Genetic Research of Hand Congenital Deformities and Advancement in Plastic and Reconstructive Treatment

  • Jinghong XuEmail author
  • Yang Wang
  • Jianmin Yao
Part of the Plastic and Reconstructive Surgery book series (PRS)


Limb bud is composed of mesodermal mesenchyma or mesodermal center and one layer of dermal layer on the external surface, and it is the initial phase of upper limb development. The development of limb bud is the result of gradual changes of various signaling molecular mechanisms in three-dimensional space, and the three axes are proximo-distal, anteroposterior, and dorsoventral, which correspond to the shoulder-finger direction, thumb-little finger direction, and forearm-palm direction in limb morphology. In order to guarantee the correct development and growth of limb bud, three categories of cell groups are of vital importance: they are apical ectodermal ridge (AER) at the lateral side of the limb bud, the progress zone (PZ) at the medial side of the limb bud, and the zone of polarizing activity (ZPA) at the posterior side of the limb bud. The signaling molecules generated by the cells in these regions decide the growth directions of the adjacent cells so that the normal growth and development of upper limb is maintained (Fig. 15.1).


  1. 1.
    Mariani FV, Martin GR. Deciphering skeletal patterning: clues from the limb. Nature. 2003;423:319–25.CrossRefPubMedGoogle Scholar
  2. 2.
    Neufeld S, Rosin JM, Ambasta A, et al. A conditional allele of Rspo3 reveals redundant function of R-spondins during mouse limb development. Genesis. 2012;50(10):741–9. doi: 10.1002/dvg.22040.CrossRefPubMedGoogle Scholar
  3. 3.
    Aoki M, Kiyonari H, Nakamura H, Okamoto H. R-spondin2 expression in the apical ectodermal ridge is essential for outgrowth and patterning in mouse limb development. Dev Growth Differ. 2008;50(2):85–95.CrossRefPubMedGoogle Scholar
  4. 4.
    Wu CI, Hoffman JA, Shy BR, et al. Function of Wnt/β-catenin in counteracting Tcf3 repression through the Tcf3-β-catenin interaction. Development. 2012;139(12):2118–29.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Nakamura T, Nakamura T, Matsumoto K. The functions and possible significance of Kremen as the gatekeeper of Wnt signalling in development and pathology. J Cell Mol Med. 2008;12(2):391–408.CrossRefPubMedGoogle Scholar
  6. 6.
    Ellwanger K, Saito H, Clément-Lacroix P. Targeted disruption of the Wnt regulator Kremen induces limb defects and high bone density. Mol Cell Biol. 2008;28(15):4875–82.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Wang B, Sinha T, Jiao K, et al. Disruption of PCP signaling causes limb morphogenesis and skeletal defects and may underlie Robinow syndrome and brachydactyly type B. Hum Mol Genet. 2011;20(2):271–85.CrossRefPubMedGoogle Scholar
  8. 8.
    Person AD, Beiraghi S, Sieben CM, et al. WNT5A mutations in patients with autosomal dominant Robinow syndrome. Dev Dyn. 2010;239(1):327–37.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Lettice LA, Williamson I, Wiltshire JH, et al. Opposing functions of the ETS factor family define Shh spatial expression in limb buds and underlie polydactyly. Dev Cell. 2012;22(2):459–67.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhao J, Ding J, Li Y, et al. HnRNP U mediates the long-range regulation of Shh expression during limb development. Hum Mol Genet. 2009;18(16):3090–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Bouldin CM, Gritli-Linde A, Ahn S, et al. Shh pathway activation is present and required within the vertebrate limb bud apical ectodermal ridge for normal autopod patterning. Proc Natl Acad Sci U S A. 2010;107(12):5489–94.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lopez-Rios J, Speziale D, Robay D, et al. GLI3 constrains digit number by controlling both progenitor proliferation and BMP-dependent exit to chondrogenesis. Dev Cell. 2012;22(4):837–48.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Hill P, Wang B, Rüther U, et al. The molecular basis of Pallister Hall associated polydactyly. Hum Mol Genet. 2007;16(17):2089–96.CrossRefPubMedGoogle Scholar
  14. 14.
    Quinn ME, Haaning A, Ware SM, et al. Preaxial polydactyly caused by Gli3 haploinsufficiency is rescued by Zic3 loss of function in mice. Hum Mol Genet. 2012;21(8):1888–96.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Patterson VL, Damrau C, Paudyal A, et al. Mouse hitchhiker mutants have spina bifida, dorso-ventral patterning defects and polydactyly: identification of Tulp3 as a novel negative regulator of the Sonic hedgehog pathway. Hum Mol Genet. 2009;18(10):1719–39.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Cameron DA, Pennimpede T, Petkovich M, et al. Tulp3 is a critical repressor of mouse hedgehog signaling. Dev Dyn. 2009;238(5):1140–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Wong SY, Reiter JF, et al. The primary cilium at the crossroads of mammalian hedgehog signaling. Curr Top Dev Biol. 2008;85:225–60.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Cui C, Chatterjee B, Francis D, et al. Disruption of Mks1 localization to the mother centriole causes cilia defects and developmental malformations in Meckel-Gruber syndrome. Dis Model Mech. 2011;4(1):43–56.CrossRefPubMedGoogle Scholar
  19. 19.
    Howard PW, Howard TL, Maurer RA, et al. Generation of mice with a conditional allele for Ift172. Transgenic Res. 2010;19(1):121–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Friedland-Little JM, Hoffmann AD, Ocbina PJ, et al. A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus. Hum Mol Genet. 2011;20(19):3725–37.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bimonte S, De Angelis A, Quagliata L, et al. Ofd1 is required in limb bud patterning and endochondral bone development. Dev Biol. 2011;349(2):179–91.CrossRefPubMedGoogle Scholar
  22. 22.
    Yin W, Ye X, Shi L, et al. TP63 gene mutations in Chinese P63 syndrome patients. J Dent Res. 2010;89(8):813–7.CrossRefPubMedGoogle Scholar
  23. 23.
    Thomason HA, Dixon MJ, Dixon J, et al. Facial clefting in Tp63 deficient mice results from altered Bmp4, Fgf8 and Shh signaling. Dev Biol. 2008;321(1):273–82.CrossRefPubMedGoogle Scholar
  24. 24.
    Shimomura Y, Wajid M, Shapiro L, et al. P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle. Development. 2008;135(4):743–53.CrossRefPubMedGoogle Scholar
  25. 25.
    Salsi V, Vigano MA, Cocchiarella F, et al. Hoxd13 binds in vivo and regulates the expression of genes acting in key pathways for early limb and skeletal patterning. Dev Biol. 2008;317(2):497–507.CrossRefPubMedGoogle Scholar
  26. 26.
    Jun KR, Seo EJ, Lee JO, et al. Molecular cytogenetic and clinical characterization of a patient with a 5.6-Mb deletion in 7p15 including HOXA cluster. Am J Med Genet A. 2011;155A(3):642–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Lu J, Tsai T, Choo S, et al. Induction of apoptosis and inhibition of cell growth by tbx5 knockdown contribute to dysmorphogenesis in Zebrafish embryos. J Biomed Sci. 2011;18:73.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Tang LY, Li L, Borchert A, et al. Molecular studies of the congenital malformation induced by Largehead Atractylodes Rhizome, the most commonly used Chinese medicine for threatened miscarriage. Mol Hum Reprod. 2012;18(12):585–92.CrossRefPubMedGoogle Scholar
  29. 29.
    Ballim RD, Mendelsohn C, Papaioannou VE, et al. The ulnar-mammary syndrome gene, Tbx3, is a direct target of the retinoic acid signaling pathway, which regulates its expression during mouse limb development. Mol Biol Cell. 2012;23(12):2362–72.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Firulli AB, Conway SJ. Phosphoregulation of Twist1 provides a mechanism of cell fate control. Curr Med Chem. 2008;15(25):2641–7.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Qin Q, Xu Y, He T, et al. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res. 2012;22(1):90–106.CrossRefPubMedGoogle Scholar
  32. 32.
    Mönnich M, Kuriger Z, Print CG, et al. A zebrafish model of Roberts syndrome reveals that Esco2 depletion interferes with development by disrupting the cell cycle. PLoS One. 2011;6(5):e20051.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Leem YE, Choi HK, Jung SY, et al. Esco2 promotes neuronal differentiation by repressing Notch signaling. Cell Signal. 2011;23(11):1876–84.CrossRefPubMedGoogle Scholar
  34. 34.
    Santen GW, Aten E, Sun Y, et al. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nat Genet. 2012;44(4):379–80.CrossRefPubMedGoogle Scholar
  35. 35.
    Shaheen R, Faqeih E, Sunker A, et al. Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome. Am J Hum Genet. 2011;89(2):328–33.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Isidor B, Pichon O, Redon R, et al. Mesomelia-synostoses syndrome results from deletion of SULF1 and SLCO5A1 genes at 8q13. Am J Hum Genet. 2010;87(1):95–100.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Farrington-Rock C, Kirilova V, Dillard-Telm L, et al. Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome. Hum Mol Genet. 2008;17(5):631–41.CrossRefPubMedGoogle Scholar
  38. 38.
    Wong YL, Behringer RR, Kwan KM, et al. Smad1/Smad5 signaling in limb ectoderm functions redundantly and is required for interdigital programmed cell death. Dev Biol. 2012;363(1):247–57.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    de Pontual L, Yao E, Callier P, et al. Germline deletion of the miR-17∼92 cluster causes skeletal and growth defects in humans. Nat Genet. 2011;43(10):1026–30.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Klopocki E, Hennig BP, Dathe K, et al. Deletion and point mutations of PTHLH cause brachydactyly type E. Am J Hum Genet. 2010;86(3):434–9.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Matsumoto K, Li Y, Jakuba C, et al. Conditional inactivation of Has2 reveals a crucial role for hyaluronan in skeletal growth, patterning, chondrocyte maturation and joint formation in the developing limb. Development. 2009;136(16):2825–35.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Schmidt K, Hughes C, Chudek JA, et al. Cholesterol metabolism: the main pathway acting downstream of cytochrome P450 oxidoreductase in skeletal development of the limb. Mol Cell Biol. 2009;29(10):2716–29.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ito T, Handa H, et al. Deciphering the mystery of thalidomide teratogenicity. Congenit Anom (Kyoto). 2012;52(1):1–7.CrossRefGoogle Scholar
  44. 44.
    Ema M, Ise R, Kato H, et al. Fetal malformations and early embryonic gene expression response in cynomolgus monkeys maternally exposed to thalidomide. Reprod Toxicol. 2010;29(1):49–56.CrossRefPubMedGoogle Scholar
  45. 45.
    Knobloch J, Jungck D, Koch A, et al. Apoptosis induction by thalidomide: critical for limb teratogenicity but therapeutic potential in idiopathic pulmonary fibrosis? Curr Mol Pharmacol. 2011;4(1):26–61.CrossRefPubMedGoogle Scholar
  46. 46.
    Knobloch J, Schmitz I, Götz K, et al. Thalidomide induces limb anomalies by PTEN stabilization, Akt suppression, and stimulation of caspase-dependent cell death. Mol Cell Biol. 2008;28(2):529–38.CrossRefPubMedGoogle Scholar
  47. 47.
    Cunningham TJ, Chatzi C, Sandell LL, et al. Rdh10 mutants deficient in limb field retinoic acid signaling exhibit normal limb patterning but display interdigital webbing. Dev Dyn. 2011;240(5):1142–50.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Owen MH, Ryan LM, Holmes LB, et al. Effects of retinoic acid on Dominant hemimelia expression in mice. Birth Defects Res A Clin Mol Teratol. 2009;85(1):36–41.CrossRefPubMedGoogle Scholar
  49. 49.
    Zhu Y, Zhou H, Zhu Y, et al. Gene expression of Hsp70, Hsp90, and Hsp110 families in normal and abnormal embryonic development of mouse forelimbs. Drug Chem Toxicol. 2011;35(4):432–44.CrossRefPubMedGoogle Scholar
  50. 50.
    Giavini E, Menegola E, et al. Are azole fungicides a teratogenic risk for human conceptus? Toxicol Lett. 2010;198(2):106–11.CrossRefPubMedGoogle Scholar
  51. 51.
    Pennimpede T, Cameron DA, MacLean GA, et al. The role of CYP26 enzymes in defining appropriate retinoic acid exposure during embryogenesis. Birth Defects Res A Clin Mol Teratol. 2010;88(10):883–94.CrossRefPubMedGoogle Scholar
  52. 52.
    Wang Z, Wang H, Xu ZM, et al. Cadmium-induced teratogenicity: association with ROS-mediated endoplasmic reticulum stress in placenta. Toxicol Appl Pharmacol. 2012;259(2):236–47.CrossRefPubMedGoogle Scholar
  53. 53.
    MacKinnon Y, Kapron CM, et al. Reduction in cadmium-induced toxicity and c-Jun N-terminal kinase activation by glutathione in cultured mouse embryonic cells. Birth Defects Res A Clin Mol Teratol. 2010;88(9):707–14.CrossRefPubMedGoogle Scholar
  54. 54.
    Elsaid AF, Koriem KM, Collins MD. Sensitivity to cadmium-chloride-induced forelimb ectrodactyly is independent of the p53 gene-dosage in the C57BL/6J mouse. Birth Defects Res A Clin Mol Teratol. 2010;88(4):223–7.PubMedGoogle Scholar
  55. 55.
    Tung EW, Winn LM, et al. Valproic acid increases formation of reactive oxygen species and induces apoptosis in postimplantation embryos: a role for oxidative stress in valproic acid-induced neural tube defects. Mol Pharmacol. 2011;80(6):979–87.CrossRefPubMedGoogle Scholar
  56. 56.
    Ornoy A. Valproic acid in pregnancy: how much are we endangering the embryo and fetus? Reprod Toxicol. 2009;28(1):1–10.CrossRefPubMedGoogle Scholar
  57. 57.
    Gelineau-van Waes J, Heller S, Bauer LK, et al. Embryonic development in the reduced folate carrier knockout mouse is modulated by maternal folate supplementation. Birth Defects Res A Clin Mol Teratol. 2008;82(7):494–507.CrossRefPubMedGoogle Scholar
  58. 58.
    Enright BP, Gu YZ, Snyder RD, et al. Effects of the histamine H1 antagonist chlorcyclizine on rat fetal palate development. Birth Defects Res B Dev Reprod Toxicol. 2010;89(6):474–84.CrossRefPubMedGoogle Scholar
  59. 59.
    Porter FD, Herman GE. Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res. 2011;52(1):6–34.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Campos EC, Cavieres MF. Evaluation of embryotoxicity of misoprostol using the whole embryo culture assay. Rev Med Chil. 2011;139(5):613–7.CrossRefGoogle Scholar
  61. 61.
    Webster WS, Abela D, et al. The effect of hypoxia in development. Birth Defects Res C Embryo Today. 2007;81(3):215–28.CrossRefPubMedGoogle Scholar
  62. 62.
    Graziano C, Carone S, Panza E, et al. Association of hereditary thrombocythemia and distal limb defects with a thrombopoietin gene mutation. Blood. 2009;114(8):1655–7.CrossRefPubMedGoogle Scholar
  63. 63.
    Schlisser AE, Yan J, Hales BF, et al. Teratogen-induced oxidative stress targets glyceraldehyde-3-phosphate dehydrogenase in the organogenesis stage mouse embryo. Toxicol Sci. 2010;118(2):686–95.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Derradji H, Bekaert S, De Meyer T, et al. Ionizing radiation-induced gene modulations, cytokine content changes and telomere shortening in mouse fetuses exhibiting forelimb defects. Dev Biol. 2008;322(2):302–13.CrossRefPubMedGoogle Scholar
  65. 65.
    Sénès FM, Catena N. Correction of forearm deformities in congenital ulnar club hand: one-bone forearm. J Hand Surg Am. 2012;37(1):159–64.CrossRefPubMedGoogle Scholar
  66. 66.
    Deroussen F, Gouron R, Juvet-Segarra M, et al. Use of an iliac crest growth plate for the development of a neo-articulation for congenital transverse deficiencies at the wrist. J Hand Surg Am. 2012;37(10):2061–7.CrossRefPubMedGoogle Scholar
  67. 67.
    Oberlin C, Korchi A, Belkheyar Z, et al. Digitalization of the second finger in type 2 central longitudinal deficiencies (clefting) of the hand. Tech Hand Up Extrem Surg. 2009;13(2):110–2.CrossRefPubMedGoogle Scholar
  68. 68.
    Tonkin MA. Thumb duplication: concepts and techniques. Clin Orthop Surg. 2012;4:1–17.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Piza-Katzer H, Baur EM, Rieger M, et al. A “simple” method for correction of the Apert’s hand. Handchir Mikrochir Plast Chir. 2008;40(5):322–9.CrossRefPubMedGoogle Scholar
  70. 70.
    Sammut D, Garagnani L. A palmar approach for insertion of a free, nonvascularized phalangeal transfer. Tech Hand Surg. 2012;16:114–7.CrossRefGoogle Scholar
  71. 71.
    Ali M, Jackson T, Rayan GM. Closing wedge osteotomy of abnormal middle phalanx for clinodactyly. J Hand Surg Am. 2009;34(5):914–8.CrossRefPubMedGoogle Scholar
  72. 72.
    Chung MS. Congenital differences of the upper extremity: classification and treatment principles. Clin Orthop Surg. 2011;3:172–7.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. and Zhejiang Science and Technology Publishing House 2017

Authors and Affiliations

  1. 1.The First Affiliated Hospital, Zhejiang UniversityHangzhouChina
  2. 2.Hangzhou Plastic Surgery HospitalHangzhouChina

Personalised recommendations