No abstract

Overall, radiographic FAI findings are quite common in a population of healthy young adults, especially in males, with a high degree of coexistence among most findings (OR > 2).

We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T [p.Arg51Cys]) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A [p.Glu49Lys]) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A [p.Arg247Gln]) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.

Background: There is an increasing understanding that extreme preterm birth carries a risk of long-term pulmonary sequelae. A study was undertaken to investigate if, and in what way, neonatal factors were associated with subsequent abnormalities on pulmonary high-resolution CT (HRCT) scanning and if pulmonary function was related to these abnormalities. Methods: HRCT scanning and pulmonary function tests were performed less than 2 weeks apart in 74/86 eligible subjects (86%) born at a gestational age of (28 weeks or with a birth weight of (1000 g within a defined area in Western Norway in 1982-5 (n = 42) or 1991-2 (n = 32). Mean age at examination was 18 and 10 years, respectively. HRCT scans were interpreted by a paediatric radiologist blinded to the clinical data using a structured system allowing scores from 0 to 50. Results: Lung parenchymal abnormalities were found in 64 subjects (86%), the median (interquartile range) score being 3.0 (1.75-5.0) points. Prolonged neonatal requirement for oxygen treatment predicted poor outcome, and an increase of 100 days increased the average HRCT score by 3.8 points (p,0.001). There was also a positive association of the severity of pulmonary function abnormalities with the extent of HRCT abnormalities, exemplified by the relation between forced expiratory volume in 1 s and total HRCT score (b = 20.090; p,0.001). Conclusions: In area-based cohorts of long-term survivors of extremely preterm birth, prolonged neonatal requirements for oxygen treatment predicted subsequent structural abnormalities on HRCT scans and in pulmonary function, and these two outcome measures were interrelated.Over the past three decades the survival rates for extremely preterm neonates have increased significantly from ,10% to .80% in developed countries.1-3 Despite major advances in treatment, the reported incidence rates for bronchopulmonary dysplasia (BPD) have remained largely unchanged, 4 and BPD is currently an important cause of chronic lung disease in children and young adults. [4][5][6] There is reason to believe that even subtle damage to the lung parenchyma in early life may be a precursor for chronic obstructive pulmonary disease (COPD) in adulthood.7 Concerns about long-term outcome for subgroups of BPD survivors were raised as early as in 1990, 8 and have also been expressed in more recent studies.1 Large cohorts of these pioneer subjects are about to reach adulthood, allowing thorough assessment of long-term outcomes. In addition to prematurity as such, we still do not fully understand the association between different neonatal factors, events or treatment with pulmonary changes in later life.We have previously reported on airway abnormalities and pulmonary hyperinflation as well as high-resolution CT (HRCT) findings for two areabased birth cohorts of extremely preterm neonates followed for up to 20 years. [9][10][11] Although there is good evidence to suggest an association of prolonged neonatal oxygen requirements with decreased pulmonary function later in life, 6 11 12 sim...