bradley, L., . . .Hallmayer, J. (2004). An investigation into sub-telomeric deletions of chromo-some 22 and pervasive developmental disorders. American Journal of MedicalGenetics B, 125, 99–104.

Phelan, M. C. (2008). Deletion 22q13.3 syndrome. Orphanet Journal of RareDisorders, 3, 14.

Phelan, M. C., Rogers, R. C., Saul, R. A., Stapleton, G. A., Sweet, K., McDermid, H.,. . . Kelly, D. P. (2001). 22q13 deletion syndrome. American Journal of MedicalGenetics, 101, 91–99.

Phelan, M. C., Thomas, G. R., Saul, R. A., Rogers, C. R., Taylor, H. A., Wenger, D. A.,& McDermid, H. E. (1992). Cytogenetic, biochemical, and molecular analysesof a 22q13 deletion. American Journal of Medical Genetics, 43, 872–876.

Phillippe, A., Boddaert, N., Vaivre-Douret, L., Robel, L., Danon-Boileau, L., Malan,V., . . . Munnich, A. (2008). Neurobehavioral profile and brain imaging study ofthe 22q13.3 deletion syndrome in childhood. Pediatrics, 122, e376–e382.

Pramparo, T., deGregori, M., Gimelli, S., Ciccone, R., Frondizi, D., Liehr, T., . . .Guerrini, R. (2008). A 7 Mb duplication at 22q13 in a girl with bipolar disorderand hippocampal malformation. American Journal of Medical Genetics A, 146 ,1754–1760.

Reiss S., & Valenti-Hein, D. (1990). Reiss Scales for Children’s Dual Diagnosis.Chicago, IL: IDS.

Reiss, S., & Valenti-Hein, D. (1994). Development of a psychopathology ratingscale for children with mental retardation. Journal of Consulting and ClinicalPsychology, 62, 28–33.

Severinsen, J. E., Als, T. D., Binderup, H., Kruse, T. A., Wang, A. G., Vang, M.,. . . Børglum, A. D. (2006). Association analyses suggest GPR24 as a sharedsusceptibility gene for bipolar affective disorder and schizophrenia. AmericanJournal of Medical Genetics B, 141, 524–533.

Severinsen, J. E., Bjarkam, C. R., Kiar-Larsen, S., Olsen, I. M., Nielson, M. M.,Blechingberg, J., . . . Børglum, A. D. (2006). Evidence implicating BRD1with brain development and susceptibility to both schizophrenia and bipolaraffective disorder. Molecular Psychiatry, 11, 1126–1138.

Sovner, R., Stone, A., & Fox, C. (1996). Ring chromosome 22 and mood disorders.Journal of Intellectual Disabilities Research, 40, 82–86.

Sparrow, S. S., Cicchetti, D. V., & Balla, D. A. (2005). Vineland-II Adaptive BehaviorScales. Circle Pines, MN: AGS.

Dow

nloa

ded

by [

Mem

oria

l Uni

vers

ity o

f N

ewfo

undl

and]

at 1

4:52

02

Dec

embe

r 20

14

18 S. R. Shaw et al.

Tsakanikos, E., Bouras, N., Costello, H., & Holt, G. (2007). Multiple exposure to lifeevents and clinical psychopathology in adults with intellectual disability. SocialPsychiatry and Psychiatric Epidemiology, 42, 24–28.

Veenstra-VanderWeele, J., & Cook, E. H. (2004). Molecular genetics of autismspectrum disorder. Molecular Psychiatry, 9, 819–832.

Weller, E. B., Weller, R. A., Fristad, M. A., Rooney, M. T., & Schecter, J. (2000).Children’s Interview for Psychiatric Symptoms (ChIPS). Journal of the AmericanAcademy of Child and Adolescent Psychiatry, 39, 76–84.

Werry, J. S. (1996). Childhood schizophrenia. In F. M. Volkmar (Ed.), Psychosis andpervasive developmental disorders in childhood and adolescence (pp. 1–48).Washington, DC: American Psychiatric Press.

Wilson, H. L., Crolla, J. A., Walker, D., Artifoni, L., Dallapiccola, B., Takano, T., . . .McDermid, H. E. (2008). Interstitial 22q13 deletions: Genes other than SHANK3have major effects of cognitive and language development. European Journalof Human Genetics, 16 , 1301–1310.

Wilson, H. L., Wong, A. C. C., Shaw, S. R., Tse, W., Stapleton, G. A., Phelan, M. C.,. . . McDermid, H. E. (2003). Molecular characterization of the 22q13 deletionsyndrome supports the role of haploinsufficiency of SHANK3/PROSAP2 in themajor neurological symptoms. Journal of Medical Genetics, 40, 575–584.

Dow

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by [

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and]

at 1

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