American Journal of Medical Genetics 133A:248 –256 (2005)
Behavioral Profiles and Symptoms of Autism in CHARGE Syndrome: Preliminary Canadian Epidemiological Data Isabel M. Smith,1* Shana L. Nichols,2 Karina Issekutz,3 and Kim Blake4 1
Departments of Pediatrics and Psychology, Dalhousie University, Halifax, Nova Scotia, Canada Department of Psychology, Dalhousie University, Halifax, Nova Scotia, Canada 3 Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada 4 Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia, Canada 2
Individuals with CHARGE syndrome were identified through the Canadian Pediatric Surveillance Program (CPSP). From this population-based cohort (n ¼ 78), we present data on developmental and behavioral characteristics for the first 13 individuals (eight males, five females) for whom assessments are complete. Standardized parent questionnaires on development and behavior were followed by a structured telephone interview, with a specific emphasis on symptoms of autistic spectrum disorder (ASD). Preliminary results confirm that individuals with CHARGE syndrome have relatively low adaptive behavior skills, motor impairments being particularly significant. Most individuals did not present with significant behavior problems; however, evidence of ASD symptoms was judged to be moderate to strong in six of the ten children who were above the age of 4–5 years. Results are discussed with reference to the challenges inherent in the diagnosis of autism in individuals with sensory impairments, and to the implications for understanding the etiology of CHARGE syndrome and of ASD. ß 2005 Wiley-Liss, Inc. KEY WORDS: CHARGE syndrome; Canadian Pediatric Surveillance Program (CPSP); coloboma; choanal atresia; deafness; visual impairment; autism; behavior; development. INTRODUCTION CHARGE syndrome is a multiple congenital anomaly condition, with some of the more common features reflected in the acronym CHARGE: Coloboma, Heart defects, Atresia choanae, Retarded growth and development, Genital hypoplasia, and Ear abnormalities [Pagon et al., 1981]. The syndrome criteria have evolved from the earliest descriptions of associations among these characteristics [Hall, 1979; Hittner et al., 1979] to general agreement regarding the physical phenotype
Grant sponsor: IWK Health Centre; Grant sponsor: E.A. Baker Foundation (Canadian National Institute for the Blind); Grant sponsor: Canadian Deafblind and Rubella Association; Grant sponsor: CHARGE Syndrome Foundation, Inc. *Correspondence to: Dr. Isabel M. Smith, IWK Health Centre, PO Box 9700, Halifax, NS, Canada B3K 6R8. E-mail:
[email protected] Received 12 December 2003; Accepted 30 September 2004 DOI 10.1002/ajmg.a.30544
ß 2005 Wiley-Liss, Inc.
of the syndrome [Blake et al., 1998; Tellier et al., 1998; Graham, 2001]. It is well established that patterns of physical abnormalities can be used to identify biologically-determined, intellectuallydisabling syndromes [O’Brien and Yule, 1995]. In many instances, these syndromes are associated with characteristic patterns of development or behavioral characteristics [Gillberg and O’Brien, 2000]. For example, behavioral phenotypes have been explored for Williams and Prader–Willi syndromes [Dykens and Rosner, 1999], velo-cardio-facial syndrome [Scherer et al., 1999; Shprintzen, 2000], and Mo¨bius syndrome [Johansson et al., 2001]. Now that the physical phenotype of CHARGE syndrome has been established, studies of the developmental and behavioral profiles of individuals with this condition have been gaining prominence (see accompanying articles, this issue). Previous investigators have noted that autism may be associated with CHARGE syndrome [Fernell et al., 1999]. Autism is a behaviorally-defined neurodevelopmental disorder that results in distinctive patterns of impairment in socialization, communication, and flexible thinking and behavior [for review and recommendations regarding diagnostic issues, see Filipek et al., 1999]. It is now recognized that autism presents along a continuum of severity (hence, our preference for the term ‘‘autistic spectrum disorder’’ or ASD). Although the majority of persons with more ‘‘classic’’ (severe) autistic symptoms are intellectually impaired, ASD can be seen at any level of cognitive ability. ASD dramatically affects the lives of individuals and families, and given its estimated prevalence of approximately 1 in 200 [Fombonne, 2003], the impact on health, educational, and social service systems is enormous [Bryson and Smith, 1998]. The behavioral syndrome of ASD may result from a variety of causes, although the strong role of genetic factors is well-recognized [Bailey et al., 1995]. The prevalence of ASD among individuals with mental handicaps is markedly higher than among the general population [Bryson and Bradley, 2003]. Over-representation of ASD has also been observed in a number of congenital conditions, including Mo¨bius syndrome [Johansson et al., 2001], Joubert syndrome [Ozonoff et al., 1999], and Smith–Lemli–Opitz syndrome [Tierney et al., 2001], independent of intellectual level. In other disorders, such as Williams syndrome, a distinct pattern of intellectual and behavioral development emerges that is quite unlike that seen in autism [but see Reiss et al., 1985]. Differential associations between congenital syndromes and symptoms of autism may have implications for understanding etiology. The above-noted association between Mo¨bius syndrome and autism, for example, provides indirect support for the theory that a subgroup of autism is accounted for by early brainstem damage [Stro¨mland et al., 1994; Rodier et al., 1996]. The significance of these findings for CHARGE and other syndromes in which symptoms of autism may be prominent is apparent [also see Stro¨mland et al., 2003]. Fernell et al. [1999]
Behavioral Profiles in CHARGE
documented three children with CHARGE who met formal diagnostic criteria for autism. In Blake’s survey of 20 adolescents and adults (13–30 years) with CHARGE syndrome [Abi Daoud et al., 2002; Blake et al., 2005], most of the adults were unable to live independently, requiring high levels of support and supervision in everyday activities. Caregivers reported that the social contacts of these adults were limited, and that 75% showed significant socializing problems relating to difficulties in initiation of activities, as well as marked repetitive and compulsive behaviors. Contributors to this journal issue, including Hartshorne and Cypher [2005], have noted that many persons with CHARGE show these and other characteristics of ASD. However, the diagnosis of autism in individuals with multiple other handicaps remains a topic of debate, and additional data are needed. The present study further investigates the behavioral profiles associated with CHARGE syndrome in participants derived from a population-based surveillance program. We hypothesize that elevated rates of ASD symptoms will be seen in CHARGE syndrome. As our surveillance project proceeds, our intention is to examine the associations between autistic behavior patterns, other adaptive behaviour, and the patterns of anomalies seen in individuals with CHARGE syndrome. Canadian Pediatric Surveillance Program This study was undertaken through the Canadian Paediatric Surveillance Program (CPSP), a national epidemiological surveillance tool established in 1996 to enhance the collection of vital data in the study of rare diseases of children and youth [Sockett, 1998]. More than 2,300 general pediatricians and specialists who provide health care to over six million Canadian children and youth participate monthly in this active surveillance program. Here, we are reporting data from the first 16 months of surveillance and begin to address the challenges associated with gathering data on developmental and behavioral patterns in CHARGE syndrome in the context of a population study. Evaluation of development, especially behavioral development, in individuals with significant multifaceted sensory and other impairments is difficult due to the lack of appropriately standardized measures. Hearing and visual impairments of varying degrees occur in most individuals with CHARGE syndrome. Balance, tactile, and feeding problems are also pervasive in this group. The heterogeneity of these impairments in CHARGE syndrome necessitates the cautious use of a variety of instruments, and the need to interpret the resulting information in light of both the nature and degree of sensory impairments. There are few guidelines as to how best to do this; our approach is to document carefully and to interpret our findings with caution. Visual impairment is of particular concern [Russell-Eggitt et al., 1990]. The identification of ASD in individuals with significant visual impairments has long been controversial. Cass [1998] emphasized the importance of differentiating autistic-like symptoms that appear to be associated with blindness (such as echolalia, motor stereotypies, and ‘‘sensory’’ behaviors) from the full syndrome of autism as manifested in the context of visual impairment. To date, however, there is no consensus as to how to diagnose autism in persons with visual impairment. Goodman and Minne [1995] conducted a pilot study in which children with congenital blindness were screened by questionnaire for co-morbid autism. Four children with probable ASD were identified from their sample of 17. This study excluded children with other disabilities (such as intellectual impairment, or other sensory or physical challenges), focusing only on the specific association between ASD and blindness. Hobson and his colleagues have also suggested that there is considerable overlap in the presentation of
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children with congenital blindness and those with autism [Brown et al., 1997]. Their findings (10 of 24 children with autistic-like presentations) suggest an even stronger relationship between visual impairment and ASD, perhaps because their sample included more children who were functioning at lower intellectual levels. Hobson et al. [1999] attempted to clarify the subtle differences between children with blindness and autistic symptomatology versus sighted children with autism. Qualitative ratings of social-affective behavior and pretend play suggested that the blind children with autism might be less impaired than sighted children with classical autism on these dimensions, whereas features such as echolalia and stereotyped movements were very common among the children without sight. Further research on social and communication development in children with visual impairment is much needed in order to advance understanding of these complex issues [Cass, 1998; Sonksen and Dale, 2002; Hobson, 2004 (personal communication)]. Of particular relevance for CHARGE syndrome, an even more limited literature exists on autism in children with hearing impairment. Jure et al. [1991] found that within a single neurological service, 4% of 1,150 children with hearing impairment also met criteria for autism. Two of these children with both hearing impairment and autism had CHARGE syndrome. Roper et al. [2003] has reported that, for clinicians, deafness overshadowed symptoms of ASD. The result was a later diagnosis of autism in low-functioning individuals with hearing impairment, versus those without. However, in the Roper et al. study the age at which parents suspected developmental abnormalities did not differ between the autistic groups with and without hearing impairment, nor did the severity of the children’s autistic symptoms. In a condition such as CHARGE syndrome that involves multiple sensory and physical abnormalities, challenges to formal diagnosis are more daunting than in the case of visual or hearing impairment alone [Jure et al., 1991]. Developmental differences imposed by sensory limitations can be mistaken for psychopathology [Freeman and Groenveld, 2000] but equally, differences may be wrongly attributed to sensory impairment and their ramifications overlooked. There is no expert consensus as to the best assessment strategy in such instances. For example, there are no guidelines regarding how to adapt current standard autism diagnostic tools to accommodate individuals with sensory impairments [Cass, 1998; Lord, 2001 (personal communication); Hobson, 2004 (personal communication)]. A significant step has been taken with the collection of data from children with CHARGE syndrome on an autism screening instrument [Hartshorne and Cypher [2005]]. This has been our initial strategy also; the step from screening to reliable formal diagnosis remains an area for further research. Additional investigation is warranted given the serious repercussions of delaying either the diagnosis of autism or of sensory impairment, evidence for both of which has been reported in instances of dual diagnosis [Jure et al., 1991; Roper et al., 2003]. A related issue concerns the intellectual status of individuals with CHARGE syndrome. Although earlier authors had indicated that mental retardation was a usual feature of CHARGE syndrome [Hall, 1979; Lin et al., 1990], this claim has been refuted by other investigators [Goldson et al., 1986; Blake and Brown, 1993]. Only a few studies other than those in this Special Issue have provided information regarding the cognitive or adaptive behavioral development of children with CHARGE syndrome [Siebert et al., 1985; Goldson et al., 1986; Lin et al., 1990; Harvey et al., 1991], and these have reported on small samples. Nonetheless, findings from these studies suggest that outcomes are more varied than indicated by earlier reports, with some children functioning intellectually within the average range, or displaying specific learning
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Smith et al.
difficulties rather than global mental retardation [also see Salem-Hartshorne and Jacob, 2005a,b]. The focus of this report is on the initial data from our national surveillance pertaining to developmental and behavioral profiles of individuals with CHARGE syndrome, particularly evidence of ASDs. MATERIALS AND METHODS: SURVEILLANCE In the context of the CPSP, pediatricians and pediatric specialists across Canada, including geneticists, received a summary of the surveillance protocol, including a brief description and case definition criteria for CHARGE syndrome. The CPSP uses a two-tiered reporting process to ascertain and investigate cases. Physicians who have previously cared, or are currently caring, for an individual with known or suspect CHARGE syndrome notify the CPSP through a monthly mailed checklist that covers all of the conditions currently under surveillance. The overall response rate for these monthly reports is 83%. Case ascertainment is monitored by tracking duplicates, which constitute 27% of reports. Physicians who identify a possible case of CHARGE syndrome then receive a detailed reporting form. This form details the clinical information in a format that follows the case definition criteria [Blake et al., 1998; also see Issekutz et al., 2005] as well as other medical information. The response rate to date for the CHARGE syndrome reporting form is 98%. This excellent compliance is due to the active involvement of pediatricians and pediatric specialists in the entire process, as well as to quarterly follow-up reminders to participants from the CPSP central office. Information about the progress of the surveillance, including the monthly compliance rates and the number of cases reported, is mailed quarterly to keep participants informed. The principal investigator for the CHARGE Syndrome Surveillance (author KB) reviews all reported cases to determine whether the data meet the case definition criteria; consultant geneticists (JG and CP; see Acknowledgements) provide consultation regarding ambiguous cases. In the first 16 months of CHARGE syndrome surveillance in Canada [Blake, 2002; Issekutz et al., 2005], there have been 78 confirmed reports of individuals with CHARGE syndrome (39 males and 39 females). Of these, 70% are under 5 years; only 15% are aged 13 years or older. Our overall preliminary incidence estimate is 3.4 per 100,000 births. MATERIALS AND METHODS The study protocol was approved by the Research Ethics Board of the IWK Health Centre (Halifax, NS). Each CPSP reporting physician asked parents for permission for the investigators to contact them, providing them with a letter describing our group’s research interests. At the time of writing, consent for contact had been received from 40/78 individuals with a confirmed diagnosis. Once parents consented to participate, questionnaires were sent, returned, and a telephone interview was scheduled. The present data are from the first 13 participants for whom interviews have been conducted. We acknowledge the preliminary nature of our data and the potential for bias in this voluntary method. With more participants, we will be in a position to conduct an analysis of the characteristics of the consenting and nonconsenting cases (based on the CPSP reporting form data). Of the questionnaires, one was developed for our specific study purposes, and collected information regarding developmental milestones and accomplishments, sensory impairments and adaptations. These parent reports corroborated and/or supplemented information contained in the reporting physicians’ submissions to the CPSP. Standardized devel-
opmental and behavioral information was gathered for individual participants based on their chronological ages and, to the extent possible, developmental or mental ages, using the following measures. Child Development Inventory (CDI) This 300-item parent-completed questionnaire requests information about developmental accomplishments for children functioning in the range from birth to age 6, and yields age-equivalent scores [Ireton, 1992]. Behavior Assessment System for Children (BASC) Parents provide ratings (never, sometimes, often, almost always) on items that describe possible child behaviors displayed over the past 6 months. Three forms are available, covering ages 2½–5, 6–11, and 12–18 years. The BASC yields the Behavioral Symptoms Index, which reflects the total number of problematic behavioral symptoms, and consists of two subscales: the Externalizing Problems Composite (reflecting difficulty with activity and conduct), and the Internalizing Problems Composite (focusing on concerns related to anxiety, mood, and somatic symptoms). The BASC also provides an Adaptive Skills Composite score that reflects such constructs as adaptability (e.g., adjusting to change) and social (e.g., interpersonal) skills [Reynolds and Kamphaus, 1998]. Social Communication Questionnaire (SCQ) This 40-item screening instrument is derived from the Autism Diagnostic Interview—Revised [Lord et al., 1994]. The purpose of the SCQ is to identify children who show an increased probablility of meeting criteria for autism. Scores are based on yes/no responses indicating the presence or absence of atypical behaviors; high scores, therefore, represent more autistic behaviors [Berument et al., 1999]. As with other autism screening tools, there are presently no guidelines for the use of the SCQ in individuals with vision or hearing impairments (but see Hartshorne et al., 2005, for progress in this area). Supporting Documentation We also requested that parents send us copies of clinical and educational reports documenting their child’s development. Sources included reports from clinicians such as speechlanguage pathologists, occupational therapists, physiotherapists, and psychologists, as well as individual program plans provided by early childhood educators, deaf-blind education specialists, and school board and rehabilitation consultants. Once questionnaires were received, a standardized, semistructured interview was conducted with parents. Vineland Adaptive Behavior Scales The Interview edition, Survey form [Sparrow et al., 1984] was used as the basis of these parent interviews. The Vineland is a measure of adaptive functioning that yields both standard scores and age equivalent scores for three domains, Communication, Daily Living Skills, and Socialization, which are associated with functional independence. A Motor Skills domain is included only for those under 6 years. The Vineland has been standardized for individuals ranging in age from birth to 19 years, and is designed to be administered to parents or other caregivers by a trained interviewer. Telephone (n ¼ 11) or in-person (n ¼ 2) interviews were conducted by author IS (an academic clinical psychologist with expertise in autism) or by a senior Clinical Psychology graduate student (SN) working under her supervision. In addition to the administration of the Vineland, the interview
Behavioral Profiles in CHARGE
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TABLE I. Major and Minor CHARGE Syndrome Criteria of Study Participants
Major criteria Coloboma Choanal atresia/stenosisa Ear anomalies External Middle Internal Cranial nerve dysfunction Facial palsy VII Hearing VIII Swallowing IX, XI Minor criteria Genital hypoplasia Male ¼ M Female ¼ F Cardiac malformations Major (M), minor (m) Cleft Lip (L), palate (P) TE fistula Characteristic face Growth deficiency Hormone replacementb
1
2
3
4
5
6
7
8
9
10
11
12
13
þ
þ
þ þ, BP
þ þ
þ þ, BP
þ
þ þ
þ
þ
þ
þ þ, BP
þ þ, BP
þ
þ þ þ
þ þ
þ þ þ
þ þ
þ þ þ
n/a þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ þ
þ þ
þ
þ
þ þ þ
þ þ þ
þ þ
þ þ þ
þ þ
þ þ
n/a þ n/a
þ þ þ
n/a þ þ
F þ
M þ
M þ
M þ
F
M þ
F
M
F
M þ
M þ
F n/a
M þ
m
M
M
M
M
M
m
m
M
þ þ
þ þ
n/a SH
þ
þ
þ þ
þ
L, P þ
þ þ þ GH
P þ þ
n/a þ þ SH
þ þ SH
P þ þ þ SH
n/a, not available. a BP, bilateral posterior choanal atresia. b SH, sex steriods; GH, growth hormone.
allowed us to clarify ambiguous responses to the questionnaires, and, importantly, to gather specific behavioral examples to support items endorsed by parents on the SCQ. Judgments regarding evidence of ASD in each individual were made by IS. These judgments were based on the accumulation of data from interviews, questionnaires, and clinical reports. RESULTS Our results focus on the CHARGE syndrome characteristics of 13 individuals (eight males, five females), their levels of adaptive functioning and behavioral profiles, especially autistic symptoms. In Table I, we present information about the CHARGE syndrome characteristics of the participants in this series, ranging in age from 2 years, 9 months to 24 years at the time of contact with parents (mean age 9 years). Six individuals demonstrate four major diagnostic criteria, and seven, three major and three minor criteria. Table II summarizes the sensory impairments for each participant.
Table III shows the Vineland Adaptive Behavior Scales results demonstrating that the overall Adaptive Behavior Composite standard scores for all participants fell within the impaired range, from below 20 to 68 [(mean of 50); expected mean for this test: 100, with SD 15]. Standard scores could not be derived for one high-functioning individual older than the standardization range (participant no. 13). Note this individual’s particularly low age-equivalent score on the Socialization domain. There was one individual for whom too many items were missing for valid scoring (participant no. 12). For the remaining participants, levels of functioning across domains were relatively even. Child Development Inventory (CDI) results are shown in Table IV for the eight cases within the appropriate developmental range for this measure (mean chronological age when questionnaires were completed: 5 years, 7 months; range: 2 years, 11 months to 11 years, 8 months). For ease of comparison, age-equivalent scores have been converted to nonstandardized developmental quotients [(age-equivalent
TABLE II. Hearing and Visual Impairments of Study Participants With CHARGE Syndrome Case no.
1
2
3
Nor
Mild
Sev Hearing Prof Vision
Nor
5
Mod
Mod
Prof b
Mod
6
7
Mod
Profa
Sev
Mod Sev
8
9
Mod
Sev
11
12
13
Sev
Mod
Mod
Mod
Prof
Sev
Prof
Prof
Prof
Nor
Mod
Mod
Mild Mod
Prof
10
Prof Prof
Mod Sev
a
4
Prof Mod
Cochlear implant. No reliable testing. Definitions-Hearing Loss: specified separately for each ear where information is available: Nor(mal). Mild hearing loss 20–40 dB; or severe or profound in one ear only, other ear normal. Mod(erate) hearing loss 41–70 dB. Sev(ere) hearing loss 71–95 dB. Prof(ound) hearing loss >95 dB. Definitions-Vision Loss: Nor(mal). Mild VA(visual acuity) 6/6–6/18 corrected in better eye; severe or profound problem with one eye only, other eye normal. Mod(erate) VA 6/24–6/36 in better eye; able to read print with simple aids and/or education assistance; defect of at least half of visual field (hemianopia); VA may be normal. Sev(ere) VA 6/60–3/60 in better eye; unable to read large print without intensive educational assistance or sophisticated aids; severe visual field defect with impaired visual acuity. Prof(ound) VA < 3/60, i.e., counting fingers, hand movements, light perception or less; very little useful vision. b
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Smith et al. TABLE III. Vineland Adaptive Behavior Scales Standard Scores* for Participants With CHARGE Syndrome
Case no. 1 2 3 4 5 6 7 8 9 10 11 12 13b Mean (SD)
Age at interview Daily (years–months) Communication living skills Socialization 3–2 3–5 4–4 5–7 4–6 4–4 5–4 5–10 9–1 12–1 17–3 23–7 24–2 6–10 (4–4)
60 82 79 48 68 53 57 43 26
