RESUMO
A 28-year-old female with PIK3CA-related segmental overgrowth presented with headaches. She also had a unilateral vestibular schwannoma (VS), as well as 3 small (<2 cm) meningiomas, which according to the Manchester consensus diagnostic criteria for neurofibromatosis 2 (NF2) is sufficient for a clinical diagnosis. Analysis of blood revealed a mosaic PIK3CA c.2740G>A (p.Gly914Arg) mutation, confirming the diagnosis of PIK3CA-related overgrowth, but no mutations in NF2 were detected. Although VS has not previously been reported in PIK3CA-related segmental overgrowth, meningiomas have, raising the question of whether this patient's VS and meningiomas represent coincidental NF2 or phenotypic extension of her overgrowth syndrome. Genetic analysis of the VS revealed a heterozygous NF2 mutation c.784C>T (p.Arg262Ter) and loss of a portion of 22q, including NF2, SMARCB1, and LZTR1 genes. These results suggest that the patient has 2 different mosaic disorders, NF2 and PIK3CA-related overgrowth. The PIK3CA mutation was also present in the VS. Confirmation of the clinical diagnosis of mosaic NF2 in this patient has implications for monitoring and highlights the possibility of co-occurrence of mosaicism for multiple rare disorders in a single patient.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Mutação , Neuroma Acústico/genética , Adulto , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Neoplasias Meníngeas/patologia , Meningioma/patologia , Mosaicismo , Neurofibromatose 2/genética , Neurofibromatose 2/patologia , Neuroma Acústico/patologia , Doenças Raras/genética , Doenças Raras/patologiaRESUMO
Pharmacogenetics is the study of the role of inheritance in variation to drug response. Drug response phenotypes can vary from adverse drug reactions at one end of the spectrum to equally serious lack of the desired effect of drug therapy at the other. Many of the current important examples of pharmacogenetics involve inherited variation in drug metabolism. Sulfate conjugation catalyzed by cytosolic sulfotransferase (SULT) enzymes, particularly SULT1A1, is a major pathway for drug metabolism in humans. Pharmacogenetic studies of SULT1A1 began over a quarter of a century ago and have advanced from biochemical genetic experiments to include cDNA and gene cloning, gene resequencing, and functional studies of the effects of single nucleotide polymorphisms (SNPs). SNP genotyping, in turn, led to the discovery of functionally important copy number variations (CNVs) in the SULT1A1 gene. This review will briefly describe the evolution of our understanding of SULT1A1 pharmacogenetics and CNV, as well as challenges involved in utilizing both SNP and CNV data in an attempt to predict SULT1A1 function. SULT1A1 represents one example of the potential importance of CNV for the evolving disciplines of pharmacogenetics and pharmacogenomics.
