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Eur J Med Genet. 2015 May;58(5):279-92. doi: 10.1016/j.ejmg.2015.03.002. Epub 2015 Mar 16.

Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome.

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Department of Paediatrics, Academic Medical Centre, Amsterdam, The Netherlands.
Department of Clinical Genetics, Guy's & St Thomas' Hospitals, London, United Kingdom.
Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands.
Institut fur Humangenetik, Universitätsklinikum, Essen, Germany.
Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
Department of Medical Genetics, Poznan University of Medical Genetics, and NZOZ Centre for Medical Genetics GENESIS, Poznań, Poland.
Università di Torino, Dipartimento di Scienze della Sanità Publica e Pediatriche, Torino, Italy.
Istituto Auxologico Italiano, IRCCS, Milano, Italy.
Genetic Unit, SARAH Network of Rehabilitation Hospitals, Brasilia, Brazil.
Department of Paediatrics, Amphia Hospital, Breda, The Netherlands.
Institut für Klinische Genetik, TU Dresden, Dresden, Germany.
Clinical Genetics Unit, Obstetric and Paediatric Department, IRCCS, Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.
Department of Clinical Genetics, Centre for Rare Diseases, Juliane Marie Centre, Copenhagen University Hospital Rigshospitalet, Denmark.
University of Groningen, University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
Department of Clinical Genetics, Erasmus MC, University Medical Centre Rotterdam, The Netherlands.
Neonatal Intensive Care Unit, Obstetric and Paediatric Department, University Hospital, Parma, Italy.
Department of Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands.
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Department of Paediatrics and Developmental Age Neurology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland.
Genetic Health Service NZ, Wellington, New Zealand.
Department of Medical Genetics, Lublin, Poland.
Podlaskie Centre of Clinical Genetics, Bialystok and Department of Perinatology, Medical University in Bialystok, Bialystok, Poland.
Division of Human Genetics, Department of Paediatrics, Inselspital, University of Bern, Bern, Switzerland.
Department of Paediatrics, Medical University of Innsbruck, Innsbruck, Austria.
Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht UMC+, Maastricht, The Netherlands.
Department of Paediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
Centre of Medical Genetics, University Hospital Antwerp, Antwerp, Belgium.
Maritime Medical Genetics Service, Halifax, Nova Scotia, Canada.
Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.
Department of Paediatrics, Academic Medical Centre, Amsterdam, The Netherlands; Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. Electronic address:


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.


EXT1; Genotype; Langer-Giedion syndrome; Multiple exostoses; Natural history; Phenotype; RAD21; Review; TRPS; TRPS1; Tricho-rhino-phalangeal syndrome

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