Rare Germline DICER1 Variants in Pediatric Patients With Cushing's Disease: What Is Their Role?

Context: The DICER1 syndrome is a multiple neoplasia disorder caused by germline mutations in the DICER1 gene. In DICER1 patients, aggressive congenital pituitary tumors lead to neonatal Cushing's disease (CD). The role of DICER1 in other corticotropinomas, however, remains unknown. Objective: To perform a comprehensive screening for DICER1 variants in a large cohort of CD patients, and to analyze their possible contribution to the phenotype. Design, setting, patients, and interventions: We included 192 CD cases: ten young-onset (age <30 years at diagnosis) patients were studied using a next generation sequencing panel, and 182 patients (170 pediatric and 12 adults) were screened via whole-exome sequencing. In seven cases, tumor samples were analyzed by Sanger sequencing. Results: Rare germline DICER1 variants were found in seven pediatric patients with no other known disease-associated germline defects or somatic DICER1 second hits. By immunohistochemistry, DICER1 showed nuclear localization in 5/6 patients. Variant transmission from one of the parents was confirmed in 5/7 cases. One patient had a multinodular goiter; another had a family history of melanoma; no other patients had a history of neoplasms. Conclusions: Our findings suggest that DICER1 gene variants may contribute to the pathogenesis of non-syndromic corticotropinomas. Clarifying whether DICER1 loss-of-function is disease-causative or a mere disease-modifier in this setting, requires further studies. Clinical trial registration: ClinicalTrials.gov: NCT00001595.

For Debate: Paediatric T1DM: DKA is Still a Problem.

Although the treatment of pediatric patients with T1DM has improved ketoacidosis (DKA) remains a frequent problem. OBJECTIVE: To estimate temporal changes in the prevalence of DKA at diagnosis of T1DM and to explore the factors associated with its occurrence. METHODS: Paediatric patients diagnosed at Cruces University Hospital (Spain) since 1997 were included. Clinical/analytical variables at diabetes onset, Hemoglobin A1c level during the first 2 years of evolution and the presence of the honeymoon phase were studied. RESULTS: In 209 patients the prevalence of DKA was stable over time and high (35.4%) especially in the youngest. 8.5% of patients had a severe DKA with a higher risk in older than 10. Partial remission occurred in 26% patients, less frequent in the youngest and in the subgroup with DKA at diagnosis. CONCLUSION: The frequency of DKA although stable, remains high and is associated with a worse evolution of the disease.

Pilot Clinical Trial of High-Flow Oxygen Therapy in Children with Asthma in the Emergency Service.

OBJECTIVES: To assess the efficacy of high-flow nasal cannula (HFNC) oxygen therapy and safety in children with asthma and moderate respiratory failure in the emergency department (ED). STUDY DESIGN: This was a prospective randomized pilot trial of children (aged 1-14 years) presenting to a tertiary academic pediatric ED with moderate-to-severe asthma exacerbations between September 2012 and December 2015. Patients with a pulmonary score (PS) ≥6 or oxygen saturation <94% with a face mask despite initial treatment (salbutamol/ipratropium bromide and corticosteroids) were randomized to HFNC or to conventional oxygen therapy. Pharmacologic treatment was at the discretion of attending physicians. The primary outcome was a decrease in PS ≥2 in the first 2 hours. Secondary outcomes included disposition, length of stay, and need for additional therapies. RESULTS: We randomly allocated 62 children to receive either HFNC (n = 30) or standard oxygen therapy (n = 32). Baseline patient characteristics were similar in the 2 groups. At 2 hours after the start of therapy, PS had decreased by ≥2 points in 16 patients in the HFNC group (53%) compared with 9 controls (28%) (P = .01). Between-group differences in disposition, length of stay, and need for additional therapies were not significant. No side effects were reported. CONCLUSION: HFNC appears to be superior to conventional oxygen therapy for reducing respiratory distress within the first 2 hours of treatment in children with moderate-to-severe asthma exacerbation refractory to first-line treatment. Further studies are needed to demonstrate its overall efficacy in the management of asthma and respiratory failure in the ED. TRIAL REGISTRATION: EudraCT: 2012-001771-36.

Recovery position significantly associated with a reduced admission rate of children with loss of consciousness.

BACKGROUND: Loss of consciousness (LOC) is often seen in children. The response of caregivers to a child with LOC has been poorly investigated. Potential caregivers (parents, teachers) seem to have a poor knowledge of the recovery position (RP)-that is, the position into which an unconscious child should be placed in order to protect the airway. OBJECTIVES: To report the management and diagnoses of LOC in childhood, and to evaluate variables associated with an increased hospital admission rate. METHODS: We conducted a prospective cohort study of consecutive children aged between 0 and 18 years diagnosed with LOC at 11 paediatric emergency departments (PEDs) of 6 European countries. The enrolment period was 3 months. Data were obtained from parental interviews, PED reports and clinical examination. RESULTS: 553 children were enrolled. The most frequent final diagnoses causing LOC were seizures (n=278, 50.3%), and vasovagal syncope (n=124, 22.4%). Caregivers put the child in the RP in 145 cases (26.2%). The RP was independently associated with a significant decrease in the admission rate (aOR=0.28; 95% CI 0.17 to 0.48; p<0.0001). CONCLUSIONS: Our study demonstrates for the first time that the RP may reduce the admission rate of infants with LOC. Caregivers often perform inadequate manoeuvres when a child becomes unconscious. Campaigns aiming at increasing knowledge of the RP should be promoted.