"Hole" Exome Sequences: The Importance of Phenotyping to Fill the Gaps in Whole Exome Sequencing.

BACKGROUND: Whole exome sequencing (WES) is commonly used for patients with nonspecific clinical features and conditions with genetic heterogeneity. However, a nondiagnostic exome does not exclude a genetic diagnosis, so history and physical examination is crucial to selecting appropriate genetic testing. CASES: We report three patients with three recognizable phenotypes: a seven-year-old female with classic Rett syndrome; a 28-year-old male with neuropathy, ataxia, and retinitis pigmentosa; and a 16-year-old male with mosaic, segmental, paternal uniparental disomy 14 who had nondiagnostic WES. CONCLUSIONS: Despite recognizable phenotypes they had diagnostic delays due to incorrect selection of genetic testing. This case series highlights the limitations of WES and reinforces the importance of utilizing patient history and physical examination to select initial testing. We will discuss appropriate testing for these patients and a consistent diagnostic algorithm that can be applied when approaching patients with unknown or uncertain clinical presentations.

Botulinum Toxin for Pediatric Migraine: A Retrospective Multisite Cohort Study.

BACKGROUND: Onabotulinum toxin A is effective in adult chronic migraine, but the efficacy is not well established in adolescent patients. The objective of this study is to describe the safety and efficacy of onabotulinum toxin A and incobotulinum toxin A for adolescent chronic migraine headache. METHODS: We performed a chart review of adolescents who received onabotulinum toxin A or incobotulinum toxin A for headache prevention. Demographic information and baseline headache characteristics were collected. The primary end point was a 50% reduction in headache frequency. Secondary outcome measures included reduction in headache frequency, repeat appointments for injections, reduction in other migraine medications, and adverse events. RESULTS: We included 51 adolescents who received at least one injection of either incobotulinum toxin A or onabotulinum toxin A for chronic migraine. Mean age at first dose was 16.0 (1.1; 13 to 17), (S.D. and range). Patients averaged 24.0 headache days per month (7.6; 4 to 28), (S.D. and range) before injection. In addition, 36 of the 51 adolescents (71%) were experiencing continuous headaches. Thirty-five (69%) adolescents had experienced 50% reduction in headache days by the time of first follow-up, which occurred on average at 16.6 weeks from initial injection (11.5; 2 to 55.7) (S.D. and range). Adolescents reported an average decrease of 13.1 headaches days per month. Only two adolescents reported side effects (4%), which were neck soreness and headache following injection. CONCLUSIONS: Botulinum toxin had better efficacy in our adolescent migraine population than has been demonstrated in other studies.

Neonatal Botulism: A Case Series Suggesting Varied Presentations.

Infantile botulism is an uncommon diagnosis and rarer still in the neonatal period. We describe three cases of neonatal-onset botulism that presented with symptoms typically (hypotonia, constipation, facial diplegia) or atypically seen in older infants (encephalopathy, seizures, and hypothermia). Our series shows a wider spectrum of clinical presentations in patients with neonatal-onset botulism. Our report also suggests that neonatal-onset botulism should be considered more broadly in the hypotonic infant, especially as the condition is treatable with intravenous botulinum-specific immune globulin.