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Home , Autism, Autism spectrum, Fragile X syndrome

Autism in : Cooccurring Conditions and Current Treatment Walter E. Kaufmann, MD,a, b Sharon A. Kidd, PhD, MPH,c Howard F. Andrews, PhD,d Dejan B. Budimirovic, MD, e Amy Esler, PhD, LP, f Barbara Haas-Givler, MEd, BCBA,g Tracy Stackhouse, MA, OTR,h Catharine Riley, PhD, MPH,i Georgina Peacock, MD, MPH, i Stephanie L. Sherman, PhD, j W. Ted Brown, MD, PhD,k Elizabeth Berry-Kravis, MD, PhDl

abstract BACKGROUND AND OBJECTIVE: Individuals with fragile X syndrome (FXS) are frequently codiagnosed with spectrum disorder (ASD). Most of our current knowledge about ASD in FXS comes from family surveys and small studies. The objective of this study was to examine the impact of the ASD diagnosis in a large clinic-based FXS population to better inform the care of people with FXS. METHODS: The study employed a data set populated by data from individuals with FXS seen at specialty clinics across the country. The data were collected by clinicians at the patient visit and by parent report for nonclinical and behavioral outcomes from September 7, 2012 through August 31, 2014. Data analyses were performed by using χ2 tests for association, t tests, and multiple logistic regression to examine the association between clinical and other factors with ASD status. RESULTS: Half of the males and nearly 20% of met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria for current ASD. Relative to the FXS-only group, the FXS with ASD (FXS+ASD) group had a higher prevalence of (20.7% vs 7.6%, P < .001), persistence of sleep problems later in childhood, increased behavior problems, especially aggressive/disruptive behavior, and higher use of α-agonists and . Behavioral services, including applied behavior analysis, appeared to be underused in children with FXS+ASD (only 26% and 16% in prekindergarten and school-age periods, respectively) relative to other populations with idiopathic ASD. CONCLUSIONS: These findings confirm among individuals with FXS an association of an ASD diagnosis with important cooccurring conditions and identify gaps between expected and observed treatments among individuals with FXS+ASD.

a Department of , Boston Children’s Hospital, Boston, Massachusetts; bGreenwood Genetic Center, Greenwood, South Carolina; cNational Fragile X Foundation, Washington, District of Columbia; dDepartment of Biostatistics, Columbia University Mailman School of Public , New York, New York; eKennedy Krieger Institute, Baltimore, Maryland; fUniversity of Minnesota, Minneapolis, Minnesota; gGeisinger Health System, Lewisburg, Pennsylvania; hDevelopmental FX, Denver, Colorado; iNational Center on Birth Defects and Developmental , Centers for Control and Prevention, Atlanta, Georgia; jDepartment of , Emory University School of Medicine, Atlanta, Georgia; kNew York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York; and Departments of lPediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, Illinois

Dr Kaufmann conceptualized and designed the analyses, contributed to data collection and interpreted the data, drafted the initial manuscript, and revised the manuscript; Dr Kidd contributed to design of the analyses, interpreted the data, and drafted and revised the manuscript; Dr Andrews analyzed and contributed to the interpretation of the data and critically reviewed and revised the manuscript; Dr Budimirovic contributed to design of the analyses, contributed to data collection and interpretation of the data, and drafted and revised the manuscript; Dr Esler contributed to data collection and interpretation of the data and critically reviewed and revised the manuscript; Ms Haas-Givler contributed to the conception and design of the analyses, contributed to data collection, and assisted with drafting of the manuscript; Ms Stackhouse contributed to the conception and design of the analyses and assisted with drafting of the manuscript; Dr Riley drafted and revised the manuscript; Dr Peacock critically reviewed and revised the manuscript; Dr Sherman contributed to the conception and design of the analyses and critically

Downloaded from www.aappublications.org/news by guest on September 24, 2021 SUPPLEMENT ARTICLE Volume 139 , Number s3, June 2017 :e 20161159 Fragile X syndrome (FXS)1, 2 is the individuals with FXS exhibit poor FXS+ASD also have a higher rate most common known inherited form , difficulties with peer of seizures than those with FXS of intellectual (ID), with relationships, social withdrawal, only. 13, 32 The increased frequency prevalence estimates of ∼1/4000 repetitive behaviors, and need for of neurologic and behavioral to 1/5000 in males and ∼1/6000 to sameness (ie, distress at apparently impairments in subjects with 1/8000 in females.3 –5 FXS is nearly small changes in daily activities). 6, 14, 15 FXS+ASD appears to result in more always due to an expanded CGG Depending on the gold standard severe educational and vocational repeat sequence (>200 repeats), research criteria used for the problems, 7 as well as more significant termed a “full , ” in the 5′ diagnosis of autism or ASD, studies therapeutic challenges, than those untranslated region of the FMR1 on males with FXS have reported that present in subjects with FXS only, located at Xq27.3. Smaller CGG 30% to 54% met diagnostic criteria although data describing these repeat expansions in the range of 55 for autism by direct assessment16 – 18 outcomes are limited. to 200 (termed the “premutation”) and 46% by parent report.19 In are associated with other clinical addition, 30% to 43% of males met The main obstacle for determining presentations, reviewed elsewhere.6, 7 diagnostic criteria for ASD20 or medical and neurobehavioral The majority of males who carry the pervasive – cooccurring conditions exacerbated full mutation have mild to moderate not otherwise specified.18 For by ASD in FXS, and their impact ID. One-third to one-half of all females, 16% to 20% met diagnostic on interventions and outcomes, is females with the full mutation have criteria for autism17 or were assigned that most studies of ASD in FXS are normal intellectual function because by parent report. 19 –22 Several studies based on small clinical research of cellular mosaicism resulting have attempted to delineate unique samples or family surveys. Small from X- inactivation features of ASD in FXS; their findings cohorts may not be generalizable to patterns. 8, 9 A high proportion of show relatively more prominent the entire population and although males and females with FXS display social withdrawal, higher levels of family surveys may produce behavioral abnormalities.6 As with anxiety, and less intense simple and accurate accounts of medical most aspects of the FXS , complex repetitive and restricted data, this type of information behavioral manifestations in FXS are behaviors as measured by ASD always needs to be confirmed in quite variable and include diagnostic instruments.6, 13 a clinical setting. The Fragile X deficits, hyperactivity/impulsivity, Online Registry With Accessible hyperarousal, anxiety, self-injurious ASD is a lifelong disorder that Research Database (FORWARD), a behavior, and impacts multiple aspects of the registry and longitudinal database, disorder (ASD).6 individual’s functioning. Comparisons provides a large sample size with between subjects with FXS with ASD clinical data for this rare disorder ASD is a developmental behaviorally (FXS+ASD) and subjects with FXS to examine the impact of ASD in defined disorder with multiple without ASD (FXS only) reveal that FXS (see Sherman et al in this etiologies. Among the genetic causes, the former group is more affected supplement). In this study, we used FXS is the most common known in many cognitive 9, 20, 23, 24 FORWARD to study the impact of inherited single-gene disorder, and behavioral areas.6, 7, 13 – 15,25 an ASD diagnosis in children and accounting for an estimated 1% to Examples of areas that are more adolescents/young adults with 6% of all cases of ASD.10, 11 ASD is problematic in those with FXS+ASD FXS in 4 key areas: (1) neurologic characterized by an impairment in than in those with FXS only include cooccurring conditions known social interaction and less developed language skills, to be associated with idiopathic and the presence of restricted and particularly receptive skills 21, 23, 26, 27; ASD, including seizures and sleep repetitive patterns of behavior, lower nonverbal cognition and IQ disorders; (2) behavioral cooccurring interests, or activities.12 Other scores28, 29; lower adaptive skills 21; conditions; (3) psychopharmacologic cooccurring behavioral abnormalities and, in small cohorts, more severe interventions targeting behavior; are often associated with these overall behavioral problems (eg, and (4) nonpharmacologic core symptoms (eg, anxiety).13 The attention problems, hyperactivity interventions. Based on past relationship between FXS and ASD is and impulsivity, anxiety, aggressive literature and clinical impressions, complex and evolving, influenced in and self-injurious behaviors).7, 30,31 we hypothesized that (1) the part by revised definitions of ASD12 Idiopathic ASD is associated with association of an ASD codiagnosis and by a better understanding of a higher rate of than seen with seizures would be confirmed, behavioral associated in the general population and, particularly by the time patients with FXS. 6 Although variable in likewise, data from a single survey reached the adolescent/young degree, a large proportion of study indicate that individuals with adult ages; (2) there would be more

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S195 frequent sleep problems requiring and 3 standardized parent-report criteria, because DSM-5 criteria were treatment in the FXS+ASD group, instruments, including the Social not available until the spring of 2013. especially in children (based on data Responsiveness Scale, Second Analyses related to neurologic in idiopathic ASD); (3) behavioral Edition (SRS-2),33, 34 the Social and behavioral problems and problems would be increased in Communication Questionnaire psychopharmacology were the group with FXS+ASD in both (SCQ), 35, 36 and the Aberrant performed for 2 selected age groups, age groups, particularly irritability/ Behavior Checklist, Community ages 3 to 11 (children, N = 348) aggression, perseverative/obsessive Edition.37, 38 The SCQ and SRS-2 are and ages 12 to 21 (adolescents/ , and sensory completed once over the 4-year young adults, N = 199), because hypersensitivity/overreactivity; period of the current study. This the impact of the ASD diagnosis on (4) use of psychopharmacology article only includes analyses of the certain parameters might differ by would be increased in the FXS+ASD SCQ data because collection of the age. 13, 21 The upper age limit was group, particularly antipsychotics SRS-2 started later in the project to chosen because pediatric patients for aggression, and predominantly accommodate the incorporation of transition to adult care between in adolescents/young adults; the update of the SRS-2. Analyses the ages of 18 and 21 years. The and (5) use of nonpharmacologic presented in this article were following variables were compared interventions, especially behavioral conducted on a fixed cross-sectional between groups of patients with interventions, such as applied data set (FORWARD Dataset, Version and without a diagnosis of ASD: behavior analysis (ABA), would 1.0) by using registry data linked to frequency of seizures occurring at be increased in the FXS+ASD clinical baseline (cross-sectional) any age, sleep problems requiring codiagnosis group, mainly in data on 713 subjects with FXS, or treatment, cooccurring children. Ultimately, the goal of the collected from September 7, 2012 behavioral problems (including current study was to examine the to August 31, 2014. After excluding attention deficits, hyperactivity, impact of the ASD diagnosis in the patients due to age considerations sensory hypersensitivity/ FXS population in a way that may and availability of data on ASD overreactivity, anxiety, obsessive begin to inform clinical and public status, almost 600 individuals compulsive disorder/perseverative health approaches. were eligible for most of the study behavior, mood swings/, analyses presented in this article. Full and irritability/aggression); use details on the creation, enrollment, of psychotropic medication for maintenance, and data quality and METHODS treatment of behavior in any of management for FORWARD are the above categories; and type of Data for this report were derived presented in an accompanying report psychotropic medication used for any from FORWARD, a multisite, in this supplement (Sherman et al). behavior. Parents were asked about observational study that includes a provision of services to the patient registry and longitudinal database Data related to ASD diagnosis during school years (preschool, using standardized clinician- and were obtained from the FORWARD elementary, and high school). parent-report data submitted clinician report form. The diagnosis These services are in the categories by 25 of the 27 fragile X clinics of ASD was ascertained with of , speech and affiliated with the Fragile X Clinic the question “Based on THIS language therapy, occupational and Research Consortium. Clinics clinic assessment, does the child therapy, sensory integration therapy, obtained institutional research CURRENTLY have a diagnosis of , psychological/ board approval from their own ASD?” (capitalized emphasis from behavioral program, institutions before enrolling families the question itself). The question was therapy, or program, tutoring, and in FORWARD. Written informed answered by the clinician by using ABA. consent was obtained at the time of Diagnostic and Statistical Manual a clinic visit from parents/guardians of Mental Disorders, Fifth Edition The frequency of characteristics is and from adult patients for whom (DSM-5) criteria12 as required by the presented as a number (percentage) legal guardianship was not required. FORWARD data collection training according to diagnosis (FXS+ASD, Data in the longitudinal database are (ie, by taking relevant clinical history FXS only) and age (within age collected yearly from participants and observation). However, during group or age groups combined). by clinicians, primarily during a the first 6 months of enrollment, The χ2 statistic was used to test for patient’s scheduled clinic visit, a small number of subjects were association between variables. For and by parents/caregivers. Data likely diagnosed using Diagnostic continuous variables, means and are collected by using a clinician and Statistical Manual of Mental their respective confidence intervals report form, a parent report form, Disorders, Fourth Edition (DSM-IV) (CIs) were obtained. Multiple logistic

Downloaded from www.aappublications.org/news by guest on September 24, 2021 S196 KAUFMANN et al TABLE 1 Seizures and Sleep Problems Associated With FXS+ASD and FXS Only, by Age Groups and All Ages, in Subjects Enrolled From September 7, 2012 Through August 31, 2014, FORWARD Database Ages 3–11 y Ages 12–21 y All Ages FXS+ASD FXS Only P FXS+ASD FXS Only P FXS+ASD FXS Only P Does/did child have seizures (ever and currently)? Total N 85 128 56 56 140 184 N (%) 12 (14.1) 8 (6.2) <.05a 17 (30.9) 6 (10.7) <.01a 29 (20.7) 14 (7.6) <.001a Is child currently on treatment of sleep problems (includes behavioral treatments) Total N 87 129 56 56 143 185 N (%) 36 (41) 46 (36) <.40 23 (41) 9 (16) <.003a 59 (41.3) 55 (29.7) <.03a FORWARD is a data set of clinician and parent-report information from specialty clinics in the FXCRC. χ2 tests for association were used to obtain P values for differences in proportions between case groups for use of services. a Signifi cant P value (a level of .05 was considered statistically signifi cant). regression was used for multivariate compared with the FXS-only group pronounced for anxiety, with only analyses related to the use of services (20.7% vs 7.6%, P < .001) (Table 1). the adolescent/young adult FXS+ASD and ASD status. Analyses were This difference was driven mostly by group showing a significantly higher performed by using the Statistical the older age group. Sleep problems occurrence of anxiety than its FXS Package for the Social Sciences (IBM requiring treatment with behavioral only counterpart (98% vs 87%). SPSS Statistics, IBM Corporation) methods or were also Mood swings/depression problems and Epi Info, Version 7.1.5.0 (Centers more common in the FXS+ASD group were less common in the data set as for Disease Control and Prevention, (all ages, 41% vs 30%, Table 1). The a whole (∼18%), and no significant Atlanta, GA). difference between the 2 diagnostic difference was observed between groups was mainly due to a higher those with and without ASD. proportion of sleep problems in the RESULTS adolescent/young adult FXS+ASD Impact of ASD Codiagnosis on Use of Briefly, there were more males (78% group (41% vs 16%, P < .003). In Psychoactive Drugs in FXS male vs 22% ), individuals the 3 to 11 years of age group, sleep that identify themselves as white problems were frequent in general, The use of psychoactive drugs (88.7%), and individuals <15 years occurring in ∼40% of children in in FXS was evaluated in 2 of age (75%) (see Sherman et al in both the FXS+ASD and FXS-only complementary ways: by drugs this supplement). The FORWARD groups. used for specific symptoms (eg, Dataset Version 1.0 included 237 anxiety) and by categories of drugs (42%) subjects who were diagnosed Impact of ASD Codiagnosis on (eg, α-adrenergic agonists). Overall, Behavioral Problems in FXS by the clinic physician as having ASD. 66% of participants with FXS of The prevalence was much higher Behavioral problems are prevalent any age were on some type of in males than in females (51% vs in FXS, regardless of ASD status psychopharmacologic treatment of 18%, P < .001). The ASD group had a and age, particularly attention common behavioral problems. Table significantly higher mean SCQ total problems and anxiety (both >75%, 3 illustrates that the only behavior score than the FXS-only group (17.2 Table 2). In general, the behavioral for which there was a significantly vs 11.6, P < .001), mean difference = problem profiles were similar in higher use of psychopharmacology 5.6 points (95% CI = 4.4–6.8). The children and adolescents/young among those with FXS+ASD was prevalence of ASD in the 3 to 11 adults. Regardless of their relative aggressive/disruptive behavior. years of age group was 42.2% (N = frequency, however, there was Concomitantly, there was a 147) and it was 45.2% (N = 90) in the a markedly higher proportion of significantly higher use of α-agonists 12 to 21 years of age group. attention problems, hyperactivity, and antipsychotics (which are hypersensitivity/overreactivity, typically used to treat aggression) in Impact of ASD Codiagnosis on perseverative/obsessive compulsive the FXS+ASD group ( Table 4). There Seizures and Sleep in FXS behavior, and irritability/aggressive were no significant differences in the Across all ages and diagnostic behavior among those with FXS+ASD use of , selective groups, the prevalence of seizures versus those with FXS only in both reuptake inhibitors (SSRIs), mood ever occurring was 13.3%. The age groups (all at least P < .02). The stabilizers, anxiolytics, or non- FXS+ASD group was more likely to difference between the FXS+ASD SSRI between FXS have had seizures at some time in life and FXS-only groups was less participants with and without ASD.

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S197 TABLE 2 Behavioral Problems Associated With FXS+ASD and FXS Only, by Age Group, in Subjects Enrolled From September 7, 2012 Through August 31, 2014, FORWARD Database Ages 3–11 y Ages 12–21 y Does the Child Currently Have This FXS+ASD (N = 144) FXS Only (N = 199) P FXS+ASD (N = 90) FXS Only (N = 109) P Behaviora: N (%) Attention problems 126 (88) 153 (77) <.01b 81 (90) 84 (77) <.02b Anxiety 120 (83) 149 (76) <.08 87 (98) 93 (87) <.006b Hypersensitivity/overreaction to 114 (82) 130 (66) <.001b 74 (87) 60 (56) <.001b stimuli/emotionally reactive Hyperactivity 108 (75) 126 (63) <.02b 57 (65) 44 (40) <.001b Irritability/aggression/agitation/ 103 (72) 76 (38) <.001b 63 (71) 39 (37) <.001b self-injury Obsessive compulsive disorder/ 95 (67) 87 (44) <.001b 64 (72) 56 (53) <.006b perseverative behavior Mood swings/depression 22 (16) 29 (15) <.79 22 (25) 22 (21) <.51 FORWARD is a data set of clinician and parent-report information from specialty clinics in the FXCRC. χ2 tests for association were used to obtain P values for differences in proportions between case groups for use of services. a Responses to this question were inconsistently answered among clinicians; 60% responded for behavior with the patient on medication and 40% responded for behavior when the patient was not on medication. b Signifi cant P value (a level of .05 was considered statistically signifi cant).

TABLE 3 Treatment of Behaviors in FXS+ASD and FXS only, by Age Group, in Subjects Enrolled From September 7, 2012 Through August 31, 2014, FORWARD Database Ages 3–11 y Ages 12–21 y Is This Behavior Being Treated With FXS+ASD (N = 111) FXS Only (N = 164) P FXS+ASD (N = 52) FXS Only (N = 70) P Medicationa, b: N (%) Anxiety 39 (35) 43 (26) <.11 33 (64) 40 (57) <.48 Aggression/disruptive behavior 36 (32) 18 (11) <.001c 32 (62) 21 (30) <.001c Attention problems 29 (26) 49 (30) <.50 24 (46) 33 (47) <.91 Depression 9 (8) 7 (4) <.18 10 (19) 12 (17) <.77 FORWARD is a data set of clinician and parent-report information from specialty clinics in the FXCRC. χ2 tests for association were used to obtain P values for differences in proportions between case groups for use of services. a Only subjects on investigational drugs were excluded from the analyses. b Subjects in FXS+ASD and FXS-only groups could be treated for >1 behavior. c Signifi cant P value (a level of .05 was considered statistically signifi cant).

Impact of ASD on Use of Services in TABLE 4 Psychotropic Drug Class Use by FXS+ASD and FXS Only, by Age Group, in Subjects Enrolled Individuals With FXS From September 7, 2012 Through August 31, 2014, FORWARD Database Ages 3–11 y Ages 12–21 y Use of services at school was Is the Child Being FXS+ASD FXS Only P FXS+ASD FXS Only P examined in 2 groups, preschool and Treated With Medication (N = 111) (N = 164) (N = 52) (N = 70) kindergarten to grade 12 (K-12), for a Behavioral both in terms of total services (ie, Problemsa, b: N (%) proportion of subjects using any Antipsychotics 31 (28) 21 (13) <.002c 32 (62) 20 (29) <.001c service, mean number of services) as SSRIs 29 (26) 31 (19) <.16 17 (33) 34 (49) <.08 well as the proportion using specific Stimulants 21 (19) 41 (25) <.24 22 (42) 33 (47) <.60 α c c services. In the preschool group, a -agonists 24 (22) 15 (9) <.004 19 (36) 9 (13) <.002 Non-SSRI 3 (3) 1 (1) <.16 5 (10) 3 (4) <.24 higher proportion of children with antidepressants FXS+ASD received any service (P < Mood stabilizers 4 (4) 1 (1) <.07 2 (4) 4 (6) <.64 .008), specifically special education Anxiolytics 4 (4) 1 (1) <.07 2 (4) 1 (1) <.40 (P < .003) and ABA services (P < .02), FORWARD is a data set of clinician and parent-report information from specialty clinics in the FXCRC. χ2 tests for association than those with FXS only ( Table 5). It were used to obtain P values for differences in proportions between case groups for use of services. a Only subjects on investigational drugs were excluded from the analyses. is of note that ABA was used less than b Subjects in FXS+ASD and FXS-only groups could be treated with >1 class of medications. any other service in the preschool c Signifi cant P value (a level of .05 was considered statistically signifi cant). period in either group. The average number of services among children preschool period (3.1 vs 2.7, mean time of the clinic visit, the more likely with FXS+ASD was significantly difference, 0.5 [95% CI = 0.1–0.8]). he/she is to have had a particular higher than for those with FXS in the Given that the older the child is at the service, we adjusted for age at the

Downloaded from www.aappublications.org/news by guest on September 24, 2021 S198 KAUFMANN et al TABLE 5 Use of Services in FXS+ASD and FXS Only, Reported for Preschool Years, in Subjects Aged 3 to 21 Years, Enrolled From September 7, 2012 Through August 31, 2014, FORWARD Database % Receiving Services (Unadjusted) Service FXS+ASD (N = 164) FXS Only (N = 211) P Adjusted Odds Ratio (95% CI)a Adjusted P Any prekindergarten services 149 (91) 171 (81) <.008b 2.33 (1.23–4.42) <.01b Speech and language therapy 142 (87) 167 (79) <.06 1.70 (0.97–2.98) <.06 Occupational/ sensory integration 129 (79) 150 (71) <.10 1.50 (0.93–2.43) <.10 therapy Special education 119 (73) 122 (58) <.003b 1.93 (1.25–3.00) <.003b Physical therapy 73 (44) 83 (39) <.31 1.24 (0.82–1.88) <.31 ABA/modifi ed ABA/other behavioral 42 (26) 34 (16) <.02b 1.83 (1.09–3.06) <.02b Parents were asked to report on all services that were used historically during the preschool period. FORWARD is a data set of clinician and parent-report information from specialty clinics in the FXCRC. χ2 tests for association were used to obtain P values for differences in proportions between case groups for use of services. a Adjusted for age (in years) at clinic visit; odds ratio, the odds of using a service given ASD+FXS status. b Signifi cant P value (a level of .05 was considered statistically signifi cant).

TABLE 6 Use of Services in FXS+ASD and FXS Only, Reported for Kindergarten Through High School Years, in Subjects Aged 5 to 21 Years, Enrolled From September 7, 2012 Through August 31, 2014, FORWARD Database % Receiving Services (Unadjusted) Service FXS+ASD (N = 143) FXS Only (N = 181) P Adjusted Odds Ratio (95% CI)a Adjusted P Any K-12 services 131 (92) 156 (86) <.13 1.73 (0.81–3.68) <.15 Speech and language 123 (86) 132 (73) <.004b 2.31 (1.30–4.12) <.005b therapy Special education 114 (80) 124 (68) <.03b 1.84 (1.09–3.09) <.02b Occupational therapy 108 (75) 106 (59) <.001b 2.18 (1.35–3.53) <.002b Social skills 62 (43) 73 (40) <.59 1.16 (0.73–1.83) <.53 Sensory integration 44 (31) 32 (18) <.006b 2.08 (1.24–3.51) <.006b therapy Psychological/ behavioral 39 (27) 36 (20) <.12 1.53 (0.91–2.58) <.11 Physical therapy 35 (24) 37 (20) <.39 1.26 (0.74–2.13) <.39 ABA 23 (16) 21 (12) <.24 1.46 (0.77–2.76) <.25 Tutoring 10 (7) 21 (12) <.16 0.59 (0.27–1.30) <.19 Vocational training 12 (8) 16 (9) <.89 1.22 (0.51–2.88) <.66 Parents were asked to report on all services that were used historically during the K-12 period. Only subjects 5 to 21 years of age were included. FORWARD is a data set of clinician and parent-report information from specialty clinics in the FXCRC. χ2 tests for association were used to obtain P values for differences in proportions between case groups for use of services. a Adjusted for age (in years) at clinic visit; odds ratio, the odds of using a service given ASD+FXS status. b Signifi cant P value (a level of .05 was considered statistically signifi cant). time of baseline visit using multiple group, a statistically significantly .005), special education (P < .02), logistic regression. The total of any higher proportion of children with (P < .002), and services (P < .01), special education FXS+ASD received special education, sensory integration therapy (P < (P < .003), and ABA (P < .02) were speech and language therapy, .006) were used significantly more used significantly more often in the occupational therapy, and sensory often in the ASD+FXS group relative ASD+FXS group relative to the FXS- integration therapy than those with to the FXS-only group in the K-12 only group during the preschool FXS only (P values ranged from period regardless of current age. P < .03 to P < .001). Similar to the Similar to the preschool period, those period, controlling for current age. preschool period, ABA services with ASD+FXS were approximately The odds ratios for these services were not used to a high degree in twice as likely to use these services indicate that the odds of service either group. The average number as those with FXS only. use among those with ASD+FXS are of services among children with approximately twice as great as FXS+ASD was significantly higher DISCUSSION among those with FXS only. than among those with FXS only (4.1 By contrast, during the K-12 period, vs 3.4, mean difference, 0.7 [95% ASD is a common codiagnosis the proportion of children receiving CI = 0.2–1.2]). Again, as was done for for patients with FXS and is any services, although somewhat the preschool period, we adjusted associated with increased severity higher in the ASD group, was not for age at the time of baseline visit of developmental and behavioral significantly greater than in the FXS- by using multiple logistic regression. symptoms. Despite the frequency only group (Table 6). In the K-12 Speech and language therapy (P < and severity of ASD in FXS, there are

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S199 still important gaps in knowledge in due to confusion with other types of into the young adult years. This many areas, ranging from diagnostic episodes (eg, abnormal behaviors). possible lack of maturation of sleep accuracy to need for and response to The clinical evaluation of in FXS+ASD has not been reported drugs and other treatments, because history by a physician allows before and, if confirmed, could be most of the available literature is nonepileptic episodes to be filtered a significant contributor to family based on small clinical or research out and is expected to result in more . samples and family surveys. The accuracy in the identification of FORWARD longitudinal database patients with a seizure history.40 As Impact of ASD Codiagnosis on constitutes a unique large-scale hypothesized, seizure history was Behavioral Problems in FXS source of clinician-acquired data associated with an ASD diagnosis, The FORWARD cohort showed a for confirming and expanding our with a stronger association in the higher prevalence of a wide range knowledge about ASD in FXS. The adolescent/young adult group of behavioral problems in the current study focused on determining because, by that age, most individuals FXS+ASD group as compared with the impact of an ASD codiagnosis in with FXS had manifested their the FXS-only group. The FXS+ASD FXS, to address specific hypotheses seizures if they were going to do so. group had the most dramatically about neurologic and behavioral This result is consistent with the increased (over the FXS-only cooccurring conditions and finding of an association between group) frequency of irritability/ treatment approaches associated seizures and an ASD codiagnosis aggression, perseverative/obsessive with the ASD codiagnosis. The in survey studies18, 29 and confirms compulsive behavior, and sensory analyses from FORWARD presented this relationship in a clinically hypersensitivity/overreactivity, as in this article are consistent with characterized population, increasing hypothesized based on behavior clinical experience and findings the likelihood of the association and patterns reported in FXS surveys18 reported in the existing literature emphasizing the concept of shared and in idiopathic ASD.47 There on ASD in the FXS population, but resulting in both was also a less obvious, but still also provide new information on the epilepsy and ASD phenotypes.41 significant, increase in frequency of magnitude of cooccurring conditions hyperactivity, attention problems, and differences in the use of services The overall frequency of significant and anxiety in the FXS+ASD group between affected groups. sleep problems (needing therapeutic with respect to the FXS-only group, intervention) in the FORWARD data although there were no differences Impact of ASD Codiagnosis on set was comparable to previous in the frequency of mood problems. Seizures and Sleep in FXS reports.42, 43 The fact that similar Although the association of The frequency of seizure history in findings were observed both in behavioral problems with FXS+ASD FXS+ASD in this FORWARD cohort is FORWARD and previous survey- serves to confirm previous smaller somewhat lower than that reported based studies confirms that parents studies, the FORWARD data set in cohorts from multiple previous consistently report sleep problems contains additional information studies,30 although it is consistent in FXS. As expected, based on high to illustrate the impact of ASD with the frequency of 16% reported frequencies of sleep dysfunction in codiagnosis in FXS on multiple from the 2005–2011 Fragile X idiopathic ASD,44 the FXS+ASD group behaviors with a defined pattern of Clinic and Research Consortium in the FORWARD data set had a strength of association with specific pilot database. 39 This difference is higher frequency of sleep problems. behavioral classes. In addition, perhaps due to ascertainment bias It has been hypothesized that the the association between ASD and in previous large studies from clinics impact of ASD codiagnosis on sleep anxiety in the FORWARD data set where the clinic’s physician was a problems would be larger in the was statistically significant for the neurologist, thus attracting patients younger group, given the tendency adolescent/young adult FXS+ASD with seizures. The FORWARD for sleep problems to be worse in group, in contrast with previous data set is probably less skewed younger children with idiopathic survey data indicating a link at because many clinics’ physicians ASD.45, 46 In fact, sleep problems all ages. 13 Overall, the frequency are developmental pediatricians or were frequent in both of the younger of reported anxiety in the FXS psychiatrists and thus would not patient groups in the FORWARD data population represented in FORWARD particularly concentrate on patients set, both those with and without was substantially higher than in needing seizure management. ASD. However, whereas the FXS-only family surveys (∼80% FORWARD Although ascertainment bias related group appeared to be more likely vs ∼50% in the National Fragile to clinical expertise would not be to grow out of their sleep problems, X Survey 13). This could be in part present in a survey study, seizures the FXS+ASD continued to have because of ascertainment bias may be overreported by parents sleep problems after early childhood resulting from recruiting participants

Downloaded from www.aappublications.org/news by guest on September 24, 2021 S200 KAUFMANN et al in a clinic setting, where patients of SSRIs in this group was lower than group. In a US national survey, autism often go for behavioral treatment. in the FXS-only group, likely due to status among individuals with FXS the common clinical experience of was significantly associated with Impact of ASD Codiagnosis on Use of better effectiveness of antipsychotics receipt of behavior management Psychoactive Drugs in FXS for symptom combinations of therapy among males, but not for In agreement with previous reports anxiety and aggression/irritability ABA specifically. 57 on the use of psychoactive drugs in often seen in those with FXS+ASD Because these types of therapies the FXS population, a high proportion (although there is a dearth of would be expected to address critical of individuals with FXS are treated literature on this 53), or due to side support needs in FXS+ASD, their with psychoactive drugs.48 – 50 This effects of disinhibition from SSRIs, underutilization in this cohort may report, however, represents the first which may occur in FXS and other be the result of limited availability. comparison of patterns of use of neurodevelopmental disorders.21 The Indeed, families of children with psychopharmacology in FXS+ASD only symptom specifically targeted idiopathic ASD are more likely to versus FXS only. As hypothesized by by psychopharmacology more report unmet needs with respect to the authors, and based on clinical commonly in those with FXS+ASD therapies compared with families of experience and the extensive use than with FXS only was aggressive/ children with other special health of antipsychotics in idiopathic disruptive behavior, a finding care needs, including provider ASD, use of antipsychotics was previously reported exclusively for inability to treat the child as a barrier significantly more prevalent in those individuals with FXS and both to obtaining therapy. 58 Nonetheless, the FXS+ASD group as compared ASD and anxiety. 13 other factors may affect provision with the FXS-only group. Although of services to individuals with overall rates of use Impact of ASD Codiagnosis on Use of Services in Individuals With FXS FXS+ASD. It is of note that ∼20% in the younger group were lower, of children with FXS+ASD of all somewhat unexpectedly, the use This study presents new data on ages in FORWARD were receiving of antipsychotics in the FXS+ASD service use in FXS with and without ABA, whereas 36% of children with group was approximately double ASD codiagnosis. As hypothesized idiopathic ASD were reported to that of the FXS-only group at both and consistent with literature be receiving ABA by parents in an age levels. This may suggest that on idiopathic ASD,54 – 56 among internet survey of treatments.59 in FXS+ASD, behavioral issues are individuals receiving services during more difficult in childhood, possibly preschool and school-time periods, Comparison and Implications for leading to the use of more potent the FXS+ASD group had a higher Idiopathic ASD medications with higher levels of proportion of children in special side effects even at a young age. A education, receiving speech and The features distinguishing greater use of α-adrenergic agonists language therapy, receiving ABA individuals codiagnosed with FXS was also found in the FXS+ASD and other behavioral services, but and ASD from those with FXS only group, which could be because of not physical therapy. It would also were similar to features known to lower cognitive functioning and be expected that the greater social distinguish individuals with ASD more severe hypersensitivity and impairment and more challenging from typically developing individuals hyperactivity relative to the FXS- educational and vocational situations or individuals with other forms of ID only group. A lower frequency of for individuals with FXS+ASD would without ASD. These features include: use was not identified in result in a greater use of services more prevalent seizure disorder, the FXS+ASD group, in contrast with related to these areas. However, in frequent sleep problems, high previous reports in idiopathic ASD the FORWARD data set, there was frequency of behavioral cooccurring populations. 51,52 Stimulants tend to a comparable proportion of FXS conditions, and high use of produce side effects of irritability and individuals with and without ASD psychoactive drugs.44, 60 – 62 Also, the aggression in individuals who have receiving behavioral services, social need for a variety of interventions ASD or other neurodevelopmental skills therapy, vocational training, during the preschool and school disorders and are lower functioning and tutoring during the K-12 period. years are also characteristic in cognitively. 13 This side effect may Also, contrary to expectations, idiopathic ASD.54 – 56, 63, 64 On the other not be as prevalent in the FXS+ASD despite the overall greater use of hand, there is a higher frequency of population, given the frequency nonpharmacologic interventions in treatment of aggressive/disruptive of patients tolerating stimulant the FXS+ASD group, there was no behavior in FXS+ASD. Similar medication. Interestingly, despite difference in the use of behavioral neurobehavioral profiles can be the frequent occurrence of anxiety in services, including ABA and social found in other genetic disorders adolescents with FXS+ASD, the use skills therapies in the school-age associated with ID and ASD, although

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S201 data are more limited compared reduced by a multipronged effort to The number of females with FXS+ASD with that available for FXS.28, 65 complement clinician assessment (N = 23) was too small to break out Perhaps unique to individuals with with the SCQ and SRS-2 instruments into the analytical groups we used. FXS and ASD is the high frequency in FORWARD. Currently, in the Therefore, our analyses, although of hypersensitivity and anxiety, 2 absence of research gold standard focused on all individuals with conditions sometimes difficult to instruments, such as an autism FXS+ASD, likely reflected the disease differentiate from each other that diagnostic observation schedule and status of males in the analyses. With can provide a unique profile of Autism Diagnostic Interview-Revised, future data collection, we hope to autistic features in FXS. A few studies clinician assessment by using increase the overall enrollment of comparing individuals with FXS and Diagnostic and Statistical Manual of females in FORWARD. ASD to those with idiopathic ASD Mental Disorders criteria would be Other limitations are specific to ASD; indicate that, although the FXS and considered the gold standard over data collected were based on the ASD group is relatively less impaired parent report. clinicians’ impression based on use in social interaction and lower-order In addition, the data in FORWARD of DSM-5 criteria, interview with restricted and repetitive behaviors, come from multiple clinics across the parent, and review of records. it is clear that problem behaviors, the country and from different In the earliest set of enrollments, nonverbal cognition, and adaptive settings, and thus are less biased before the release of DSM-5, DSM-IV behavior impairment are comparable than data coming from any single was used. Although there were only or more severely affected.25, 26, 66,67 clinic. Consequently, this study a few months of enrollment during Nevertheless, these studies suggest showcases the power of natural the period of DSM-IV use, this may that the data presented here history projects, such as have impacted the diagnosis of have important implications for FORWARD, to characterize critical ASD+FXS. The current study is one characterizing idiopathic ASD. phenotypes, interventions, and other of the first studies to use DSM-5 knowledge gaps in a rare disease criteria to classify FXS patients as Strengths and Limitations population. having cooccurring ASD. In fact, a recent study analyzed caregiver We believe that clinician assessment Although the data collected in responses to survey questions about as used in FORWARD has several FORWARD are extremely valuable, their child with FXS pertaining to advantages over parent report, we recognize inherent limitations diagnostic criteria for ASD based particularly as it applies to FXS. in terms of comprehensiveness on DSM-IV versus DSM-5 and found Parents of children with FXS will and completeness. There was that fewer individuals with FXS are recognize similar and overlapping inconsistency in responses to some likely to meet ASD criteria based on behaviors between the FXS items on the clinician report form, DSM-5.68 Although most individuals behavioral phenotype and ASD, and which were identified through a with FXS met repetitive behavior likely do not have the knowledge comprehensive data review and criteria, fewer individuals met the base to determine Diagnostic and process evaluation. Anchoring of more stringent DSM-5 criteria for Statistical Manual of Mental Disorders responses to questions with specific impairment in social interaction. criteria. Parents may also be unclear instructions is being carried out to Thus, the ASD group identified in this about the accuracy of the child’s improve the consistency of future article may be different from ASD diagnosis if the label of ASD was data collection for these items. In groups in previous studies on FXS only provided for obtaining services. particular, as shown in Table 2, and ASD, and the aforementioned Parents may also not know of the questions about the presence of survey work would suggest it would ASD diagnosis given that the key problem behaviors were answered be a more severely affected group diagnosis is FXS; this could be due to inconsistently. Data on services than previous groups classified based a delayed or absent ASD diagnosis (Tables 5 and 6) may be prone to on DSM-IV. once FXS is confirmed due to a lack of recall inaccuracy, because parents additional diagnostic diligence. Given were asked to report on the It must also be recognized that the complexities of the behavioral history of services used during the clinical setting is affected phenotype of FXS, diagnostic 2 different time periods, both of by constraints in the use of measures that allow for greater which may have occurred long clinical services, such as medical depth in symptom evaluation may be ago. Despite these limitations, bias insurance, and the skewed nature needed to be certain of the diagnosis toward FXS+ASD or FXS is not of the ascertained population (eg, of ASD in individuals with FXS. We that likely because the data were individuals at both ends of the hope that in the future, diagnostic collected without regard to these spectrum of behavioral severity may uncertainty can be additionally classifications. be underrepresented). Parents of

Downloaded from www.aappublications.org/news by guest on September 24, 2021 S202 KAUFMANN et al patients with milder symptoms may significant group differences. This care for them. To acknowledge the not seek care from a specialty clinic, study confirmed earlier reports work of each clinic contributing data and those patients with more severe based on smaller samples or family to FORWARD, we list the clinical symptoms may not be able to attend surveys and revealed new findings, director, their affiliation, and the year a clinic due to severe behavioral some with potential implications they joined the FXCRC. The list is cooccurring conditions (eg, anxiety, for clinical management and public alphabetical by state. obsessive compulsive disorder). health approaches to addressing Additional information about the the needs of this population. limitations of FORWARD is Greater frequency of seizures and discussed in an accompanying certain behavioral cooccurring ABBREVIATIONS article by Sherman et al in this conditions, such as aggressive/ ABA: applied behavior analysis supplement. disruptive behavior, in those with ASD: autism spectrum disorder FXS+ASD have considerable impact CI: confidence interval on the management of the affected DSM-IV: Diagnostic and CONCLUSIONS population. Underuse of behavioral Statistical Manual of The current study was focused on the services, including ABA, social Mental Disorders, Fourth impact of ASD codiagnosis in FXS in training, tutoring, and vocational Edition terms of neurologic and behavioral training, in individuals with FXS+ASD DSM-5: Diagnostic and Statistical cooccurring conditions and treatment is of some concern considering the Manual of Mental approaches, and used a larger sample core nature of ASD and its associated Disorders, Fifth Edition than any previous study conducted cognitive and learning challenges. 69 FORWARD: Fragile X Online on a population codiagnosed with The data reported in this study can Registry With FXS and ASD. Therefore, this study guide future research in the FXS and Accessible Research was able to provide a more robust ASD fields. Database description of the population affected FXCRC: Fragile X Clinical by both FXS and ASD because it Research Consortium included a large enough sample ACKNOWLEDGMENTS FXS: fragile X syndrome population to be able to do analyses We thank the National Fragile FXS+ASD: FXS with ASD by age group; by specific cooccurring X Foundation for their support, FXS only: FXS without ASD conditions, of which some are encouragement, and commitment ID: relatively infrequent (eg, seizures); to establish the Fragile X Clinical K-12: kindergarten to grade 12 and by particular medications Research Consortium (FXCRC). We SCQ: Social Communication or services. Because many of the thank Don Bailey, Melissa Raspa, Questionnaire variables studied occur only in a and Anne Wheeler for their input SRS-2: Social Responsiveness fraction of the population in either into FORWARD. Importantly, Scale, Second Edition the FXS+ASD or FXS-only group, large FORWARD could only exist with SSRI: selective serotonin numbers, such as those available in the effort of families who have FXS reuptake inhibitor FORWARD, may be needed to see and the clinicians and teams who

reviewed and revised the manuscript; Dr Brown contributed to data collection and critically reviewed and revised the manuscript; Dr Berry-Kravis contributed to the conception and design of the analyses, contributed to data collection and interpretation of the data, and drafted and revised the manuscript; and all authors approved the fi nal manuscript as submitted and agreed to be accountable for all aspects of the work. The fi ndings and conclusions in this report are those of the authors and do not necessarily represent the offi cial position of the Centers for Disease Control and Prevention. DOI: https://doi. org/ 10. 1542/ peds. 2016- 1159F Accepted for publication Jan 24, 2017 Address correspondence to Walter E. Kaufmann, MD, Center for Translational Research, Greenwood Genetic Center, 113 Gregor Mendel Cir, Greenwood, SC 29646. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: Dr Kaufmann is a consultant to Neuren, Edison, Newron, EryDel, Marinus, and GW Pharmaceuticals and has received funding to his institution from Ipsen and Eloxx; Dr Berry-Kravis has received funding to her institution from Seaside Therapeutics, Novartis, Roche, Alcobra, and Neuren

Downloaded from www.aappublications.org/news by guest on September 24, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S203 Pharmaceuticals to consult on trial design and conduct clinical trials in fragile X syndrome; and from Asuragen, Inc to develop testing standards for FMR1 testing; and also has grant funding from the National Institutes of Health, the Merck Foundation, and the Centers for Disease Control and Prevention; the other authors have indicated they have no fi nancial relationships relevant to this article to disclose. FUNDING: Supported by cooperative agreements 5U01DD000231 and 5U19DD000753-02 with the Centers for Disease Control and Prevention. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential confl icts of interest to disclose.

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