Ocular and Periorbital Anthropometry in the Newborn

To provide standard reference values relating to a number of ocular and periorbital anthropometric parameters in the newborn, inner canthal, outer canthal and outer orbital distances were measured in 625 healthy newborns of gestational ages 27-44 weeks. Mean and SD values for these measurements and for inner canthal, canthal and length of palpebral fissure indices derived from these measurements were calculated for boy and girl infants and for infants of different degrees of prematurity. Boy infants showed significantly higher values for inner canthal, outer canthal and periorbital distances (p \u3c 0.01, p \u3c 0.05, p \u3c 0.01). No significant sex differences were observed for palpebral fissure length nor for the inner canthal and canthal indices. Inner canthal, canthal indices and length of palpebral fissure were also found to be essentially comparable in term, preterm and small for gestational age infant groups while significant dif­ferences (p \u3c 0.001) were established among inner canthal, outer canthal and periorbital distance measurements.Our results also indicate that in the newborn, a value exceeding 7.5% for inner canthal index indicates hypertelorism and a value over 43% for canthal index is compatible with a diagnosis of ocular pseudohypertelorism

Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable: molecular pathology of mutations in PAH exon 11

In about 20-30% of phenylketonuria (PKU) patients, phenylalanine (Phe) levels can be controlled by cofactor 6R-tetrahydrobiopterin (BH(4)) administration. The phenylalanine hydroxylase (PAH) genotype has a predictive value concerning BH(4)-response and therefore a correct assessment of the mutation molecular pathology is important. Mutations that disturb the splicing of exons (e.g. interplay between splice site strength and regulatory sequences like exon splicing enhancers (ESEs)/exon splicing silencers (ESSs)) may cause different severity of PKU. In this study, we identified PAH exon 11 as a vulnerable exon and used patient derived lymphoblast cell lines and PAH minigenes to study the molecular defect that impacted pre-mRNA processing. We showed that the c.1144T>C and c.1066-3C>T mutations cause exon 11 skipping, while the c.1139C>T mutation is neutral or slightly beneficial. The c.1144T>C mutation resides in a putative splicing enhancer motif and binding by splicing factors SF2/ASF, SRp20 and SRp40 is disturbed. Additional mutations in potential splicing factor binding sites contributed to elucidate the pathogenesis of mutations in PAH exon 11. We suggest that PAH exon 11 is vulnerable due to a weak 3' splice site and that this makes exon 11 inclusion dependent on an ESE spanning position c.1144. Importantly, this implies that other mutations in exon 11 may affect splicing, since splicing is often determined by a fine balance between several positive and negative splicing regulatory elements distributed throughout the exon. Finally, we identified a pseudoexon in intron 11, which would have pathogenic consequences if activated by mutations or improved splicing conditions. Exonic mutations that disrupt splicing are unlikely to facilitate response to BH(4) and may lead to inconsistent genotype-phenotype correlations. Therefore, recognizing such mutations enhances our ability to predict the BH(4)-response