title: Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome.
abstract: Tricho-rhino-phalangeal syndrome (TRPS) is characterized by craniofacial and skeletal abnormalities, and subdivided in TRPS I, caused by mutations in TRPS1, and TRPS II, caused by a contiguous gene deletion affecting (amongst others) TRPS1 and EXT1. We performed a collaborative international study to delineate phenotype, natural history, variability, and genotype-phenotype correlations in more detail. We gathered information on 103 cytogenetically or molecularly confirmed affected individuals. TRPS I was present in 85 individuals (22 missense mutations, 62 other mutations), TRPS II in 14, and in 5 it remained uncertain whether TRPS1 was partially or completely deleted. Main features defining the facial phenotype include fine and sparse hair, thick and broad eyebrows, especially the medial portion, a broad nasal ridge and tip, underdeveloped nasal alae, and a broad columella. The facial manifestations in patients with TRPS I and TRPS II do not show a significant difference. In the limbs the main findings are short hands and feet, hypermobility, and a tendency for isolated metacarpals and metatarsals to be shortened. Nails of fingers and toes are typically thin and dystrophic. The radiological hallmark are the cone-shaped epiphyses and in TRPS II multiple exostoses. Osteopenia is common in both, as is reduced linear growth, both prenatally and postnatally. Variability for all findings, also within a single family, can be marked. Morbidity mostly concerns joint problems, manifesting in increased or decreased mobility, pain and in a minority an increased fracture rate. The hips can be markedly affected at a (very) young age. Intellectual disability is uncommon in TRPS I and, if present, usually mild. In TRPS II intellectual disability is present in most but not all, and again typically mild to moderate in severity. Missense mutations are located exclusively in exon 6 and 7 of TRPS1. Other mutations are located anywhere in exons 4-7. Whole gene deletions are common but have variable breakpoints. Most of the phenotype in patients with TRPS II is explained by the deletion of TRPS1 and EXT1, but haploinsufficiency of RAD21 is also likely to contribute. Genotype-phenotype studies showed that mutations located in exon 6 may have somewhat more pronounced facial characteristics and more marked shortening of hands and feet compared to mutations located elsewhere in TRPS1, but numbers are too small to allow firm conclusions.
authors: Department of Paediatrics, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Saskia M
authors: SM
authors: Maas
authors: Department of Clinical Genetics, Guy's & St Thomas' Hospitals, London, United Kingdom.
authors: Adam C
authors: AC
authors: Shaw
authors: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Hennie
authors: H
authors: Bikker
authors: Institut fur Humangenetik, Universitätsklinikum, Essen, Germany.
authors: Hermann-Josef
authors: HJ
authors: Lüdecke
authors: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Karin
authors: K
authors: van der Tuin
authors: Department of Medical Genetics, Poznan University of Medical Genetics, and NZOZ Centre for Medical Genetics GENESIS, Poznań, Poland.
authors: Magdalena
authors: M
authors: Badura-Stronka
authors: Università di Torino, Dipartimento di Scienze della Sanità Publica e Pediatriche, Torino, Italy.
authors: Elga
authors: E
authors: Belligni
authors: Università di Torino, Dipartimento di Scienze della Sanità Publica e Pediatriche, Torino, Italy.
authors: Elisa
authors: E
authors: Biamino
authors: Istituto Auxologico Italiano, IRCCS, Milano, Italy.
authors: Maria Teresa
authors: MT
authors: Bonati
authors: Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasilia, Brazil.
authors: Daniel R
authors: DR
authors: Carvalho
authors: Department of Paediatrics, Academic Medical Centre, Amsterdam, The Netherlands.
authors: JanMaarten
authors: J
authors: Cobben
authors: Department of Paediatrics, Amphia Hospital, Breda, The Netherlands.
authors: Stella A
authors: SA
authors: de Man
authors: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Nicolette S
authors: NS
authors: Den Hollander
authors: Institut für Klinische Genetik, TU Dresden, Dresden, Germany.
authors: Nataliya
authors: N
authors: Di Donato
authors: Clinical Genetics Unit, Obstetric and Paediatric Department, IRCCS, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
authors: Livia
authors: L
authors: Garavelli
authors: Department of Clinical Genetics, Centre for Rare Diseases, Juliane Marie Centre, Copenhagen University Hospital Rigshospitalet, Denmark.
authors: Sabine
authors: S
authors: Grønborg
authors: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
authors: Johanna C
authors: JC
authors: Herkert
authors: Department of Clinical Genetics, Erasmus MC, University Medical Centre Rotterdam, The Netherlands.
authors: A Jeannette M
authors: AJ
authors: Hoogeboom
authors: Department of Medical Genetics, Poznan University of Medical Genetics, and NZOZ Centre for Medical Genetics GENESIS, Poznań, Poland.
authors: Aleksander
authors: A
authors: Jamsheer
authors: Department of Medical Genetics, Poznan University of Medical Genetics, and NZOZ Centre for Medical Genetics GENESIS, Poznań, Poland.
authors: Anna
authors: A
authors: Latos-Bielenska
authors: Department of Clinical Genetics, Erasmus MC, University Medical Centre Rotterdam, The Netherlands.
authors: Anneke
authors: A
authors: Maat-Kievit
authors: Neonatal Intensive Care Unit, Obstetric and Paediatric Department, University Hospital, Parma, Italy.
authors: Cinzia
authors: C
authors: Magnani
authors: Department of Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Carlo
authors: C
authors: Marcelis
authors: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Inge B
authors: IB
authors: Mathijssen
authors: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Maartje
authors: M
authors: Nielsen
authors: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
authors: Ellen
authors: E
authors: Otten
authors: Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
authors: Lilian B
authors: LB
authors: Ousager
authors: Department of Paediatrics and Developmental Age Neurology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
authors: Jacek
authors: J
authors: Pilch
authors: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Astrid
authors: A
authors: Plomp
authors: Genetic Health Service NZ, Wellington, New Zealand.
authors: Gemma
authors: G
authors: Poke
authors: Department of Medical Genetics, Lublin, Poland.
authors: Anna
authors: A
authors: Poluha
authors: Podlaskie Centre of Clinical Genetics, Bialystok and Department of Perinatology, Medical University in Bialystok, Bialystok, Poland.
authors: Renata
authors: R
authors: Posmyk
authors: Division of Human Genetics, Department of Paediatrics, Inselspital, University of Bern, Bern, Switzerland.
authors: Claudine
authors: C
authors: Rieubland
authors: Università di Torino, Dipartimento di Scienze della Sanità Publica e Pediatriche, Torino, Italy.
authors: Margharita
authors: M
authors: Silengo
authors: Department of Clinical Genetics, Erasmus MC, University Medical Centre Rotterdam, The Netherlands.
authors: Marleen
authors: M
authors: Simon
authors: Department of Paediatrics, Medical University of Innsbruck, Innsbruck, Austria.
authors: Elisabeth
authors: E
authors: Steichen
authors: Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht UMC+, Maastricht, The Netherlands.
authors: Connie
authors: C
authors: Stumpel
authors: Department of Paediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors: Katalin
authors: K
authors: Szakszon
authors: Department of Paediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors: Edit
authors: E
authors: Polonkai
authors: Centre of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
authors: Jenneke
authors: J
authors: van den Ende
authors: Maritime Medical Genetics Service, Halifax, Nova Scotia, Canada.
authors: Antony
authors: A
authors: van der Steen
authors: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
authors: Ton
authors: T
authors: van Essen
authors: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors: Arie
authors: A
authors: van Haeringen
authors: Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.
authors: Johanna M
authors: JM
authors: van Hagen
authors: University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
authors: Joke B G M
authors: JB
authors: Verheij
authors: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
authors: Marcel M
authors: MM
authors: Mannens
authors: Department of Paediatrics, Academic Medical Centre, Amsterdam, The Netherlands; Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address: r.c.hennekam@amc.uva.nl.
authors: Raoul C
authors: RC
authors: Hennekam
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D015826:Langer-Giedion Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D012097:Repressor Proteins; D014157:Transcription Factors / Q000235:genetics*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C108387:TRPS1 protein, human; D014157:Transcription Factors
keywords: EXT1; Genotype; Langer-Giedion syndrome; Multiple exostoses; Natural history; Phenotype; RAD21; Review; TRPS; TRPS1; Tricho-rhino-phalangeal syndrome