Purpose: Kaposiform lymphangiomatosis (KLA) is a rare, frequently aggressive, systemic disorder of the lymphatic vasculature, occurring primarily in children. Even with multimodal treatments, KLA has a poor prognosis and high mortality rate secondary to coagulopathy, effusions and systemic involvement. We hypothesized that, as has recently been found for other vascular anomalies, KLA may be caused by somatic mosaic variants affecting vascular development. Methods: We performed exome sequencing of tumor samples from five individuals with KLA, along with samples from uninvolved control tissue in three of the five. We used digital PCR (dPCR) to validate the exome findings and to screen KLA samples from six other individuals. Results: We identified a somatic activating NRAS variant (c.182A>G, p.Q61R) in lesional tissue from 10/11 individuals, at levels ranging from 1–28%, that was absent from the tested control tissues. Conclusion: The activating NRAS p.Q61R variant is a known ‘hotspot’ variant, frequently identified in several types of human cancer, especially melanoma. KLA, therefore, joins a growing group of vascular malformations and tumors caused by somatic activating variants in the RAS/PI3K/mTOR signalling pathways. This discovery will expand treatment options for these high risk patients as there is potential for use of targeted RAS pathway inhibitors.

BackgroundRapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients.MethodsWe sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons.ResultsThe analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations.ConclusionsClinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0314-x) contains supplementary material, which is available to authorized users.

BackgroundConflict in healthcare is a well-recognised but under-examined phenomenon. Little is known about the prevalence and causes of conflict across paediatric specialties.ObjectiveTo report the frequency and characteristics of conflict in a paediatric hospital.Design and settingAn explanatory sequential mixed-method approach was adopted. A bespoke questionnaire recorded frequency, severity, cause and staff involved in conflict prospectively. Data were recorded for the same two 12-week periods in 2013 and 2014, in one UK children's teaching hospital. Data were analysed using descriptive statistics and correlation, the findings of which informed the construction of a semistructured interview schedule. Qualitative interviews were conducted with six key informant healthcare professionals to aid data interpretation; interviews were analysed thematically.Results136 individual episodes of conflict were reported. The three most common causes were ‘communication breakdown’, ‘disagreements about treatment’ and ‘unrealistic expectations’. Over 448 h of healthcare professional time was taken up by these conflicts; most often staff nurses, consultants, doctors in training and matrons. The mean severity rating was 4.9 out of 10. Qualitative interviews revealed consensus regarding whether conflicts were ranked as low, medium or high severity, and explanations regarding why neurology recorded the highest number of conflicts in the observed period.ConclusionsConflict is prevalent across paediatric specialties, and particularly in neurology, general paediatrics and neonatology. Considerable staff time is taken in managing conflict, indicating a need to focus resources on supporting staff to resolve conflict, notably managing communication breakdown.