Carolyn Bridgemohan

Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders

Background: Segmental duplications at breakpoints (BP4–BP5) of chromosome 15q13.2q13.3 mediate a recurrent genomic imbalance syndrome associated with mental retardation, epilepsy, and/or electroencephalogram (EEG) abnormalities. Patients: DNA samples from 1445 unrelated patients submitted consecutively for clinical array comparative genomic hybridisation (CGH) testing at Children’s Hospital Boston and DNA samples from 1441 individuals with autism from 751 families in the Autism Genetic Resource Exchange (AGRE) repository. Results: We report the clinical features of five patients with a BP4–BP5 deletion, three with a BP4–BP5 duplication, and two with an overlapping but smaller duplication identified by whole genome high resolution oligonucleotide array CGH. These BP4–BP5 deletion cases exhibit minor dysmorphic features, significant expressive language deficits, and a spectrum of neuropsychiatric impairments that include autism spectrum disorder, attention deficit hyperactivity disorder, anxiety disorder, and mood disorder. Cognitive impairment varied from moderate mental retardation to normal IQ with learning disability. BP4–BP5 covers ∼1.5 Mb (chr15:28.719–30.298 Mb) and includes six reference genes and 1 miRNA gene, while the smaller duplications cover ∼500 kb (chr15:28.902–29.404 Mb) and contain three reference genes and one miRNA gene. The BP4–BP5 deletion and duplication events span CHRNA7, a candidate gene for seizures. However, none of these individuals reported here have epilepsy, although two have an abnormal EEG. Conclusions: The phenotype of chromosome 15q13.2q13.3 BP4–BP5 microdeletion/duplication syndrome may include features of autism spectrum disorder, a variety of neuropsychiatric disorders, and cognitive impairment. Recognition of this broader phenotype has implications for clinical diagnostic testing and efforts to understand the underlying aetiology of this syndrome.

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.

Patient- and Family-Centered Care Coordination: A Framework for Integrating Care for Children and Youth Across Multiple Systems

Understanding a care coordination framework, its functions, and its effects on children and families is critical for patients and families themselves, as well as for pediatricians, pediatric medical subspecialists/surgical specialists, and anyone providing services to children and families. Care coordination is an essential element of a transformed American health care delivery system that emphasizes optimal quality and cost outcomes, addresses family-centered care, and calls for partnership across various settings and communities. High-quality, cost-effective health care requires that the delivery system include elements for the provision of services supporting the coordination of care across settings and professionals. This requirement of supporting coordination of care is generally true for health systems providing care for all children and youth but especially for those with special health care needs. At the foundation of an efficient and effective system of care delivery is the patient-/family-centered medical home. From its inception, the medical home has had care coordination as a core element. In general, optimal outcomes for children and youth, especially those with special health care needs, require interfacing among multiple care systems and individuals, including the following: medical, social, and behavioral professionals; the educational system; payers; medical equipment providers; home care agencies; advocacy groups; needed supportive therapies/services; and families. Coordination of care across settings permits an integration of services that is centered on the comprehensive needs of the patient and family, leading to decreased health care costs, reduction in fragmented care, and improvement in the patient/family experience of care.

Promoting Optimal Development: Screening for Behavioral and Emotional Problems

By current estimates, at any given time, approximately 11% to 20% of children in the United States have a behavioral or emotional disorder, as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Between 37% and 39% of children will have a behavioral or emotional disorder diagnosed by 16 years of age, regardless of geographic location in the United States. Behavioral and emotional problems and concerns in children and adolescents are not being reliably identified or treated in the US health system. This clinical report focuses on the need to increase behavioral screening and offers potential changes in practice and the health system, as well as the research needed to accomplish this. This report also (1) reviews the prevalence of behavioral and emotional disorders, (2) describes factors affecting the emergence of behavioral and emotional problems, (3) articulates the current state of detection of these problems in pediatric primary care, (4) describes barriers to screening and means to overcome those barriers, and (5) discusses potential changes at a practice and systems level that are needed to facilitate successful behavioral and emotional screening. Highlighted and discussed are the many factors at the level of the pediatric practice, health system, and society contributing to these behavioral and emotional problems.

Understanding pediatric inner-city asthma: an explanatory model approach.

Explanatory models (EMs) for asthma among inner‐city school‐age children and their families were examined as a means of better understanding health behaviors. Children and parents were interviewed about their concepts of asthma etiology, asthma medications, and alternative therapies. Drawings were elicited from children to understand their beliefs about asthma. Nineteen children with 17 mothers from a variety of cultural backgrounds were interviewed. Among children, contagion was the primary EM for asthma etiology (53%). Twenty‐five percent of children reported fear of dying from asthma, while fear of their child dying from asthma was reported by 76% of mothers. Mothers reported a variety of EMs, some culturally specific, but the majority reported biomedical concepts of etiology, pathophysiology, and triggers. Although 76% of mothers knew the names of more than one of their childrens medications, 47% thought their childs medications all had similar functions. Thirty‐five percent of families used herbal treatments and 35% incorporated religion into asthma treatment. Seventy‐one percent of families had discontinued medications and 23% reported currently not giving anti‐inflammatory medication. Reasons for discontinuing daily medications included fears of unknown side effects (53%), addiction (18%), tachyphylaxis (18%), and feeling that their child was being given too much medicine (23%). The traditional focus of asthma education is not sufficient to ensure adherence. Asthma education for children should address their views of etiology and fears about dying from asthma. Conversations with parents about their EMs and beliefs about medications and alternative therapies could assist in understanding and responding to parental concerns and choices about medications and help achieve better adherence.

Teaching paediatric residents about learning disorders: use of standardised case discussion versus multimedia computer tutorial

Background  We developed a standardised case‐based educational exercise on the topic of childhood learning disorders, and a multimedia computerised adaptation of this exercise, as part of a national curriculum project based on the Bright Futures guidelines.

Child and family characteristics associated with age of diagnosis of an autism spectrum disorder in a tertiary care setting.

Objective: To identify child and family characteristics associated with age of diagnosis of autism spectrum disorder (ASD) in a tertiary care setting using objective, standardized assessments ensuring diagnostic validity and timing. Methods: The authors conducted a chart review of children who received their initial ASD diagnosis from 2007 to 2011. Child variables included gender, birth order, cognitive functioning, and for children ⩽36 months, language and adaptive assessments. Family variables included insurance, maternal age, maternal education, sibling or family member with ASD, and number of children in the house. Primary outcome was age of ASD diagnosis. The authors ran multiple regression models evaluating the impact of child and family variables on the total sample and on the subsample of children ⩽36 months. Results: Median age of diagnosis was 2.9 years (range, 15 mo–13.8 yr; n = 591). In the total sample, significant predictors of earlier age of diagnosis were later birth order, higher maternal education, fewer children in the house, and a sibling with ASD. In a separate analysis of children ⩽36 months of age (n = 315) with additional data for language and adaptive assessments, significant predictors of younger age of diagnosis were higher cognitive and adaptive functioning, lower receptive and expressive language, and having a sibling with ASD. Conclusions: This study suggests that both family and child characteristics play an important role in the early identification of ASD and that predictive variables may vary based on a childs age. Future research should help to elucidate this finding so that screening measures and policies aimed at early identification can target the most predictive factors.

Feasibility of Conducting Autism Biomarker Research in the Clinical Setting

Objective: Recruitment and completion of research activities during regular clinical care has the potential to increase research participation in complex neurodevelopmental disorders. We evaluated the feasibility, and effect on clinical care, of conducting biomarker research within a subspecialty clinical visit for autism spectrum disorder (ASD). Methods: Children, aged 5 to 10 years, were recruited by providers in ASD clinics at 5 institutions. Biomarkers collected were growth measurements, head circumference, neurologic and dysmorphology examinations, digit ratio (2D:4D) measurement, and platelet serotonin and urinary melatonin sulfate excretion levels. Parents completed the Aberrant Behavior Checklist—Community and a medical/demographic questionnaire. Cognitive level was abstracted from the medical record. Parents and clinicians completed surveys on the effect of the study on the clinical visit. Results: Eighty-three children and their caregivers participated. Factors limiting participation included difficulty reaching families by phone and parent concern about the study blood draw requirement. All children completed at least 4 of 7 planned research activities. Demographic factors, educational placement, and child behavior were not associated with completion of study activities. Lower nonverbal cognitive function was weakly associated with fewer activities completed. Forty-four percent of clinicians reported an effect of the research study on the clinical visit. However, neither parent-reported nor clinician-reported effect was associated with the degree of study activity completion. Conclusion: Recruiting study participants in the context of scheduled ASD clinical visits required significant effort. However, once recruited, participants completed most study activities, regardless of behavioral symptom severity. Research activities did not adversely affect the clinical visit.

A Workforce Survey on Developmental-Behavioral Pediatrics

The aging and increasingly female DBP workforce is at risk of burnout because of long wait lists, increased patient complexity, and high levels of nonreimbursed care. BACKGROUND AND OBJECTIVES: Developmental-behavioral conditions are common, affecting ∼15% of US children. The prevalence and complexity of these conditions are increasing despite long wait times and a limited pipeline of new providers. We surveyed a convenience sample of the developmental-behavioral pediatric (DBP) workforce to determine current practices, workforce trends, and future needs. METHODS: An electronic survey was e-mailed to 1568 members of the American Academy of Pediatrics Section on Developmental and Behavioral Pediatrics and Council on Children with Disabilities, the Society for Developmental and Behavioral Pediatrics, and the National Association of Pediatric Nurse Practitioners Developmental and Behavioral Mental Health Special Interest Group. RESULTS: The response rate was 48%. There were 411 fellowship-trained physicians, 147 nonfellowship-trained physicians, and 125 nurse practitioners; 61% were women, 79% were white, and 5% were Hispanic. Physicians had a mean of 29 years since medical school graduation, and one-third planned to retire in 3 to 5 years. Nurse practitioners were earlier in their careers. Respondents reported long wait times for new appointments, clinician burnout, increased patient complexity and up to 50% additional time spent per visit in nonreimbursed clinical-care activities. Female subspecialists spent more time per visit in billable and nonbillable components of clinical care. CONCLUSIONS: The DBP workforce struggles to meet current service demands, with long waits for appointments, increased complexity, and high volumes of nonreimbursed care. Sex-based practice differences must be considered in future planning. The viability of the DBP subspecialty requires strategies to maintain and expand the workforce, improve clinical efficiency, and prevent burnout.