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.

Not Really "The Same Thing".

CASE: Susie is a 10-year-old girl who is followed by a developmental-behavioral pediatrician for attention-deficit/hyperactivity disorder (ADHD), combined type and challenging behaviors. Susie has been treated with extended-release methylphenidate HCl 36 mg daily and extended-release guanfacine 1 mg daily for the past year. Susie attended an evidence-based summer treatment program for ADHD for 8 weeks over the summer, and the family has continued to attend monthly behavioral therapy visits with a local child psychologist.Parents report that, until recently, Susie's symptoms of ADHD were well controlled. Susie had a positive start to the school year but has had increasing difficulties over the past month. Specifically, Susie's classroom teacher has communicated that she is having difficulty maintaining attention, is easily distracted, and is missing several homework assignments. While obtaining a careful interim history, Susie's parents report that there have not been any changes or new stresses in the home or school environments. They were pleased with the behavioral guidance provided during the summer treatment program and have continued to use those strategies.Further discussion revealed that parents noticed a change in the appearance of Susie's methylphenidate tablets when the prescription was last filled. Although the previous prescriptions were filled with oblong, white tablets, the most recent prescription was filled with round, white tablets. Susie's parents contacted the pharmacy and were told that Susie's prescription was filled with "the same thing as before." The pharmacist explained that the tablets looked different because the manufacturer had changed in order to comply with the preferences of Susie's insurance provider. What would be your next steps in Susie's care?

Developmental screening: is there enough time?

OBJECTIVES: The American Academy of Pediatrics recommends routine developmental screening in well-child care. Providers cite time restraints as a limitation preventing its widespread adoption. The objectives were to determine whether routine screening lengthened well-visits and was associated with changes in parent satisfaction and report of anticipatory guidance. METHODS: Visits before and after implementation of routine screening were timed. Parents whose children were seen before or after screening began were contacted to query their perceptions of the visit. RESULTS: There was no change in visit lengths after the screener was included. With screening, more parents reported their provider talked about their concerns, and that their questions were answered. There were no changes in parent satisfaction ratings or reports of anticipatory guidance discussions. CONCLUSIONS: The perceived obstacle that routine screening requires more time than pediatricians have should not prevent its adoption. Screening tools may empower some parents otherwise reluctant to raise concerns unsolicited.

Barking vocalizations and shaking movements in a 13-year old girl.

CASE: Erica is a 13-year old female who was hospitalized for a 4-week history of "barking" noises and 2 weeks of generalized shaking episodes. Four weeks prior to admission, she had a viral upper respiratory infection (URI) with cough which was treated with over-the-counter cough syrup. After resolution of the URI, she developed a persistent cough that turned into a "bark"-like vocalization. Both the mother and patient demonstrated the bark as an "arf" sound like that of a small dog at times, a large dog at others. These vocalizations were unrelenting, occurring 3-10 times per minute only while awake. They were not precipitated by any known factors nor were there alleviating factors. She could not voluntarily suppress the sound. In addition to the vocalizations, episodes of generalized shaking of the extremities began 2 weeks prior to admission. According to Erica's mother, each episode lasted about 10-60 seconds and occurred 30-40 times a day only when she was awake. These episodes were not rhythmic or symmetric, and they were not associated with bowel or bladder incontinence. There was no alteration of consciousness following the episodes. Erica denied any recollection of the barking or shaking.The medical evaluation did not reveal an etiology. It included a complete physical examination, a neurological examination, biochemical laboratory studies, and a negative video EEG study that captured 10 episodes of shaking. Child psychiatry was consulted. Erica was a pleasant, quiet female with slightly constricted affect and a normal speech pattern. She reported that she was a straight-A honors student who had difficulty trusting others; she said that she had no friends, only "associates." She said that she had periods of feeling "sad" and crying easily, but could not identify any recent stressful event. Episodes of barking and shaking diminished during the hospitalization. Erica was discharged home with outpatient psychiatric follow-up.

Health Care Transition Planning Among Adolescents with Autism Spectrum Disorder.

Improving the health care transition process for youth with autism spectrum disorder (ASD) is critically important. This study was designed to examine the overall national transition core outcome among youth with ASD and each of the component measures of health care transition planning. Fewer than 10% of youth with ASD meet the national transition core outcome. Among youth with ASD, there is greater disparity in health care transition planning for non-Hispanic black youth, youth with family income <400% of the federal poverty line, and youth with more severe activity limitation. Continued advocacy, research, and training efforts are needed to reduce disparities in receipt of health care transition planning services for youth with ASD.

Developmental Screening With Spanish-Speaking Families in a Primary Care Setting.

Cultural beliefs may influence parents' willingness to raise concerns on a developmental screener. Our study evaluated the performance of the Parents' Evaluation of Developmental Status (PEDS) in an urban community health center where 75% of families are Spanish speaking. Our primary outcome was the presence of parent-reported concerns either in the medical record or on the PEDS before the PEDS was introduced compared with after it became routine care (post-PEDS). Covariates included family language and child age, gender, and risk status. The adjusted odds of a concern being identified was 1.5 times greater in the post-PEDS period for Developmental concerns and 2.1 times greater for Behavioral concerns. There was no association with family language indicating that the PEDS performs equally well for English- and Spanish-speaking families. The systematic inclusion of developmental screening as part of culturally competent primary care may aid in reducing current disparities in the identification of developmental concerns.

Barking vocalizations and shaking movements in a 13-year old girl.

CASE: Erica is a 13-year old female who was hospitalized for a 4-week history of "barking" noises and 2 weeks of generalized shaking episodes. Four weeks prior to admission, she had a viral upper respiratory infection (URI) with cough which was treated with over-the-counter cough syrup. After resolution of the URI, she developed a persistent cough that turned into a "bark"-like vocalization. Both the mother and patient demonstrated the bark as an "arf" sound like that of a small dog at times, a large dog at others. These vocalizations were unrelenting, occurring 3-10 times per minute only while awake. They were not precipitated by any known factors nor were there alleviating factors. She could not voluntarily suppress the sound. In addition to the vocalizations, episodes of generalized shaking of the extremities began 2 weeks prior to admission. According to Erica's mother, each episode lasted about 10-60 seconds and occurred 30-40 times a day only when she was awake. These episodes were not rhythmic or symmetric, and they were not associated with bowel or bladder incontinence. There was no alteration of consciousness following the episodes. Erica denied any recollection of the barking or shaking. The medical evaluation did not reveal an etiology. It included a complete physical examination, a neurological examination, biochemical laboratory studies, and a negative video EEG study that captured 10 episodes of shaking. Child psychiatry was consulted. Erica was a pleasant, quiet female with slightly constricted affect and a normal speech pattern. She reported that she was a straight-A honors student who had difficulty trusting others; she said that she had no friends, only "associates." She said that she had periods of feeling "sad" and crying easily, but could not identify any recent stressful event. Episodes of barking and shaking diminished during the hospitalization. Erica was discharged home with outpatient psychiatric follow-up.

Developmental screening and parents' written comments: an added dimension to the parents' evaluation of developmental status questionnaire.

OBJECTIVE: The aim of this study was to better understand the utility of using the Parents' Evaluation of Developmental Status (PEDS) in well-child visits by analyzing themes and patterns in parents' written responses on the PEDS form. METHODS: We reviewed a consecutive sample of medical records with PEDS forms for children aged 6 months to 9 years (site 1) and 3 to 5 years (site 2). We recorded the concerns that parents identified in response to the 10 PEDS questions along with demographic information. We then categorized parents' written comments about those concerns according to comment content. We used qualitative and quantitative methods for analysis. RESULTS: We collected 752 PEDS forms. Ninety percent of the parents endorsed at least 1 concern (94.6% on the English forms versus 69.7% on the Spanish forms; P < .001). Parents qualified 27.5% of their concerns with a written comment. In 23.9% of cases in which parents identified a concern and provided a written comment, the content of the comment did not match the question's intent; rates of mismatch were similar for the English and Spanish forms. Among comments regarding behavioral concerns, 12% reflected a misunderstanding of age-appropriate behavior. Medical concerns accounted for 14.1% of the comments; these concerns were more common on English forms (61.3%) than on Spanish forms (1.7%) (P < .08). More than one-fourth of the comments reported behavior or development that was on target or advanced for the child's age. CONCLUSIONS: Parents frequently used the PEDS forms to communicate additional concerns regarding their child or provide positive feedback on their child's progress. The inappropriate developmental expectations, limited health literacy, and culturally distinct comments on the PEDS forms reinforce the importance of using screening tools to enhance the care provided during visits but not to replace patient-provider communication.

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.

Routine developmental screening implemented in urban primary care settings: more evidence of feasibility and effectiveness.

OBJECTIVES: The purpose of this study was to examine the feasibility and effectiveness of implementation of validated developmental screening by using the Parents' Evaluation of Developmental Status in 2 urban pediatric practices. DESIGN AND METHODS: We implemented the Parents' Evaluation of Developmental Status at Boston Children's Hospital Primary Care Center and at Joseph Smith Community Health Center as quality improvement initiatives. Each practice offered screening to all of the patients attending well-child care visits between 6 months and 8 years of age. The implementation process was investigated by using preimplementation and postimplementation surveys and a focus group of pediatric primary care providers. To assess outcomes, such as changes in identification rates and referrals for developmental and behavioral concerns, we reviewed medical charts of all of the 2- and 3-year-olds present at Children's Hospital Primary Care Center well-child care visits in the periods before and after screening implementation. RESULTS: Providers found routine screening easier than expected and feasible to conduct in a busy primary care setting. The practice change resulted in screening of 61.6% of eligible children. Compared with same-aged children before screening, after screening was implemented more behavioral concerns were detected in the 2-year-old group, and more children with developmental concerns were identified in the 3-year-old group. Referral rates for additional evaluation increased only for 3-year-olds, although the types of referrals (ie, audiology and early intervention) were consistent as those found before screening started. CONCLUSIONS: Implementation of validated screening by using the Parents' Evaluation of Developmental Status was feasible in large, urban settings. Effectiveness was demonstrated via chart review documenting an increased rate of identification of developmental and behavioral concerns. Perceived obstacles, such as the time requirement, should not prevent widespread adoption of screening.

Attention deficit/hyperactivity disorder: complexities and controversies.

PURPOSE OF REVIEW: Attention deficit/hyperactivity disorder continues to be a prevalent childhood behavioral disorder, with significant clinical and media interest. Providers must be current with research findings that impact the evolving understanding of this complex entity. This article summarizes recent progress in our view of attention deficit/hyperactivity disorder, with emphasis on controversies around diagnosis and treatment, and future management directions. RECENT FINDINGS: Literature about attention deficit/hyperactivity disorder in 2005 further enhanced our understanding of the genetic contribution to the expression of attention deficit/hyperactivity disorder, with exploration of sophisticated genetic models and their dynamic interaction with exposures and experiences. Previous literature focuses on conventional treatment; new developments in pharmacological/alternative options add to treatment choices, but have brought well publicized controversies. Furthermore, optimal management continues to gain evidence-based support. SUMMARY: Attention deficit/hyperactivity disorder is a subject of great interest to families, providers, researchers, and public forums. Scientific investigation supports a primary genetic contribution, but the relationship of molecular bases and environmental exposures appears intricate and complex. With increased awareness of this disorder, diagnostic dilemmas and medication side effects are more widely understood, topics particularly important to clinicians. Stimulant treatment remains the mainstay of intervention, but new delivery forms and nonstimulant options are potential therapies as well.

Update: attention deficit/hyperactivity disorder in the primary care office.

PURPOSE OF REVIEW: Attention-deficit/hyperactivity disorder (AD/HD) affects 7.5% of children, making it among the more common behavioral disorders of childhood. Pediatricians increasingly are expected to recognize AD/HD, as well as diagnose and manage it in the primary care setting. This article reviews recent developments in the care of the pediatric AD/HD patient, with emphasis on information enhancing primary care management. RECENT FINDINGS: Studies published in 2004 provide evidence to guide the treatment of AD/HD. The AD/HD literature continues to support the important role of genetics in its etiology. The absence of universal genetic or neuroimaging findings indicates that history from multiple sources and physical exam remain the standard diagnostic method. Comorbid medical problems, such as sleep disruption and growth suppression, continue to be better understood in the setting of AD/HD, as do the substantial impacts of comorbid learning and psychiatric disorders. Despite great interest in alternative, nonstimulant and behavioral treatments, methylphenidate and amphetamine-based medications remain the mainstay of AD/HD intervention. SUMMARY: AD/HD is a common medical condition with implications for long-term safety and life function, such as academic success, accident occurrence, and drug use. Identification and treatment is increasingly based in the primary care office, where children must be monitored for co-occurring disorders and referred for additional supports when necessary. Tools and guidelines provided by the American Academy of Pediatrics (AAP) provide a framework for consistent and competent AD/HD care supported by current evidence.

Trends in referral to a single encopresis clinic over 20 years.

OBJECTIVE: To compare the characteristics of children with encopresis referred to a single encopresis clinic over the course of 20 years, including symptoms, previous diagnostic and therapeutic interventions, and parental attitudes. METHODS: A retrospective study was conducted of an encopresis clinic at a tertiary care pediatric hospital. Questionnaires at initial evaluation elicited information about bowel habits, soiling, previous evaluations, previous treatments, and parental attitudes. RESULTS: In 503 children with encopresis, the average age of referral dropped from 115 months during the earliest 5 years to 77 months during the most recent 5 years. Children who had soiling for >3 years before referral decreased from 63% to 12%. The use of barium enema before referral decreased from 14% to 5%, as did psychological evaluation, from 25% to 14%. Previous therapy with enemas decreased from 45% to 27%. Mineral oil use remained at approximately 50%, and 20% of children had no previous treatment. Symptoms at referral and parental attitudes did not change across the years. CONCLUSIONS: Children are now referred at an earlier age to our tertiary encopresis clinic. The number of invasive and psychological evaluations has decreased before referral. However, treatment by many primary care providers before the referral has not changed. These data may suggest that pediatricians have increased awareness of encopresis and greater appreciation of its primarily physical rather than psychological nature. Additional studies will be needed to determine how these factors affect outcome.

Factors associated with difficult toilet training.

OBJECTIVE: To identify temperament and behavioral patterns in children with difficult toilet training and to compare those children with same-aged toilet-trained children. METHODS: We compared 46 referred clinic patients who were difficult toilet trainers (DTT) with 62 comparison children (CC) using the Carey-McDevitt Behavioral Style Questionnaire, the Parenting Scale, and a questionnaire of toilet-training history. RESULTS: CC were more likely to have easy temperaments (odds ratio [OR]: 33.51). DTT were more likely to be less adaptable (OR: 3.12), more negative in mood (OR: 2.79), less persistent (OR: 2.97), and lower in approach (OR: 1.85). DTT were more likely than CC to be constipated (OR: 3.52), although 55% of CC were constipated. DTT were likely to hide to stool (74%) and to ask for pull-ups in which to leave stool (37%). Parenting styles did not differ between the groups. CONCLUSIONS: Although the referral population may be inherently biased, these data suggest that difficult toilet training is associated with difficult temperamental traits and constipation in affected children.

The effect of chronic or intermittent hypoxia on cognition in childhood: a review of the evidence.

OBJECTIVE: A review of the evidence concerning the effect of chronic or intermittent hypoxia on cognition in childhood was performed by using both a systematic review of the literature and critical appraisal criteria of causality. Because of the significant impact of behavioral disorders such as attention-deficit/hyperactivity disorder on certain cognitive functions as well as academic achievement, the review also included articles that addressed behavioral outcomes. METHODS: Both direct and indirect evidence were collected. A structured Medline search was conducted from the years 1966-2000 by using the OVID interface. Both English- and non-English-language citations were included. Significant articles identified by the reviewers up to 2003 were also included. To be included as direct evidence, an article needed to be an original report in a peer-reviewed journal with data on cognitive, behavioral, or academic outcomes in children up to 14 years old, with clinical conditions likely to be associated with exposure to chronic or intermittent hypoxia. Indirect evidence from other reviews and publications in closely related fields, including experimental studies in adults, was used to help formulate conclusions. Two reviewers screened abstracts and titles. Each article included as direct evidence received a structured evaluation by 2 reviewers. Adjudication of differences was performed by a group of 2 reviewers and a research consultant. After this review, tables of evidence were constructed that were used as the basis for group discussion and consensus development. Indirect evidence assigned by topic to specific reviewers was also presented as part of this process. A formal procedure was used to rank the studies by design strength. The critical appraisal criteria for causation described in Evidence Based Pediatrics and Child Health (Moyer V, Elliott E, Davis R, et al, eds. London, United Kingdom: BMJ Books; 2000:46-55) were used to develop consensus on causality. RESULTS: A total of 788 literature citations were screened. For the final analysis, 55 articles met the criteria for inclusion in the direct evidence. Of these, 43 (78.2%) reported an adverse effect. Of the 37 controlled studies, 31 (83.8%) reported an adverse effect. Adverse effects were noted at every level of arterial oxygen saturation and for exposure at every age level except for premature newborns. The studies were classified into 5 clinical categories: congenital heart disease (CHD), sleep-disordered breathing (SDB), asthma, chronic ventilatory impairment, and respiratory instability in infants. Two of these categories, CHD and SDB, which accounted for 42 (76.4%) of the included articles, fulfilled the Evidence Based Pediatrics and Child Health criteria for causation. The indirect evidence included 8 reviews, 1 meta-analysis, and 10 original reports covering the fields of adult anoxia, animal research, SDB in adults, natural and experimental high-altitude studies, perinatal hypoxic-ischemic encephalopathy, anemia, and carbon-monoxide poisoning. The studies of high-altitude and carbon-monoxide poisoning provided evidence for causality. CONCLUSIONS: Adverse impacts of chronic or intermittent hypoxia on development, behavior, and academic achievement have been reported in many well-designed and controlled studies in children with CHD and SDB as well as in a variety of experimental studies in adults. This should be taken into account in any situation that may expose children to hypoxia. Because adverse effects have been noted at even mild levels of oxygen desaturation, future research should include precisely defined data on exposure to all levels of desaturation.