Establishing the phenotypic spectrum of ZTTK syndrome by analysis of 52 individuals with variants in SON.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management.

Short-term effects of neuromuscular blockade on global and regional lung mechanics, oxygenation and ventilation in pediatric acute hypoxemic respiratory failure.

BACKGROUND: Neuromuscular blockade (NMB) has been shown to improve outcome in acute respiratory distress syndrome (ARDS) in adults, challenging maintaining spontaneous breathing when there is severe lung injury. We tested in a prospective physiological study the hypothesis that continuous administration of NMB agents in mechanically ventilated children with severe acute hypoxemic respiratory failure (AHRF) improves the oxygenation index without a redistribution of tidal volume V T toward non-dependent lung zones. METHODS: Oxygenation index, PaO2/FiO2 ratio, lung mechanics (plateau pressure, mean airway pressure, respiratory system compliance and resistance), hemodynamics (heart rate, central venous and arterial blood pressures), oxygenation [oxygenation index (OI), PaO2/FiO2 and SpO2/FiO2], ventilation (physiological dead space-to-V T ratio) and electrical impedance tomography measured changes in end-expiratory lung volume (EELV), and V T distribution was measured before and 15 min after the start of continuous infusion of rocuronium 1 mg/kg. Patients were ventilated in a time-cycled, pressure-limited mode with pre-set V T. All ventilator settings were not changed during the study. RESULTS: Twenty-two patients were studied (N = 18 met the criteria for pediatric ARDS). Median age (25-75 interquartile range) was 15 (7.8-77.5) weeks. Pulmonary pathology was present in 77.3%. The median lung injury score was 9 (8-10). The overall median CoV and regional lung filling characteristics were not affected by NMB, indicating no ventilation shift toward the non-dependent lung zones. Regional analysis showed a homogeneous time course of lung inflation during inspiration, indicating no tendency to atelectasis after the introduction of NMB. NMB decreased the mean airway pressure (p = 0.039) and OI (p = 0.039) in all patients. There were no significant changes in lung mechanics, hemodynamics and EELV. Subgroup analysis showed that OI decreased (p = 0.01) and PaO2/FiO2 increased (p = 0.02) in patients with moderate or severe PARDS. CONCLUSIONS: NMB resulted in an improved oxygenation index in pediatric patients with AHRF. Distribution of V T and regional lung filling characteristics were not affected.