Heterogeneity of mutational mechanisms and modes of inheritance in auriculocondylar syndrome.

BACKGROUND: Auriculocondylar syndrome (ACS) is a rare craniofacial disorder consisting of micrognathia, mandibular condyle hypoplasia and a specific malformation of the ear at the junction between the lobe and helix. Missense heterozygous mutations in the phospholipase C, ß 4 (PLCB4) and guanine nucleotide binding protein (G protein), α inhibiting activity polypeptide 3 (GNAI3) genes have recently been identified in ACS patients by exome sequencing. These genes are predicted to function within the G protein-coupled endothelin receptor pathway during craniofacial development. RESULTS: We report eight additional cases ascribed to PLCB4 or GNAI3 gene lesions, comprising six heterozygous PLCB4 missense mutations, one heterozygous GNAI3 missense mutation and one homozygous PLCB4 intragenic deletion. Certain residues represent mutational hotspots; of the total of 11 ACS PLCB4 missense mutations now described, five disrupt Arg621 and two disrupt Asp360. The narrow distribution of mutations within protein space suggests that the mutations may result in dominantly interfering proteins, rather than haploinsufficiency. The consanguineous parents of the patient with a homozygous PLCB4 deletion each harboured the heterozygous deletion, but did not present the ACS phenotype, further suggesting that ACS is not caused by PLCB4 haploinsufficiency. In addition to ACS, the patient harbouring a homozygous deletion presented with central apnoea, a phenotype that has not been previously reported in ACS patients. CONCLUSIONS: These findings indicate that ACS is not only genetically heterogeneous but also an autosomal dominant or recessive condition according to the nature of the PLCB4 gene lesion.

Perinatal complications and long-term neurodevelopmental outcome of infants with intrauterine growth restriction.

OBJECTIVE: The objective of the study was to evaluate perinatal and long-term complications of fetuses with intrauterine growth restriction (IUGR) compared with constitutionally small for gestational age (SGA) ones. STUDY DESIGN: The outcome of infants with IUGR and SGA born at the Medical University Graz (Austria) between 2003 and 2009 was retrospectively analyzed. Group assignment was based on birthweight, Doppler ultrasound, and placental morphology. The primary outcome was neurodevelopmental delay at 2 years corrected age. The secondary outcomes were perinatal complications. RESULTS: We included 219 IUGR and 299 SGA infants for perinatal and 146 and 215 for long-term analysis. Fetuses with IUGR were delivered earlier (35 vs 38 weeks) and had higher rates of mortality (8% vs 1%; odds ratio [OR], 8.3) as well as perinatal complications (24.4% vs 1.0%; OR, 31.6). The long-term outcome was affected by increased risk for neurodevelopmental impairment (24.7% vs 5.6%; OR, 5.5) and growth delay (21.2% vs 7.4%; OR, 3.4). CONCLUSION: IUGR infants are subject to an increased risk for adverse short- and long-term outcome compared with SGA children.

Neonatal outcome and two-year follow-up after expectant management of second trimester rupture of membranes.

OBJECTIVE: To assess neonatal outcome and 2-year follow-up of pregnancies complicated by second trimester preterm premature rupture of membranes (PPROM). METHODS: A retrospective review of obstetric and neonatal records for 87 pregnancies (56 singletons, 6 twins, 1 triplet) with PPROM between 14+0 and 24+6 weeks of gestation. Patients received antibiotics and steroids for fetal lung maturity once they reached 24 weeks of gestation. Placentas were examined histopathologically. Surviving infants were followed-up at 2 years of age. RESULTS: Median latency from PPROM to delivery was 4 days. Survival rate of 56 singletons was 45% (25/56); and 13 died in hospital. Survival rate of infants discharged from hospital was 23% (12/56). Chorioamnionitis was seen histologically in 42% (5/12) of surviving infants compared with 92% (12/13) of those that died in hospital. Of the 12 surviving infants, 50% had a normal neurological and developmental outcome at 2 years of age. CONCLUSION: Gestational age, birth weight, and histologic chorioamnionitis have prognostic importance in pregnancies complicated by PPROM. Surviving infants have a 50% chance of achieving an adequate health status at 2 years of age.