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Last updated: 8/8/2023
Years published: 1989, 1994, 2000, 2002, 2003, 2011, 2016, 2019, 2023
NORD gratefully acknowledges Raymond A. Clarke, PhD, Associate Professor, Discipline of Psychiatry, University of New South Wales, Sydney, Australia, for assistance in the preparation of this report.
Summary
Klippel-Feil syndrome (KFS) is a rare skeletal disorder characterized by the congenital fusion of two or more vertebrae of the cervical spine within the neck. Some affected individuals may also have an abnormally short neck, restricted movement of the head and neck and a low hairline at the back of the head (posterior hairline). The disorder is present at birth (congenital), but mild cases may go undiagnosed until later life when symptoms worsen or first become apparent. In some individuals, KFS can be associated with a variety of additional symptoms and physical abnormalities. These may include abnormal curvature of the spine (scoliosis) and/or vertebral instability, spina bifida occulta, raised scapula (Sprengelโs deformity), absent rib(s) and other rib defects including cervical ribs, other skeletal abnormalities including skeletal malformations of the ear, nose, mouth and larynx including hearing impairment and cleft palate, malformations of the head and facial (craniofacial) area; anomalies of the urinary tract and/or kidney including absent or horse-shoe kidney; or structural abnormalities of the heart (congenital heart defects), mirror movements, webbing of the digits and digital hypoplasia. In addition, in some cases, neurological complications may result due to associated spinal cord injury. KFS may occur as an isolated abnormality (Klippel-Feil anomaly) or as a syndrome with associated anomalies.
In many individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). In other cases, KFS may be inherited in an autosomal dominant or autosomal recessive pattern. Researchers had determined that some cases of KFS were associated with changes (variants or mutations) of the GDF6 gene. Variants in the GDF6 gene also cause multiple synostosis syndrome type 4 (SYSN4) which is very difficult to distinguish from KFS because SYSN4 is also congenital and progressive with vertebral fusion from a very early age. Some people were wrongly diagnosed with KFS but in fact have SYSN4.
Introduction
KFS was originally described in the medical literature in 1912 by doctors Maurice Klippel and Andre Feil.
KFS is a rare skeletal condition in which there is abnormal union and fusion of two or more vertebrae within the neck. The spinal column or backbone is made up of 33 irregularly shaped bones known as vertebrae. These bones are divided into different categories. The first seven vertebrae, beginning at the base of the skull, are known as the cervical vertebrae. KFS primarily affects the cervical vertebrae.
The specific symptoms associated with KFS vary greatly from one person to another. Historically, KFS was associated with a classic triad of symptoms, specifically abnormally short neck, restricted movement of the head and neck, and a low hairline at the back of the head (posterior hairline). However, researchers have determined that these symptoms may define one class of KFS, which accounts for less than 50 percent of affected individuals.
In addition to the fusion of certain vertebrae, KFS can be associated with a wide variety of additional anomalies affecting many different organ systems of the body. The progression and severity of KFS can vary greatly depending upon the specific associated complications and the Class of KFS. Some cases may be mild; others may cause serious, life-long complications.
It is important to note that affected individuals will not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Approximately 30 percent of affected individuals have additional skeletal abnormalities, such as fusion of certain ribs or other rib defects; abnormal sideways curvature of the spine (scoliosis); or a condition known as Sprengelโs deformity. This condition is characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and the development of a lump at the base of the neck due to elevation of the shoulder blade. Also, in some individuals with KFS, a portion of the spinal cord may be exposed due to incomplete closure of certain vertebrae (spina bifida occulta). Associated findings may include the presence of a tuft of hair or dimple over the underlying abnormality and, in some cases, leg weakness, an inability to control urination (urinary incontinence), or other findings. As mentioned above, KFS type II may be associated with incomplete development of one half of certain vertebrae (hemivertebrae) and fusion of the first vertebra of the neck (atlas) with the bone at the back of the skull (occipital bone).
Approximately 25 to 50 percent of individuals with KFS also have hearing impairment. Such hearing loss may result from impaired transmission of sound from the outer or middle ear to the inner ear (conductive hearing loss); failed transmission of sound impulses from the inner ear to the brain (sensorineural hearing loss); or both (mixed hearing loss). Conductive hearing loss in association with vertebral fusion is also present in individuals with multiple synostosis syndrome type 4 (SYSN4).
Various eye (ocular) abnormalities may also be associated with KFS, such as deviation of one eye toward the other (cross-eye or convergent strabismus); involuntary, rapid eye movements (nystagmus); or absence or defects of ocular tissue (colobomas). In addition, some affected individuals may have other abnormalities of the head and facial (craniofacial) area including facial asymmetry, in which one side of the face appears dissimilar from other side, with one eye higher than the other. There may also be abnormal twisting of the neck (torticollis), causing the head to be rotated into an abnormal position. According to some reports, approximately 17 percent of individuals with KFS also have incomplete closure of the roof of the mouth (cleft palate).
KFS may sometimes be associated with additional physical abnormalities. These may include structural malformations of the heart (congenital heart defects), particularly ventricular septal defects (VSDs). VSDs are characterized by the presence of an abnormal opening in the fibrous partition (septum) that separates the two lower chambers of the heart. Some individuals may also have kidney (renal) defects, such as underdevelopment (hypoplasia) or absence (agenesis) of one or both kidneys; abnormal renal rotation or placement (ectopia); or swelling of the kidneys with urine (hydronephrosis) due to blockage or narrowing of the tubes (ureters) that carry urine to the bladder.
Some individuals with the disorder may also develop neurological complications due to associated spinal cord injury. Such injury may result from instability of cervical vertebrae. For example, unfused vertebral segments adjacent to fused cervical vertebrae may be abnormally mobile (hypermobile), making them vulnerable to increased stress, which in turn may lead to vertebral instability or degenerative changes. Associated neurological complications tend to develop between the second and third decades of life and may occur spontaneously or following minor trauma. Such complications may include pain; abnormal sensations (paresthesia), such as tingling, prickling, or burning; or involuntary muscle movements accompanying certain voluntary actions (synkinesia or mirror movements). In addition, some individuals may develop increased reflex reactions (hyperreflexia); weakness or paralysis of one side of the body (hemiplegia) or of the legs and the lower part of the body (paraplegia); or impairment of certain nerves that emerge from the brain (cranial nerve palsies).
In most individuals with KFS, the condition appears to occur randomly for unknown reasons (sporadically). However, in other cases, familial patterns have been reported that indicate autosomal dominant or autosomal recessive inheritance. Most likely, KFS is multifactorial, which means that several different factors including genetic factors all play some causative role. In addition, different genetic changes can cause KFS (genetic heterogeneity) in different people.
Researchers have determined that some familial cases of KFS are associated with autosomal dominant transmission. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. For autosomal dominant inheritance the risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy. The risk is the same for males and females.
In 2008, researchers determined that some cases of autosomal dominant and sporadic KFS are caused by mutations of the GDF6 gene. The GDF6 gene produces a growth factor that is involved in the production and function of cartilage in the developing embryo. Cartilage is the specialized tissue that serves as a buffer or cushion at joints. Most of the skeleton of an embryo consists of cartilage, which is slowly converted to bone. Researchers have determined that the growth factor produced by the GDF6 gene is essential to the proper function of the spinal discs found between the vertebrae. These discs provide flexibility and protection for the spinal cord. How mutations of the GDF6 gene contribute to the full spectrum of symptoms and physical findings associated with KFS is not yet known. Multiple synostosis 4 (SYNS4) is also associated with the mutations in the GDF gene.
Some cases of KFS have been reported that seem to suggest autosomal recessive inheritance. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.
The specific underlying causes and mechanisms that are associated with KFS are not fully understood. However, the condition appears to result from failure of the proper division (segmentation) of embryonic tissue that normally develops into vertebrae. As explained above, some cases are linked to mutations of the GDF6 gene which regulates the ossification of cartilage which can affect both congenital bone formation and progressive ossification after birth. Other cases may be due to mutations in other genes or other causes. Further research is needed to learn more about the various underlying mechanisms that may be responsible for KFS, and the exact roles genetic and other factors ultimately play in the development of the disorder.
The exact incidence of the disorder is unknown, although reports estimate that the condition occurs in approximately one in 42,000-50,000 live births. KFS affects females more frequently than males. More specifically, approximately 65 percent of affected individuals are female. According to reports in the medical literature, KFS type II appears to be the most common form of the condition.
KFS may be diagnosed at birth based upon a thorough clinical evaluation, identification of characteristic physical findings, and specialized tests. Diagnostic studies may include advanced imaging techniques, such as magnetic resonance imaging (MRI), to help characterize the open spaces (interspaces) between certain cervical and other vertebrae, the extent of abnormal vertebral union or fusion, and possible impingement of vertebrae on the spinal cord. During MRI, a magnetic field and radio waves form detailed cross-sectional images of internal structures. Additional specialized tests may also be conducted to help detect and/or characterize other abnormalities that may be associated with KFS (e.g., hearing impairment, congenital heart defects, renal abnormalities, eye defects, etc.).
Treatment
The treatment of KFS is directed toward the specific symptoms and associated physical findings that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan an affected individualโs treatment. These professionals may include pediatricians; surgeons; physicians who diagnose and treat disorders of the skeleton, muscles, joints, and related tissues (orthopedists); physicians who specialize in neurological disorders (neurologists); physicians who diagnose and treat heart abnormalities (cardiologists); specialists who assess and treat hearing problems (audiologists); eye specialists (ophthalmologists); and/or other health care professionals.
Therapy for KFS can include a variety of conservative measures including the use of cervical collars, braces, traction, non-steroidal anti-inflammatory drugs (NSAIDs) and various pain medications (analgesics).
Because some affected individuals may have an increased risk of neurological complications, they should be regularly monitored by physicians. In addition, they should avoid activities that could lead to trauma or injury to cervical vertebrae.
In some individuals with KFS, treatment may include surgical repair of certain skeletal, auditory, ocular, cardiac, renal or other abnormalities potentially associated with the disorder. For example, in those with cervical spinal cord compression, surgery may be conducted to correct such compression or associated vertebral instability. The surgical procedures performed will depend upon the severity of the anatomical abnormalities, their associated symptoms, and other factors.
In addition, some individuals with hearing impairment may benefit from the use of specialized hearing aids. Genetic counseling may also be of benefit for individuals with KFS and their families.
The identification of mutations in the GDF6 gene in some cases of KFS should lead to new avenues for treatment of the disorder. Research into the GDF6 gene and its role in the development of KFS are ongoing.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
Contact for additional information about Klippel-Feil syndrome research:
Dr. Raymond A. Clarke
Ingham Institute of Medical Research
School of Psychiatry
University of New South Wales
email: [email protected]
Tel.: (61)-425210270
TEXTBOOKS
Driscoll DJ, Rigamonti D, Gailloud P. Klippel-Feil Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:720.
Jones KL. Smithโs Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, Pa: W.B. Saunders Company; 1997:618-19.
JOURNAL ARTICLES
Clarke RA, Fang Z, Murrell D, Sheriff T and Eapen V. GDF6 knockdown in a family with multiple synostosis syndrome and speech impairment. Genes (Basel). 2021 Sep; 12(9): 1354. Published online 2021 Aug 29. doi: 10.3390/genes12091354
Tassabehj 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.
Paul I, Badmanaban B, Campalani G. Patients with Klippel-Feil syndrome should have imaging of the subclavian artery and its branches prior to coronary artery bypass grafting. Interact Cardiovasc Thorac Surg. 2007;6:403-405.
Vaidyanathan S, Huges PL, Soni BM, Singh G, Sett P. Klippel-Feil syndrome โ the risk of cervical spinal cord injury: a case report. BMC Family Practice. 2002;3:6.
Clarke RA, et al. Heterogeneity in Klippel-Feil syndrome: a new classification. Pediatr Radiol. 1998;28:967-74.
McGaughran JM, et al. Audiological abnormalities in the Klippel-Feil syndrome. Arch Dis Child. 1998;79:352-55.
Rouvreau P, et al. Assessment and neurologic involvement of patients with cervical spine congenital synostosis as in Klippel-Feil syndrome: study of 19 cases. J Pediatr Orthop B. 1998;7:179-85.
Thompson E, et al. Autosomal dominant Klippel-Feil anomaly with cleft palate. Clin Dysmorphol. 1998;7:11-15.
Theiss SM, et al. The long-term follow-up of patients with Klippel-Feil syndrome and congenital scoliosis. Spine. 1997;22:1219-22.
Thomsen MN, et al. Scoliosis and congenital anomalies associated with Klippel-Feil syndrome types I-III. Spine. 1997;22:396-401.
Clarke RA, Singh S, McKenzie H, Kearsley JH, Yip MY. Familial Klippel-Feil syndrome and paracentric inversion inv(8)(q22.2q23.3). Am J Hum Genet. 1995;57:1364-1370.
INTERNET
Lewis TR. Klippel-Feil syndrome. Medscape. Updated: Apr 20, 2021.Available at: https://emedicine.medscape.com/article/1264848-overview Accessed Nov 22, 2022.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:118100; Last Update: 01/22/2019. Available at: https://www.ncbi.nlm.nih.gov/omim/118100 Accessed Nov 22, 2022.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:214300; Last Update:12/30/2014. Available at: https://www.ncbi.nlm.nih.gov/omim/214300 Accessed Nov 22, 2022.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
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