Polydactyly and syndactyly linked to GLI3 and TBX5 mutations: A pediatric case report

Abstract

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.

Keywords

Poly-syndactyly / Congenital Limb Malformations / Genetic Variants in Limb Development / Pediatric Orthopedics / Case reports

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki.

Informed Consent Statement

Written informed consent has been obtained from the patient to publish this paper.

Funding

This research received no external funding.

Data Availability

Data shared are in accordance with consent provided by participants on the use of confidential data.

Conflicts of Interest

The authors declare no conflict of interest.

References

[1] S. Malik, Polydactyly: phenotypes, genetics and classification, Clin. Genet. 85 (3) (2014) 203-212.

[2] D.K. Bubshait, A review of polydactyly and its inheritance: connecting the dots, 16 dicembre, Medicine (Baltimore) 101 (50) (2022) e32060.

[3] Castilla E., Paz J., Mutchinick O., Giorgiutti E.,Gelman Z. Polydactyly: A Genetic Study in South America.

[4] M.C. Farrugia, J. Calleja-Agius, Polydactyly: a review, Neonatal Netw. 35 (3) (2016) 135-142.

[5] W. Blauth, A.T. Olason, Classification of polydactyly of the hands and fee, Arch. Orthop. Trauma Surg. 107 (6) (1988) 334-344.

[6] S. Malik, S. Ullah, M. Afzal, K. Lal, S. Haque, Clinical and descriptive genetic study of polydactyly: a Pakistani experience of 313 cases, Clin. Genet. 85 (5) (2014) 482-486.

[7] L.G. Biesecker, Polydactyly: How many disorders and how many genes? 2010 update, Dev. Dyn. maggio 240 (5) (2011) 931-942.

[8] Z. Kyriazis, P. Kollia, I. Grivea, N. Stefanou, S. Sotiriou, Z.H. Dailiana, Polydactyly: clinical and molecular manifestations, 18 gennaio, World J. Orthop. 14 (1) (2023) 13-22.

[9] T. Naruse, M. Takahara, M. Takagi, K.C. Oberg, T. Ogino, Busulfan‐induced central polydactyly, syndactyly and cleft hand or foot: a common mechanism of disruption leads to divergent phenotypes (agosto), Dev. Growth Differ. 49 (6) (2007) 533-541.

[10] S.A. Temtamy, V.A. McKusick, The genetics of hand malformations, Birth Defects Orig. Artic. Ser. [ Internet] (1978) (Disponibile su), 〈 https://pubmed.ncbi.nlm. nih.gov/215242/〉.

[11] D.J. Goldstein, M. Kambouris, R.E. Ward, Familial crossed polysyndactyly, Am. J. Med. Genet. 50 (1994) 215-223.

[12] E.E. Castilla, M. da Graca Dutra, R. Lugarinho da Fonseca, J.E. Paz, Hand and foot postaxial polydactyly: two different traits, Hand Foot Posta Polydactyly Two Differ. Traits 73 (1997) 48-54.

[13] I.M. Orioli, E.E. Castilla, Thumb/hallux duplication and preaxial polydactyly type I, Thumbhallux Duplic. Preaxial Polydactyly Type I. 82 (1999) 219-224.

[14] S. Malik, Syndactyly: phenotypes, genetics and current classification, Eur. J. Hum. Genet. 20 (8) (2012) 817-824.

[15] T. Braun, J. Trost, W. Pederson, Syndactyly release, Semin Plast. Surg. 30 (04) (2016) 162-170.

[16] S. Mahindroo, S. Tabaie, Syndactyly in the pediatric population: a review of the literature, 14 marzo, Cureus [Internet] (2023) 14 marzo 〈 https://www.cureus. com/articles/140955-syndactyly-in-the-pediatric-population-a-review-of-the-literature〉.

[17] H. Ahmed, H. Akbari, A. Emami, M.R. Akbari,Genetic overview of syndactyly and polydactyly, Plast. Reconstr. Surg. - Glob. Open. 5 (11) (2017) e1549.

[18] R. Patel, S.K. Singh, V. Bhattacharya, A. Ali, Novel GLI3 pathogenic variants in complex pre- and postaxial polysyndactyly and Greig cephalopolysyndactyly syndrome, Am. J. Med. Genet. A 185 (2021) 97-104.

[19] Umm-e-Kalsoom S. Basit S. Kamran-ul-Hassan Naqvi M. Ansar W. Ahmad, Genetic mapping of an autosomal recessive postaxial polydactyly type A to chromosome 13q13.3-q21.2 and screening of the candidate genes, Hum. Genet. 131 (2012) 415-422.

[20] F. Ni, G. Han, R. Guo, H. Cui, B. Wang, Q. Li, A novel frameshift mutation of GLI3 causes isolated postaxial polydactyly, Ann. Plast. Surg. 82 (2019) 570-573.

[21] G. Gillessen‐Kaesbach, F. Majewski, Bilateral complete polysyndactyly (type IV Haas), Am. J. Med. Genet. 38 (1) (1991) 29-31.

[22] S. Lohan, M. Spielmann, S.C. Doelken, R. Flöttmann, F. Muhammad, S.M. Baig, M. Wajid, W. Hülsemann, R. Habenicht, K.W. Kjaer, S.J. Patil, K.M. Girisha, H.H. Abarca-Barriga, S. Mundlos, E. Klopocki, Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type poly-syndactyly and Laurin-Sandrow syndrome, Clin. Genet. (2014) 318-325.

[23] D. Wieczorek, B. Pawlik, Y. Li, N.A. Akarsu, A. Caliebe, K.J. May, B. Schweiger, F.R. Vargas, S. Balci, G. Gillessen-Kaesbach, B. Wollnik, A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type poly-syndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb, Hum. Mutat. 31 (2010) 81-89.

[24] S. Kang, M. Rosenberg, V.D. Ko, L.G. Biesecker, Gene structure and allelic expression assay of the human GLI3 gene, 17 novembre, Hum. Genet. 101 (2) (1997) 154-157.

[25] Y. Litingtung, R.D. Dahn, Y. Li, J.F. Fallon, C. Chiang, Shh and Gli3 are dispensable for limb skeleton formation but regulate digit number and identity, Nat. Agosto 418 (6901) (2002) 979-983.

[26] H. Iwasaki, K. Nakano, K. Shinkai, Y. Kunisawa, M. Hirahashi, Y. Oda, et al., Hedgehog G li 3 activator signal augments tumorigenicity of colorectal cancer via upregulation of adherence‐related genes. Cancer Sci. 104 (3) (2013) 328-336.

[27] Z. Zhang, P. Sui, A. Dong, J. Hassell, P. Cserjesi, Y.T. Chen, et al., Preaxial polydactyly: interactions among ETV, TWIST1 and HAND2 control anterior-posterior patterning of the limb, 15 ottobre, Development 137 (20) (2010) 3417-3426.

[28] M.A. Renault, J. Roncalli, J. Tongers, S. Misener, T. Thorne, K. Jujo, et al., The hedgehog transcription factor Gli 3 modulates angiogenesis, 9 ottobre, Circ. Res. 105 (8) (2009) 818-826.

[29] S.J. Matissek, S.F. Elsawa, GLI3: a mediator of genetic diseases, development and cancer, Cell Commun. Signal 18 (1) (2020) 54.

[30] G.A. Tanteles, S. Michaelidou, E. Loukianou, V. Christophidou-Anastasiadou, K.A. Kleopa, Novel GLI3 mutation in a GreekCypriot patient with Greig cepha-lopolysyndactyly syndrome, 24 (2015) 102-105.

[31] H. Fujioka, T. Ariga, K. Horiuchi, M. Otsu, H. Igawa, K. Kawashima, Y. Yamamoto, T. Sugihara, Y. Sakiyama, Molecular analysis of non-syndromic preaxial polydactyly: preaxial polydactyly type-IV and preaxial polydactyly type-I, Clin. Genet. 67 (2005) 429-433.

[32] L.C. Weng, A.W. Hall, S.H. Choi, S.J. Jurgens, J. Haessler, N.A. Bihlmeyer, et al., Genetic determinants of electrocardiographic p-wave duration and relation to atrial fibrillation, Circ. Genom. Precis Med. 13 (5) (ottobre 2020)387-395.

[33] F.S. Rathjens, A. Blenkle, L.M. Iyer, A. Renger, F. Syeda, C. Noack, et al., Preclinical evidence for the therapeutic value of TBX5 normalization in arrhythmia control, 7 luglio, Cardiovasc. Res. 117 (8) (2021) 1908-1922.

[34] A.M. Markunas, P.K.R. Manivannan, J.E. Ezekian, A. Agarwal, W. Eisner, K. Alsina, et al., TBX5 ‐encoded T‐box transcription factor 5 variant T223M is associated with long QT syndrome and pediatric sudden cardiac death, Am. J. Med. Genet. A. Marzo 185 (3) (2021) 923-929.

[35] D.A. McDermott, M.C. Bressan, J. He, J.S. Lee, S. Aftimos, M. Brueckner, et al., TBX5 genetic testing validates strict clinical criteria for holt-oram syndrome, Pedia Res. 58 (5) (2005) 981-986.

[36] M. Gupta, A. Dosu, J. Makan, Holt-oram syndrome: an incidental diagnosis, 11 maggio, Cureus [Internet] (2022) 11 maggio 〈 https://www.cureus.com/articles/95344-holt-oram-syndrome-an-incidental-diagnosis〉.

[37] C.A. Goldfarb, L.B. Wall, Holt-Oram syndrome, J. Hand Surg. Agosto 39 (8) (2014) 1646-1648.

[38] R.A. Newbury-Ecob, R. Leanage, J.A. Raeburn, I.D. Young, Holt-Oram syndrome: a clinical genetic study, J. Med. Genet. 33 (4) (1996) 300-307.

[39] B. Kumar, S. Agstam,Holt-Oram syndrome: hands are the clue to the diagnosis, Int. J. Appl. Basic Med. Res. 9 (4) (2019) 248.

[40] J.F. Ma, F. Yang, S.N. Mahida, L. Zhao, X. Chen, M.L. Zhang, et al., TBX5 mutations contribute to early-onset atrial fibrillation in Chinese and Caucasians, 1 marzo, Cardiovasc. Res. 109 (3) (2016) 442-450.

[41] I.S. Kathiriya, K.S. Rao, G. Iacono, W.P. Devine, A.P. Blair, S.K. Hota, et al., Modeling human TBX5 haploinsufficiency predicts regulatory networks for con-genital heart disease (febbraio), Dev. Cell 56 (3) (2021) 292-309.