Apparently synonymous substitutions in FGFR2affect splicing and result in mild Crouzon syndrome

Background: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2. Case presentation: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis. Conclusions: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations

Apparently synonymous substitutions in FGFR2affect splicing and result in mild Crouzon syndrome

Background: Mutations of fibroblast growth factor receptor 2 (FGFR2) account for a higher proportion of genetic cases of craniosynostosis than any other gene, and are associated with a wide spectrum of severity of clinical problems. Many of these mutations are highly recurrent and their associated features well documented. Crouzon syndrome is typically caused by heterozygous missense mutations in the third immunoglobulin domain of FGFR2. Case presentation: Here we describe two families, each segregating a different, previously unreported FGFR2 mutation of the same nucleotide, c.1083A>G and c.1083A>T, both of which encode an apparently synonymous change at the Pro361 codon. We provide experimental evidence that these mutations affect normal FGFR2 splicing and document the clinical consequences, which include a mild Crouzon syndrome phenotype and reduced penetrance of craniosynostosis. Conclusions: These observations add to a growing list of FGFR2 mutations that affect splicing and provide important clinical information for genetic counselling of families affected by these specific mutations. </p

Surgical Correction of Craniofacial Microsomia: Evaluation of Interventions in 565 Patients at Three Major Craniofacial Units

Aims Craniofacial microsomia is characterized by an asymmetric, hypoplasia of derivatives of the first and second pharyngeal arch, leading to a variety of phenotypic presentations. Studies on surgical correction of patients with CRANIOFACIAL MICROSOMIA have small cohorts, leaving controversial opinions on the optimal treatment modality, the indication for surgery and the optimal timing of surgery. The purpose of this study was to evaluate the types of, timing of, and total number of surgical corrections performed and the number of surgical procedures in correlation to the severity of the phenotype. Patients and Methods A retrospective chart study was conducted including patients diagnosed with CRANIOFACIAL MICROSOMIA from three large craniofacial units. Demographic, radiographic, and clinical information was obtained, including type and number of surgical procedures and age at the time of surgery. Results A total of 565 patients were included. In total, 443 (78.4 percent) of all patients underwent some form of surgery during their life, varying from skin tag removal to major craniofacial operations. The number of surgical interventions was higher with increasing severity of phenotype, bilateral presentation, and a younger age at the first intervention. Conclusions Multiple surgical corrections are frequently seen in patients with a more severe or bilateral presentation. Furthermore, those who are treated earlier in life for correction of asymmetry of the mandible will undergo significantly more surgical procedures to correct the asymmetry later on, independent of the Pruzansky-Kaban type mandible. A prospective international multicenter study is designed with a uniform registration and outcome measurement tool to identify the optimal treatment strateg

P2-17-04: Induction of Tamoxifen Metabolism by Rifampicin: A Worrying Drug-Drug Interaction.

Abstract Background Tamoxifen (Tam) undergoes extensive biotransformation into several metabolites, including the highly active metabolite endoxifen. Differences in metabolism, influenced by both genetic and environmental factors, largely contribute to the inter-individual variability in endoxifen plasma concentrations, potentially affecting the efficacy of Tam. Conflicting results between CYP2D6 genotype/phenotype and endoxifen concentrations have been observed. A reason for this discrepancy may be that CYP3A4 may have a more crucial role in the formation of endoxifen than previously thought (de Graan et al, JCO, in press). Hypothesizing that induction of CYP3A4 and CYP2D6 could lead to increased endoxifen levels, a prospective study was activated evaluating the effects of enzyme induction by rifampicin (Rif) on the plasma pharmacokinetics (PK) of Tam and its metabolites. Methods: A randomized cross-over study design was used, with each patient serving as her own control. Breast cancer patients on steady state Tam therapy (20 or 40 mg once daily) were included. Patients underwent two periods of plasma sampling covering 24 hrs each, once using Tam alone, and once after 15 days of oral Rif (600 mg daily) taken in combination with Tam. Patients were randomized for sampling sequence 1) Tam alone followed by Rif/Tam versus 2) Rif/Tam followed by Tam alone. PK sampling in sequence 2 was performed after a 30-day wash-out period of Rif. Tam and its main metabolites ND-Tam, 4-OH-Tam and endoxifen were quantitated by a validated LC-MS/MS method. PK parameters, including area under the plasma-concentration time curve (AUC) and maximum concentration (Cmax) of all four compounds were calculated (WinNonLin program) and compared (with or without Rif) using a two-sided paired t-test. For safety reasons an interim-analysis was performed after 4 patients. Results: The interim-analysis showed that concentrations of Tam and its metabolites were significantly decreased during Rif/Tam co-administration as compared to Tam administration alone (see table). Especially endoxifen exposure was decreased by a mean of 69%. Based on these data it was decided to stop further enrollment in this study. Conclusions: Concentrations of Tam and its main metabolites decreased significantly after induction by rifampicin. Potentially contributing factors include further metabolism of Tam-metabolites into other inactive metabolites or conjugates (i.e. glucuronides) or a decreased oral availability of Tam. Further pharmacokinetic analyses, including the analysis of glucuronides and other metabolites, will be performed to better understand the mechanism behind these findings. Based upon these data, combining rifampicin with Tam should be avoided. Similar drug-drug interactions may exist between Tam and other strong CYP inducers, such as St John's wort and phenytoin. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-17-04.</jats:p

Alcohol and drugs in seriously injured drivers in six European countries.

The objective of this study was to determine the presence of alcohol and drugs in drivers severely injured in traffic crashes in six European countries. Data were collected from 2492 seriously injured drivers of cars and vans in Belgium, Denmark, Finland, Italy, Lithuania, and the Netherlands, between 2007 and 2010. Toxicological analysis was performed with chromatographic techniques on whole blood for 23 substances. The percentage of drivers positive for at least one psychoactive substance ranged between 28% (Lithuania) and 53% (Belgium). Alcohol (≥0.1 g/L) was the most common finding with the highest percentage in Belgium (42.5%). Among the alcohol-positive drivers, 90.5% had a blood alcohol count (BAC) ≥0.5 g/L and 65.7% had a BAC ≥1.3 g/L. Benzodiazepines (0.0-10.2%) and medicinal opioids (0.5-7.8%) were the most prevailing medicinal drugs, but half of the concentrations were lower than therapeutic. Cannabis (0.5-7.6%) was the most prevailing illicit drug. Alcohol was found in combination with drugs in 2.3-13.2% of the drivers. Drug combinations were found in 0.5-4.3% of the drivers. This study confirms the high prevalence of psychoactive substances in injured drivers, but we observed large differences between the participating countries. Alcohol was the most common finding, followed by cannabis and benzodiazepines. Notable are the many drivers having a BAC ≥ 1.3 g/L. The majority of the substances were found in combination with another psychoactive substance, mostly alcohol. The high prevalence of high BACs and combinations (compared to roadside surveys) suggest that those drivers are most at risk and that preventive actions should target them preferentiall