Bullying and ADHD: Which Came First and Does it Matter?

CASE: Aiden, a 13-year-old boy in the sixth grade who is relatively new to your practice, is seen for follow-up after his routine physical last month when you noted concerns for possible attention-deficit hyperactivity disorder (ADHD) and gave the family Vanderbilt Scales to complete. Aiden has a family history of ADHD, specific learning disabilities, and mood disorder.His mother reports that she is concerned about how Aiden is doing at school; his teachers are complaining that he is not doing his work, and she is worried that he may be kept back in school. Aiden first began having trouble in the third grade. He was retained in the fourth grade for academic and behavioral reasons. Now his mother has been receiving calls about him not paying attention, distracting others, and staring at his paper. At home, he does not want to do homework and gets very frustrated. In fifth grade, he had a psychoeducational evaluation and was found not eligible for services. His achievement testing showed average scores in reading, math, and writing. Cognitive testing demonstrated average scores for verbal and nonverbal abilities and memory but was significantly below average for processing speed. Aiden continues to have problems now in into the sixth grade.You speak with Aiden in the office and ask him about school. He says, "It's bad. I'm failing." He believes his major problems at school are that he is not doing his homework, he easily becomes frustrated, and he argues with the teachers. He has supportive relationships with his family and friends at school. He gets along well with some of his teachers, noting that he loves his science teacher even though she is tough and "gives hard homework." He describes his history teacher as "annoying." When you ask what he means he states this teacher "Can be not nice and says mean things. She picks on me a lot." His description is consistent with the use of shaming as a behavior he experiences at school.You review the completed parent and teacher Vanderbilt forms; both are consistent and concerning for combined type ADHD. You discuss the diagnosis of ADHD with his mother and both agree to revisit pharmacotherapy in September when the school year resumes. You give her resources on ADHD and classroom accommodations and discuss requesting a 504 plan at school. You also discuss behavioral therapy to better address his self-regulation skills.A week later, you receive a telephone call from Aiden's mother. "Aiden got home today and he is more upset than I have ever seen him! His teacher told him in front of the class that he would probably stay back a year and now he is saying there is no point in going to school." She is not aware if retention has been recommended for Aiden.What would you say to Aiden's mother? What would you do next?

Copy number variation plays an important role in clinical epilepsy.

OBJECTIVE: To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center. METHODS: We identified patients with International Classification of Diseases, ninth revision (ICD-9) codes for epilepsy or seizures and clinical CMA testing performed between October 2006 and February 2011 at Boston Children's Hospital. We reviewed medical records and included patients who met criteria for epilepsy. We phenotypically characterized patients with epilepsy-associated abnormalities on CMA. RESULTS: Of 973 patients who had CMA and ICD-9 codes for epilepsy or seizures, 805 patients satisfied criteria for epilepsy. We observed 437 copy number variants (CNVs) in 323 patients (1-4 per patient), including 185 (42%) deletions and 252 (58%) duplications. Forty (9%) were confirmed de novo, 186 (43%) were inherited, and parental data were unavailable for 211 (48%). Excluding full chromosome trisomies, CNV size ranged from 18kb to 142Mb, and 34% were >500kb. In at least 40 cases (5%), the epilepsy phenotype was explained by a CNV, including 29 patients with epilepsy-associated syndromes and 11 with likely disease-associated CNVs involving epilepsy genes or "hotspots." We observed numerous recurrent CNVs including 10 involving loss or gain of Xp22.31, a region described in patients with and without epilepsy. INTERPRETATION: Copy number abnormalities play an important role in patients with epilepsy. Because the diagnostic yield of CMA for epilepsy patients is similar to the yield in autism spectrum disorders and in prenatal diagnosis, for which published guidelines recommend testing with CMA, we recommend the implementation of CMA in the evaluation of unexplained epilepsy.

Bullying and ADHD: which came first and does it matter?

CASE: Aiden, a 13-year-old boy in the sixth grade who is relatively new to your practice, is seen for follow-up after his routine physical last month when you noted concerns for possible attention-deficit hyperactivity disorder (ADHD) and gave the family Vanderbilt Scales to complete. Aiden has a family history of ADHD, specific learning disabilities, and mood disorder.His mother reports that she is concerned about how Aiden is doing at school; his teachers are complaining that he is not doing his work, and she is worried that he may be kept back in school. Aiden first began having trouble in the third grade. He was retained in the fourth grade for academic and behavioral reasons. Now his mother has been receiving calls about him not paying attention, distracting others, and staring at his paper. At home, he does not want to do homework and gets very frustrated. In fifth grade, he had a psychoeducational evaluation and was found not eligible for services. His achievement testing showed average scores in reading, math, and writing. Cognitive testing demonstrated average scores for verbal and nonverbal abilities and memory but was significantly below average for processing speed. Aiden continues to have problems now in into the sixth grade.You speak with Aiden in the office and ask him about school. He says, "It's bad. I'm failing." He believes his major problems at school are that he is not doing his homework, he easily becomes frustrated, and he argues with the teachers. He has supportive relationships with his family and friends at school. He gets along well with some of his teachers, noting that he loves his science teacher even though she is tough and "gives hard homework." He describes his history teacher as "annoying." When you ask what he means he states this teacher "Can be not nice and says mean things. She picks on me a lot." His description is consistent with the use of shaming as a behavior he experiences at school.You review the completed parent and teacher Vanderbilt forms; both are consistent and concerning for combined type ADHD. You discuss the diagnosis of ADHD with his mother and both agree to revisit pharmacotherapy in September when the school year resumes. You give her resources on ADHD and classroom accommodations and discuss requesting a 504 plan at school. You also discuss behavioral therapy to better address his self-regulation skills.A week later, you receive a telephone call from Aiden's mother. "Aiden got home today and he is more upset than I have ever seen him! His teacher told him in front of the class that he would probably stay back a year and now he is saying there is no point in going to school." She is not aware if retention has been recommended for Aiden.What would you say to Aiden's mother? What would you do next?

SOX12 and NRSN2 are candidate genes for 20p13 subtelomeric deletions associated with developmental delay.

20p13 telomeric/subtelomeric deletions are clinically significant but are currently under-investigated. So far only five molecularly delineated cases have been reported in literature and no candidate genes have been sufficiently implicated. Here, we present six new deletion cases identified by chromosomal microarray analysis (CMA). We also review 32 cases combined from literature and databases. We found that most 20p13 deletion patients exhibit significant developmental delay. Dysmorphic features are common but a consistent pattern was not recognized. Reduced cognitive ability was frequent. Based on pathogenic deletions delineated in this study, we mapped the smallest overlapping region and identified two nervous system expressing genes (SOX12 and NRSN2) as candidate genes that may be involved in the developmental defects in 20p13 microdeletion.

Clinical genetic testing for patients with autism spectrum disorders.

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region.

PURPOSE: Williams-Beuren syndrome is among the most well-characterized microdeletion syndromes, caused by recurrent de novo microdeletions at 7q11.23 mediated by nonallelic homologous recombination between low copy repeats flanking this critical region. However, the clinical phenotype associated with reciprocal microduplication of this genomic region is less well described. We investigated the molecular, clinical, neurodevelopmental, and behavioral features of seven patients with dup(7)(q11.23), including two children who inherited the microduplication from one of their parents, to more fully characterize this emerging microduplication syndrome. METHODS: Patients were identified by array-based comparative genomic hybridization. Clinical examinations were performed on seven affected probands, and detailed cognitive and behavioral evaluations were carried out on four of the affected probands. RESULTS: Our findings confirm initial reports of speech delay seen in patients with dup(7)(q11.23) and further delineate and expand the phenotypic spectrum of this condition to include communication, social interactions, and repetitive interests that are often observed in individuals diagnosed with autism spectrum disorders. CONCLUSIONS: Array-based comparative genomic hybridization is a powerful means of detecting genomic imbalances and identifying molecular etiologies in the clinic setting, including genomic disorders such as Williams-Beuren syndrome and dup(7)(q11.23). We propose that dup(7)(q11.23) syndrome may be as frequent as Williams-Beuren syndrome and a previously unrecognized cause of language delay and behavioral abnormalities. Indeed, these individuals may first be referred for evaluation of autism, even if they do not ultimately meet diagnostic criteria for an autism spectrum disorder.