The MAP3K7 gene: Further delineation of clinical characteristics and genotype/phenotype correlations.

Mitogen-activated protein 3 kinase 7 (MAP3K7) encodes the ubiquitously expressed transforming growth factor ß-activated kinase 1, which plays a crucial role in many cellular processes. Mutationsin the MAP3K7 gene have been linked to two distinct disorders: frontometaphyseal dysplasia type 2 (FMD2) and cardiospondylocarpofacial syndrome (CSCF). The fact that different mutations can induce two distinct phenotypes suggests a phenotype/genotype correlation, but no side-by-side comparison has been done thus far to confirm this. Here, we significantly expand the cohort and the description of clinical phenotypes for patients with CSCF and FMD2 who carry mutations in MAP3K7. Our findings support that in contrast to FMD2-causing mutations, CSCF-causing mutations in MAP3K7 have a loss-of-function effect. Additionally, patients with pathogenic mutations in MAP3K7 are at risk for (severe) cardiac disease, have symptoms associated with connective tissue disease, and we show overlap in clinical phenotypes of CSCF with Noonan syndrome (NS). Together, we confirm a molecular fingerprint of FMD2- versus CSCF-causing MAP3K7 mutations and conclude that mutations in MAP3K7 should be considered in the differential diagnosis of patients with syndromic congenital cardiac defects and/or cardiomyopathy, syndromic connective tissue disorders, and in the differential diagnosis of NS.

Mild cerebellar injury does not significantly affect cerebral white matter microstructural organization and neurodevelopmental outcome in a contemporary cohort of preterm infants.

BackgroundPreterm birth is associated with an increased risk of cerebellar injury. The aim of this study was to assess the impact of cerebellar hemorrhages (CBH) on cerebral white matter microstructural tissue organization and cerebellar volume at term-equivalent age (TEA) in extremely preterm infants. Furthermore, we aimed to evaluate the association between CBH and neurodevelopmental outcome in late infancy.MethodsA total of 24 preterm infants with punctate CBH were included and each matched to two preterm control infants. T1-, T2-weighted images and diffusion-weighted imaging were acquired on a 3T magnetic resonance imaging (MRI) system. Regions of interest were drawn on a population-specific neonatal template and automatically registered to individual fractional anisotropy (FA) maps. Brain volumes were automatically computed. Neurodevelopmental outcome was assessed using the Bayley scales of Infant and Toddler Development at 2 years of corrected age.ResultsCBHs were not significantly related to FA in the posterior limb of the internal capsule and corpus callosum or to cerebellar volume. Infants with CBH did not have poorer neurodevelopmental outcome compared with control infants.ConclusionThese findings suggest that the impact of mild CBH on early macroscale brain development may be limited. Future studies are needed to assess the effects of CBH on long-term neurodevelopment.