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Eur J Hum Genet. 2015 Aug;23(8):1068-71. doi: 10.1038/ejhg.2014.243. Epub 2014 Nov 5.

p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas.

Author information

1
IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy.
2
1] IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy [2] PRABB-Centro Integrato di Ricerca, Campus Bio-Medico University, Rome, Italy.
3
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.
4
1] IRCCS-Casa Sollievo della Sofferenza Hospital, Mendel Institute, Rome, Italy [2] San Camillo-Forlanini Hospital, Rome, Italy.
5
Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
6
Pediatric Division, Department of Clinical Sciences, Rare Diseases Regional Centre, Polytechnic University of Marche Ospedali Riuniti, Ancona, Italy.
7
Genetics and Molecular Medicine Unit, Anna Meyer Children's University Hospital, Florence, Italy.
8
Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Padova, Italy.
9
Department of Dermatology, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy.
10
Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
11
Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

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.

PMID:
25370043
PMCID:
PMC4795103
DOI:
10.1038/ejhg.2014.243
[Indexed for MEDLINE]
Free PMC Article

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