Cognitive-behavioral features of children with WolfЦHirschhorn syndrome Preliminary report of 12 cases.код для вставкиСкачать
American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 148C:252– 256 (2008) A R T I C L E Cognitive-Behavioral Features of Children With Wolf–Hirschhorn Syndrome: Preliminary Report of 12 Cases GENE S. FISCH,* AGATINO BATTAGLIA, BARBARA PARRINI, JANEY YOUNGBLOM, AND RICHARD SIMENSEN As a subset of genetic abnormalities, subtelomeric deletions have been found in 7–10% of individuals with mental retardation (MR). One subtelomeric deletion, Wolf-Hirschhorn syndrome (WHS), causes mild to severe MR, but the cognitive-behavioral features of individuals with WHS have not been studied systematically. To that end, we administered a comprehensive cognitive-behavioral battery to 12 children with WHS, ages 4–17 years, who also had some expressive language. Using the Stanford-Binet (4th Edition), we found cognitive deficits ranged from mild to severe, with mean IQ ¼ 44.1. Interviewing parents with the Vineland Adaptive Behavior Scales, we found mean adaptive behavior score (DQ) ¼ 37.3, with females exhibiting slightly higher scores than males. Cognitive profiles indicated relative strengths in Verbal and Quantitative Reasoning. Adaptive behavior profiles noted significant relative strengths in the Socialization Domain. These cognitive-behavioral profiles differed from children with other subtelomeric deletion syndromes, 2q37 or 8p23. Attention deficits and hyperactivity (ADHD) were observed in 7/12 (58%) of the children we tested. One child attained a score on the Child Autism Rating Scale (CARS) suggestive of mild autism. We conclude that different genetic disorders, which cause MR, produce diverse cognitive-behavioral profiles. Consequently, cognitive-behavioral profiles of children with MR need to be assessed more comprehensively. ß 2008 Wiley-Liss, Inc. KEY WORDS: genetics; Wolf–Hirschhorn syndrome; subtelomeric deletions; mental retardation; adaptive behavior; ADHD; autism; learning impairment; cognitive-behavioral profiles How to cite this article: Fisch GS, Battaglia A, Parrini B, Youngblom J, Simensen R. 2008. Cognitive-behavioral features of children with Wolf–Hirschhorn syndrome: Preliminary report of 12 cases. Am J Med Genet Part C Semin Med Genet 148C:252–256. INTRODUCTION Gene S. Fisch is currently Senior Biostatistician and Research Professor at NYU Colleges of Dentistry and Nursing, and Adjunct Professor at Yeshiva University. His research interests include genetic disorders that produce learning impairment and/or autism. He has studied cognitivebehavioral development in children with the fragile X mutation, William–Beurens syndrome, and Neurofibromatosis Type 1. He is also interested in the epistemology of pervasive developmental disabilities and autism. Agatino Battaglia is Contract Professor of Child Neuropsychiatry at the Postgraduate Medical School, University of Pisa, Italy; and Adjunct Professor of Pediatrics at the University of Utah Health Sciences Center, Division of Medical Genetics, Department of Pediatrics, Salt Lake City, UT, USA. He is board certified in Clinical Pediatrics and in Neurology. He is Director of the Clinical Dysmorphology Unit, Head of the Center for the Study of Congenital Malformation Syndromes, and Director of Research in Neuropsychiatric Genetics, at the Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry, Calambrone (Pisa), Italy. He has a strong research interest in clinical dysmorphology, neuropsychiatric genetics, and clinical neurophysiology. Dr. Barbara Parrini is a psychologist working at the Stella MarisClinical Research Institute for Child and Adolescent Neuropsychiatry. She has strong research interests in the neuropsychological and behavioural profiles of individuals with chromosomal and pervasive developmental disorders. Janey Youngblom is Professor of Biology, California State University, Stanislaus. Her interests include microarray analysis of individuals with deletion 8p23, and the training genetic counselors. Richard Simensen is a neuropsychologist at the Greenwood Genetics Center, South Carolina. His research interests include studies of children with the fragile X mutation, William-Beurens syndrome, and X-linked mental retardation. *Correspondence to: Gene S. Fisch, Ph.D., Bluestone Clinical Research Center, NYU Colleges of Dentistry & Nursing, 421 First Ave., 2nd Fl., New York, NY 10010. E-mail: email@example.com DOI 10.1002/ajmg.c.30185 Published online 16 October 2008 in Wiley InterScience (www.interscience.wiley.com) ß 2008 Wiley-Liss, Inc. The role genetics has played in causing cognitive impairment has become better understood over the last 50 years as cytogenetic and microarray techniques have evolved and made possible identification of defects that may be found on individual chromosomes. At the same time, molecular genetic techniques are now able to detect single gene and contiguous gene genotypes. A decade ago, Sarimski  reported that there were about 1,000 genetic causes of mental retardation (MR), and their phenotypes were many and varied. It now appears that genetic abnormalities that produce MR occur in more than 1% of the general population [Fisch, 2000]. As a subgroup of genotypes, subtelomeric deletions have been detected in 7 – 10% of individuals with MR [Lam et al., 2006], as well ARTICLE as in children diagnosed with autism [Koolen et al., 2004]. Given their relatively infrequent occurrence, studies assessing cognitive ability and other aspects of behavior in individuals with these abnormalities have been problematic. One such subtelomeric deletion that produces MR is deletion 4p16 [also known as Wolf–Hirschhorn syndrome (WHS)]. WHS is associated with a variety of clinical features: growth retardation, unusual craniofacial features; seizures, and developmental delay, among others [Lurie et al., 1980]. Surprisingly, only recently has the natural history of WHS been assessed [Battaglia et al., 1999]. In addition, there has been only one study of speech and language in a small group of children with WHS [Sabbadini et al., 2002]. Attempts have been made to identify genotype–phenotype correlations [Zollino et al., 2000], but cognitive-behavioral aspects of individuals associated with the genotype have not been studied systematically. This is Attempts have been made to identify genotype–phenotype correlations, but cognitive-behavioral aspects of individuals associated with the genotype have not been studied systematically. unfortunate since cognitive-behavioral profiles and age-related features of cognitive-behavioral deficits may permit researchers to describe more completely the natural history of the disorder, and draw inference about brain development. Therefore, the purpose of our study was to determine the cognitive profiles, adaptive and maladaptive behavior profiles, aspects of temperament and emotional behavior, attentiveness and activity levels, and to ascertain autism status in children diagnosed with WHS. The results we present here are preliminary findings in our ongoing study of cognitive-behavioral features of children with subtelomeric deletions. AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) METHODS Participants Twelve children with WHS, diagnosed previously by fluorescent in situ hybridization, ages 4–17 years. Six children were male, six were female. As expressive speech and language are essential features of our standard cognitive test, inclusion criteria for cognitive testing required that children be able to communicate verbally and have some expressive speech and language. Participants were recruited from six major sites in two countries: the USA (N ¼ 10); and from Pisa, Italy (N ¼ 2). As part of our ongoing investigation of cognitive features of subtelomeric deletion syndromes we had previously studied seven children with 2q37 deletion and seven with 8p23 deletion. Materials Participants with WHS were administered a cognitive-behavioral battery which consisted of five standardized valid and reliable instruments to assess behavior. Cognitive-Behavioral Measures Cognitive abilities were obtained using the Stanford-Binet (4th Edition) (SBFE). The SBFE contains standard area scores (SAS) for four major areas of assessment: verbal reasoning (VR); abstract/visual reasoning (AVR); quantitative reasoning (QR); and short-term memory (STM). Adaptive behavior skills were assessed with the Vineland adaptive behavior scale (VABS) contains four domains: communication; daily living skills (DLS); socialization; and motor skills for children less than 6-year of age. The VABS also contains two scales to assess Maladaptive Behavior. Attention/Activity Activity levels and attentiveness were assessed using the Conners rating scale (CRS). The CRS examines several scales associated with behavioral genotypes: oppositional; cognitive problems/ inattention; hyperactivity; anxious/shy; perfectionism; social problems; and 253 psychosomatic problems. More importantly, DSM-IV symptoms/indices specifically associated with attention deficit disorder (ADD) and attention deficit/ hyperactivity disorder (ADHD) can be obtained from the CRS. Emotionality/Temperament To evaluate the child’s emotionality and temperament, parents completed the child behavior checklist (CBCL). The CBCL assesses emotional behavior along two major dimensions: internalizing and externalizing behaviors. Internalizing behaviors contain the following scales: withdrawn; somatic complaints; anxious/ depressed; social problems; thought problems; attention. externalizing behaviors contain two scales: delinquent; aggressive. Autism To ascertain the child’s status with regard to autism, The child autism rating scale (CARS) was employed. The CARS consists of 15 subscales associated with DSM-IV criteria associated with autistic behavior. Each item is rated from ‘‘0’’ (behavior typical for a child that age) to ‘‘4’’ (Extremely abnormal behavior for a child that age). Item scores are summed and summated scores 30 are considered in the autism range. Procedure To obtain measures of their cognitive abilities, one of us (G.S.F.) administered the SBFE to all 10 children recruited from sites in the U.S. Children recruited for the study in Italy were administered the Griffiths (N ¼ 1) or the Leiter (N ¼ 1). IQ scores from the Griffiths and the Leiter are strongly correlated with the SBFE. All participants’ parents or caregivers were interviewed using the VABS and CARS. All parents and caregivers also completed the CRS and CBCL. All assessments in the U.S. were scored by one of us (G.S.F.). RESULTS Mean IQ score for our sample of children with WHS was 44.1 (range: 254 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 33–64). When we compared males (n ¼ 6) to females (n ¼ 6) we found no significant differences between the two groups. Mean IQ score for females was 45 (range: 33–60); for males, mean IQ was 43 (range: 36–64). Mean IQ scores for children in the WHS group were compared to mean IQ scores for children with two other subtelomeric deletion syndromes: 2q37 (n ¼ 7) or 8p23 (n ¼ 7). The results are shown in Figure 1. Mean IQ scores for children with WHS were lower than those for the other subtelomeric deletion syndromes, but the differences were not statistically significant. Mean adaptive behavior (DQ) score for children with WHS was 37.3 (range: 19–63). We also compared DQ scores for males and females. Results show that the mean DQ score for females was 41.67 (range19–63) was higher than the mean DQ for males, 33.0 (range 23– 47), but the difference in the mean DQ scores was not statistically significant. Mean DQ scores for children in the WHS group were compared to mean DQ scores for children with deletion 2q37 and 8p23. The results are shown in Figure 2. Mean DQ scores for children with WHS were lower than those with other subtelomeric deletions, but the differences were not statistically significant. To examine cognitive profiles in children with WHS, we analyzed their SAS scores, after which we compared mean SAS scores for verbal reasoning, abstract/visual reasoning, quantitative reasoning, and short-term memory, to their respective mean SAS scores for children with deletion 2q37 and 8p23. Results are shown in Figures 3a,b. In Figure 3a, mean VR (49.67) and QR (49.86) SAS scores were greater than mean AVR (43.88) and STM (43) SAS scores, but the differences were not statistically significant. The three subtelomeric genotypes and Standard Area were compared statistically using a mixed effects ANOVA model. Results (see Table I) show that there Figure 1. Mean composite IQ scores (SD) for children with subtelomeric deletions 2q37, 8p23, and 4p16. Figure 2. Mean composite DQ scores (SD) for children with subtelomeric deletions 2q37, 8p23, and 4p16. ARTICLE are statistically significant differences in the SAS patterns of subtelomeric deletion genotypes (P < 0.02), but individual SAS areas were not significantly different statistically across genotypes (Fig. 4). Adaptive behavior profiles were similarly evaluated. We computed mean Communication, DLS, Socialization Domain scores for children with WHS, after which we compared those scores with mean domain scores for the other two subtelomeric deletions. Results show that, among children with WHS, mean Socialization score (51.75) was significantly higher than mean Communication score (38.42) or DLS (32.67) Results show that, among children with WHS, mean Socialization score (51.75) was significantly higher than mean Communication score. (w2 ¼ 5.94; P ¼ 0.05). When domain scores for children with WHS were compared with the other two subtelomeric deletions, however, no statistically significant differences were found. Using the CRS, we calculated the proportion of children whose activity levels and lack of attentiveness were consistent with a diagnosis of ADD or ADHD. Among children with WHS, 7/ 12 (58%) of the children in our sample met those criteria. Among children with 2q37, 5/7 (72%) met those criteria, while 4/7 (58%) children with 8p23 met those criteria. Using the CBCL, we computed the proportion children with WHS who had significant emotional problems. We found that, despite their strong Socialization skills, 5/12 (42%) were recognized with social problems, 4/12 (33%) attention problems, and 1/12 (8%) was considered to have thought problems. Finally, using the CARS, we interviewed parents and examined participants to ascertain the autism status of children with WHS. We found one child (8%) whose CARS score 30. This was ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 255 a much lower proportion than that which was observed in children with deletion 2q37 (3/7 or 42%) or 8p23 (5/7 or 58%). Figure 3. a,b: Mean SAS scores from the SBFE for children with subtelomeric deletions 2q37, 8p23, and 4p16. TABLE I. Mixed Effects Model to Examine the Effects of Subtelomeric Genotype and SBFE Standard Area on SAS Scores for Children With 2q37, 8p23, or WHS Effect Genotype Area Genotype area Num DF Den DF F-value Pr > F 2 3 6 55 55 55 3.82 0.46 0.17 0.0279 0.7113 0.9847 Figure 4. a,b: Mean domain scores from the VABS for children with subtelomeric deletions 2q37, 8p23, and 4p16. Finally, using the CARS, we interviewed parents and examined participants to ascertain the autism status of children with WHS. We found one child whose CARS score 30. This was a much lower proportion than that which was observed in children with deletion 2q37 or 8p23. SUMMARY AND DISCUSSION Microdeletions in the 4p16.3 region are variable in size but may produce similar clinical features in the phenotype that characterizes WHS. Zollino et al.  found that the severity of the WHS phenotype is related to the deletion size and region. At this preliminary stage of our study, however, we are unable to ascertain a relationship between deletion size and cognitive-behavioral abilities. Moreover, by excluding children who have no expressive speech and language, we are likely assessing children who are functioning at the upper end of cognitive ability for this disorder. Nonetheless, it will be important to establish a genotype–phenotype relationship in children with WHS; and, we hope to expand this aspect of our study. To elaborate the phenotype more completely, we examined the cognitive skills and behavioral repertoire of 12 children, ages 4–17 years, who were diagnosed with WHS and who have some speech and expressive language. We found that their cognitive deficits ranged from mild to severe MR. In general, their cognitive abilities were lower than children with other subtelomeric deletions, 2q37 and 8p23. 256 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) Children with WHS exhibited relative strengths in Verbal and Quantitative Reasoning, and relative weaknesses in Abstract/Visual Reasoning and Short-term Memory. The pattern of strengths and weaknesses found in children with WHS differs from those we observed in children with deletions 2q37 and 8p23 who present relatively flat Children with WHS exhibited relative strengths in Verbal and Quantitative Reasoning, and relative weaknesses in Abstract/Visual Reasoning and Short-term Memory. The pattern of strengths and weaknesses found in children with WHS differs from those we observed in children with deletions 2q37 and 8p23 cognitive profiles. The inability to attain statistical significance between strengths in verbal and quantitative reasoning on the one hand, and weaknesses in abstract/visual reasoning and short-term memory on the other, is likely due to the variability in SAS scores relative to the small sample size. Previously, we characterized the cognitive-behavioral profiles in children with other genetic disorders that produce MR—the fragile X mutation (FRAXA) and William-Beurens syndrome (WBS)— and found a similar pattern of strengths and weaknesses [Fisch et al., 2007] in verbal and quantitative reasoning. However, verbal reasoning scores for children with FRAXA or WBS were significantly higher than those with WHS (P < 0.03; data not shown). Children with WHS also scored lower on quantitative reasoning, abstract/ visual reasoning, and short-term memory, but these scores were not significantly lower (data not shown). Adaptive behavior skills of all children with WHS we assessed were lower than adequate. However, children with WHS exhibit a significant relative strength in Socialization compared to their communication and daily living skills. In comparison, children with deletion 2q37 or 8p23 display a low, relatively flat profile of adaptive behavior skills. However, Socialization scores of children with deletion 2q37 or 8p23 were not significantly different from those with WHS. When compared to children we tested previously who were diagnosed with FRAXA or WBS, children with WHS had significantly different pattern of adaptive behavior domain skills (P < 0.0001; data not shown) and marginally lower individual domain skills (P ¼ 0.06; data not shown). We also noted hyperactivity levels and inattentiveness in children with WHS that are consistent with a diagnosis of ADD or ADHD. However, ADHD and ADD are frequently observed comorbid features of individuals with MR. We also found high rates of ADHD in subtelomeric deletions 2q37 and 8p23. Emotional and temperament problems were found primarily to be associated with impediments to relating well socially and difficulty maintaining attention. Autistic-like behavior plays a less prominent role in children with WHS than among other children with subtelomeric deletions. In our study, we found that children with 2q37 and 8p23 have much higher rates of autism than children with WHS. Our study of children with WHS supports our conviction that different genetic disorders produce differing cognitive-behavioral profiles; and, that cognitive-behavioral profiles of children with genetic disorders that produce MR or LD need to be explored more comprehensively. ACKNOWLEDGMENTS We thank Wendy Trout, President of the Wolf-Hirschhorn Parent Support Group, for inviting families of children ARTICLE with WHS to participate in our study; Faith Callis-Daley, genetics counselor from Columbus OH, who contacted families of children with 8p23; and Marnie Beacham, Salt Lake City, UT, who contacted families of children with 2q37. We gratefully acknowledge the support from the Fondation Jérôme Lejeune, Paris, France, who provided funding for our project, without which we could not have performed our study. REFERENCES Battaglia A, Carey JC, Cederholm P, Viskochil DH, Brothman AR, Galasso C. 1999. Natural history of Wolf-Hirschhorn syndrome: Experience with 15 cases. Pediatrics 103:830–836. Fisch GS. 2000. Psychology genetics. Am J Med Genet 97:109–111. Fisch GS, Carpenter N, Howard-Peebles PN, Holden JJ, Tarleton J, Simensen R, Nance W. 2007. 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