Klippel-Feil syndrome: rare clinical associations and significance

Abstract

Klippel–Feil syndrome (KFS) is a rare congenital disorder characterized by fusion of cervical vertebrae and accompanied by a wide spectrum of systemic anomalies. This narrative review summarizes current knowledge on the genetic basis, clinical spectrum, and rare associations of KFS with implications for multidisciplinary care. Recent genetic studies have identified variants in several developmental pathways, suggesting an emerging concept of oligogenic inheritance and variable expressivity. Clini-cally, beside the classic triad of short neck, low posterior hairline, and restricted cervical motion, pati-ents may present with scoliosis, Sprengel deformity, craniovertebral junction abnormalities, split cord malformations, posterior fossa lesions, and genitourinary and cardiovascular anomalies. Otologic invol-vement, including conductive or sensorineural hearing loss and cochlear implant challenges, further complicates management. Awareness of potential difficult airway and spinal cord vulnerability is cru-cial for anesthesiologists and surgeons. Early recognition, systematic screening for associated anomalies, and coordinated follow-up are essential to prevent complications and optimize long-term outcomes. We narratively reviewed recent clinical, radiologic, and genetic literature to contextualize reported prevalen-ces and rare associations.

Keywords

• Klippel-Feil syndrome
• congenital abnormalities
• spinal diseases

Ethical Statement

There is no requirement of ethical approval. Since this article is a review article.

Klippel-Feil sendromu: nadir klinik ilişkiler ve önemi

Abstract

Klippel–Feil sendromu (KFS), servikal vertebraların konjenital füzyonu ile karakterize, çok sayıda sistemik anomali ile birlikte görülebilen nadir bir gelişimsel bozukluktur. Bu derlemede, KFS’nin gene-tik altyapısı, klinik özellikleri ve nadir eşlik eden durumları güncel literatür ışığında ele alınmakta; multidisipliner yaklaşımın önemi vurgulanmaktadır. Son yapılan genetik çalışmalar, birden fazla geli-şimsel yolakta saptanan varyantları ortaya koymuş olup, tek genli bir mekanizmadan ziyade değişken ekspresyonla seyreden, ortaya çıkmakta olan oligenik bir katkıya işaret etmektedir. Klinik olarak, kısa boyun, düşük posterior saç çizgisi ve servikal hareket kısıtlılığından oluşan klasik triada ek olarak; skolyoz, Sprengel deformitesi, kraniovertebral bileşke anomalileri, split kord malformasyonları, poste-rior fossa patolojileri ile genitoüriner ve kardiyovasküler anomaliler eşlik edebilir. Ayrıca iletim tipi veya sensörinöral işitme kaybı gibi otolojik tutulumlar ve bu hastalarda koklear implant uygulamala-rında karşılaşılan teknik güçlükler, klinik yönetimi daha karmaşık hâle getirebilir. Anestezi ve cerrahi girişimler sırasında zor havayolu yönetimi ve spinal kord yaralanması riski açısından dikkatli olunması büyük önem taşımaktadır. Erken tanı, eşlik eden anomalilere yönelik sistematik tarama ve disiplinler arası koordineli izlem, komplikasyonların önlenmesi ve uzun dönem klinik sonuçların iyileştirilmesi açısından kritik rol oynamaktadır. Bildirilen prevalansları ve nadir birliktelikleri bağlamsallaştırmak amacıyla güncel klinik, radyolojik ve genetik literatür narratif olarak gözden geçirilmiştir.

Keywords

• Klippel-Feil sendromu
• konjenital anomaliler
• spinal hastalıklar

Ethical Statement

Bu yazı derleme türünde olduğundan etik kurul onayına gerek yoktur.

References

1. 1. Ding L, Wang X, Sun Y, et al. Prevalence and Risk Factors of Surgical Treatment for Klippel-Feil Synd-rome. Front Surg 2022;9:885989.
2. 2. Menger RP, Rayi A, Notarianni C. Klippel Feil Syndrome. [Updated 2024 May 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publis-hing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK493157/
3. 3. Ekin EE, Altunrende ME. Klippel-Feil syndrome: Should additional examination be conducted? Eur Spine J 2024;33(6):2347-53.
4. 4. Frikha R. Klippel-Feil syndrome: a review of the literature. Clin Dysmorphol 2020;29(1):35-7.
5. 5. Samartzis D, Kalluri P, Herman J, Lubicky JP, Shen FH. 2008 Young Investigator Award: The role of congenitally fused cervical segments upon the space available for the cord and associated symptoms in Klippel-Feil patients. Spine (Phila Pa 1976) 2008;33(13):1442-50.
6. 6. Mahiroğullari M, Ozkan H, Yildirim N, Cilli F, Gü-demez E. Klippel-Feil sendromu ve eşlik eden do-ğumsal anomaliler: 23 olgunun incelenmesi [Klip-pel-Feil syndrome and associated congenital ab-normalities: evaluation of 23 cases]. Acta Orthop Traumatol Turc 2006;40(3):234-9.
7. 7. Stewart C, Otto AL, Fisher M, et al. Otolaryngologi-cal Presentations of Klippel-Feil Syndrome: A Sys-tematic Review. Cureus 2024;16(11):e73986.
8. 8. Siddiqui F, Talal Ashraf M, Khuzzaim Khan M, et al. A Comprehensive Approach to the Diagnosis and Management of Klippel Feil Syndrome. Arch Razi Inst 2023;78(6):1868-72.

9. 9. Jae-Min Park A, Nelson SE, Mesfin A. Klippel-Feil Syndrome: Clinical Presentation and Management. JBJS Rev 2022;10(2):e21.00166.
10. 10. Moses JT, Williams DM, Rubery PT, Mesfin A. The prevalence of Klippel-Feil syndrome in pediatric patients: analysis of 831 CT scans. J Spine Surg 2019;5(1):66-71.
11. 11. Samartzis DD, Herman J, Lubicky JP, Shen FH. Classification of congenitally fused cervical pat-terns in Klippel-Feil patients: epidemiology and ro-le in the development of cervical spine-related symptoms. Spine (Phila Pa 1976) 2006;31(21):E798-E804.
12. 12. Pai VV, Lowe LH, Castillo M, Huang BY, Shao L. Posterior fossa dermoid cysts in association with Klippel-Feil syndrome: report of three cases. AJNR Am J Neuroradiol 2007;28(10):1926-8.
13. 13. Adorno A, Alafaci C, Sanfilippo F, et al. Malignant teratoma in Klippel-Feil syndrome: a case report and review of the literature. J Med Case Rep 2015;9:229.
14. 14. Yildirim N, Arslanoğlu A, Mahiroğullari M, Sahan M, Ozkan H. Klippel-Feil syndrome and associated ear anomalies. Am J Otolaryngol 2008;29(5):319-25.
15. 15. Reddy YM, Lepcha A, Augustine AM, Philip A. Cochlear Implant in Klippel-Feil Syndrome: Chal-lenges and Concerns. Indian J Otolaryngol Head Neck Surg 2022;74 (Suppl 3):3901-5.
16. 16. Sakai M, Miyake H, Shinkawa A, Komatsu N. Klip-pel-Feil syndrome with conductive deafness and histological findings of removed stapes. Ann Otol Rhinol Laryngol 1983;92(2 Pt 1):202-6.
17. 17. Dubey SP, Ghosh LM. Klippel-Feil syndrome with congenital conductive deafness: report of a case and review of literature. Int J Pediatr Otorhinolaryngol 1993;25(1-3):201-8.
18. 18. Kenna MA, Irace AL, Strychowsky JE, et al. Oto-laryngologic Manifestations of Klippel-Feil Synd-rome in Children. JAMA Otolaryngol Head Neck Surg. 2018;144(3):238-43.
19. 19. Stelzer JW, Flores MA, Mohammad W, Esplin N, Mayl JJ, Wasyliw C. Klippel-Feil Syndrome with Sprengel Deformity and Extensive Upper Extremity Deformity: A Case Report and Literature Review. Case Rep Orthop 2018;2018:5796730.
20. 20. Hensinger RN, Lang JE, MacEwen GD. Klippel-Feil syndrome; a constellation of associated anomalies. J Bone Joint Surg Am 1974;56(6):1246-53.
21. 21. Litrenta J, Bi AS, Dryer JW. Klippel-Feil Syndro-me: Pathogenesis, Diagnosis, and Management. J Am Acad Orthop Surg 2021;29(22):951-60.
22. 22. Niewchas A, Alkhatib S, Stewart C, et al. Cardio-vascular Findings in Klippel-Feil Syndrome: A Systematic Review. Cureus 2024;16(10):e72540.
23. 23. Karim Ahmed A, Howell EP, Harward S, et al. Split cord malformation in adults: Literature review and classification. Clin Neurol Neurosurg 2020;193:105733.
24. 24. Wang X, Yu Y, Yang N, Xia L. Incidence of intras-pinal abnormalities in congenital scoliosis: a sys-tematic review and meta-analysis. J Orthop Surg Res 2020;15(1):485.
25. 25. Srinivasan ES, Mehta VA, Smith GC, Than KD, Terry AR. Klippel-Feil Syndrome with Cervical Di-astematomyelia in an Adult with Extensive Cer-vicothoracic Fusions: Case Report and Review of the Literature. World Neurosurg 2020;139:274-80.
26. 26. Vaidyanathan S, Hughes PL, Soni BM, Singh G, Sett P. Klippel-Feil syndrome - the risk of cervical spi-nal cord injury: a case report. BMC Fam Pract 2002;3:6.
27. 27. Smith BA, Griffin C. Klippel-Feil syndrome. Ann Emerg Med 1992;21(7):876-9.
28. 28. Sreenivasan R, Sharma R, Borkar SA, et al. Cervical Split Cord Malformations: A Systematic Review. Neurol India 2020;68(5):994-1002.
29. 29. Zhang JF, Strelko O, Komarov O, et al. Cervical Diastematomyelia: A Case Presentation and Syste-matic Review. J Neurol Surg Rep 2024;85(2):e74-e82.
30. 30. Andronikou S, Fieggeru AG. Klippel-Feil syndrome with cervical diastematomyelia in an 8-year-old boy. Pediatr Radiol 2001;31(9):636.
31. 31. Tian Y, Fan D, Xu N, Wang S. "Sandwich Defor-mity" in Klippel-Feil syndrome: A "Full-Spectrum" presentation of associated craniovertebral junction abnormalities. J Clin Neurosci 2018;53:247-9.
32. 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.
33. 33. Ali M, Iliev B, Enchev Y, Boshev G, Demirci A. Unique Case of Cervical Split Cord Malformation Type II and Klippel-Feil Syndrome in a Male Pati-ent Symptomatically Treated With Ultrasound-Guided Botulinum Toxin Injection. Cureus 2024;16(9):e69531.
34. 34. Zhang JF, Strelko O, Komarov O, et al. Cervical Diastematomyelia: A Case Presentation and Syste-matic Review. J Neurol Surg Rep 2024;85(2):e74-e82.
35. 35. Samartzis D, Kalluri P, Herman J, Lubicky JP, Shen FH. Cervical scoliosis in the Klippel-Feil patient. Spine (Phila Pa 1976) 2011;36(23):E1501-8.
36. 36. 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.
37. 37. Moore WB, Matthews TJ, Rabinowitz R. Genitouri-nary anomalies associated with Klippel-Feil synd-rome. J Bone Joint Surg Am 1975;57(3):355-7.
38. 38. Lorente R, Mariscal G, Lorente A. Incidence of geni-tourinary anomalies in congenital scoliosis: syste-matic review and meta-analysis. Eur Spine J 2023;32(11):3961-9.
39. 39. Masuda H, Arikawa K, Yuda T, Taira A. Total ano-malous pulmonary venous connection associated with Klippel-Feil syndrome: a case report. The Ja-panese Journal of Thoracic Surgery 1991;44(5):417-20.
40. 40. Bridglal RM. Cardiopulmonary Complications of Klippel-Feil Syndrome: A Case Report. Cureus 2024;16(8):e67303.
41. 41. Baga N, Chusid EL, Miller A. Pulmonary disability in the Klippel-Feil syndrome. A study of two sib-lings. Clin Orthop Relat Res 1969;67:105-10.
42. 42. Teoh DC, Williams DL. Adult Klippel-Feil synd-rome: haemodynamic instability in the prone posi-tion and postoperative respiratory failure. Anaesth Intensive Care 2007;35(1):124-7.
43. 43. Tracy MR, Dormans JP, Kusumi K. Klippel-Feil syndrome: clinical features and current understan-ding of etiology. Clin Orthop Relat Res 2004;(424):183-90.
44. 44. Xu N, Hung KL, Gong X, et al. Genetic insights into the 'sandwich fusion' subtype of Klippel-Feil syndrome: novel FGFR2 mutations identified by 21 cases of whole-exome sequencing. Orphanet J Rare Dis 2024;19(1):141.
45. 45. Clarke RA, Catalan G, Diwan AD, Kearsley JH. Heterogeneity in Klippel-Feil syndrome: a new classification. Pediatr Radiol 1998;28(12):967-74.
46. 46. Agrawal A, Badve AM, Swarnkar N, Sarda K. Disc prolapse and cord contusion in a case of Klippel-Feil syndrome following minor trauma. Indian J Orthop 2009;43(2):210-2.
47. 47. Bhavana Chowdary M, S M, Kumar D, Kk A. A Case Report of Klippel-Feil Syndrome Presenting as Tet-raplegia. Cureus 2023;15(6):e41241.
48. 48. Zhang S, Wang Z, Zhang S, et al. Brown Sequard syndrome in a patient with Klippel-Feil syndrome following minor trauma: a case report and literature review. BMC Musculoskelet Disord 2023;24(1):722.
49. 49. Graillon T, Pech-Gourg G, Adetchessi T, Metellus P, Dufour H, Fuentes S. Double traumatic cervical spine lesion (odontoid fracture and spinal cord injury) and Klippel-Feil syndrome. Neurochirurgie. 2012;58(6):372-5.
50. 50. Karasick D, Schweitzer ME, Vaccaro AR. The trau-matized cervical spine in Klippel-Feil syndrome: imaging features. AJR Am J Roentgenol 1998;170(1):85-8.
51. 51. Chua CC, Cruz MAB. Anesthetic Management of a Patient with Klippel-Feil Syndrome for Laparosco-pic Pelvic Surgery: A Case Report. Acta Med Phi-lipp 2024;58(9):48-53.
52. 52. Chura M, Odo N, Foley E, Bora V. Cervical Defor-mity and Potential Difficult Airway Management in Klippel-Feil Syndrome. Anesthesiology 2018;128(5):1007.
53. 53. Stallmer ML, Vanaharam V, Mashour GA. Congeni-tal cervical spine fusion and airway management: a case series of Klippel-Feil syndrome. J Clin Anesth 2008;20(6):447-51.
54. 54. Hase Y, Kamekura N, Fujisawa T, Fukushima K. Repeated anesthetic management for a patient with Klippel-Feil syndrome. Anesth Prog 2014;61(3):103-6.
55. 55. Khawaja OM, Reed JT, Shaefi S, Chitilian HV, Sandberg WS. Crisis resource management of the airway in a patient with Klippel-Feil syndrome, congenital deafness, and aortic dissection. Anesth Analg 2009;108(4):1220-5.
56. 56. Ahuja V, Kazal S, Gombar S, Thapa D, Bahadur R. Glidescope(®) for predicted difficult airway in Klippel-Feil Syndrome. J Anaesthesiol Clin Phar-macol 2012;28(4):532-4.
57. 57. Altay N, Yüce HH, Aydoğan H, Dörterler ME. Airway management in newborn with Klippel-Feil syndrome. Braz J Anesthesiol 2016;66(5):551-3.
58. 58. Kavanagh T, Jee R, Kilpatrick N, Douglas J. Electi-ve cesarean delivery in a parturient with Klippel-Feil syndrome. Int J Obstet Anesth 2013;22(4):343-8.
59. 59. Jena BR, Mishra RK, Dube SK, Rath GP, Malik V, Gurjar HK. Perioperative Management of a Child with Klippel-Feil Syndrome and Severe Uncorrec-ted Aortic Stenosis Undergoing Cervical Spine Sta-bilization. J Pediatr Neurosci 2021;16(3):257-60.