Further delineation of Malan syndrome

Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall–Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only

Effect of the CYP3A5, CYP3A4, CYP3A7, ABCB1, POR and NR1I2 genes in the pharmacokinetics of tacrolimus in a pediatric cohort with stable serum concentrations after renal transplantation: study protocol.

BACKGROUND: Therapeutic response to pharmacological therapy in humans shows large intrapatient and interpatient variability both in treatment efficacy and adverse drug reactions (ADR). Part of this variability can be explained by genetic polymorphisms in genes encoding TAC metabolism related proteins. The aim of this study is to evaluate the contribution of genetic variation in the CYP3A4, CYP3A5, CYP3A7, POR, NR1I2 and ABCB1 genes to this variability in order to achieve a better understanding of TAC pharmacokinetics and a more personalized approach for TAC dosing in a cohort of pediatric patients with stable serum concentrations after renal transplantation. METHODS AND DESIGN: This is a unicenter retrospective cross-sectional study. The protocol was approved by the Clinical Research Ethics Committee of the La Paz University Hospital (Madrid, Spain) and will be carried in this same hospital. 50 pediatric patients with stable serum concentrations after renal transplantation are expected to be included. Peripheral blood samples will be collected for molecular analysis (pharmacogenetics studies) and AUC estimation (C0, C1 and C3 hours after TAC administration). DISCUSSION: To date there are not dosing algorithms that can explain accurately TAC metabolism. The incorporation of a complete pharmacogenetic (PhGx) profile into these algorithms may help in the individualization and optimization of TAC treatment in pediatric renal transplant patients. STUDY REGISTRATION: FC/HULP_002/201

Effect of the CYP3A5, CYP3A4, CYP3A7, ABCB1, POR and NR1I2 genes in the phar- macokinetics of tacrolimus in a pediatric cohort with stable serum concentrations after renal transplantation: study protocol

Estellés A., Lapunzina P., Borobia AM., Carcas AJ., Effect of the CYP3A5, CYP3A4, CYP3A7, ABCB1, POR and NR1I2 genes in the pharmacokinetics of tacrolimus in a pediatric cohort with stable serum concentrations after renal transplantation: study protocol. IBJ Clin Pharmacol 2017 1(1):e0005. Funding: The authors have no financial relationships relevant to this article to disclose. Competing Interests: The authors have no financial relationships relevant to this article to disclose BACKGROUND: Therapeutic response to pharmacological therapy in humans shows large intrapatient and interpatient variability both in treatment efficacy and adverse drug reactions (ADR). Part of this variability can be explained by genetic polymorphisms in genes encoding TAC metabolism related proteins. The aim of this study is to evaluate the contribution of genetic variation in the CYP3A4, CYP3A5, CYP3A7, POR, NR1I2 and ABCB1 genes to this variability in order to achieve a better understanding of TAC pharmacokinetics and a more personalized approach for TAC dosing in a cohort of pediatric patients with stable serum concentrations after renal transplantation