Faculty Bibliography

The prevalence of autism spectrum disorders (ASDs) has increased 20-fold over the past 50 years to >1% of US children. Although twin studies attest to a high degree of heritability, the genetic risk factors are still poorly understood. We analyzed data from two independent populations using u-statistics for genetically structured wide-locus data and added data from unrelated controls to explore epistasis. To account for systematic, but disease-unrelated differences in (non-randomized) genome-wide association studies (GWAS), a correlation between P-values and minor allele frequency with low granularity data and for conducting multiple tests in overlapping genetic regions, we present a novel study-specific criterion for 'genome-wide significance'. From recent results in a comorbid disease, childhood absence epilepsy, we had hypothesized that axonal guidance and calcium signaling are involved in autism as well. Enrichment of the results in both studies with related genes confirms this hypothesis. Additional ASD-specific variations identified in this study suggest protracted growth factor signaling as causing more severe forms of ASD. Another cluster of related genes suggests chloride and potassium ion channels as additional ASD-specific drug targets. The involvement of growth factors suggests the time of accelerated neuronal growth and pruning at 9-24 months of age as the period during which treatment with ion channel modulators would be most effective in preventing progression to more severe forms of autism. By extension, the same computational biostatistics approach could yield profound insights into the etiology of many common diseases from the genetic data collected over the last decade.

BACKGROUND: Standardized pediatric hospitalist and orthopaedic co-management of spinal fusion patients may improve quality processes and outcomes. This approach has not been studied in a general academic center. OBJECTIVE: Estimate relative effects and feasibility of the interventions on quality outcomes, length of stay (LOS), catheter-acquired urinary tract infections (CAUTI), medica- tion errors, and pain scores. DESIGN AND SETTING: Retrospective cohort using inter- rupted time series, analyzing data from 83 patients aged 5 to 18 years admitted for posterior spinal fusion (PSF) in 2009 (N = 27), 2010 (N = 28), and 2011 (N = 28) on a children's service at a general academic tertiary care center. INTERVENTIONS: Multimodal approach to standardizing pediatric PSF postoperative care with interdepartmental development of order sets, clinical care guidelines, and routine pediatric hospitalist co-management of all pediatric PSF patients. MEASUREMENTS: Chi-square analysis of order set use, guideline use measured by proxy medication and documenta- tion data. ANOVA for comparison of CAUTI and medication error rate and multivariate linear regression of LOS and pain scores. RESULTS: Pediatric hospitalist co-management documen- tation increased from 64% to 80%. Guideline use increased from 40% to 79%, and order set use was < 15%. CAUTI and medication error ratios remained low. Adjusted mean LOS decreased by 0.8 days (p = 0.039, 95% CI 0.7, 1.1). Pain scores did not differ. CONCLUSION: Interdisciplinary, clinical guideline devel- opment and postoperative co-management significantly decreased hospital LOS in pediatric PSF patients. In a general academic medical center, this change may be at- tributed to a pediatric hospitalist academic team, a universal co-management process with well-communicated roles, and a pediatric hospital-based physician development of and adherence to standardized practice.

Brugada syndrome (BrS) is rare genetic disorder, which manifests as syncope or sudden death caused by polymorphic ventricular tachycardia. Diagnosis is based on symptoms and characteristic electrocardiography findings. Identification of mutations in SCN5A support the diagnosis, but the yield is low. According to experts, BrS patients with a history of cardiac arrest should have insertion of an automatic implantable cardiac defibrillator and asymptomatic patients can be managed conservatively. Treatment challenges occur in patients with "intermediate" clinical characteristics and in populations where there is paucity of data such as with neonates and children. We discuss the case of a woman with BrS who is faced with decision challenges in the postpartum period. Should her newborn have testing? When? Will deferment of testing impose an unreasonable uncertainty due to delay of diagnosis? Or conversely, will premature workup impose an unnecessary intervention?

A 14-year-old, 86 kg, female treated with piperacillin-tazobactam [cumulative dose of 114.75 g (1.3 g/kg)] for a bone-related infection developed neutropenia and bone marrow suppression/cell line destruction after 10 days of treatment. Reported cases of piperacillin-induced myelosuppression in adults typically occur after 15 days of therapy, and this adolescent received a much shorter duration of therapy. As we are beginning to understand how the frequent use of antibiotics in the pediatric population affects their unique microbiome, which may have long-term implications on their health, we also need to consider if adverse event profiles are distinct or different in children. While this case will not answer these important questions, it underscores the need for further investigation. One could postulate that pediatric pharmacovigilance is better served by restricting data mining analysis to a smaller pediatric subset, as adverse/possible events in children cannot be solely compared to or tabulated with adult data. Further studies are needed to determine pediatric-specific drug safety profiles for piperacillin-tazobactam and other drugs used in the pediatric population

OBJECTIVE: To develop a reliable rating scale to assess functional capacity in children with familial dysautonomia, evaluate changes over time, and determine whether severity within a particular functional category at a young age affected survival. STUDY DESIGN: Ten functional categories were retrospectively assessed in 123 patients with familial dysautonomia at age 7 years +/- 6 months. Each of the 10 Functional Severity Scale categories (motor development, cognitive ability, psychological status, expressive speech, balance, oral coordination, frequency of dysautonomic crisis, respiratory, cardiovascular, and nutritional status) were scored from 1 (worst or severely affected) to 5 (best or no impairment). Changes over time were analyzed further in 22 of the 123 patients who were also available at ages 17 and 27 years. RESULTS: Severely impaired cardiovascular function and high frequency of dysautonomic crisis negatively affected survival (P < .005 and P < .001, respectively). In the 22 individuals followed up to age 27 years, psychological status significantly worsened (P = .01), and expressive speech improved (P = .045). From age 17 to 27 years, balance worsened markedly (P = .048). CONCLUSION: The Functional Severity Scale is a reliable tool to measure functional capacity in patients with familial dysautonomia. The scale may prove useful in providing prognosis and as a complementary endpoint in clinical trials.

An adolescent female with Moebius syndrome developed paroxysmal hypertension, orthostatic hypotension and autonomic symptoms. Common causes of dysautonomia were excluded by the work-up, which supported a diagnosis of baroreflex failure. Neurological testing suggested dysfunction of the tenth cranial nerve as the etiology. This report suggests that baroreflex dysfunction should be considered in Moebius syndrome patients displaying autonomic symptoms.

Familial dysautonomia (FD) is caused by an intronic splice mutation in the IKBKAP gene that leads to partial skipping of exon 20 and tissue-specific reduction in I-kappa-B kinase complex-associated protein/elongation protein 1 (IKAP/ELP-1) expression. Kinetin (6-furfurylaminopurine) has been shown to improve splicing and increase WT IKBKAP mRNA and IKAP protein expression in FD cell lines and carriers. To determine whether oral kinetin treatment could alter mRNA splicing in FD subjects and was tolerable, we administered kinetin to eight FD individuals homozygous for the splice mutation. Subjects received 23.5 mg/Kg/d for 28 d. An increase in WT IKBKAP mRNA expression in leukocytes was noted after 8 d in six of eight individuals; after 28 d, the mean increase compared with baseline was significant (p = 0.002). We have demonstrated that kinetin is tolerable in this medically fragile population. Not only did kinetin produce the desired effect on splicing in FD patients but also that effect seems to improve with time despite lack of dose change. This is the first report of a drug that produces in vivo mRNA splicing changes in individuals with FD and supports future long-term trials to determine whether kinetin will prove therapeutic in FD patients. ABBREVIATIONS::

As a screening tool to identify symptoms of autonomic dysfunction, the Pediatric Autonomic Symptoms Scale was administered to parents of children with familial dysautonomia, autism spectrum disorders, and age-matched controls. The total scores for the presence of symptoms were compared among the 3 groups for each section and overall. The Pediatric Autonomic Symptoms Scale distinguished controls from children with familial dysautonomia and autism spectrum disorders with scores from each section and overall scores. Familial dysautonomia children scored significantly higher in visceral symptoms, while children with autism spectrum disorders scored significantly higher in psychosocial symptoms. In familial dysautonomia, the concordance for the presence of symptoms within sections and overall scores ranged from 71% to 100%. The concordance for absence of autonomic dysfunction symptoms in controls ranged from 75% to 87.5%. The Pediatric Autonomic Symptoms Scale is comprehensive and can profile autonomic dysfunction in the 2 neurodevelopmental disorders. Its usefulness in other pediatric disorders remains to be studied.