Editor’s note: This is Part 1 of a 2-part series. Part 2 will be featured in the January/February 2025 edition of Applied Radiology .

Introduction

Klippel-Feil syndrome (KFS) is a rare congenital fusion of the cervical spinal column, sometimes with concurrent involvement of the thoracic and lumbar vertebrae ( Figure 1 ).^{1 - 5}It was first described by Maurice Klippel and Andre Feil in 1912, with the presence of 3 classical clinical signs. The triad, which is seen in some but not all patients, consists of a short neck, limited neck movement, and low posterior hairline.²

The lack of robust population screening studies performed for KFS makes it difficult to present an exact incidence for the disease; ²however, an incidence between 1 in 40,000 to 42,000 is commonly cited.^{2, 6, 7}A 3:2 ratio has been reported in favor of a female predominance, ⁸yet these statistics are difficult to determine because KFS often goes undetected and has a variety of clinical presentations.²As such, more recent data suggest that the occurrence of KFS in the general population is much higher. A large retrospective review of cervical trauma CT scans found that the prevalence of KFS was 0.0058% (1 in 172) with a slight male predominance, ⁶while a prospective multicenter study of patients undergoing symptomatic cervical spinal myelopathy surgery found that 5 of 131 (~3.81%) patients had KFS.⁷

To assist in diagnosing KFS, classification systems based on morphology and etiology have been proposed.¹The original classification model by Maurice Klippel and Andre Feil divided KFS into 3 subtypes based on fusion extent. Advancements in genetics have greatly improved our understanding of associated molecular changes and form the basis of a new genetic subtype classification presented by Clark et al.^{1, 2}

In the following review, we place particular emphasis on the embryology, molecular pathology, imaging diagnosis, clinical associations, and treatment of KFS.

Spinal Embryology

Understanding the embryological development of the spine is crucial for diagnosing developmental disorders of the spine, including KFS. The embryogenesis of the vertebrae begins during gastrulation.⁹The paraxial mesoderm forms around the notochord and, as neurulation progresses, matures and segments into somites on both sides of the neural tube.¹⁰Local signals cause the somites to assume a patterned and segmented appearance. From there, the dorsal somites become the dermomyotome, while the ventral somites differentiate into the sclerotome.¹⁰

The dermomyotome differentiates into muscle cells and the dermis of the skin, while the sclerotome forms the spine.¹¹Owing to sclerotomal rostrocaudal polarity, it undergoes resegmentation. The rostral part of the sclerotome becomes the caudal half of one vertebral body while the caudal part of the same sclerotome becomes the rostral half of subjacent vertebral body.¹⁰Sections of adjacent sclerotomes then join to form the centrum, which stimulates the surrounding bone to develop into the vertebral body.^{11, 12}Concurrently, the notochord within the vertebral bodies degenerates, while the notochord remaining in the interspaces gives rise to the nuclei pulposi of the intervertebral discs.¹²

Pathoembryology of Vertebrae in Klippel-Feil Syndrome

KFS results from the improper segmentation of cervical vertebrae during embryogenesis, which leads to the anomalous formation of intervertebral discs.^{11, 12}As segmentation progresses caudally, vertebral ossification progresses rostrally.^{1, 13}The bidirectional nature of this process may be significant in the pathogenesis of KFS.

In KFS, the C1 vertebrae fails to develop its centrum and is therefore unable to direct the normal development of the surrounding bone. C1 remains attached to the portion of C2, which forms the odontoid process. This also prevents development of the intervertebral disc between C1 and C2.¹When the C2 vertebral body and the rostral odontoid process fail to fuse, the resulting abnormality known as os odontoideum occurs.¹⁴

The notochord also influences initial spinal cord development. During weeks 3 and 4 of gestation, the neural folds fuse dorsally to form the neural tube, a spinal cord precursor. The parallel formation of vertebrae and the spinal cord provides a possible explanation for the synchronous presence of congenital spinal cord abnormalities and vertebral bone anomalies.¹²

KFS is also commonly associated with a variety of other abnormalities of anomalous embryogenesis, including the Sprengel deformity of the scapula.¹⁵At the end of the eighth week of gestation, the scapula descends into its thoracic position. Given that the scapula and midcervical vertebrae develop simultaneously, correlation between KFS and Sprengel deformity is not surprising.¹²

Classification

The variability of KFS has made it challenging to establish specific criteria for diagnosis and treatment. Advancements in genetics and imaging techniques have contributed to the understanding of its etiology and pathophysiology.

Klippel-Feil Classification System

Maurice Klippel and Andre Feil originally presented a case report featuring a 46-year-old French tailor with extreme discomfort in his neck secondary to fusion of the cervical and upper thoracic vertebrae.¹⁶Based on their observations and examination of patients with similar symptoms, they proposed the first classification model for KFS ( Table 1 ). They divided the syndrome into 3 types based on the extent of vertebral fusion.^{1, 5, 8, 16}Type 1 is commonly associated with the classic clinical triad of KFS ( Figure 2 ).¹⁷

Table 1.

Klippel-Feil Classification System

Subtypes	Vertebral Fusion
I	Massive fusion (3 or more levels) of cervical and upper thoracic vertebra with synostosis
II	Fusion at 1 or 2 interspaces with other cervical spine anomalies, for example, hemivertebrae, atlanto-occipital fusion
III	Cervical fusion associated with lower thoracic or lumbar fusion

Gunderson Modifications to the Klippel-Feil Classification System

The Klippel-Feil classification system of KFS has since been re-evaluated. One study by Gunderson et al ¹⁸included radiographic examination of 121 family members of patients with KFS. They demonstrated definitive cervical fusion in 11 probands and 11 relatives, with an additional 7 relatives having related cervical abnormalities. They reported that C2-3 fusion is inherited in an autosomal-dominant fashion, while C5-6 is inherited autosomal recessively, and variable cervical fusion is inherited dominantly with variable expression and penetrance. They also reported that types I and III are more severe, presenting with associated neurological and cardiac anomalies.¹⁸

Clark Classification System

In 1998, Clark proposed a classification system that considers genetic inheritance patterns in addition to morphologic presentation.¹Clark examined 3 KFS families using radiography and cytogenetic banding and found distinct variations in the timing of the postnatal vertebrae fusion and gross morphology.

Based on these differences, and to address genetic heterogeneity, they proposed a new classification system ( Table 2 ). They defined KF1 as C1 rostral fusion, which is inherited recessively. KF2 entails C2 ± 3 fusion and has dominant inheritance. KF3 usually presents as a single fusion in the ±C3 region, but also includes C5-6 fusion with recessive inheritance. Lastly, KF4 may be an X-linked vertebral fusion with a synchronous presentation of Wildervanck syndrome.¹

Table 2.

Clark Classification of Klippel-Feil Syndrome and a Comparison with Klippel-Feil Classification System

Class	Vertebral Fusion	Inheritance	Associated Anomalies	Overlap with Klippel-Feil Classification
KF1	C1 fusion	Recessive	Short neck, cardiac, craniofacial, aural, ocular, limb	Types I-III
KF2	C2-3 fusion	Dominant	Craniofacial, aural, tolaryngeal, skeletal, limb	Types I-III
KF3	Isolated fusions	Recessive or reduced penetrance	Craniofacial, facial dysmorphology	Type II
KF4	Cervical vertebrae fusion	Possibly X-linked	Aural, ocular, cardiac, abducens palsy	-

Adapted From Clark et al.¹

Molecular Genetics of Spinal Development

KFS is characterized by a substantial variation in combinations of genetic and clinical presentation.^{1, 16, 19}Of the genes that have been studied, several show a strong association with familial KFS, as summarized in Table 3 .^{19 - 32}

Table 3.

Molecular Genetics of Klippel-Feil Syndrome Development ^{19 - 32}

Gene/Pathway	Role	Mutations
GDF6	Chromosome 8 involvement, joint and vertebral development, joint fusion	Missense mutations, incomplete penetrance in carpal and tarsal fusions
Notch pathway	Vertebral segmental disorders, somitogenesis, embryonic patterning	Mutations in Notch1, Dll1, Dll3, Hes7, Psen1, Lfng, defects in segment borders and rostrocaudal polarity
PAX genes	Somite segmentation, development	Mutations linked to aniridia and Waardenburg syndrome, PAX1 mutation linked with KFS
HOX complexes	Vertebral development	Hoxd3 mutations cause occipitalization of atlas, Hoxd4 mutations cause supernumerary cervical vertebrae
BAZ1B	Association with Klippel-Feil syndrome

Sporadic Incidence

While recent studies have shown familial inheritance, KFS has historically been understood to exhibit a largely sporadic incidence without a family history of consanguinity, potentially pointing to a significant influence of environmental or multifactorial determinants.^{33, 34}Tredwell examined similarities between fetal alcohol syndrome (FAS) and KFS, ³⁵finding common physical abnormalities, such as fused cervical vertebrae, microcephaly, and thoracic cage abnormalities.

While 20% of patients with KFS had 1 cervical level involved and 50% had 4 or more involved levels, patients with FAS had rates of 53% and 5%, respectively. They also noted that alcohol was unlikely to be a contributing factor in KFS but were unable to determine a specific alternative teratogen.

Conclusion

In Part 1 our review, we have detailed the embryological development and genetic basis of KFS. This foundational understanding is essential for enhancing diagnostic accuracy and developing targeted therapeutic interventions for KFS. Part 2 of this review will focus on the clinical manifestations and diagnostic strategies for KFS.

References

1. Clarke RA Catalan G Diwan AD Kearsley JH . Heterogeneity in Klippel-Feil syndrome: a new classification. Pediatr Radiol. 1998; 28 ( 12 ): 967 - 974. 10.1007/s002470050511

2. Tracy MR Dormans JP Kusumi K . Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin Orthop Relat Res. 2004; 424 ( 424 ): 183 - 190.

3. Goto M Nishimura G Nagai T Yamazawa K Ogata T . Familial Klippel–Feil anomaly and t(5;8)(q35.1;p21.1) translocation. American J of Med Genetics Pt A. 2006; 140A ( 9 ): 1013 - 1015. 10.1002/ajmg.a.31198

4. Samartzis D Herman J Lubicky JP Shen FH . Sprengel’s deformity in Klippel-Feil syndrome. Spine (Phila Pa 1976). 2007; 32 ( 18 ): E512 - 6. 10.1097/BRS.0b013e318133fcf8

5. Klippel M . Un cas d’absence des vertebres cervicales avec cage thoracique remontent justu’a la base du crane. Novelle Inconographic de las Salpetriere. 1912; 25: 223 - 250.

6. Gruber J Saleh A Bakhsh W Rubery PT Mesfin A . The prevalence of Klippel-Feil syndrome: a computed tomography-based analysis of 2,917 patients. Spine Deform. 2018; 6 ( 4 ): 448 - 453. 10.1016/j.jspd.2017.12.002

7. Nouri A Tetreault L Zamorano JJ Mohanty CB Fehlings MG . Prevalence of Klippel-Feil syndrome in a surgical series of patients with cervical spondylotic myelopathy: analysis of the prospective, multicenter aospine North America study. Global Spine J. 2015; 5 ( 4 ): 294 - 299. 10.1055/s-0035-1546817

8. Thomsen MN Schneider U Weber M Johannisson R Niethard FU . Scoliosis and congenital anomalies associated with Klippel-Feil syndrome types I-III. Spine (Phila Pa 1976). 1997; 22 ( 4 ): 396 - 401. 10.1097/00007632-199702150-00008

9. Sadler TW . Embryology of neural tube development. American J of Med Genetics Pt C. 2005; 135C ( 1 ): 2 - 8. 10.1002/ajmg.c.30049

10. Saga Y Takeda H . The making of the somite: molecular events in vertebrate segmentation. Nat Rev Genet. 2001; 2 ( 11 ): 835 - 845. 10.1038/35098552

11. Kaplan KM Spivak JM Bendo JA . Embryology of the spine and associated congenital abnormalities. Spine J. 2005; 5 ( 5 ): 564 - 576. 10.1016/j.spinee.2004.10.044

12. Ulmer JL Elster AD Ginsberg LE Williams III DW . Klippel-feil syndrome: CT and MR of acquired and congenital abnormalities of cervical spine and cord. J Comput Assist Tomog. 1993; 17 ( 2 ): 215 - 224. 10.1097/00004728-199303000-00010

13. Couly GF Coltey PM Le Douarin NM . The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development. 1993; 117 ( 2 ): 409 - 429. 10.1242/dev.117.2.409

14. Morgan MK Onofrio BM Bender CE . Familial os odontoideum: case report. J Neurosurg. 1989; 70 ( 4 ): 636 - 639. 10.3171/jns.1989.70.4.0636

15. Floemer F Magerkurth O Jauckus C Lütschg J Schneider JF . Klippel-Feil syndrome and sprengel deformity combined with an intraspinal course of the left subclavian artery and a bovine aortic arch variant. AJNR Am J Neuroradiol. 2008; 29 ( 2 ): 306 - 307. 10.3174/ajnr.A0878

16. Naikmasur VG Sattur AP Kirty RN Thakur AR . Type III Klippel-Feil syndrome: case report and review of associated craniofacial anomalies. Odontology. 2011; 99 ( 2 ): 197 - 202. 10.1007/s10266-011-0004-7

17. Karasick D Schweitzer ME Vaccaro AR . The traumatized cervical spine in Klippel-Feil syndrome: imaging features. AJR Am J Roentgenol. 1998; 170 ( 1 ): 85 - 88. 10.2214/ajr.170.1.9423605

18. Gunderson CH Greenspan RH Glaser GH Lubs HA . The Klippel-Feil syndrome: genetic and clinical reevaluation of cervical fusion. Medicine (Baltimore). 1967; 46 ( 6 ): 491 - 512. 10.1097/00005792-196711000-00003

19. 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 ( 8 ): 1017 - 1027. 10.1002/humu.20741

20. McGaughran JM Oates A Donnai D Read AP Tassabehji M . Mutations in PAX1 may be associated with Klippel-Feil syndrome. Eur J Hum Genet. 2003; 11 ( 6 ): 468 - 474. 10.1038/sj.ejhg.5200987

21. Mortlock DP Guenther C Kingsley DM . A general approach for identifying distant regulatory elements applied to the Gdf6 gene. Genome Res. 2003; 13 ( 9 ): 2069 - 2081. 10.1101/gr.1306003

22. Settle SH Jr 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 ( 1 ): 116 - 130. 10.1016/s0012-1606(02)00022-2

23. Chang C Hemmati-Brivanlou A . Xenopus GDF6, a new antagonist of noggin and a partner of BMPs. Development. 1999; 126 ( 15 ): 3347 - 3357. 10.1242/dev.126.15.3347

24. Nakamura Y Nakaya H Saito N Wakitani S . Coordinate expression of BMP-2, BMP receptors and noggin in normal mouse spine. J Clin Neurosci. 2006; 13 ( 2 ): 250 - 256. 10.1016/j.jocn.2005.05.011

25. Clarke RA Singh S McKenzie H Kearsley JH Yip M-Y . Familial Klippel-Feil syndrome and paracentric inversion inv(8)(q22.2q23.3). Am J Hum Genet. 1995; 57 ( 6 ): 1364 - 1370.

26. Pourquié O Kusumi K . When body segmentation goes wrong. Clin Genet. 2001; 60 ( 6 ): 409 - 416. 10.1034/j.1399-0004.2001.600602.x

27. Chi N Epstein JA . Getting your Pax straight: Pax proteins in development and disease. TRENDS Genet. 2002; 18 ( 1 ): 41 - 47. 10.1016/s0168-9525(01)02594-x

28. Krumlauf R . Hox genes in vertebrate development. Cell. 1994; 78 ( 2 ): 191 - 201. 10.1016/0092-8674(94)90290-9

29. David KM Thorogood PV Stevens JM Crockard HA . The dysmorphic cervical spine in Klippel-Feil syndrome: interpretations from developmental biology. Neurosurg Focus. 1999; 6 ( 6 ): E3. 10.3171/foc.1999.6.6.4

30. Condie BG Capecchi MR . Mice homozygous for a targeted disruption of Hoxd-3 (Hox-4.1) exhibit anterior transformations of the first and second cervical vertebrae, the atlas and the axis. Development. 1993; 119 ( 3 ): 579 - 595. 10.1242/dev.119.3.579

31. Lufkin T Mark M Hart CP et al. Homeotic transformation of the occipital bones of the skull by ectopic expression of a homeobox gene. Nature. 1992; 359 ( 6398 ): 835 - 841. 10.1038/359835a0

32. Li Z Zhao S Cai S et al. The mutational burden and oligogenic inheritance in Klippel-Feil syndrome. BMC Musculoskelet Disord. 2020; 21 ( 1 ): 220. 10.1186/s12891-020-03229-x

33. Braga M Pederzoli M Beretta S et al. Agenesis of the right internal carotid artery and Klippel-Feil syndrome: case report. Spine (Phila Pa 1976). 2009; 34 ( 20 ): E740 - 2. 10.1097/BRS.0b013e3181b41181

34. Da Silva EO . Autosomal recessive Klippel-Feil syndrome. J Med Genet. 1982; 19 ( 2 ): 130 - 134: 130. 10.1136/jmg.19.2.130

35. Tredwell SJ Smith DF Macleod PJ Wood BJ . Cervical spine anomalies in fetal alcohol syndrome. Spine (Phila Pa 1976). 1982; 7 ( 4 ): 331 - 334. 10.1097/00007632-198207000-00002