title: Syndrome disintegration: Exome sequencing reveals that Fitzsimmons syndrome is a co-occurrence of multiple events.
abstract: In 1987 Fitzsimmons and Guilbert described identical male twins with progressive spastic paraplegia, brachydactyly with cone shaped epiphyses, short stature, dysarthria, and "low-normal" intelligence. In subsequent years, four other patients, including one set of female identical twins, a single female child, and a single male individual were described with the same features, and the eponym Fitzsimmons syndrome was adopted (OMIM #270710). We performed exome analysis of the patient described in 2009, and one of the original twins from 1987, the only patients available from the literature. No single genetic etiology exists that explains Fitzsimmons syndrome; however, multiple different genetic causes were identified. Specifically, the twins described by Fitzsimmons had heterozygous mutations in the SACS gene, the gene responsible for autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), as well as a heterozygous mutation in the TRPS1, the gene responsible in Trichorhinophalangeal syndrome type 1 (TRPS1 type 1) which includes brachydactyly as a feature. A TBL1XR1 mutation was identified in the patient described in 2009 as contributing to his cognitive impairment and autistic features with no genetic cause identified for his spasticity or brachydactyly. The findings show that these individuals have multiple different etiologies giving rise to a similar phenotype, and that "Fitzsimmons syndrome" is in fact not one single syndrome. Over time, we anticipate that continued careful phenotyping with concomitant genome-wide analysis will continue to identify the causes of many rare syndromes, but it will also highlight that previously delineated clinical entities are, in fact, not syndromes at all. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.|Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Armour
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.|Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Amanda
authors.initials: A
authors.lastname: Smith
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Taila
authors.initials: T
authors.lastname: Hartley
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.|Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Jodi Warman
authors.initials: JW
authors.lastname: Chardon
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.|Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Sarah
authors.initials: S
authors.lastname: Sawyer
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montreal, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Raoul
authors.initials: R
authors.lastname: Hennekam
authors.affiliation: Department of Human Genetics, McGill University, Montreal, Canada.
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.affiliation: Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.affiliation: Nottingham Clinical Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, Nottingham, UK.
authors.forename: Mohnish
authors.initials: M
authors.lastname: Suri
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.|Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
mesh_terms: D059327:Brachydactyly / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics*; D004401:Dysarthria / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D059472:Exome / Q000235:genetics; D005260:Female; D005385:Fingers / Q000002:abnormalities / Q000503:physiopathology; D006201:Hair Diseases / Q000235:genetics / Q000503:physiopathology; D006360:Heat-Shock Proteins / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015826:Langer-Giedion Syndrome / Q000235:genetics / Q000503:physiopathology; D008297:Male; D009128:Muscle Spasticity / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D009666:Nose / Q000002:abnormalities / Q000503:physiopathology; D009687:Nuclear Proteins / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D020754:Spinocerebellar Ataxias / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C404403:SACS protein, human; C473691:TBL1XR1 protein, human; C108387:TRPS1 protein, human; D014157:Transcription Factors
keywords: ARSACS; Fitzsimmons syndrome; Trichorhinophalangeal syndrome type 1; concomitant mutations; exome sequencing; syndrome