title: A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines.
abstract: Noonan syndrome with multiple lentigines (NSML), formerly referred to as LEOPARD syndrome, is a rare autosomal-dominant condition, characterized by multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, growth retardation, and sensorineural deafness. To date, PTPN11, RAF1, and BRAF have been reported to be causal for NSML. We report on a 13-year-old Japanese boy, who was diagnosed with NSML. He was found to have a novel heterozygous missense variant (c.305A > G; p.E102G) in MAP2K1, a gene mostly causal for cardio-facio-cutaneous syndrome (CFCS). He manifested fetal macrosomia, and showed hypotonia and poor sucking in the neonatal period. He had mild developmental delay, and multiple lentigines appearing at approximately age 3 years, as well as flexion deformity of knees bilaterally, subtle facial characteristics including ocular hypertelorism, sensorineural hearing loss, and precocious puberty. He lacked congenital heart defects or hypertrophic cardiomyopathy, frequently observed in patients with NSML, mostly caused by PTPN11 mutations. He also lacked congenital heart defects, characteristic facial features, or intellectual disability, frequently observed in those with CFCS caused by MAP2K1 or MAP2K2 mutations. This may be the first patient clinically diagnosed with NSML, caused by a mutation in MAP2K1.
authors.affiliation: Division of Medical Genetics, Nagano Children's Hospital, Azumino, Japan; Department of Medical Genetics, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Nishi
authors.forename: Seiji
authors.initials: S
authors.lastname: Mizuno
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nanjo
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosho
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis; D019066:Facies; D006579:Heterozygote; D006801:Humans; D044542:LEOPARD Syndrome / Q000175:diagnosis* / Q000235:genetics*; D048369:MAP Kinase Kinase 1 / Q000235:genetics*; D048370:MAP Kinase Kinase 2 / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype
chemical_list: D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: MAP2K1; Noonan syndrome with multiple lentigines (NSML); cardio-facio-cutaneous syndrome (CFCS)