title: p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas.
abstract: Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C>T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C>T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.
authors.affiliation: IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pinna
authors.affiliation: IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Lanari
authors.affiliation: IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Daniele
authors.affiliation: IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Consoli
authors.affiliation: IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Agolini
authors.affiliation: 1] IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy [2] PRABB-Centro Integrato di Ricerca, Campus Bio-Medico University, Rome, Italy.
authors.forename: Katia
authors.initials: K
authors.lastname: Margiotti
authors.affiliation: 1] IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy [2] Division of Medical Genetics, Department of Molecular Medicine, San Camillo-Forlanini Hospital, Sapienza University, Rome, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Bottillo
authors.affiliation: 1] IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy [2] San Camillo-Forlanini Hospital, Rome, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Torrente
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bruselles
authors.affiliation: IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Fusilli
authors.affiliation: Pediatric Division, Department of Clinical Sciences, Rare Diseases Regional Centre, Polytechnic University of Marche Ospedali Riuniti, Ancona, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ficcadenti
authors.affiliation: Genetics and Molecular Medicine Unit, Anna Meyer Children's University Hospital, Florence, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bargiacchi
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: Eva
authors.initials: E
authors.lastname: Trevisson
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Forzan
authors.affiliation: Department of Dermatology, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Giustini
authors.affiliation: Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Leoni
authors.affiliation: Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
authors.affiliation: Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Digilio
authors.affiliation: Bambino Gesù Children Hospital, IRCCS, Rome, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Clementi
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: De Luca
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D005817:Genetic Counseling; D006801:Humans; D020125:Mutation, Missense; D009455:Neurofibroma / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009456:Neurofibromatosis 1 / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D025542:Neurofibromin 1 / Q000235:genetics*; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype
chemical_list: D025542:Neurofibromin 1