{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:00:19Z","timestamp":1790240419233,"version":"4.1.0"},"reference-count":114,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T00:00:00Z","timestamp":1651017600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81571994, 81870432 and 81570567"],"award-info":[{"award-number":["81571994, 81870432 and 81570567"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Natural Science Foundation of Guangdong Province, China","award":["2020A1515010054"],"award-info":[{"award-number":["2020A1515010054"]}]},{"name":"The Li Ka Shing Shantou University Foundation","award":["L1111 2008"],"award-info":[{"award-number":["L1111 2008"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>A comprehensive summary of recent knowledge in syndactyly (SD) is important for understanding the genetic etiology of SD and disease management. Thus, this review article provides background information on SD, as well as insights into phenotypic and genetic heterogeneity, newly identified gene mutations in various SD types, the role of HOXD13 in limb deformities, and recently introduced modern surgical techniques for SD. This article also proposes a procedure for genetic analysis to obtain a clearer genotype\u2013phenotype correlation for SD in the future. We briefly describe the classification of non-syndromic SD based on variable phenotypes to explain different phenotypic features and mutations in the various genes responsible for the pathogenesis of different types of SD. We describe how different types of mutation in HOXD13 cause various types of SD, and how a mutation in HOXD13 could affect its interaction with other genes, which may be one of the reasons behind the differential phenotypes and incomplete penetrance. Furthermore, we also discuss some recently introduced modern surgical techniques, such as free skin grafting, improved flap techniques, and dermal fat grafting in combination with the Z-method incision, which have been successfully practiced clinically with no post-operative complications.<\/jats:p>","DOI":"10.3390\/genes13050771","type":"journal-article","created":{"date-parts":[[2022,4,27]],"date-time":"2022-04-27T13:40:57Z","timestamp":1651066857000},"page":"771","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Recent Advances in Syndactyly: Basis, Current Status and Future Perspectives"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4925-6990","authenticated-orcid":false,"given":"Tahir","family":"Zaib","sequence":"first","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hibba","family":"Rashid","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Microbiology, Abasyn University, Peshawar 25000, Pakistan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5134-0377","authenticated-orcid":false,"given":"Hanif","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5721-944X","authenticated-orcid":false,"given":"Xiaoling","family":"Zhou","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3325-8062","authenticated-orcid":false,"given":"Pingnan","family":"Sun","sequence":"additional","affiliation":[{"name":"Stem Cell Research Center, Shantou University Medical College, Shantou 515041, China"},{"name":"Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou 515041, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1093\/oxfordjournals.aje.a121356","article-title":"Incidence of selected congenital malformations in Iowa","volume":"94","author":"Hay","year":"1971","journal-title":"Am. J. Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1002\/ajmg.1320050406","article-title":"Syndactyly: Frequency of specific types","volume":"5","author":"Castilla","year":"1980","journal-title":"Am. J. Med. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"14","DOI":"10.2174\/1874325001206010014","article-title":"The epidemiology, genetics and future management of syndactyly","volume":"6","author":"Jordan","year":"2012","journal-title":"Open Orthop. J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1038\/sj.ejhg.5201492","article-title":"Evidence for clinical and genetic heterogeneity of syndactyly type I: The phenotype of second and third toe syndactyly maps to chromosome 3p21.31","volume":"13","author":"Malik","year":"2005","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1053\/jhsu.2001.26121","article-title":"The incidence and epidemiology of congenital upper limb anomalies: A total population study","volume":"26","author":"Giele","year":"2001","journal-title":"J. Hand Surg. Am."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/j.1741-4520.2009.00244.x","article-title":"Syndactyly lethal: New mutation with multiple malformations occurring in Sprague Dawley rats","volume":"49","author":"Fujii","year":"2009","journal-title":"Congenit. Anom."},{"key":"ref_7","first-page":"1","article-title":"The genetics of hand malformations","volume":"14","author":"Temtamy","year":"1978","journal-title":"Birth Defects Orig. Artic. Ser."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/ejhg.2012.14","article-title":"Syndactyly: Phenotypes, genetics and current classification","volume":"20","author":"Malik","year":"2012","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.1002\/ajmg.a.32377","article-title":"Complex toe syndactyly with characteristic facial phenotype: A new syndrome?","volume":"146A","author":"Sobreira","year":"2008","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","first-page":"1579","article-title":"Genetic heterogeneity in type III familial cutaneous syndactyly and linkage to chromosome 7q36","volume":"161A","author":"Shamseldin","year":"2013","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/BF00453148","article-title":"Tibial hypo-\/aplasia with preaxial syn- and polydactyly","volume":"109","author":"Andersen","year":"1990","journal-title":"Arch. Orthop. Trauma Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1086\/303028","article-title":"Localization of a gene for syndactyly type 1 to chromosome 2q34-q36","volume":"67","author":"Bosse","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Dai, L., Liu, D., Song, M., Xu, X., Xiong, G., Yang, K., Zhang, K., Meng, H., Guo, H., and Bai, Y. (2014). Mutations in the homeodomain of HOXD13 cause syndactyly type 1-c in two Chinese families. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0096192"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"945","DOI":"10.1093\/hmg\/5.7.945","article-title":"Genomic structure of HOXD13 gene: A nine polyalanine duplication causes synpolydactyly in two unrelated families","volume":"5","author":"Akarsu","year":"1996","journal-title":"Hum. Mol. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1111\/j.1399-0004.2007.00935.x","article-title":"Synpolydactyly: Clinical and molecular advances","volume":"73","author":"Malik","year":"2008","journal-title":"Clin. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1093\/hmg\/4.8.1453","article-title":"Localization of the syndactyly type II (synpolydactyly) locus to 2q31 region and identification of tight linkage to HOXD8 intragenic marker","volume":"4","author":"Sarfarazi","year":"1995","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1126\/science.272.5261.548","article-title":"Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13","volume":"272","author":"Muragaki","year":"1996","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/sj.ejhg.5200497","article-title":"Physical map of a 1.5 mb region on 12p11.2 harbouring a synpolydactyly associated chromosomal breakpoint","volume":"8","author":"Debeer","year":"2000","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1111\/j.1399-0004.2006.00620.x","article-title":"Genetic heterogeneity of synpolydactyly: A novel locus SPD3 maps to chromosome 14q11.2-q12","volume":"69","author":"Malik","year":"2006","journal-title":"Clin. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1002\/ajmg.a.20382","article-title":"A family with X-linked recessive fusion of metacarpals IV and V","volume":"124A","author":"Lonardo","year":"2004","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1093\/hmg\/6.1.123","article-title":"Localization of a gene for oculodentodigital syndrome to human chromosome 6q22-q24","volume":"6","author":"Gladwin","year":"1997","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1002\/humu.21142","article-title":"A specific mutation in the distant sonic hedgehog (SHH) cis-regulator (ZRS) causes Werner mesomelic syndrome (WMS) while complete ZRS duplications underlie Haas type polysyndactyly and preaxial polydactyly (PPD) with or without triphalangeal thumb","volume":"31","author":"Wieczorek","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S100","DOI":"10.1016\/j.main.2008.07.029","article-title":"Syndactyly","volume":"27","author":"Samson","year":"2008","journal-title":"Chir. Main"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1007\/s00431-013-2071-y","article-title":"Confirmation of genetic homogeneity of syndactyly type IV and triphalangeal thumb-polysyndactyly syndrome in a Chinese family and review of the literature","volume":"172","author":"Dai","year":"2013","journal-title":"Eur. J. Pediatr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1111\/cge.12352","article-title":"Microduplications encompassing the Sonic hedgehog limb enhancer ZRS are associated with Haas-type polysyndactyly and Laurin-Sandrow syndrome","volume":"86","author":"Lohan","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1002\/ajmg.1320110414","article-title":"Syndactyly type V","volume":"11","author":"Robinow","year":"1982","journal-title":"Am. J. Med. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1086\/511387","article-title":"Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome","volume":"80","author":"Zhao","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.ejmg.2013.04.007","article-title":"Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation","volume":"56","author":"Khan","year":"2013","journal-title":"Eur. J. Med. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.ajhg.2010.03.004","article-title":"LRP4 mutations alter Wnt\/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome","volume":"86","author":"Li","year":"2010","journal-title":"Am. J. Hum. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1136\/jmg.2009.073833","article-title":"Genomic rearrangements of the GREM1-FMN1 locus cause oligosyndactyly, radio-ulnar synostosis, hearing loss, renal defects syndrome and Cenani--Lenz-like non-syndromic oligosyndactyly","volume":"47","author":"Dimitrov","year":"2010","journal-title":"J. Med. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"868","DOI":"10.1136\/jmg.35.10.868","article-title":"Mesoaxial complete syndactyly and synostosis with hypoplastic thumbs: An unusual combination or homozygous expression of syndactyly type I?","volume":"35","author":"Percin","year":"1998","journal-title":"J. Med. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1002\/ajmg.a.30656","article-title":"Autosomal recessive mesoaxial synostotic syndactyly with phalangeal reduction maps to chromosome 17p13.3","volume":"134","author":"Malik","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"17054","DOI":"10.1038\/hgv.2017.54","article-title":"A novel homozygous missense mutation in BHLHA9 causes mesoaxial synostotic syndactyly with phalangeal reduction in a Pakistani family","volume":"4","author":"Khan","year":"2017","journal-title":"Hum. Genome Var."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/S0266-7681(02)00306-6","article-title":"Long-term results of syndactyly correction: Full-thickness versus split-thickness skin grafts","volume":"28","author":"Deunk","year":"2003","journal-title":"J. Hand Surg. Br."},{"key":"ref_35","first-page":"482","article-title":"Hereditary syndactylia in a Chinese family","volume":"84","author":"Hsu","year":"1965","journal-title":"Chin. Med. J."},{"key":"ref_36","first-page":"368","article-title":"Type II syndactyly","volume":"20","author":"Cross","year":"1968","journal-title":"Am. J. Hum. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Malik, S., Girisha, K.M., Wajid, M., Roy, A.K., Phadke, S.R., Haque, S., Ahmad, W., Koch, M.C., and Grzeschik, K.H. (2007). Synpolydactyly and HOXD13 polyalanine repeat: Addition of 2 alanine residues is without clinical consequences. BMC Med. Genet., 8.","DOI":"10.1186\/1471-2350-8-78"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/BF00438491","article-title":"Total syndactylia and total radioulnar synostosis in 2 brothers. A contribution on the genetics of syndactylia","volume":"101","author":"Cenani","year":"1967","journal-title":"Z. Kinderheilkd."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.bjps.2004.10.024","article-title":"A variant of Cenani-Lenz syndactyly (CLS): Review of the literature and attempt of classification","volume":"58","author":"Harpf","year":"2005","journal-title":"Br. J. Plast. Surg."},{"key":"ref_40","first-page":"S7","article-title":"Genetics of congenital hand malformations","volume":"27","year":"2008","journal-title":"Chir. Main"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1002\/ajmg.10061","article-title":"Confirmation of genetic homogeneity of syndactyly type 1 in an Iranian family","volume":"104","author":"Ghadami","year":"2001","journal-title":"Am. J. Med. Genet."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s10038-021-00963-5","article-title":"Novel HOXD13 variants in syndactyly type 1b and type 1c, and a new spectrum of TP63-related disorders","volume":"67","author":"Patel","year":"2022","journal-title":"J. Hum. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"473","DOI":"10.3892\/mmr.2017.6576","article-title":"Identification of a missense HOXD13 mutation in a Chinese family with syndactyly type I-c using exome sequencing","volume":"16","author":"Deng","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/j.cca.2012.02.015","article-title":"A novel non-synonymous mutation in the homeodomain of HOXD13 causes synpolydactyly in a Chinese family","volume":"413","author":"Wang","year":"2012","journal-title":"Clin. Chim. Acta"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1136\/jmg.39.11.852","article-title":"Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13","volume":"39","author":"Debeer","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.bone.2019.07.012","article-title":"A rare TTC30B variant is identified as a candidate for synpolydactyly in a Chinese pedigree","volume":"127","author":"Du","year":"2019","journal-title":"Bone"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1136\/jmg.39.2.98","article-title":"The fibulin-1 gene (FBLN1) is disrupted in a t(12;22) associated with a complex type of synpolydactyly","volume":"39","author":"Debeer","year":"2002","journal-title":"J. Med. Genet."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3315\/jdcr.2012.1094","article-title":"Oculodentodigital Syndrome with Syndactyly Type III in a Pakistani consanguineous family","volume":"6","author":"Nishat","year":"2012","journal-title":"J. Dermatol. Case Rep."},{"key":"ref_49","first-page":"271","article-title":"Type III syndactyly and oculodentodigital dysplasia: A clinical spectrum","volume":"4","author":"Fryns","year":"1993","journal-title":"Genet. Couns."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1002\/ajmg.a.61757","article-title":"Large duplication in LMBR1 gene in a large Chinese pedigree with triphalangeal thumb polysyndactyly syndrome","volume":"182","author":"Xu","year":"2020","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"130","DOI":"10.3389\/fgene.2020.00130","article-title":"Sub-Exome Target Sequencing in a Family With Syndactyly Type IV Due to a Novel Partial Duplication of the LMBR1 Gene: First Case Report in Fujian Province of China","volume":"11","author":"Shi","year":"2020","journal-title":"Front. Genet."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1097\/MCD.0000000000000311","article-title":"Cenani-Lenz syndactyly in siblings with a novel homozygous LRP4 mutation and recurrent hypoglycaemia","volume":"29","author":"Steel","year":"2020","journal-title":"Clin. Dysmorphol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.ejmg.2017.05.004","article-title":"Novel splice mutation in LRP4 causes severe type of Cenani-Lenz syndactyly syndrome with oro-facial and skeletal symptoms","volume":"60","author":"Afzal","year":"2017","journal-title":"Eur. J. Med. Genet."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"e3143","DOI":"10.1002\/jgm.3143","article-title":"Novel missense alteration in LRP4 gene underlies Cenani-Lenz syndactyly syndrome in a consanguineous family","volume":"22","author":"Alrayes","year":"2020","journal-title":"J. Gene Med."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Hettiaracchchi, D., Bonnard, C., Jayawardana, S.M.A., Ng, A.Y.J., Tohari, S., Venkatesh, B., Reversade, B., Singaraja, R., and Dissanayake, V.H.W. (2018). Cenani-Lenz syndactyly syndrome\u2014A case report of a family with isolated syndactyly. BMC Med. Genet., 19.","DOI":"10.1186\/s12881-018-0646-1"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1136\/jmedgenet-2013-101659","article-title":"Whole exome sequencing identifies FGF16 nonsense mutations as the cause of X-linked recessive metacarpal 4\/5 fusion","volume":"50","author":"Jamsheer","year":"2013","journal-title":"J. Med. Genet."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1111\/cga.12439","article-title":"Whole exome sequencing identified a novel frameshift variant in the BHLHA9 in an Iranian family with mesoaxial synostotic syndactyly","volume":"61","author":"Sedighzadeh","year":"2021","journal-title":"Congenit. Anom."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.ejmg.2018.08.005","article-title":"A novel insertion and deletion mutation in the BHLHA9 underlies polydactyly and mesoaxial synostotic syndactyly with phalangeal reduction","volume":"62","author":"Ullah","year":"2019","journal-title":"Eur. J. Med. Genet."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/ajmg.a.60694","article-title":"Cenani-Lenz syndrome and other related syndactyly disorders due to variants in LRP4, GREM1\/FMN1, and APC: Insight into the pathogenesis and the relationship to polyposis through the WNT and BMP antagonistic pathways","volume":"179","author":"Alkuraya","year":"2019","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1038\/ejhg.2013.210","article-title":"Mutation of fibulin-1 causes a novel syndrome involving the central nervous system and connective tissues","volume":"22","author":"Bohlega","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1136\/jmg.2008.057646","article-title":"Triphalangeal thumb-polysyndactyly syndrome and syndactyly type IV are caused by genomic duplications involving the long range, limb-specific SHH enhancer","volume":"45","author":"Sun","year":"2008","journal-title":"J. Med. Genet."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/j.1399-0004.2012.01866.x","article-title":"A novel frameshift mutation of the GLI3 gene in a family with broad thumbs with\/without big toes, postaxial polydactyly and variable syndactyly of the hands\/feet","volume":"82","year":"2012","journal-title":"Clin. Genet."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"542004","DOI":"10.3389\/fgene.2020.542004","article-title":"A Novel Nonsense GLI3 Variant Is Associated With Polydactyly and Syndactyly in a Family by Blocking the Sonic Hedgehog Signaling Pathway","volume":"11","author":"Xiang","year":"2020","journal-title":"Front. Genet."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Hettiarachchi, D., Panchal, H., Lai, P.S., and Dissanayake, V.H.W. (2020). Novel variant in NSDHL gene associated with CHILD syndrome and syndactyly- a case report. BMC Med. Genet., 21.","DOI":"10.1186\/s12881-020-01094-y"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e22816","DOI":"10.1097\/MD.0000000000022816","article-title":"EEC-LM-ADULT syndrome caused by R319H mutation in TP63 with ectrodactyly, syndactyly, and teeth anomaly: A case report","volume":"99","author":"Otsuki","year":"2020","journal-title":"Medicine"},{"key":"ref_66","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mirzaa, G., and Amemiya, A. (1993). TP63-Related Disorders. GeneReviews\u00ae, University of Washington."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1177\/1055665620954090","article-title":"Dental and Craniofacial Characteristics in Patients With 14Q22.1-Q22.2 Deletion: A Case Series","volume":"58","author":"Roelandt","year":"2021","journal-title":"Cleft Palate Craniofacial J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e22740","DOI":"10.1097\/MD.0000000000022740","article-title":"Clinical characterization and outcome of prolonged heart rate-corrected QT interval among children with syndactyly","volume":"99","author":"Han","year":"2020","journal-title":"Medicine"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.cca.2020.03.017","article-title":"Identification of novel missense mutations associated with non-syndromic syndactyly in two vietnamese trios by whole exome sequencing","volume":"506","author":"Ngoc","year":"2020","journal-title":"Clin. Chim. Acta"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1002\/humu.23417","article-title":"Mutations in the fourth beta-propeller domain of LRP4 are associated with isolated syndactyly with fusion of the third and fourth fingers","volume":"39","author":"Chien","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1055\/s-0038-1669364","article-title":"A Case of Nonsyndromic Unilateral Cleft Hand with Central Polydactyly, Syndactyly, and Thumb Hypoplasia: Support for a Common Etiology","volume":"11","author":"Duran","year":"2019","journal-title":"J. Hand Microsurg."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1177\/1753193413496945","article-title":"Central and ulnar cleft hands: A review of concurrent deformities in a series of 47 patients and their pathogenesis","volume":"39","year":"2014","journal-title":"J. Hand Surg."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Zou, Q., Tian, Z., Zheng, J., Zhi, X., Du, X., Shu, J., and Cai, C. (2019). A novel missense in GLI3 possibly affecting one of the zinc finger domains may lead to postaxial synpolydactyly: Case report. BMC Med. Genet., 20.","DOI":"10.1186\/s12881-019-0889-5"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1086\/346090","article-title":"Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia","volume":"72","author":"Paznekas","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"e74","DOI":"10.2337\/dc18-0011","article-title":"Zygodactyly (Syndactyly Type A1) Associated With Midfoot Charcot Neuropathy and Diabetes","volume":"41","author":"McConville","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1038\/376479a0","article-title":"Homeotic genes and the evolution of arthropods and chordates","volume":"376","author":"Carroll","year":"1995","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.ymgme.2013.10.012","article-title":"Human HOX gene disorders","volume":"111","author":"Quinonez","year":"2014","journal-title":"Mol. Genet. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"3181","DOI":"10.1002\/ajmg.a.32426","article-title":"Identification of a HOXD13 mutation in a VACTERL patient","volume":"146A","author":"Wong","year":"2008","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/ajmg.a.30971","article-title":"A 72-year-old Danish puzzle resolved--comparative analysis of phenotypes in families with different-sized HOXD13 polyalanine expansions","volume":"138","author":"Kjaer","year":"2005","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_80","first-page":"601","article-title":"Synpolydactyly in a Chinese kindred: Mutation detection, prenatal ultrasonographic and molecular diagnosis","volume":"28","author":"Jin","year":"2011","journal-title":"Zhonghua Yi Xue Yi Chuan Xue Za Zhi"},{"key":"ref_81","first-page":"847","article-title":"A G220V substitution within the N-terminal transcription regulating domain of HOXD13 causes a variant synpolydactyly phenotype","volume":"18","author":"Fantini","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Zaib, T., Ji, W., Saleem, K., Nie, G., Li, C., Cao, L., Xu, B., Dong, K., Yu, H., and Hao, X. (2019). A heterozygous duplication variant of the HOXD13 gene caused synpolydactyly type 1 with variable expressivity in a Chinese family. BMC Med. Genet., 20.","DOI":"10.1186\/s12881-019-0908-6"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1620\/tjem.249.93","article-title":"A Nonsense Mutation in HOXD13 Gene from A Chinese Family with Non-Syndromic Synpolydactyly","volume":"249","author":"Guo","year":"2019","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1111\/cga.12173","article-title":"Exome sequencing identifies a novel nonsense mutation of HOXD13 in a Chinese family with synpolydactyly","volume":"57","author":"Wang","year":"2017","journal-title":"Congenit. Anom."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/ajmg.a.37464","article-title":"A homozygous HOXD13 missense mutation causes a severe form of synpolydactyly with metacarpal to carpal transformation","volume":"170","author":"Ibrahim","year":"2016","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/jhg.2011.84","article-title":"A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance","volume":"56","author":"Kurban","year":"2011","journal-title":"J. Hum. Genet."},{"key":"ref_87","first-page":"2067186","article-title":"A Review of the Phenotype of Synpolydactyly Type 1 in Homozygous Patients: Defining the Relatively Long and Medially Deviated Big Toe with\/without Cupping of the Forefoot as a Pathognomonic Feature in the Phenotype","volume":"2020","year":"2020","journal-title":"Biomed. Res. Int."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"731278","DOI":"10.3389\/fgene.2021.731278","article-title":"A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype-Phenotype Correlations","volume":"12","author":"Guo","year":"2021","journal-title":"Front. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1074\/jbc.M510900200","article-title":"Hoxd13 and Hoxa13 directly control the expression of the EphA7 Ephrin tyrosine kinase receptor in developing limbs","volume":"281","author":"Salsi","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1002\/dvdy.310","article-title":"Nonframeshifting indel variations in polyalanine repeat of HOXD13 gene underlies hereditary limb malformation for two Chinese families","volume":"250","author":"Zu","year":"2021","journal-title":"Dev. Dyn."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1016\/j.ejmg.2010.10.007","article-title":"Polyalanine repeat expansion mutation of the HOXD13 gene in a Chinese family with unusual clinical manifestations of synpolydactyly","volume":"54","author":"Gong","year":"2011","journal-title":"Eur. J. Med. Genet."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1055\/s-0037-1602142","article-title":"Occurrence of Synpolydactyly and Omphalocele in a Fetus with a HOXD13 Mutation","volume":"6","author":"Radhakrishnan","year":"2017","journal-title":"J. Pediatr. Genet."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.gene.2013.09.040","article-title":"A splice donor site mutation in HOXD13 underlies synpolydactyly with cortical bone thinning","volume":"532","author":"Shi","year":"2013","journal-title":"Gene"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"128e","DOI":"10.1097\/PRS.0b013e3181a80777","article-title":"Reconstruction of congenital differences of the hand","volume":"124","author":"Bates","year":"2009","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"39","DOI":"10.5435\/00124635-200401000-00006","article-title":"Surgical treatment of congenital syndactyly of the hand","volume":"12","author":"Dao","year":"2004","journal-title":"J. Am. Acad. Orthop. Surg."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"387","DOI":"10.5312\/wjo.v10.i11.387","article-title":"Epidemiology of syndactyly in New York State","volume":"10","author":"Swarup","year":"2019","journal-title":"World J. Orthop."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1591","DOI":"10.4045\/tidsskr.13.0147","article-title":"Treatment of congenital syndactyly of the fingers","volume":"133","author":"Kvernmo","year":"2013","journal-title":"Tidsskr. Den Nor. Legeforening"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1016\/j.jhsa.2012.06.033","article-title":"Complex syndactyly: Aesthetic and objective outcomes","volume":"37","author":"Goldfarb","year":"2012","journal-title":"J. Hand Surg. Am."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ocl.2015.08.015","article-title":"Congenital Anomalies of the Hand--Principles of Management","volume":"47","author":"Little","year":"2016","journal-title":"Orthop. Clin. N. Am."},{"key":"ref_100","first-page":"333","article-title":"Congenital syndactyly: Case by case analysis of 47 patients","volume":"21","author":"Bezuti","year":"2013","journal-title":"Acta Ortop\u00e9dica Bras."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1080\/02844310802556968","article-title":"Advantages of open treatment for syndactyly of the foot: Defining its indications","volume":"43","author":"Hikosaka","year":"2009","journal-title":"Scand. J. Plast. Reconstr. Surg. Hand Surg."},{"key":"ref_102","first-page":"130","article-title":"Polydactyly and syndactyly as the most common congenital disorders of the limbs","volume":"54","year":"2008","journal-title":"Ann. Acad. Med. Stetin."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"rjaa517","DOI":"10.1093\/jscr\/rjaa517","article-title":"Syndactyly","volume":"2020","author":"Geoghegan","year":"2020","journal-title":"J. Surg. Case Rep."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e3068","DOI":"10.1097\/GOX.0000000000003068","article-title":"Using Dermal Fat Graft to Release Complex Syndactyly: A New Method","volume":"8","author":"Senda","year":"2020","journal-title":"Plast. Reconstr. Surg. Glob. Open"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1177\/1753193420981842","article-title":"The use of abdominal flaps for complex syndactyly release: A case series","volume":"46","author":"Pei","year":"2021","journal-title":"J. Hand Surg."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1016\/j.bjps.2021.05.012","article-title":"Aesthetic reconstruction for syndactyly using the \u201cgradation skin graft\u201d from the plantar instep area","volume":"74","author":"Sasaki","year":"2021","journal-title":"J. Plast. Reconstr. Aesthet. Surg."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.fas.2021.02.006","article-title":"Surgical treatment in child\u2019s congenital toe syndactyly: Risk factor of recurrence, complication and poor clinical outcomes","volume":"28","author":"Langlais","year":"2022","journal-title":"Foot Ankle Surg."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.jhsa.2019.01.017","article-title":"Interdigitating Rectangular Flaps and Dorsal Pentagonal Island Flap for Syndactyly Release","volume":"44","author":"Yoon","year":"2019","journal-title":"J. Hand Surg. Am."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"63.e61","DOI":"10.1016\/j.jhsa.2019.03.009","article-title":"Dorsal Hexagon Local Flap Without Skin Graft for Web Reconstruction of Congenital Syndactyly","volume":"45","author":"Wang","year":"2020","journal-title":"J. Hand Surg. Am."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1097\/PRS.0000000000004798","article-title":"Aesthetic Comparison of Two Different Types of Web-Space Reconstruction for Finger Syndactyly","volume":"142","author":"Yuan","year":"2018","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_111","first-page":"1127","article-title":"Surgical Treatment of Congenital Type V Thumb Syndactyly","volume":"30","author":"Tang","year":"2016","journal-title":"Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1142\/S0218810412970088","article-title":"Treatment of keloid formation following syndactyly division: Surgical technique","volume":"17","author":"Kong","year":"2012","journal-title":"Hand Surg."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1177\/1558944719828003","article-title":"National Patterns in Surgical Management of Syndactyly: A Review of 956 Cases","volume":"15","author":"Chouairi","year":"2020","journal-title":"Hand"},{"key":"ref_114","first-page":"692","article-title":"Whole genome sequencing: A qualitative leap forward in genetic studies","volume":"54","author":"Gobernado","year":"2012","journal-title":"Rev. Neurol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/5\/771\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:01:43Z","timestamp":1760137303000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/5\/771"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,27]]},"references-count":114,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["genes13050771"],"URL":"https:\/\/doi.org\/10.3390\/genes13050771","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,27]]}}}