The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Steven E.r. Hovius - One of the best experts on this subject based on the ideXlab platform.
-
A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in Triphalangeal Thumb–polysyndactyly syndrome
Genetics in Medicine, 2018Co-Authors: Jacob W P Potuijt, Steven E.r. Hovius, Martijn Baas, Rivka Sukenik-halevy, Hannie Douben, Picard Nguyen, Deon J Venter, Renee Gallagher, Sigrid M. A. Swagemakers, Christianne A. Van NieuwenhovenAbstract:Purpose The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of Triphalangeal Thumb–polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. Methods We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. Results Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). Conclusion Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.
-
A multidisciplinary review of Triphalangeal Thumb.
The Journal of hand surgery European volume, 2018Co-Authors: Jacob W P Potuijt, Robert-jan H Galjaard, Peter J. Van Der Spek, Christianne A. Van Nieuwenhoven, Nadav Ahituv, Kerby C. Oberg, Steven E.r. HoviusAbstract:Despite being a rare congenital limb anomaly, Triphalangeal Thumb is a subject of research in various scientific fields, providing new insights in clinical research and evolutionary biology. The findings of Triphalangeal Thumb can be predictive for other congenital anomalies as part of an underlying syndrome. Furthermore, Triphalangeal Thumb is still being used as a model in molecular genetics to study gene regulation by long-range regulatory elements. We present a review that summarizes a number of scientifically relevant topics that involve the Triphalangeal Thumb phenotype. Future initiatives involving multidisciplinary teams collaborating in the field of Triphalangeal Thumb research can lead to a better understanding of the pathogenesis and molecular mechanisms of this condition as well as other congenital upper limb anomalies.
-
Triphalangeal Thumb: clinical features and treatment
The Journal of hand surgery European volume, 2018Co-Authors: Steven E.r. Hovius, Jacob W P Potuijt, Christianne A. Van NieuwenhovenAbstract:Triphalangeal Thumb is a rare congenital anomaly in which the Thumb has three phalanges. Clinical presentation of Triphalangeal Thumb can vary considerably and can be present in both hands or unilateral. The Thumb can be long with a finger-like appearance. The presence of clinodactyly depends on the shape of the extra phalanx varying from wedge-shaped to rectangular. Various joints, ligaments, muscles, and tendons of the first ray can be hypoplastic or absent, with varying degrees of stiffness or instability. The aim of surgical treatment is to reconstruct or correct the anatomic anomalies to obtain greater function and a more acceptable appearance. In our series, operations varied from removal of the delta phalanx with ligament reconstruction to multiple osteotomies and rebalancing of soft tissues. Results in these often complex cases can be rewarding if the surgeon has sufficient knowledge of the underlying anatomic differences. This review summarizes our current concepts of presentation and management of the Triphalangeal Thumb.
-
A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in Triphalangeal Thumb-polysyndactyly syndrome.
Genetics in medicine : official journal of the American College of Medical Genetics, 2018Co-Authors: Jacob W P Potuijt, Steven E.r. Hovius, Martijn Baas, Rivka Sukenik-halevy, Hannie Douben, Picard Nguyen, Deon J Venter, Renee Gallagher, Sigrid M. A. Swagemakers, Christianne A. Van NieuwenhovenAbstract:The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of Triphalangeal Thumb–polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.
-
Outcome of two types of surgical correction of the extra phalanx in Triphalangeal Thumb: is there a difference?
The Journal of hand surgery European volume, 2015Co-Authors: J. M. Zuidam, R. W. Selles, M. De Kraker, Steven E.r. HoviusAbstract:The surgical strategy of treatment of the opposable Triphalangeal Thumb is correction of the radio-ulnar deviation, reduction of the additional length and joint stabilization. The commonest procedures are: (1) removal of the extra phalanx and stabilization of the remaining joint; and (2) a combined reduction osteotomy with resection of the distal joint followed by arthrodesis. We treated 20 patients (33 hands). In 17 hands the extra phalanx was removed, and in 16 hands we used the combined osteotomy procedure of distal joint removal and arthrodesis. None of the patients in either group had an unstable interphalangeal joint. The mean radial or ulnar deviation in the interphalangeal joint was 5° degrees and 9°, respectively. Mean active flexion in the interphalangeal joint was 35° and 46°, respectively, in the two groups. Results for both procedures are similar, for both objective measures and self-rated function and activities of daily living. Either surgical approach seems reliable.Therapeutic, Level of evidence: Level III.
Jane A. Evans - One of the best experts on this subject based on the ideXlab platform.
-
Triphalangeal Thumb in association with split hand/foot: a phenotypic marker for SHFM3?
Birth defects research. Part A Clinical and molecular teratology, 2007Co-Authors: Alison M. Elliott, Martin H. Reed, Jane A. EvansAbstract:BACKGROUND At least five distinct loci have been implicated in split hand foot malformation (SHFM). Establishing genotype/phenotype correlations at the chromosomal level may elucidate responsible developmental genes and improve patient management. In our analysis of previously published genetically mapped SHFM cases, preaxial hand involvement was a significant discriminating variable, most commonly seen at the SHFM3 locus (OMIM 600095) at 10q24. Of the 47 SHFM3 patients analyzed, 15 (31.9%) had Triphalangeal Thumb (TPT), a limb finding not reported at any other locus. METHODS The association of TPT/split foot, in particular, prompted us to review the literature for similar cases. RESULTS We ascertained a number of unmapped familial and sporadic cases with TPT/split foot, including a group of patients with Triphalangeal Thumb-brachyectrodactyly syndrome. Certain trends were similar in both SHFM3 and these unmapped literature cases. With respect to gender, 7/12 (58%) of mapped SHFM3 cases with TPT/split foot were male whereas 5/12 (42%) were female, compared with 22/50 (44%) males and 28/50 (56%) females among unmapped cases (P=0.3715). Individuals in both groups usually had bilateral involvement, with 67 and 60% showing bilateral TPT among mapped and literature cases, respectively (P=0.6714). Bilateral involvement of the feet was even more striking (83% of SHFM3 patients and 96% of literature cases; P=0.0808). CONCLUSIONS Patients with TPT/split foot may in fact represent SHFM3 cases and should be evaluated for genomic rearrangements at 10q24. TPT may be identified only by radiographic analysis, emphasizing the importance of imaging these patients and their family members.
-
Triphalangeal Thumb in association with split hand foot a phenotypic marker for shfm3
Birth Defects Research Part A-clinical and Molecular Teratology, 2007Co-Authors: Alison M. Elliott, Martin H. Reed, Jane A. EvansAbstract:BACKGROUND At least five distinct loci have been implicated in split hand foot malformation (SHFM). Establishing genotype/phenotype correlations at the chromosomal level may elucidate responsible developmental genes and improve patient management. In our analysis of previously published genetically mapped SHFM cases, preaxial hand involvement was a significant discriminating variable, most commonly seen at the SHFM3 locus (OMIM 600095) at 10q24. Of the 47 SHFM3 patients analyzed, 15 (31.9%) had Triphalangeal Thumb (TPT), a limb finding not reported at any other locus. METHODS The association of TPT/split foot, in particular, prompted us to review the literature for similar cases. RESULTS We ascertained a number of unmapped familial and sporadic cases with TPT/split foot, including a group of patients with Triphalangeal Thumb-brachyectrodactyly syndrome. Certain trends were similar in both SHFM3 and these unmapped literature cases. With respect to gender, 7/12 (58%) of mapped SHFM3 cases with TPT/split foot were male whereas 5/12 (42%) were female, compared with 22/50 (44%) males and 28/50 (56%) females among unmapped cases (P=0.3715). Individuals in both groups usually had bilateral involvement, with 67 and 60% showing bilateral TPT among mapped and literature cases, respectively (P=0.6714). Bilateral involvement of the feet was even more striking (83% of SHFM3 patients and 96% of literature cases; P=0.0808). CONCLUSIONS Patients with TPT/split foot may in fact represent SHFM3 cases and should be evaluated for genomic rearrangements at 10q24. TPT may be identified only by radiographic analysis, emphasizing the importance of imaging these patients and their family members.
Christianne A. Van Nieuwenhoven - One of the best experts on this subject based on the ideXlab platform.
-
Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild Triphalangeal Thumb phenotypes.
Journal of medical genetics, 2020Co-Authors: Jacob W P Potuijt, Christianne A. Van Nieuwenhoven, Jeannette Hoogeboom, Esther De Graaff, R. J. H. GaljaardAbstract:Backgroun: The of zone of polarizing activity regulatory sequence (ZRS) is a regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog expression in the limb bud. Variants in the ZRS are generally fully penetrant and can cause Triphalangeal Thumb (TPT) and polydactyly in affected families. Objective: In thisreport, we describe two families with mild phenotypical presentation Methods: Weperformed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing. Results: In familyI, a novel 165A>G variant in the ZRS(g.156584405A>G, GRCh37/Hg19) was found. Infamily II, we identified a 295T>C variant inthe ZRS (g.156584535T>C, GRCh37/Hg19). Family members of both families who werepresumed to be unaffected shared the variant in the ZRS with affected familymembers, suggesting reduced penetrance of the genotype. However, clinicalexamination of these unaffected family members revealed minor anomalies likebroad Thumbs and lack of Thumb opposition. As the phenotype in affected patients is remarkably mild, we suggest that theseZRS variants are minimally disruptive for Sonic Hedgehog expression andtherefore can result in subclinical phenotypes. Conclusion: Our study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT.
-
A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in Triphalangeal Thumb–polysyndactyly syndrome
Genetics in Medicine, 2018Co-Authors: Jacob W P Potuijt, Steven E.r. Hovius, Martijn Baas, Rivka Sukenik-halevy, Hannie Douben, Picard Nguyen, Deon J Venter, Renee Gallagher, Sigrid M. A. Swagemakers, Christianne A. Van NieuwenhovenAbstract:Purpose The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of Triphalangeal Thumb–polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. Methods We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. Results Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). Conclusion Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.
-
A multidisciplinary review of Triphalangeal Thumb.
The Journal of hand surgery European volume, 2018Co-Authors: Jacob W P Potuijt, Robert-jan H Galjaard, Peter J. Van Der Spek, Christianne A. Van Nieuwenhoven, Nadav Ahituv, Kerby C. Oberg, Steven E.r. HoviusAbstract:Despite being a rare congenital limb anomaly, Triphalangeal Thumb is a subject of research in various scientific fields, providing new insights in clinical research and evolutionary biology. The findings of Triphalangeal Thumb can be predictive for other congenital anomalies as part of an underlying syndrome. Furthermore, Triphalangeal Thumb is still being used as a model in molecular genetics to study gene regulation by long-range regulatory elements. We present a review that summarizes a number of scientifically relevant topics that involve the Triphalangeal Thumb phenotype. Future initiatives involving multidisciplinary teams collaborating in the field of Triphalangeal Thumb research can lead to a better understanding of the pathogenesis and molecular mechanisms of this condition as well as other congenital upper limb anomalies.
-
Triphalangeal Thumb: clinical features and treatment
The Journal of hand surgery European volume, 2018Co-Authors: Steven E.r. Hovius, Jacob W P Potuijt, Christianne A. Van NieuwenhovenAbstract:Triphalangeal Thumb is a rare congenital anomaly in which the Thumb has three phalanges. Clinical presentation of Triphalangeal Thumb can vary considerably and can be present in both hands or unilateral. The Thumb can be long with a finger-like appearance. The presence of clinodactyly depends on the shape of the extra phalanx varying from wedge-shaped to rectangular. Various joints, ligaments, muscles, and tendons of the first ray can be hypoplastic or absent, with varying degrees of stiffness or instability. The aim of surgical treatment is to reconstruct or correct the anatomic anomalies to obtain greater function and a more acceptable appearance. In our series, operations varied from removal of the delta phalanx with ligament reconstruction to multiple osteotomies and rebalancing of soft tissues. Results in these often complex cases can be rewarding if the surgeon has sufficient knowledge of the underlying anatomic differences. This review summarizes our current concepts of presentation and management of the Triphalangeal Thumb.
-
A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in Triphalangeal Thumb-polysyndactyly syndrome.
Genetics in medicine : official journal of the American College of Medical Genetics, 2018Co-Authors: Jacob W P Potuijt, Steven E.r. Hovius, Martijn Baas, Rivka Sukenik-halevy, Hannie Douben, Picard Nguyen, Deon J Venter, Renee Gallagher, Sigrid M. A. Swagemakers, Christianne A. Van NieuwenhovenAbstract:The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of Triphalangeal Thumb–polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.
J. C. Zenteno - One of the best experts on this subject based on the ideXlab platform.
-
Triphalangeal Thumb and brachyectrodactyly syndrome : an uncommon entity with evidence of geographic distribution
Clinical genetics, 2008Co-Authors: J. C. Zenteno, M. Aguinaga, V. Chavez, N. Sastré, M. R. Rivera, Susana Kofman-alfaroAbstract:A new Mexican family with the Triphalangeal Thumb-brachyectrodactyly syndrome is described. The proposita, a 17-year-old female, showed the classic malformation pattern: Triphalangeal Thumb, brachysyndactyly in the hands and ectrodactyly in the feet. Several members of the family had similar malformations, and others presented minor manifestations of the disease (brachydactyly and nail dysplasia). This is the fourth familial case reported in the literature with the Triphalangeal Thumb and brachyectrodactyly complex and the third of Mexican origin, reflecting a geographical predominance in the occurrence of this uncommon pathology.
-
mutational analysis of hoxd13 and hoxa13 genes in the Triphalangeal Thumb brachyectrodactyly syndrome
Journal of Orthopaedic Research, 2002Co-Authors: A Perezcabrera, Susana Kofmanalfaro, J. C. ZentenoAbstract:Abstract The Triphalangeal Thumb–brachyectrodactyly syndrome is a very rare autosomal dominant disorder of unknown etiology characterized by an unusual pattern of limb malformations: Triphalangeal Thumbs and brachyectrodactyly in the hands, and ectrodactyly in the feet. In a previous report, we described the clinical and radiographical features of three related subjects with the disease and suggest that due to the unusual combination of limb defects and to its phenotypic similarity with the limb malformative pattern induced by disrupting the Hoxd13 gene in mouse, the Triphalangeal Thumb–brachyectrodactyly syndrome might be caused by mutations in a HOX gene. After sequencing the entire coding region of HOXD13 and the highly conserved homeodomain encoding region of HOXA13, we do not detect any deleterious mutation in any of the patients excluding that alterations at these sequences are responsible for the disease. Mutations in regulatory regions of these genes or in other genes involved in limb development might be responsible for the disease.
-
Mutational analysis of HOXD13 and HOXA13 genes in the Triphalangeal Thumb–brachyectrodactyly syndrome
Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2002Co-Authors: A. Pérez-cabrera, Susana Kofman-alfaro, J. C. ZentenoAbstract:Abstract The Triphalangeal Thumb–brachyectrodactyly syndrome is a very rare autosomal dominant disorder of unknown etiology characterized by an unusual pattern of limb malformations: Triphalangeal Thumbs and brachyectrodactyly in the hands, and ectrodactyly in the feet. In a previous report, we described the clinical and radiographical features of three related subjects with the disease and suggest that due to the unusual combination of limb defects and to its phenotypic similarity with the limb malformative pattern induced by disrupting the Hoxd13 gene in mouse, the Triphalangeal Thumb–brachyectrodactyly syndrome might be caused by mutations in a HOX gene. After sequencing the entire coding region of HOXD13 and the highly conserved homeodomain encoding region of HOXA13, we do not detect any deleterious mutation in any of the patients excluding that alterations at these sequences are responsible for the disease. Mutations in regulatory regions of these genes or in other genes involved in limb development might be responsible for the disease.
Jacob W P Potuijt - One of the best experts on this subject based on the ideXlab platform.
-
Variable expression of subclinical phenotypes instead of reduced penetrance in families with mild Triphalangeal Thumb phenotypes.
Journal of medical genetics, 2020Co-Authors: Jacob W P Potuijt, Christianne A. Van Nieuwenhoven, Jeannette Hoogeboom, Esther De Graaff, R. J. H. GaljaardAbstract:Backgroun: The of zone of polarizing activity regulatory sequence (ZRS) is a regulatory element residing in intron 5 of LMBR1 and regulates Sonic Hedgehog expression in the limb bud. Variants in the ZRS are generally fully penetrant and can cause Triphalangeal Thumb (TPT) and polydactyly in affected families. Objective: In thisreport, we describe two families with mild phenotypical presentation Methods: Weperformed a field study for clinical evaluation and sequenced the ZRS for variantsusing Sanger sequencing. Results: In familyI, a novel 165A>G variant in the ZRS(g.156584405A>G, GRCh37/Hg19) was found. Infamily II, we identified a 295T>C variant inthe ZRS (g.156584535T>C, GRCh37/Hg19). Family members of both families who werepresumed to be unaffected shared the variant in the ZRS with affected familymembers, suggesting reduced penetrance of the genotype. However, clinicalexamination of these unaffected family members revealed minor anomalies likebroad Thumbs and lack of Thumb opposition. As the phenotype in affected patients is remarkably mild, we suggest that theseZRS variants are minimally disruptive for Sonic Hedgehog expression andtherefore can result in subclinical phenotypes. Conclusion: Our study underlines the importance of accurate clinical examination and appropriate genetic counselling in families with mild cases of TPT.
-
A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in Triphalangeal Thumb–polysyndactyly syndrome
Genetics in Medicine, 2018Co-Authors: Jacob W P Potuijt, Steven E.r. Hovius, Martijn Baas, Rivka Sukenik-halevy, Hannie Douben, Picard Nguyen, Deon J Venter, Renee Gallagher, Sigrid M. A. Swagemakers, Christianne A. Van NieuwenhovenAbstract:Purpose The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of Triphalangeal Thumb–polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. Methods We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. Results Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). Conclusion Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.
-
A multidisciplinary review of Triphalangeal Thumb.
The Journal of hand surgery European volume, 2018Co-Authors: Jacob W P Potuijt, Robert-jan H Galjaard, Peter J. Van Der Spek, Christianne A. Van Nieuwenhoven, Nadav Ahituv, Kerby C. Oberg, Steven E.r. HoviusAbstract:Despite being a rare congenital limb anomaly, Triphalangeal Thumb is a subject of research in various scientific fields, providing new insights in clinical research and evolutionary biology. The findings of Triphalangeal Thumb can be predictive for other congenital anomalies as part of an underlying syndrome. Furthermore, Triphalangeal Thumb is still being used as a model in molecular genetics to study gene regulation by long-range regulatory elements. We present a review that summarizes a number of scientifically relevant topics that involve the Triphalangeal Thumb phenotype. Future initiatives involving multidisciplinary teams collaborating in the field of Triphalangeal Thumb research can lead to a better understanding of the pathogenesis and molecular mechanisms of this condition as well as other congenital upper limb anomalies.
-
Triphalangeal Thumb: clinical features and treatment
The Journal of hand surgery European volume, 2018Co-Authors: Steven E.r. Hovius, Jacob W P Potuijt, Christianne A. Van NieuwenhovenAbstract:Triphalangeal Thumb is a rare congenital anomaly in which the Thumb has three phalanges. Clinical presentation of Triphalangeal Thumb can vary considerably and can be present in both hands or unilateral. The Thumb can be long with a finger-like appearance. The presence of clinodactyly depends on the shape of the extra phalanx varying from wedge-shaped to rectangular. Various joints, ligaments, muscles, and tendons of the first ray can be hypoplastic or absent, with varying degrees of stiffness or instability. The aim of surgical treatment is to reconstruct or correct the anatomic anomalies to obtain greater function and a more acceptable appearance. In our series, operations varied from removal of the delta phalanx with ligament reconstruction to multiple osteotomies and rebalancing of soft tissues. Results in these often complex cases can be rewarding if the surgeon has sufficient knowledge of the underlying anatomic differences. This review summarizes our current concepts of presentation and management of the Triphalangeal Thumb.
-
A point mutation in the pre-ZRS disrupts sonic hedgehog expression in the limb bud and results in Triphalangeal Thumb-polysyndactyly syndrome.
Genetics in medicine : official journal of the American College of Medical Genetics, 2018Co-Authors: Jacob W P Potuijt, Steven E.r. Hovius, Martijn Baas, Rivka Sukenik-halevy, Hannie Douben, Picard Nguyen, Deon J Venter, Renee Gallagher, Sigrid M. A. Swagemakers, Christianne A. Van NieuwenhovenAbstract:The zone of polarizing activity regulatory sequence (ZRS) is an enhancer that regulates sonic hedgehog during embryonic limb development. Recently, mutations in a noncoding evolutionary conserved sequence 500 bp upstream of the ZRS, termed the pre-ZRS (pZRS), have been associated with polydactyly in dogs and humans. Here, we report the first case of Triphalangeal Thumb–polysyndactyly syndrome (TPT-PS) to be associated with mutations in this region and show via mouse enhancer assays how this mutation leads to ectopic expression throughout the developing limb bud. We used linkage analysis, whole-exome sequencing, Sanger sequencing, fluorescence in situ hybridization, multiplex ligation-dependent probe amplification, single-nucleotide polymorphism array, and a mouse transgenic enhancer assay. Ten members of a TPT-PS family were included in this study. The mutation was linked to chromosome 7q36 (LOD score 3.0). No aberrations in the ZRS could be identified. A point mutation in the pZRS (chr7:156585476G>C; GRCh37/hg19) was detected in all affected family members. Functional characterization using a mouse transgenic enhancer essay showed extended ectopic expression dispersed throughout the entire limb bud (E11.5). Our work describes the first mutation in the pZRS to be associated with TPT-PS and provides functional evidence that this mutation leads to ectopic expression of this enhancer within the developing limb.
