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

Saskia M. Maas, Adam C. Shaw, Hennie Bikker, Hermann Josef Lüdecke, Karin van der Tuin, Magdalena Badura-Stronka, Elga Belligni, Elisa Biamino, Maria Teresa Bonati, Daniel R. Carvalho, JanMaarten Cobben, Stella A. de Man, Nicolette S. Den Hollander, Nataliya Di Donato, Livia Garavelli, Sabine Grønborg, Johanna C. Herkert, A. Jeannette M Hoogeboom, Aleksander Jamsheer, Anna Latos-BielenskaAnneke Maat-Kievit, Cinzia Magnani, Carlo Marcelis, Inge B. Mathijssen, Maartje Nielsen, Ellen Otten, Lilian B. Ousager, Jacek Pilch, Astrid Plomp, Gemma Poke, Anna Poluha, Renata Posmyk, Claudine Rieubland, Margharita Silengo, Marleen Simon, Elisabeth Steichen, Connie Stumpel, Katalin Szakszon, Edit Polonkai, Jenneke van den Ende, Antony van der Steen, Ton van Essen, Arie van Haeringen, Johanna M. van Hagen, Joke B G M Verheij, Marcel M. Mannens, Raoul C. Hennekam

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)279-292
Number of pages14
JournalEuropean Journal of Medical Genetics
Volume58
Issue number5
DOIs
Publication statusPublished - May 1 2015

Fingerprint

Genotype
Phenotype
Mutation
Exons
Gene Deletion
Missense Mutation
Nose
Intellectual Disability
Foot
Hand
Craniofacial Abnormalities
Multiple Hereditary Exostoses
Eyebrows
Haploinsufficiency
Epiphyses
Metacarpal Bones
Metatarsal Bones
Metabolic Bone Diseases
Genetic Association Studies
Toes

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Maas, S. M., Shaw, A. C., Bikker, H., Lüdecke, H. J., van der Tuin, K., Badura-Stronka, M., ... Hennekam, R. C. (2015). Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome. European Journal of Medical Genetics, 58(5), 279-292. https://doi.org/10.1016/j.ejmg.2015.03.002

Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome. / Maas, Saskia M.; Shaw, Adam C.; Bikker, Hennie; Lüdecke, Hermann Josef; van der Tuin, Karin; Badura-Stronka, Magdalena; Belligni, Elga; Biamino, Elisa; Bonati, Maria Teresa; Carvalho, Daniel R.; Cobben, JanMaarten; de Man, Stella A.; Den Hollander, Nicolette S.; Di Donato, Nataliya; Garavelli, Livia; Grønborg, Sabine; Herkert, Johanna C.; Hoogeboom, A. Jeannette M; Jamsheer, Aleksander; Latos-Bielenska, Anna; Maat-Kievit, Anneke; Magnani, Cinzia; Marcelis, Carlo; Mathijssen, Inge B.; Nielsen, Maartje; Otten, Ellen; Ousager, Lilian B.; Pilch, Jacek; Plomp, Astrid; Poke, Gemma; Poluha, Anna; Posmyk, Renata; Rieubland, Claudine; Silengo, Margharita; Simon, Marleen; Steichen, Elisabeth; Stumpel, Connie; Szakszon, Katalin; Polonkai, Edit; van den Ende, Jenneke; van der Steen, Antony; van Essen, Ton; van Haeringen, Arie; van Hagen, Johanna M.; Verheij, Joke B G M; Mannens, Marcel M.; Hennekam, Raoul C.

In: European Journal of Medical Genetics, Vol. 58, No. 5, 01.05.2015, p. 279-292.

Research output: Contribution to journalArticle

Maas, SM, Shaw, AC, Bikker, H, Lüdecke, HJ, van der Tuin, K, Badura-Stronka, M, Belligni, E, Biamino, E, Bonati, MT, Carvalho, DR, Cobben, J, de Man, SA, Den Hollander, NS, Di Donato, N, Garavelli, L, Grønborg, S, Herkert, JC, Hoogeboom, AJM, Jamsheer, A, Latos-Bielenska, A, Maat-Kievit, A, Magnani, C, Marcelis, C, Mathijssen, IB, Nielsen, M, Otten, E, Ousager, LB, Pilch, J, Plomp, A, Poke, G, Poluha, A, Posmyk, R, Rieubland, C, Silengo, M, Simon, M, Steichen, E, Stumpel, C, Szakszon, K, Polonkai, E, van den Ende, J, van der Steen, A, van Essen, T, van Haeringen, A, van Hagen, JM, Verheij, JBGM, Mannens, MM & Hennekam, RC 2015, 'Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome', European Journal of Medical Genetics, vol. 58, no. 5, pp. 279-292. https://doi.org/10.1016/j.ejmg.2015.03.002
Maas SM, Shaw AC, Bikker H, Lüdecke HJ, van der Tuin K, Badura-Stronka M et al. Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome. European Journal of Medical Genetics. 2015 May 1;58(5):279-292. https://doi.org/10.1016/j.ejmg.2015.03.002
Maas, Saskia M. ; Shaw, Adam C. ; Bikker, Hennie ; Lüdecke, Hermann Josef ; van der Tuin, Karin ; Badura-Stronka, Magdalena ; Belligni, Elga ; Biamino, Elisa ; Bonati, Maria Teresa ; Carvalho, Daniel R. ; Cobben, JanMaarten ; de Man, Stella A. ; Den Hollander, Nicolette S. ; Di Donato, Nataliya ; Garavelli, Livia ; Grønborg, Sabine ; Herkert, Johanna C. ; Hoogeboom, A. Jeannette M ; Jamsheer, Aleksander ; Latos-Bielenska, Anna ; Maat-Kievit, Anneke ; Magnani, Cinzia ; Marcelis, Carlo ; Mathijssen, Inge B. ; Nielsen, Maartje ; Otten, Ellen ; Ousager, Lilian B. ; Pilch, Jacek ; Plomp, Astrid ; Poke, Gemma ; Poluha, Anna ; Posmyk, Renata ; Rieubland, Claudine ; Silengo, Margharita ; Simon, Marleen ; Steichen, Elisabeth ; Stumpel, Connie ; Szakszon, Katalin ; Polonkai, Edit ; van den Ende, Jenneke ; van der Steen, Antony ; van Essen, Ton ; van Haeringen, Arie ; van Hagen, Johanna M. ; Verheij, Joke B G M ; Mannens, Marcel M. ; Hennekam, Raoul C. / Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome. In: European Journal of Medical Genetics. 2015 ; Vol. 58, No. 5. pp. 279-292.
@article{302ca4ed910542cf8b1306f27fd1900a,
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.",
keywords = "EXT1, Genotype, Langer-Giedion syndrome, Multiple exostoses, Natural history, Phenotype, RAD21, Review, Tricho-rhino-phalangeal syndrome, TRPS, TRPS1",
author = "Maas, {Saskia M.} and Shaw, {Adam C.} and Hennie Bikker and L{\"u}decke, {Hermann Josef} and {van der Tuin}, Karin and Magdalena Badura-Stronka and Elga Belligni and Elisa Biamino and Bonati, {Maria Teresa} and Carvalho, {Daniel R.} and JanMaarten Cobben and {de Man}, {Stella A.} and {Den Hollander}, {Nicolette S.} and {Di Donato}, Nataliya and Livia Garavelli and Sabine Gr{\o}nborg and Herkert, {Johanna C.} and Hoogeboom, {A. Jeannette M} and Aleksander Jamsheer and Anna Latos-Bielenska and Anneke Maat-Kievit and Cinzia Magnani and Carlo Marcelis and Mathijssen, {Inge B.} and Maartje Nielsen and Ellen Otten and Ousager, {Lilian B.} and Jacek Pilch and Astrid Plomp and Gemma Poke and Anna Poluha and Renata Posmyk and Claudine Rieubland and Margharita Silengo and Marleen Simon and Elisabeth Steichen and Connie Stumpel and Katalin Szakszon and Edit Polonkai and {van den Ende}, Jenneke and {van der Steen}, Antony and {van Essen}, Ton and {van Haeringen}, Arie and {van Hagen}, {Johanna M.} and Verheij, {Joke B G M} and Mannens, {Marcel M.} and Hennekam, {Raoul C.}",
year = "2015",
month = "5",
day = "1",
doi = "10.1016/j.ejmg.2015.03.002",
language = "English",
volume = "58",
pages = "279--292",
journal = "European Journal of Medical Genetics",
issn = "1769-7212",
publisher = "Elsevier Masson SAS",
number = "5",

}

TY - JOUR

T1 - Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome

AU - Maas, Saskia M.

AU - Shaw, Adam C.

AU - Bikker, Hennie

AU - Lüdecke, Hermann Josef

AU - van der Tuin, Karin

AU - Badura-Stronka, Magdalena

AU - Belligni, Elga

AU - Biamino, Elisa

AU - Bonati, Maria Teresa

AU - Carvalho, Daniel R.

AU - Cobben, JanMaarten

AU - de Man, Stella A.

AU - Den Hollander, Nicolette S.

AU - Di Donato, Nataliya

AU - Garavelli, Livia

AU - Grønborg, Sabine

AU - Herkert, Johanna C.

AU - Hoogeboom, A. Jeannette M

AU - Jamsheer, Aleksander

AU - Latos-Bielenska, Anna

AU - Maat-Kievit, Anneke

AU - Magnani, Cinzia

AU - Marcelis, Carlo

AU - Mathijssen, Inge B.

AU - Nielsen, Maartje

AU - Otten, Ellen

AU - Ousager, Lilian B.

AU - Pilch, Jacek

AU - Plomp, Astrid

AU - Poke, Gemma

AU - Poluha, Anna

AU - Posmyk, Renata

AU - Rieubland, Claudine

AU - Silengo, Margharita

AU - Simon, Marleen

AU - Steichen, Elisabeth

AU - Stumpel, Connie

AU - Szakszon, Katalin

AU - Polonkai, Edit

AU - van den Ende, Jenneke

AU - van der Steen, Antony

AU - van Essen, Ton

AU - van Haeringen, Arie

AU - van Hagen, Johanna M.

AU - Verheij, Joke B G M

AU - Mannens, Marcel M.

AU - Hennekam, Raoul C.

PY - 2015/5/1

Y1 - 2015/5/1

N2 - 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.

AB - 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.

KW - EXT1

KW - Genotype

KW - Langer-Giedion syndrome

KW - Multiple exostoses

KW - Natural history

KW - Phenotype

KW - RAD21

KW - Review

KW - Tricho-rhino-phalangeal syndrome

KW - TRPS

KW - TRPS1

UR - http://www.scopus.com/inward/record.url?scp=84928829503&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84928829503&partnerID=8YFLogxK

U2 - 10.1016/j.ejmg.2015.03.002

DO - 10.1016/j.ejmg.2015.03.002

M3 - Article

C2 - 25792522

AN - SCOPUS:84928829503

VL - 58

SP - 279

EP - 292

JO - European Journal of Medical Genetics

JF - European Journal of Medical Genetics

SN - 1769-7212

IS - 5

ER -