title: Variability in clinical and neuropsychological features of individuals with MAP2K1 mutations.
abstract: Mutations in MAP2K1, a gene expressed within the RAS-mitogen activated protein kinase (RAS/MAPK) pathway, are generally associated with the clinical phenotype of cardiofaciocutaneous syndrome. Here we describe two male patients (ages 16 and 20 years) with mutations in MAP2K1 and heterogeneous clinical presentations. Both young men had short stature, some facial features suggesting a RASopathy and minimal cardiac involvement. Detailed medical and neuropsychological findings are presented alongside a comprehensive review of features of patients with MAP2K1 mutations reported in the literature. Published studies have indicated that cognitive functioning of individuals with MAP2K1 mutations can range from severe intellectual disability to mildly below average. Neither of the individuals presented here had severe intellectual disability, and one had intellectual functioning within the average range. Neurodevelopmental concerns that were common among our two patients included fine motor difficulties, slow processing speed, reduced attention span, learning disabilities, and diminished energy/alertness. Taken together, our findings demonstrate that mutations in MAP2K1, which are frequently associated with neurological complications and intellectual disability, can be associated with a milder clinical and neurocognitive profile more typical of individuals with Noonan syndrome. Variability of expression may arise from a complex interplay between RAS/MAPK pathway genotype, epigenetics, medical and obstetric factors, and environmental influences. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Elizabeth I
authors.initials: EI
authors.lastname: Pierpont
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Margaret
authors.initials: M
authors.lastname: Semrud-Clikeman
authors.affiliation: Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota.|Children's Hospitals and Clinics of Minnesota, St. Paul, Minnesota.
authors.forename: Mary Ella
authors.initials: ME
authors.lastname: Pierpont
mesh_terms: D000223:Adaptation, Psychological; D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics; D004644:Emotions; D019066:Facies; D005183:Failure to Thrive / Q000175:diagnosis / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D008297:Male; D009154:Mutation; D009483:Neuropsychological Tests; D010641:Phenotype; D012919:Social Behavior; D055815:Young Adult
chemical_list: D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human
keywords: MAP2K1; MEK1; Noonan syndrome; RASopathies; behavior; cardiofaciocutanous syndrome; cognitive; neuropsychological; phenotype