Late Surfactant Administration in Very Preterm Neonates With Prolonged Respiratory Distress and Pulmonary Outcome at 1 Year of Age: A Randomized Clinical Trial.

IMPORTANCE: Although immature neonate survival has improved, there is an increased risk of developing bronchopulmonary dysplasia, leading to significant respiratory morbidity. Measures to reduce bronchopulmonary dysplasia are not always effective or have important adverse effects. OBJECTIVE: To evaluate the effect of late surfactant administration in infants with prolonged respiratory distress on ventilation duration, respiratory outcome at 36 weeks' postmenstrual age, and at 1 year postnatal age. DESIGN, SETTING, AND PARTICIPANTS: Double-blind randomized clinical trial at 13 level III French perinatal centers. Participants included 118 neonates at less than 33 weeks' gestation who still required mechanical ventilation on day 14 (SD, 2) with fraction of inspired oxygen of more than 0.30. All survivors were eligible for follow-up. We performed an intent-to-treat analysis. INTERVENTIONS: Infants received 200 mg/kg of poractant alfa (surfactant) or air after randomization. At 1 year, after parents' interview, infants underwent physical examination by pediatricians not aware of the randomization. MAIN OUTCOMES AND MEASURES: The duration of ventilation was the primary outcome. The combined outcome of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age and respiratory morbidity at 1 year of age were the main secondary outcome measures. RESULTS: Of the 118 infants who participated in the study, 65 (55%) were male. Fraction of inspired oxygen requirements dropped after surfactant, but not air, for up to 24 hours after instillation (0.36 [0.11] vs 0.43 [0.18]; P < .005). Severe bronchopulmonary dysplasia/death rates at 36 weeks' postmenstrual age were similar (27.1% vs 35.6%; P = .32). Less surfactant-treated infants needed rehospitalization for respiratory problems after discharge (28.3% vs 51.1%; P = .03); 39.5% vs 50% needed respiratory physical therapy (P = .35). No difference was observed for weight (7.8 [1.2] kg vs 7.6 [1.1] kg), height (69 [5] cm vs 69 [3] cm), and head circumference (44.4 [1.7] cm vs 44.2 [1.7] cm) measured at follow-up, nor for neurodevelopment outcome. CONCLUSIONS AND RELEVANCE: Late surfactant administration did not alter the early course of bronchopulmonary dysplasia. However, surfactant-treated infants had reduced respiratory morbidity prior to 1 year of age. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01039285.

Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.

Spontaneous pathologic arterial calcifications in childhood can occur in generalized arterial calcification of infancy (GACI) or in pseudoxanthoma elasticum (PXE). GACI is associated with biallelic mutations in ENPP1 in the majority of cases, whereas mutations in ABCC6 are known to cause PXE. However, the genetic basis in subsets of both disease phenotypes remains elusive. We hypothesized that GACI and PXE are in a closely related spectrum of disease. We used a standardized questionnaire to retrospectively evaluate the phenotype of 92 probands with a clinical history of GACI. We obtained the ENPP1 genotype by conventional sequencing. In those patients with less than two disease-causing ENPP1 mutations, we sequenced ABCC6. We observed that three GACI patients who carried biallelic ENPP1 mutations developed typical signs of PXE between 5 and 8 years of age; these signs included angioid streaks and pseudoxanthomatous skin lesions. In 28 patients, no disease-causing ENPP1 mutation was found. In 14 of these patients, we detected pathogenic ABCC6 mutations (biallelic mutations in eight patients, monoallelic mutations in six patients). Thus, ABCC6 mutations account for a significant subset of GACI patients, and ENPP1 mutations can also be associated with PXE lesions in school-aged children. Based on the considerable overlap of genotype and phenotype of GACI and PXE, both entities appear to reflect two ends of a clinical spectrum of ectopic calcification and other organ pathologies, rather than two distinct disorders. ABCC6 and ENPP1 mutations might lead to alterations of the same physiological pathways in tissues beyond the artery.