Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case report
Background: Polydactyly and syndactyly, which are commonly encountered congenital limb deformities, rarely occur together and are linked with significant genetic mutations. This report sheds light on a unique co-presentation involving mutations in both the GLI3 and TBX5 genes, offering a deeper unde...
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KeAi Communications Co., Ltd.
2025-03-01
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| Series: | Global Medical Genetics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S269994042400033X |
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| author | R. Leonardi G. Pellino E. Floridia M. Lo Bianco M. Ruggieri SY. Cho V. Pavone P. Pavone A. Polizzi |
| author_facet | R. Leonardi G. Pellino E. Floridia M. Lo Bianco M. Ruggieri SY. Cho V. Pavone P. Pavone A. Polizzi |
| author_sort | R. Leonardi |
| collection | DOAJ |
| description | Background: Polydactyly and syndactyly, which are commonly encountered congenital limb deformities, rarely occur together and are linked with significant genetic mutations. This report sheds light on a unique co-presentation involving mutations in both the GLI3 and TBX5 genes, offering a deeper understanding of the genetic interactions that may influence limb development. This case report is important to increase our knowledge on genetic bases of limb malformations. Case presentation: We report the case of an 8-month-old boy, born to non-consanguineous parents, presenting with both polydactyly and syndactyly in his limbs, in particular, complete syndactyly between the third to fifth fingers and post-axial polydactyly of the feet. His father showed a similar phenotype. Genetic testing identified a pathogenic heterozygous variant in the GLI3 gene (c .3762 T > A, p.(Tyr1254 *)) and a variant of uncertain significance in the TBX5 gene (c .1063 C>T, p.(Arg355Cys)). Conclusions: This case highlights the complex nature of diagnosing and managing congenital limb deformities driven by genetic factors. It underscores the critical importance of comprehensive genetic testing in determining the etiology of limb malformations. The GLI3 variant, classified according to ACMG guidelines as a class IV mutation, likely results in a truncated protein due to a premature stop codon, confirmed by family segregation analysis indicating its paternal origin, suggesting autosomal dominant inheritance. Notably, the TBX5 gene variant, often associated with Holt-Oram syndrome—which is characterized by only hand skeletal anomalies and early-onset atrial fibrillation—suggests a risk of developing cardiac issues that are not currently present but may emerge as the child grows. This potential for evolving clinical manifestations necessitates vigilant long-term monitoring and may influence future medical management and therapeutic approaches. |
| format | Article |
| id | doaj-art-c63ac835c2404204bba5c27c0f2f5aaa |
| institution | OA Journals |
| issn | 2699-9404 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | KeAi Communications Co., Ltd. |
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| series | Global Medical Genetics |
| spelling | doaj-art-c63ac835c2404204bba5c27c0f2f5aaa2025-08-20T02:03:46ZengKeAi Communications Co., Ltd.Global Medical Genetics2699-94042025-03-0112110003310.1016/j.gmg.2024.100033Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case reportR. Leonardi0G. Pellino1E. Floridia2M. Lo Bianco3M. Ruggieri4SY. Cho5V. Pavone6P. Pavone7A. Polizzi8Postgraduate Training Program in Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, ItalyPostgraduate Training Program in Genetics, Department of Clinical and Molecular Biomedicine Ingrassia, University of Catania, ItalySchool of Medicine, Department of Clinical and Experimental Medicine, University of Catania, Catania, ItalyPostgraduate Training Program in Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, ItalyUnit of Clinical Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, ItalyDepartment of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South KoreaDepartment of General Surgery and Medical Surgical Specialties, Section of Orthopedics and Traumatology, A.O.U. Policlinico, University of Catania, Via Santa Sofia 78, Catania 95123, ItalyUnit of Clinical Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Unit of Catania, Institute for Biomedical Research and Innovation, National Council of Research, Catania, Italy; Correspondence to: Department of Pediatrics, AOU Policlinico, University of Catania, Via S. Sofia 78, Catania 95123, Italy.Unit of Clinical Pediatrics, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy; Department of Educational Science, University of Catania, Catania 95100, ItalyBackground: Polydactyly and syndactyly, which are commonly encountered congenital limb deformities, rarely occur together and are linked with significant genetic mutations. This report sheds light on a unique co-presentation involving mutations in both the GLI3 and TBX5 genes, offering a deeper understanding of the genetic interactions that may influence limb development. This case report is important to increase our knowledge on genetic bases of limb malformations. Case presentation: We report the case of an 8-month-old boy, born to non-consanguineous parents, presenting with both polydactyly and syndactyly in his limbs, in particular, complete syndactyly between the third to fifth fingers and post-axial polydactyly of the feet. His father showed a similar phenotype. Genetic testing identified a pathogenic heterozygous variant in the GLI3 gene (c .3762 T > A, p.(Tyr1254 *)) and a variant of uncertain significance in the TBX5 gene (c .1063 C>T, p.(Arg355Cys)). Conclusions: This case highlights the complex nature of diagnosing and managing congenital limb deformities driven by genetic factors. It underscores the critical importance of comprehensive genetic testing in determining the etiology of limb malformations. The GLI3 variant, classified according to ACMG guidelines as a class IV mutation, likely results in a truncated protein due to a premature stop codon, confirmed by family segregation analysis indicating its paternal origin, suggesting autosomal dominant inheritance. Notably, the TBX5 gene variant, often associated with Holt-Oram syndrome—which is characterized by only hand skeletal anomalies and early-onset atrial fibrillation—suggests a risk of developing cardiac issues that are not currently present but may emerge as the child grows. This potential for evolving clinical manifestations necessitates vigilant long-term monitoring and may influence future medical management and therapeutic approaches.http://www.sciencedirect.com/science/article/pii/S269994042400033XPoly-syndactylyCongenital Limb MalformationsGenetic Variants in Limb DevelopmentPediatric OrthopedicsCase reports |
| spellingShingle | R. Leonardi G. Pellino E. Floridia M. Lo Bianco M. Ruggieri SY. Cho V. Pavone P. Pavone A. Polizzi Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case report Global Medical Genetics Poly-syndactyly Congenital Limb Malformations Genetic Variants in Limb Development Pediatric Orthopedics Case reports |
| title | Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case report |
| title_full | Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case report |
| title_fullStr | Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case report |
| title_full_unstemmed | Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case report |
| title_short | Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case report |
| title_sort | polydactyly and syndactyly linked to gli3 and tbx5 mutations a pediatric case report |
| topic | Poly-syndactyly Congenital Limb Malformations Genetic Variants in Limb Development Pediatric Orthopedics Case reports |
| url | http://www.sciencedirect.com/science/article/pii/S269994042400033X |
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