Document Type : Review


1 Department of Anatomical Sciences and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.

2 Neurosciences Research Center, Alzahra Hospital, Isfahan University of Medical Sciences, Isfahan, Iran.


Congenital fusion of cervical vertebrae is a rare anomaly. In this condition, two fused vertebrae appear structurally and functionally as one. This anomaly may be symptomatic or asymptomatic. Myelopathy, limitation in neck movement, muscular atrophy and regional sensory loss are examples of probable morbidity associated with this anomaly. Combination of genetic and environmental factors are involved in pathogenesis of this anomaly. Malformation of notochord, poor performance of retinoids, decreased local blood supply of spine and alteration in genes expression, especially members of Hox and Pax family genes are some of the proposed reasons of congenital fusion of cervical vertebrae. Diagnosis of this congenital anomaly in childhood seems to have an important role in prevention of probable secondary disorders in adulthood. We offer to clinicians that after performing careful physical tests and noticing the presence of signs and symptoms that mentioned in this paper, if a patient suspected to have congenital fusion of cervical vertebrae, genetic tests ought to be performed.


 Small size and foramen transversarium are characteristics features of seven cervical vertebrae. Each cervical vertebra has the following features: the superior surface of centrum is concave and that’s inferior surface is convex, each transverse process perforated by a foramen transversarium, the spinous process is bifid (except 7th vertebrae), and the shape of vertebral foramen is three-sided (1-3).
For many years, cervical region abnormalities were of attention mainly to clinicians. Congenital fusion of cervical vertebrae (CFCV) is an uncommon but well-known disorder. Some clinicians consider CFCV as an accidental finding of radiological survey, independent to any disease, whilst others estimate that CFCV might be a reason for secondary changes and mobility trouble of adjacent vertebrae (4-7). Most common fusions are between the facet joints of the second and third cervical vertebrae (C2 and C3) (8). Some clinical signs and symptoms such as shortening of cervical spine, webbing of the neck, malformations of osseous tissue, trouble of neck movement, hemi-vertebrae, kyphosis and lowered line of hair can occur following CFCV (9,10). One of the secondary effects of CFCV on the adjacent level is formation of osteophyte (11).
A complex sequence of events occurs through development of vertebral column. Changes in the pattern of development in each phase can result in malformation of vertebral column. Diagnosis of these congenital abnormalities with help of basic embryological knowledge, physical tests and radiological assessments seems to have an important role in prevention of secondary disorders and in reducing the side effects of surgery (12). Somites are derived from paraxial mesoderm, and sclerotomal portion of somites contributes to the developing of vertebrae(13). One of the proposed reason of CFCV is disturbance in normal spinal segmentation during embryological development, following decrease in local blood supply between 3th to 8th week of embryonic period (14). Alterations of Hox genes expression play an important role in pathogenesis of CFCV (15-17). This paper deals first with normal development of cervical vertebrae, followed by description and embryological etiology of congenital fusion of cervical vertebrae.

Literature review
1. Normal development of cervical vertebrae
At the 8th week of embryonic life, organogenesis is usually complete (18). During this phase, formation of cervical vertebrae occurs following migration, segmentation and chondrification process. At the 6th week, chondrification centers are recognized and ossification of the centrum and lamina occurs at the 8th week of gestational age (19). In humans, formation of somites initiates along the dorsal side of developing embryo in the 20th day of embryonic life (20). They comprise the precursors of vertebral skeleton, trunk muscles and spinal cord meninges (21). In a short time after formation, each somite separates into two subdivisions, the sclerotome or ventromedial portion and dermomyotome or dorsolateral portion of the somite. Vertebrae and ribs originate from the sclerotome. Following the migration of ventral sclerotomal cell to surround the notochord, centrum is forms. Vertebral arch and spinous process are formed from dorsal sclerotomal cell surrounding the neural tube and more laterally located sclerotomal cell forms the transvers process and ribs (22-25).
With progression of development, resegmentation procedure occurs, this term refer to normally fusion between the caudal half of each sclerotome and cranial half of the adjacent sclerotome. The space between cranial and caudal portions of original sclerotome segment filled with mesenchymal cells. These cells do not proliferate and contribute to formation of annulus fibrosus portion of intervertebral disc. Another portion of intervertebral disc is nucleus pulposus that is surrounded with annulus fibrosus and is the remnant of embryonic notochord (26-28).

1.2.Genes and regulation of vertebral development
Precise survey of vertebral development presents valuable information about the main roles of genes in all phase of development. Regulatory functions of genes were proven in differentiation, migration and ossification of vertebral precursor cells. In addition to the roles of many genes in vertebral development, Hox and Pax genes are considered more than other genes.  
Vertebra Hox genes play a key role in patterning of vertebrae (17,29). Controlling the body plan during establishment of cranial-caudal axis is one of the important functions of Hox genes (30,31).In mammals, determining the type of segment structure (vertebrae in human) is mediated with Hox genes (30). Hox genes contain a specific DNA sequence that is known as homeobox (30,32,33).
 Pax genes encode a family of nine proteins (Pax1 to Pax9), and based on difference in structural domain, divided into four groups (Pax family group I to IV)(34,35). During organogenesis, Pax proteins have a critical functions (36) and any alteration in Pax genes expression cause significant abnormalities in embryo(37-41). Among the Pax proteins, Pax1 and Pax9 are expressed during skeletal development (42-45). During vertebral evolution, both pax1 and pax9 activate the expression of Bapx1, an expressed protein in the sclerotome(43,46).
1.3. Development of 1st and 2nd cervical vertebrae
Unusual morphology and distinctive origin of 1st and 2nd cervical vertebrae (atlas and axis respectively) is the reason of being called atypical cervical vertebrae. The main unique feature of atlas is the absence of vertebral body. The atlas consists of two lateral masses connected by anterior and posterior arch. In the rotational movement of the atlas and head around the cranially projection of axis (called odontoid process) (47,48).
Proatlas (not found in human) is formed from fusion between lowest occipital somite and the 1st cervical somite. In normal development, proatlas cells contribute to the formation of superior portion of the axis dense. The 1st, 2nd and 3rd cervical somites contribute to the formation of C1 and C2 vertebral primordia. C1 and C2 vertebral primordia are involved in the formation of inferior portion of dense, axis body, lateral masses and anterior/posterior arch of atlas (49,50).

2. Congenital fusion of cervical vertebrae
Congenital anomalies of the vertebral column do not have a low incidence (51). When two vertebrae fused together, two vertebrae appear structurally and functionally as one (10). In referred condition, the fusion of vertebrae results in more biomechanical pressure in relating segments leading to premature deteriorating changes at relating motion segments (52). During blastemal stage, combination of genetic and environmental factors are involved in pathogenesis of CFCV(1). CFCV may be symptomatic or asymptomatic; myelopathy is one of the serious clinical features of CFCV in some patients. CFCV may be associated with klippel- feil syndrome and limited neck movement; muscular atrophy and sensory loss may also be observed (10, 53-56). In this portion, we surveyed the molecular embryology of CFCV etiology.
Malformations of notochord (chorda dorsalis) is one of the primary proposed reason of CFCV (1,10,57,58). Retinoids are one of the main factors that are involved in pathogenesis of skeletal anomalies such as abnormal axial skeleton, disordered segmentation of notochord, oversized vertebrae and CFCV (27,59,60). Retinoids may have a key role in establishment of somites (61,62). The retinoids have effects on evolution of the vertebrae via regulation of Hox genes, which are important in vertebral development (63-66). Some studies suggest that decrease in local blood supply of spine in embryonic life is the leading cause of CFCV (1,10).
Common site of CFCV is between facet joint of C2 and C3 (8,67-70). Many studies have found association between cervical anomalies, especially fusion of C2 and C3, and dental malocclusion, fetal alcohol syndrome, cleft lip and plate(71-75).

2.1. Occipitalization of the atlas
Because of juxtaposition to the spinomedullary region, atlanto-occipital fusion or atlas occipitalization is considered as important congenital malformations in skull base (76). As regards, both Arnold-chiari malformation and atlas occipitalization cause obstruction of foramen magnum , not all atlas occipitalization can be distinguished from Arnold-chiari (77,78). In Arnold-chiari malformation, portions of cerebellum are located below the foramen magnum (79,80). Some surveys reported that the occurrence of atlas occipitalization differs from 0.5 to 1.0% in Caucasians (76,81).
 A wide range of signs and symptoms can be produced with atlas occipitalization, which differ from headache to full blown neurological syndrome (82,83). During embryonic development, failure of segmentation between lowest occipital sclerotome and the 1st cervical sclerotome is the main cause of atlas occipitalization (47,83). Fusion between the 2nd and 3rd cervical vertebrae with instability of the atlanto-axial articulation is observed in almost 70% of patients with atlas occipitalization (52).

2.2. Atlanto-axial subluxation
Atlanto-axial subluxation (AAS) is a disorder of atlas (C1) and axis (C2) and is characterized with abnormal fusion between anterior facet of atlas and facet of axis. AAS causes impairment in rotational movement of the neck. It may be associated with dislocation of the lateral mass of C1 on C2 (84-86). In other words, AAS may occur with or without C1-C2 dislocation (87). AAS may be acquired (as result of trauma) or inherited (87).Congenitally, AAS may be associated with some conditions such as klippel-feil syndrome (56,88,89), Down syndrome (90,91), Marfan syndrome (92), Morquio syndrome (93,94) and Grisel syndrome(95,96).

2.3. Genetically etiology of CFCV
So far, many genes in the evolution and pathogenesis of cervical vertebrae have been studied.; The chromosomal address of Human Pax1 gene is 20p11.2 (97,98). Alterations in expression of this gene have been associated with some vertebral anomalies (99-101). Hox genes encode transcriptional regulatory proteins that play a key role in control of axial skeletal formation. (102). HoxPG3, HoxPG4 and HoxPG5 are examples of Hox family genes involved in establishing morphologies in the cervical skeleton (17). Mutations in some members of Hox genes family have been associated with cervical vertebrae anomalies (103-106).

Clinical embryology is one of the most important parts of medical sciences, and detailed scrutiny of embryological etiology of anomalies plays an important role in reducing the incidence of this anomalies. Early diagnosis of these anomalies will be helpful in recording the change due to an injury, aging, or progressive degenerative process. We offer to clinicians, after performing careful physical tests and noticing the presence of signs and symptoms that mentioned in this paper, if a patient suspected to have CFCV, genetic tests ought to be performed.

We would like to thank Isfahan Neurosciences Research Center of Alzahra Hospital for their assistance in preparing this manuscript.

Conflict of Interest
The authors declare no conflict of interest.

  1. Borujeni MJS, Purzaki M, Bakhtiari A, et al. A Rare Anatomical Variation of the Cervical Vertebrae Characterized by the Abnormal Fusion between C4 and C5. Global Journal of Medicine Researches and Studies. 2014;1:57-60.
  2. Mishra GP, Bhatnagar S, Singh B, et al. Anatomical Variations in Foramen Transversarium of Typical Cervical Vertebrae and Clinical Significance. Int J Biomed Res. 2014;5:405-407.
  3. Gupta R, Kapoor K, Sharma A, et al. Morphometry of typical cervical vertebrae on dry bones and CT scan and its implications in transpedicular screw placement surgery. Surg Radiol Anat. 2013;35:181-189.
  4. Guille JT, Miller A, Bowen JR, et al. The natural history of Klippel-Feil syndrome: clinical, roentgenographic, and magnetic resonance imaging findings at adulthood. J Pediatr Orthop. 1995;15:617-626.
  5. Hensinger RN. Congenital anomalies of the cervical spine. Clin Orthop Relat Res. 1991;264:16-38.
  6. Knoplich J. Isolated vertebral blocks in the cervical spine. Rev Paul Med. 1991;110:2-7.
  7. Lee CK, Weiss AB. Isolated congenital cervical block vertebrae below the axis with neurological symptoms. Spine. 1981;6:118-124.
  8. Patcas R, Tausch D, Pandis N, et al. Illusions of fusions: Assessing cervical vertebral fusion on lateral cephalograms, multidetector computed tomographs, and cone-beam computed tomographs. Am J Orthod Dentofacial Orthop. 2013;143:213-220.
  9. Tiwari A, Chandra N, Naresh M, et al. Congenital abnormal cervical vertebrae-a case report. J Anat Soc India. 2002;5168-5169.
  10. Erdil H, Yildiz N, Cimen M. Congenital fusion of cervical vertebrae and its clinical significance. J Anat Soc India. 2003;52:125-127.
  11. Shankar VV, Kulkarni RR. Block vertebrae: Fusion of axis with the third cervical vertebrae-a case report. Int J Anatomical Variations. 2011;4:15-18.
  12. Bhagwat VB, Porwal SS, Dhapate SS, Patil NP. Fusion of second with third cervicalvertebra and its embryological basis. J Int Acad Res Multidisciplinary. 2014;2:320-323.
  13. Gadow HF. The evolution of the vertebral column. Cambridge University Press; 2014.
  14. Imran S, Pujari D, Uzair S. Congenitally Fused Cervical Vertebrae. Anatomica Karnatakaan International Journal. 2012;6:73-75.
  15. Wellik DM, Capecchi MR. Hox10 and Hox11 genes are required to globally pattern the mammalian skeleton. Science. 2003;301:363-367.
  16. Carapuço M, Nóvoa A, Bobola N, et al. Hox genes specify vertebral types in the presomitic mesoderm. Genes Dev. 2005;19:2116-2121.
  17. Mallo M, Wellik DM, Deschamps J. Hox genes and regional patterning of the vertebrate body plan. Dev Biol. 2010;344:7-15.
  18. Archer E, Batnitzky S, Franken E, et al . Congenital dysplasia of C2–6. Pediatr Radiol. 1977;6:121-122.
  19. Oh YM, Eun JP, Koh EJ, et al. Posterior arch defects of the cervical spine: a comparison between absent pedicle syndrome and spondylolysis. Spine J. 2009;9:e1-e5.
  20. Buttitta L, Tanaka TS, Chen AE, et al. Microarray analysis of somitogenesis reveals novel targets of different WNT signaling pathways in the somitic mesoderm. Dev Biol. 2003;258:91-104.
  21. Cox M, Serra R. Development of the Intervertebral Dis. In: Shapiro IM, Risbud MVm editors. The Intervertebral Disc. Springer Vienna; 2014 p.33-51.
  22. Hautier L, Weisbecker V, Sánchez-Villagra MR, et al. Skeletal development in sloths and the evolution of mammalian vertebral patterning. Proc Natl Acad Sci USA. 2010;107:18903-18908.
  23. Jaqueira LMF, Armond MC, Pereira LJ, et al. Determining skeletal maturation stage using cervical vertebrae: evaluation of three diagnostic methods. Braz Oral Res. 2010;24:433-437.
  24. Sohn P, Cox M, Chen D, et al.  Molecular profiling of the developing mouse axial skeleton: a role for Tgfbr2 in the development of the intervertebral disc. BMC Dev Biol. 2010;10:29.
  25. Nowlan NC, Sharpe J, Roddy KA, et al. Mechanobiology of embryonic skeletal development: insights from animal models. Birth Defects Res C Embryo Today. 2010;90:203-213.
  26. Pang D, Thompson DN. Embryology and bony malformations of the craniovertebral junction. Childs Nerv Syst. 2011;27:523-564.
  27. Risbud MV, Schaer TP, Shapiro IM. Toward an understanding of the role of notochordal cells in the adult intervertebral disc: from discord to accord. Dev Dyn. 2010;239:2141-2148.
  28. Smith LJ, Nerurkar NL, Choi KS, et al. Degeneration and regeneration of the intervertebral disc: lessons from development. Dis Model Mech. 2011;4:31-41.
  29. Kuraku S, Meyer A. The evolution and maintenance of Hox gene clusters in vertebrates and the teleost-specific genome duplication. Int J Dev Biol. 2009;53:765.
  30. Pearson JC, Lemons D, McGinnis W. Modulating Hox gene functions during animal body patterning. Nat Rev Genet. 2005;6:893-904.
  31. Hoegg S, Meyer A. Hox clusters as models for vertebrate genome evolution. Trends Genet. 2005;21:421-424.
  32. Rath MF, Rohde K, Klein DC, et al. Homeobox genes in the rodent pineal gland: roles in development and phenotype maintenance. Neurochem Res. 2013;38:1100-1112.
  33. Lemons D, McGinnis W. Genomic evolution of Hox gene clusters. Science. 2006;313:1918-1922.
  34. Lang D, Powell SK, Plummer RS, et al. PAX genes: roles in development, pathophysiology, and cancer. Biochem Pharmacol. 2007;73:1-14.
  35. Robson EJ, He SJ, Eccles MR. A PANorama of PAX genes in cancer and development. Nat Rev Cancer. 2006;6:52-62.
  36. Buckingham M, Relaix F. The role of Pax genes in the development of tissues and organs: Pax3 and Pax7 regulate muscle progenitor cell functions. Annu Rev Cell Dev Biol. 2007;23:645-673.
  37. Stoykova A, Gruss P. Roles of Pax-genes in developing and adult brain as suggested by expression patterns. J Neurosci. 1994;14:1395-412.
  38. Dressler GR, Wilkinson JE, Rothenpieler UW, et al. Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities. Nature. 1993;362:65-67.
  39. Epstein DJ, Vekemans M, Gros P. splotch (Sp2H), a mutation affecting development of the mouse neural tube, shows a deletion within the paired homeodomain of Pax-3. Cell. 1991;67:767-774.
  40. Sosa-Pineda B, Chowdhury K, Torres M, et al. The Pax4 gene is essential for differentiation of insulin-producing β cells in the mammalian pancreas. Nature. 1997;386:399-402.
  41. St-Onge L, Sosa-Pineda B, Chowdhury K, et al. Pax6 is required for differentiation of glucagon-producing α-cells in mouse pancreas. Nature. 1997;387:406-409.
  42. Peters H, Wilm B, Sakai N, et al. Pax1 and Pax9 synergistically regulate vertebral column development. Development. 1999;126:5399-408.
  43. Wallin J, Wilting J, Koseki H, et al. The role of Pax-1 in axial skeleton development. Development. 1994;120:1109-1121.
  44. Sonnesen L. Associations between the cervical vertebral column and craniofacial morphology. Int J Dent. 2010;2010.
  45. Sonnesen L, Nolting D, Engel U, et al. Cervical vertebrae, cranial base, and mandibular retrognathia in human triploid fetuses. Am J Med Genet A. 2009;149:177-187.
  46. Rodrigo I, Hill RE, Balling R, et al. Pax1 and Pax9 activate Bapx1 to induce chondrogenic differentiation in the sclerotome.Development.2003;130:473-482.
  47. Menezes AH. Craniocervical developmental anatomy and its implications. Childs Nerv Syst. 2008;24:1109-1122.
  48. Piatt Jr JH, Grissom LE. Developmental anatomy of the atlas and axis in childhood by computed tomography: Clinical article. J Neurosurg Pediatr. 2011;8:235-243.
  49. Karwacki GM, Schneider J. Normal ossification patterns of atlas and axis: a CT study. AJNR Am J Neuroradiol. 2012;33:1882-1887.
  50. Di Ieva A, Bruner E, Haider T, et al. Skull base embryology: a multidisciplinary review. Childs Nerv Syst. 2014;30:991-1000.
  51. McRae D, Barnum A. Occipitalization of the atlas. Am J Roentgenol Radium Ther Nucl Med. 1953;70:23.
  52. Soni P, Sharma V, Sengupta J. Cervical vertebrae anomalies-incidental findings on lateral cephalograms. Angle Orthod.2008;78:176-180.
  53. Samartzis D, Herman J, Lubicky JP, et al. Classification of congenitally fused cervical patterns in Klippel-Feil patients: epidemiology and role in the development of cervical spine-related symptoms. Spine. 2006;31:E798-E804.
  54. Tracy M, Dormans J, Kusumi K. Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin Orthop Relat Res. 2004;424:183-190.
  55. Faisal Khilji M. Klippel-Feil syndrome. Chinese Journal of Contemporary Neurology and Neurosurgery. 2013;13:1049-1050.
  56. Hsieh MH, Yeh KT, Chen IH, et al. Cervical Klippel-Feil syndrome progressing to myelopathy following minor trauma. Tzu Chi Medical Journal. 2012;6:47-50.
  57. Saraga-Babić M, Saraga M. Role of the notochord in the development of cephalic structures in normal and anencephalic human fetuses. Virchows Arch A Pathol Anat Histopathol. 1993;422:161-8.
  58. Schlitt M, Dempsey PJ, Kent Robinson R. Cervical butterfly-block vertebra a case report. Clin Imaging. 1989;13:167-170.
  59. Kessel M, Gruss P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell. 1991;67:89-104.
  60. Lohnes D, Mark M, Mendelsohn C, et al. Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants. Development. 1994;120:2723-2748.
  61. Sakai Y, Meno C, Fujii H, et al. The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo. Genes Dev. 2001;15:213-225.
  62. Ishioka A, Jindo T, Kawanabe T, et al. Retinoic acid-dependent establishment of positional information in the hindbrain was conserved during vertebrate evolution. Dev Biol. 2011;350:154-168.
  63. Wellik DM. Hox Genes and Vertebrate Axial Pattern. Curr Top Dev Biol. 2009;88:257-278.
  64. Kashyap V, Gudas LJ, Brenet F, et al. Epigenomic reorganization of the clustered Hox genes in embryonic stem cells induced by retinoic acid. J Biol Chem. 2011;286:3250-3260.
  65. Rhinn M, Dollé P. Retinoic acid signalling during development. Development. 2012;139:843-858.
  66. Parker HJ, Bronner ME, Krumlauf R. A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates. Nature. 2014;514:490-493.
  67. McRae DL. The significance of abnormalities of the cervical spine. Caldwell lecture. Am J Roentgenol Radium Ther Nucl Med. 1960;84:3-25.
  68. Klimo Jr P, Rao G, Brockmeyer D. Congenital anomalies of the cervical spine. Neurosurg Clin N Am. 2007;18:463-478.
  69. Sonnesen L, Kjær I. Cervical vertebral body fusions in patients with skeletal deep bite. TEur J Orthod. 2007;29:464-470.
  70. Sonnesen L, Petri N, Kjær I, Svanholt P. Cervical column morphology in adult patients with obstructive sleep apnoea. Eur J Orthod . 2008;30:521-526.
  71. Tredwell SJ, Smith DF, Macleod PJ, et al. Cervical spine anomalies in fetal alcohol syndrome. Spine.1982;7:331-334.
  72. Rajion ZA, Townsend GC, Netherway DJ, et al. A three-dimensional computed tomographic analysis of the cervical spine in unoperated infants with cleft lip and palate. Cleft Palate Craniofac J. 2006;43:513-518.
  73. Sandham A. Cervical vertebral anomalies in cleft lip and palate. Cleft Palate J. 1986;23:206-214.
  74. Ross R, Lindsay W. The cervical vertebrae as a factor in etiology of cleft palate. Cleft Palate J. 1965;36:273.
  75. Horswell BB. The incidence and relationship of cervical spine anomalies in patients with cleft lip and/or palate. J Oral Maxillofac Surg. 1991;49:693-697.
  76. Al-Motabagani MA, Surendra M. Total occipitalization of the atlas. Anat Sci Int. 2006;81:173-180.
  77. Kassim N, Latiff A, Das S, et al. Atlanto-occipital fusion: an osteological study with clinical implications. Bratisl Lek Listy. 2009;111:562-565.
  78. Campos Dd, Silva THd, Ellwanger JH, et al. Atlanto-occipital fusion and its neurological complications: a case report. J Morphol Sci. 2012;29:111-13.
  79. Smith RM, Garza I, Robertson CE. Chronic CSF leak causing syringomyelia and pseudo-Arnold-Chiari malformation. Neurology. 2015;85:1994.
  80. Grazzi L, Andrasik F. Headaches and Arnold-Chiari Syndrome: When to Suspect and How to Investigate. Curr Pain Headache Rep. 2012;16:350-353.
  81. Murlimanju B, Prabhu L, Paul M, et al. Variant morphogenesis of squamous part of occipital bone in human skulls. J Morphol Sci. 2010;27:139-141.
  82. Bose A, Shrivastava S. Partial occipitalization of atlas. International Journal of Anatomical Variations. 2013;6:81-84.
  83. Bodon G, Glasz T, Olerud C. Anatomical changes in occipitalization: is there an increased risk during the standard posterior approach? Eur Spine J. 2013;22:512-516.
  84. Phillips WA, Hensinger R. The management of rotatory atlanto-axial subluxation in children. J Bone Joint Surg Am. 1989;71:664-668.
  85. Kawabe N, Hirotani H, Tanaka O. Pathomechanism of atlantoaxial rotatory fixation in children. J Pediatr Orthop. 1989;9:569-574.
  86. Muñiz AE, Belfer RA. Atlantoaxial rotary subluxation in children. Pediatr Emerg Care. 1999;15:25-29.
  87. Lustrin ES, Karakas SP, Ortiz AO, et al. Pediatric Cervical Spine: Normal Anatomy, Variants, and Trauma. Radiographics.2003;23:539-560.
  88. Bertolini G, Trotta M, Caldin M. A skeletal disorder in a dog resembling the Klippel–Feil Syndrome with Sprengel’s Deformity in humans. J Small Anim Pract. 2015;56:213-217.
  89. Ogihara N, Takahashi J, Hirabayashi H, et al. Surgical treatment of Klippel–Feil syndrome with basilar invagination. Eur Spine J. 2013;22:380-387.
  90. Kuroki H, Kubo S, Hamanaka H, et al. Posterior occipito-axial fixation applied C2 laminar screws for pediatric atlantoaxial instability caused by Down syndrome: Report of 2 cases. Int J Spine Surg. 2012;6(1):210-5.
  91. Lee KY, Lee KS, Weon YC. Asymptomatic moyamoya syndrome, atlantoaxial subluxation and basal ganglia calcification in a child with Down syndrome. Korean J Pediatr. 2013;56:540-543.
  92. Tsang AK, Taverne A, Holcombe T. Marfan syndrome: a review of the literature and case report. Spec Care Dentist. 2013;33:248-254.
  93. Charrow J, Alden TD, Breathnach CAR, et al. Diagnostic evaluation, monitoring, and perioperative management of spinal cord compression in patients with Morquio syndrome. Mol Genet Metab. 2015;114:11-18.
  94. Theroux MC, Nerker T, Ditro C, et al. Anesthetic care and perioperative complications of children with Morquio syndrome. Paediatr Anaesth. 2012;22:901-907.
  95. Pilge H, Prodinger PM, Bürklein D, et al.  Nontraumatic Subluxation of the Atlanto-Axial Joint as Rare Form of Aquired Torticollis: Diagnosis and Clinical Features of the Grisel’s Syndrome. Spine. 2011;36:E747-E751.
  96. Reichman EF, Shah J. Grisel Syndrome: An Unusual and Often Unrecognized Cause of Torticollis. Pediatr Emerg Care. 2015;31:577-580.
  97. Stapleton P, Weith A, Urbánek P, et al. Chromosomal localization of seven PAX genes and cloning of a novel family member, PAX-9. Nature genetics. Nat Genet. 1993;3:292-298.
  98. Schnittger S, Gopal Rao V, Deutsch U, et al. Pax1, a member of the paired box-containing class of developmental control genes, is mapped to human chromosome 20p11.2 by in situ hybridization (ISH and FISH). Genomics. 1992;14:740-744.
  99. McGaughran J, Oates A, Donnai D, et al. Mutations in PAX1 may be associated with Klippel–Feil syndrome. Eur J Hum Genet. 2003;11:468-474.
  100. Giampietro P, Raggio C, Reynolds C, et al.  An analysis of PAX1 in the development of vertebral malformations. Clin Genet.2005;68:448-453.
  101. Giampietro PF, Blank RD, Raggio CL, et al. Congenital and idiopathic scoliosis: clinical and genetic aspects. Clin Med Res. 2003;1:125-136.
  102. Garcia-Fernandez J. Hox, ParaHox, ProtoHox: facts and guesses. Heredity. 2004;94:145-152.
  103. McIntyre DC, Rakshit S, Yallowitz AR, Loken L, Jeannotte L, Capecchi MR, et al. Hox patterning of the vertebrate rib cage. Development. 2007;134:2981-2989.
  104. Condie BG, Capecchi MR. Mice with targeted disruptions in the paralogous genes hoxa-3 and hoxd-3 reveal synergistic interactions. Nature. 1994;370:304-307.
  105. Burke AC, Nelson CE, Morgan BA, et al. Hox genes and the evolution of vertebrate axial morphology. Development. 1995;121:333-346.
  106. Gaunt SJ. Conservation in the Hox code during morphological evolution. Int J Dev Biol.  1994;38:549-552.
  107. Selleri L, Depew MJ, Jacobs Y, et al. Requirement for Pbx1 in skeletal patterning and programming chondrocyte proliferation and differentiation. Development. 2001;128:3543-35457.
  108. Soshnikova N, Dewaele R, Janvier P, et al. Duplications of hox gene clusters and the emergence of vertebrates. Dev Biol. 2013;378:194-199.
  109. Jukkola T, Trokovic R, Maj P, et al. Meox1Cre: a mouse line expressing Cre recombinase in somitic mesoderm. Genesis. 2005;43:148-153.
  110. Bayrakli F, Guclu B, Yakicier C, et al. Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype. BMC Genet. 2013;14:95.
  111. Uehara M, Yashiro K, Mamiya S, et al. CYP26A1 and CYP26C1 cooperatively regulate anterior–posterior patterning of the developing brain and the production of migratory cranial neural crest cells in the mouse. Dev Biol. 2007;302:399-411.
  112. Maclean G, Dollé P, Petkovich M. Genetic disruption of CYP26B1 severely affects development of neural crest derived head structures, but does not compromise hindbrain patterning. Dev Dyn. 2009;238:732-745.
  113. Abu-Abed S, Dollé P, Metzger D, et al.  The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes Dev. 2001;15:226-240.
  114. Mortlock DP, Guenther C, Kingsley DM. A general approach for identifying distant regulatory elements applied to the Gdf6 gene.Genome Res. 2003;13:2069-2081.
  115. Settle Jr SH, Rountree RB, Sinha A, et al. Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse  Gdf6  and Gdf5  genes. Dev Biol. 2003;254:116-130.
  116. Tassabehji M, Fang ZM, Hilton EN, et al. Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome. Hum Mutat. 2008;29:1017-1027.