Klippel–Feil syndrome explained

Klippel-Feil syndrome
Synonyms:	Congenital dystrophia brevicollis, cervical vertebral fusion syndrome
Specialty:	Paediatrics, orthopaedics
Symptoms:	Cervical spine fusion, scoliosis, spina bifida, heart defect, respiratory problems, other syndromic features
Onset:	Congenital
Causes:	Genetic mutations
Risks:	Family history
Prognosis:	Shorter life expectancy in some cases
Frequency:	1 in 40,000 to 42,000 births, females more affected than males

Klippel–Feil syndrome (KFS), also known as cervical vertebral fusion syndrome, is a rare congenital condition characterized by the abnormal fusion of any two of the seven bones in the neck (cervical vertebrae).^[1] It can result in a limited ability to move the neck and shortness of the neck, resulting in the appearance of a low hairline. Most people only have one or two of those symptoms so it may not be noticeable without medical imaging.^[2]

The syndrome is difficult to diagnose, as it occurs in a group of patients affected with many different abnormalities who can only be unified by the presence of fused or segmental cervical vertebrae.^[3] KFS is not always genetic and not always known about on the date of birth.

The disease was initially reported in 1884 by Maurice Klippel and André Feil from France.^[4] In 1919, in his Doctor of Philosophy thesis,^[5] André Feil suggested another classification of the syndrome, encompassing not only deformation of the cervical spine, but also deformation of the lumbar and thoracic spine.

Signs and symptoms

KFS is associated with many other abnormalities of the body, hence thorough evaluation of all patients with fused cervical vertebrae at birth is required. Furthermore, it is unclear whether KFS is a unique disease, or if it is one part of a spectrum of congenital spinal deformities.

KFS is usually diagnosed after birth. The most common signs of the disorder are restricted mobility of the neck and upper spine and a shortened neck with the appearance of a low hairline at the back of the head.

Associated abnormalities may include: ^{[6] [7] [8] [9] [10]}

• Scoliosis (sideways curvature of the spine)
• Spina bifida
• Problems with the reproductive organs, kidneys and the ribs
• Cleft palate
• Dental problems (delayed dentition, cavities, missing teeth)
• Respiratory problems
• Heart defects
• Short stature
• Duane syndrome
• Srb's anomaly
• Sprengel's deformity

The disorder also may be associated with abnormalities of the head and face, skeleton, sex organs, muscles, brain and spinal cord, arms, legs and fingers.

Genetics

See also: Dominance (genetics). Mutations of the GDF6, GDF3 and MEOX1 gene are associated with KFS. The cause of the condition is unknown in individuals with KFS who do not have mutations of these two genes. GDF6 and GDF3 provide the body with instructions for making proteins involved in regulating the growth and maturation of bone and cartilage. GDF6 specifically is involved in the formation of vertebral bones, among others, and establishing boundaries between bones in skeletal development. GDF3 is involved with bone and cartilage growth. Mutations of GDF6, GDF3 and MEOX1 cause a reduced number of functional proteins that are coded by these genes, but it is unclear exactly how a shortage in these proteins leads to incomplete separation of the vertebrae in people with KFS. However, when the GDF6 gene was removed in mice, the result was the fusion of bones.^[11]

These mutations can be inherited in two ways:

• Autosomal dominant inheritance, where one copy of the altered gene in each cell is sufficient to cause the disorder, is especially associated with C2-C3 fusion.
• Autosomal recessive inheritance, where both copies of a gene contain mutations, is especially associated with C5-C6 fusion.
• Another autosomal dominant form (mapped on locus 8q22.2), known as KFS with laryngeal malformation, has been identified. It is also known as segmentation syndrome 1.^[12]

Diagnosis

The heterogeneity of KFS has made it difficult to outline the diagnosis as well as the prognosis for this disease.

Classification

In 1912, Maurice Klippel and Andre Feil independently provided the first descriptions of KFS. They described patients who had a short, webbed neck; decreased range of motion (ROM) in the cervical spine; and a low hairline. Feil subsequently classified the syndrome into three categories:

• Type I—Fusion of C2 and C3 with occipitalization of the atlas. In 1953, further complications were later reported by McRae; flexion and extension is concentrated within the C1 and C2 vertebrae. As with aging, the odontoid process can become hypermobile, narrowing the space where the spinal cord and brain stem travel (spinal stenosis).
• Type II—Long fusion below C2 with an abnormal occipital-cervical junction. Similar to the C2-C3 fusion of McRae and could be viewed as a more elaborate variation. Flexion, extension, and rotation are all concentrated in the area of an abnormal odontoid process or poorly developed ring of C1 which cannot withstand the effects of aging.
• Type III—A single open interspace between two fused segments. Cervical spine motion is concentrated at single open articulation. This hypermobility may lead to instability or degenerative osteoarthritis. This pattern can be recognized as the cervical spine is often seen to be at an angle or hinge at this open segment.

A classification scheme for KFS was proposed in 1919 by Andre Feil, which accounted for cervical, thoracic, and lumbar spine malformations.^[13]

However, in 2006, Dino Samartzis and colleagues proposed three classification-types that specifically addressed the cervical spine anomalies and their associated cervical spine-related symptoms, with additional elaboration on various time-dependent factors regarding this syndrome.^[14]

Treatment

Treatment for KFS is symptomatic and may include surgery to relieve cervical or craniocervical instability and constriction of the spinal cord, and to correct scoliosis.

If symptomatic treatment fails, spinal surgery may provide relief. Adjacent segment disease and scoliosis are two examples of common symptoms associated with Klippel–Feil syndrome, and they may be treated surgically. The three categories treated for types of spinal cord deficiencies are massive fusion of the cervical spine (Type I), the fusion of 1 or 2 vertebrae (Type II), and the presence of thoracic and lumbar spine anomalies in association with type I or type II Klippel–Feil syndrome (Type III).

Adjacent segment disease can be addressed by performing cervical disc arthroplasty using a device such as the Bryan cervical disc prosthesis.^[15] The option of the surgery is to maintain range of motion and attenuate the rate of adjacent segment disease advancement without fusion.^[16] Another type of arthroplasty that is becoming an alternate choice to spinal fusion is Total Disc Replacement. Total disc replacement objective is to reduce pain or eradicate it.^[17] Spinal fusion is commonly used to correct spinal deformities such as scoliosis. Arthrodesis is the last resort in pain relieving procedures, usually when arthroplasties fail.

Prognosis

The prognosis for most individuals with KFS is good if the disorder is treated early and appropriately. Activities that can injure the neck should be avoided, as they may contribute to further damage. Other diseases associated with the syndrome can be fatal if not treated, or if found too late to be treatable.^[18]

In less than 30% of cases, individuals with KFS will present with heart defects.^[19] If these heart defects are present, they often lead to a shortened life expectancy, the average being 35–45 years of age among males and 40–50 among females. This condition is similar to the heart failure seen in gigantism.^[20]

Epidemiology

The prevalence of KFS is unknown due to the lack of studies to determine its prevalence.^[21] It is estimated to occur 1 in 40,000 to 42,000 newborns worldwide. In addition, females seem to be affected slightly more often than males.

Notable cases

Ancient

• A case of a child in Switzerland was discovered in a necropolis dated between 4500 and 4000 BC.^[22]
• In 2009, archaeologists excavating at a Neolithic site of the Đa Bút culture of northern Vietnam discovered the remains of a young man around age 25, "Burial 9", living between 2000 BC and 1500 BC with Klippel–Feil syndrome, who had apparently been supported by his subsistence-level community for at least a decade before his death.^{[23] [24] [25]}
• The 18th Dynasty Egyptian pharaoh Tutankhamun is believed by some to have had Klippel–Feil syndrome,^[26] though others dispute this claim.^[27]

Contemporary

• English cricketer Gladstone Small^[28]
• "Big" Ed Brown from the TLC series, 90 Day Fiancé.
• Kansas City Chiefs wide receiver Justyn Ross.

References

This article incorporates information in the public domain prepared by the National Institute of Neurological Disorders and Stroke.

Notes and References

1. Andrews, James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. .
2. Web site: Klippel-Feil syndrome. Genetics Home Reference. U.S. National Library of Medicine. en. 2018-08-18.
3. Web site: Klippel-Feil Syndrome . HONselect . 2013-01-20 . 2018-06-12 . https://web.archive.org/web/20180612141209/http://www.hon.ch/HONselect/RareDiseases/EN/C05.116.099.370.535.html . dead .
4. Belykh. Evgenii. Malik. Kashif. Simoneau. Isabelle. Yagmurlu. Kaan. Lei. Ting. Cavalcanti. Daniel D.. Byvaltsev. Vadim A.. Theodore. Nicholas. Preul. Mark C.. July 2016. Monsters and the case of L. Joseph: André Feil's thesis on the origin of the Klippel-Feil syndrome and a social transformation of medicine. Neurosurgical Focus. 41. 1. E3. 10.3171/2016.3.FOCUS15488. 1092-0684. 27364256. free.
5. Feil A. These de medicine, Paris. L'absence et la diminution des vertèbres cervicales (étude clinique et pathogénique); le syndrome de réduction numérique cervicales. . 1919.
6. Web site: Klippel-Feil syndrome. Genetics Home Reference. U.S. National Library of Medicine. en. 2018-08-18.
7. Paradowska, Szeląg, Sławecki. 2007. Klippel−Feil Syndrome – Review of the Literature. dead. Dent. Med. Probl.. https://web.archive.org/web/20151001052200/http://www.dmp.am.wroc.pl/artykuly/DMP_2007444491.pdf. 2015-10-01. 2015-09-30.
8. Dental team management for a patient with Klippel-Feil syndrome: case report. Special Care in Dentistry. 2009-12-01. 1754-4505. 19886936. 244–248. 29. 6. 10.1111/j.1754-4505.2009.00101.x. Marina de Deus Moura. de Lima. Karem Lopez. Ortega. Luis Carlos Arias. Araújo. Marcelo Melo. Soares. Marina Helena Cury Gallottini. de Magalhães.
9. Book: Marchiori. Dennis. Clinical Imaging - E-Book: With Skeletal, Chest and Abdomen Pattern Differentials. 2004. Elsevier Health Sciences. 978-0323071277. 25 January 2018. en.
10. Farsetti P, Weinstein SL, Caterini R, De Maio F, Ippolito E . Sprengel's deformity: long-term follow-up study of 22 cases . J Pediatr Orthop B . 12 . 3 . 202–10 . May 2003 . 12703036 . 10.1097/01202412-200305000-00007. Book: Sarwark . JF . LaBella . CR . Pediatric Orthopaedics and Sports Injuries: A Quick Reference Guide . American Academy of Pediatrics . Elk Grove Village IL . 2010 . 231–4 .
11. Tassabehji M, Fang ZM, Hilton EN, etal . Mutations in GDF6 are associated with vertebral segmentation defects in Klippel-Feil syndrome . Hum. Mutat. . 29 . 8 . 1017–27 . August 2008 . 18425797 . 10.1002/humu.20741 . 5276691 . free .
12. Web site: Segmentation syndrome 1 | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program . 2009-06-13 . 2012-05-31 . https://web.archive.org/web/20120531191627/http://rarediseases.info.nih.gov/GARD/Disease.aspx?diseaseID=6838 . dead .
13. Feil A. L'absence et la diminuaton des vertebres cervicales (etude cliniqueet pathogenique); le syndrome dereduction numerique cervicales. Theses de Paris; 1919.
14. Samartzis DD, Herman J, Lubicky JP, Shen FH . Classification of congenitally fused cervical patterns in Klippel-Feil patients: epidemiology and role in the development of cervical spine-related symptoms . Spine . 31 . 21 . E798–804 . 2006 . 17023841 . 10.1097/01.brs.0000239222.36505.46 . 19744236 .
15. Goffin J, Casey A, Kehr P, etal . Preliminary clinical experience with the Bryan Cervical Disc Prosthesis . Neurosurgery . 51 . 3 . 840–5; discussion 845–7 . September 2002 . 12188968 . 10.1227/00006123-200209000-00048. 41447240 .
16. Papanastassiou ID, Baaj AA, Dakwar E, Eleraky M, Vrionis FD . Failure of cervical arthroplasty in a patient with adjacent segment disease associated with Klippel-Feil syndrome . Indian J Orthop . 45 . 2 . 174–7 . March 2011 . 21430874 . 3051126 . 10.4103/0019-5413.77139 . free .
17. Phillips FM, Garfin SR . Cervical disc replacement . Spine . 30 . 17 Suppl . S27–33 . September 2005 . 16138062 . 10.1097/01.brs.0000175192.55139.69. 46420208 . free .
18. Book: Nursing care of the pediatric neurosurgery patient. Cathy C. Cartwright. Donna C. Wallace. 3 May 2007. 978-3-540-29703-1. 205–. Springer . 25 December 2010.
19. Web site: Klippel Feil syndrome - About the Disease - Genetic and Rare Diseases Information Center . 2020-10-15 . 2021-04-11 . https://web.archive.org/web/20210411150809/https://rarediseases.info.nih.gov/diseases/10280/klippel-feil-syndrome . dead .
20. McGaughran JM, Kuna P, Das V. October 1998. Audiological abnormalities in the Klippel-Feil syndrome. Arch. Dis. Child.. 79. 4. 352–5. 10.1136/adc.79.4.352. 1717726. 9875048.
21. Angeli, E., Wagner, J., Lawrick, E., Moore, K., Anderson, M., Soderland, L., & Brizee, A. (2010, May 5). General format title. Retrieved from http://owl.english.purdue.edu/owl/resource/560/01/
22. Web site: Aspects historiques.
23. Web site: Oldest Known Paralyzed Human Discovered . 2014-01-18 . bot: unknown . https://archive.today/20120710173417/http://dsc.discovery.com/news/2009/08/06/paralyzed-human.html . 2012-07-10 .
24. Tilley. Lorna. Oxenham. Marc F. Survival against the odds: Modeling the social implications of care provision to seriously disabled individuals. International Journal of Paleopathology. March 2011. 1. 1. 35–42. 10.1016/j.ijpp.2011.02.003. 29539340. 1885/54871. free.
25. News: Gorman. James. Ancient Bones That Tell a Story of Compassion. 12 April 2015. The New York Times. 17 December 2012, New York edition, D1. The New York Times. 2012-12-17.
26. News: Tutankhamun shows his face 80 years after tomb is opened . The Telegraph . London. 2007-07-12 . 2002-09-29 . Barrow . Becky .
27. Boyer RS, Rodin EA, Grey TC, Connolly RC . The skull and cervical spine radiographs of Tutankhamen: a critical appraisal . AJNR. American Journal of Neuroradiology . 24 . 6 . 1142–7 . 2003 . 12812942 . 8149017 .
28. News: Hughes. Simon. Small gains from wealth of partners. Cricinfo. 1997-09-05. 2007-12-13.