Klippel-Feil syndrome …

Developmental Malformations

Updated 08.06.2024
Released 05.19.1999
Expires For CME 08.06.2027

Klippel-Feil syndrome

Authors: Aparna M Prabhu MD MRCP, Juan P Solano Romero MD

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Editor: Ganeshwaran H Mochida MD

Klippel-Feil syndrome

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Introduction

Overview

In this article, the authors review the basic biological issues surrounding the pathogenesis, natural history, clinical manifestations, and progression of Klippel-Feil syndrome. This rare and complex disorder is characterized by the fusion of two or more cervical vertebrae (above or below C3) with a clinical expression in a triad: short neck, decreased range of neck movements, and a low hairline.

Klippel-Feil syndrome usually presents as a sporadic condition, but autosomal dominant or autosomal recessive inheritance patterns have been described. Genes associated with dominant forms are GDF3 and GDF6. Most genes related to Klippel-Feil syndrome are involved in proper bone development. The protein produced from the GDF6 gene is necessary for the formation of bones and joints, including those in the spine. Two genes associated with recessive conditions, MEOX1 and RIPPLY2, have been identified in consanguineous families. On occasion, Klippel-Feil syndrome is associated with other disorders, thus complicating the clinical course. Recent discoveries have centered primarily on associated conditions, complications, and their treatment, much of which involves corrective surgery.

Key points

	• Klippel-Feil syndrome is a rare and complex disorder characterized by the fusion of two or more cervical vertebrae (above or below C3) and a triad of short neck, decreased range of neck movements, and a low hairline.
	• This is a multifactorial but sporadic condition with a genetic autosomal dominant or recessive component.
	• Several genes (GDF3, GDF6, MEOX1, HOX, SGM1, PAX 1, and RIPPLY2) have been identified; the search for other candidate genes is ongoing.
	• On occasion, Klippel-Feil syndrome is associated with other anomalies or conditions, thus complicating the clinical course.
	• Recent discoveries have centered primarily on associated conditions, complications, and their treatment, much of which involves corrective surgery.

Historical note and terminology

Klippel-Feil syndrome is a condition involving the fusion of cervical vertebrae and associated changes in neck length and mobility. The clinical triad of short neck, decreased range of neck movements, and a low hairline was described first by Maurice Klippel and Andre Feil in 1912 (Klippel and Feil 1912). About 34% to 74% of patients present with the full triad (88; 108). Some authors state that those patients with Klippel-Feil who do not have a clinical picture involving the full triad have been named Klippel-Feil variant (121). The characteristic changes were also recognized in an Egyptian mummy from 500 BC and in descriptions dating from the 13th to 16th centuries (86; 43; 32). Feil later defined three subtypes in what is considered the first classification (30). Since then, many papers have been published with different, newer classification systems, reflecting the heterogeneity of the syndrome (106).

Multiple spinal and extra-spinal anomalies make this a heterogeneous condition (125). Most cases are sporadic, although we know there are different genetic forms because of the autosomal dominant and autosomal recessive cases that have been recognized. Several genes involved in spinal segmentation and resegmentation have been identified, including GDF3, GDF6, MEOX1, HOX, PAX 1, and RIPPLY2, and have shown correlation with a corresponding categorical match with the classifications (19; 16).

Clinical manifestations

Presentation and course

Because of a high asymptomatic rate, many patients with Klippel-Feil syndrome are misdiagnosed or not diagnosed. At a glance, those patients with Klippel-Feil syndrome typically have short necks; during a deeper investigation various spinal and extra-spinal anomalies can be discovered. Klippel-Feil syndrome is characterized by a triad of two or more cervical vertebrae (above or below C3) fusion, a short neck, and a low hairline. Symptomatic patients present with either one or a combination of neck pain, neck stiffness, or neck shortening.

Symptoms

A variable degree of neck shortening is present, but sometimes may be extreme. In severe cases, the patient’s head appears to give an impression that is resting directly on the shoulders. Perhaps enhancing this impression is the shape of the trapezius muscles, which are prominently flared laterally (between mastoid process and acromion), giving a web neck appearance--called pterygium colli. In a review of 75 patients, 90% experienced muscle, joint, or nerve pain that was associated with the number of cervical fusions rather than surgical procedures (96). Neck pain is a complaint in up to 90% of the patients (96) and can extend into the back, interscapular region, shoulders, and arms (ie, cervicalgia) (92) and can be long-lasting (12) and worsening at the end of the third decade of life. Of the many cases of isolated Klippel-Feil syndrome and those associated with additional medical conditions (even several cases of situs inversus) (53; 14), no molecular or genetic culprit has been identified as an underlying mechanism.

Spine and central nervous system-related anomalies.

Cervical spinal anomalies. In Klippel-Feil syndrome, the clinical landmark of short neck on inspection is a consequence of a lack of spinal segmentation that appears as the fusion of two or more of the cervical spine segments and has a variable influence on the shape of the neck. The most common levels of congenitally fused segments were C2-3 (54.9%) and C5-6 (9.2%) (24). Butterfly vertebrae are observed, and the incidence reported is variable depending on the revised series of cases, ranging from only rarely (55) to present in up to 50% of the patients (139). The clinical triad of a short neck, decreased range of neck movements, and low posterior hairline is present in a variable range, depending on the series of cases, between 34% and 74% of patients (88; 108). Anomalies of the odontoid process and atlas have also been reported (03; 23; 148).

Thoracic, lumbar, and sacral anomalies. Kyphoscoliosis with deformations of the thoracic cage may cause pulmonary hypertension and respiratory failure (119). Spinal fusion out of the cervical spine is also considered part of Klippel-Feil syndrome. Congenital lumbar fusion of spinal segments has been described in a single patient with Klippel-Feil syndrome (70) and another patient with C2-T3 congenital fusion with spinal cord compression (133).

Spinal cord anomalies and cranial nerve involvement. The spinal cord has been reported to have a significantly reduced diameter in patients with Klippel-Feil syndrome (05), although this is not a constant finding among the vast series. Other neurologic impairments manifest in approximately one half of the patients and include synkinesis, facial nerve palsy, spasticity, lower extremity mirror movements, hemiplegia, paraplegia, triplegia, or quadriplegia (137). Synkinesis, also known as mirror movements, is the involuntary movement of homologous muscles during voluntary movements of contralateral body regions (also described in asymmetric Parkinson disease and corticobasal syndrome) (21). This phenomenology has been described in patients with Klippel-Feil syndrome and concomitant diastematomyelia (137). Transient quadriplegia with extreme or maximal range neck movements may be present in affected patients and mimic cervical cord neurapraxia (03) with concomitant craniovertebral junction anomaly. The cord may be altered by a neurenteric cyst (13; 115). Cerebral angiolipoma has been reported in a patient with Klippel-Feil syndrome, bifid thumb, and tracheoesophageal fistula (130). Arachnoid or dermoid cysts may also involve the fourth ventricle or cranio cervicothoracic spine (60; 105) and have also been described concomitantly with Klippel-Feil syndrome. In one case, the authors suggested that squamous cell carcinoma may have developed secondary to dedifferentiation of a dermoid cyst (89) and malignant teratoma (01).

Auditory and laryngeal apparatus anomalies. Hearing deficits and pinna malformations can occur in up to 60% of patients. Hearing abnormalities can be either conductive, sensorineural, or mixed and may be reported in nearly 50% of patients with a conductive hearing deficit when assessed in detail by an ENT physician (58). Affected individuals may have microtia; stenosis of the external ear canal; malformations of ossicles, tympanic cavity, or temporal bones; inner ear dysplasia; deformed internal acoustic canal; or wide vestibular aqueduct (144). A laryngeal malformation can produce voice impairment or aphonia related to the inflexibility of the laryngeal cartilages (58).

Optic or ocular apparatus anomaly. Eye anomalies such as strabismus, nystagmus, or chorioretinal atrophy occur in 20% of patients. Eyelid abnormalities have been recognized (22).

Sprengel anomaly or congenital elevation of the scapula. Sprengel anomaly or congenital elevation of the scapula may accompany Klippel-Feil syndrome. Unilateral, bilateral (present in up to 30% of individuals), or familial forms may be seen and do not appear to be related to the severity of cervical change. Signs and symptoms of associated conditions, such as Sprengel deformity, facial anomalies, and ocular pathology, are often noticed first and lead to the diagnosis of Klippel-Feil syndrome (107; 69). There is a report of one case of Sprengel anomaly and spinal cord tethering, which can be a significant risk during spinal anesthesia procedures (118). The association of Sprengel anomaly and Klippel Feil syndrome with an omovertebral bone (anomalous bony extension of the scapula) may result in cervical myelopathy, which has been reported in adult patients (107; 34; 78; 98; 95).

Other neural tube defects and musculoskeletal anomalies. Descriptive cases have included the presence of cervical or fused ribs, kyphosis, scoliosis, spina bifida occulta, and sacral agenesis. One patient with multiple neural tube defects, including sacral agenesis, lipomyelomeningocele, split cord malformation, and tethered cord, also had Klippel-Feil syndrome (112). There are reports of neuroschisis with Klippel-Feil syndrome, and authors insist on suspecting neuroschisis when Klippel-Feil syndrome is accompanied by syringomyelia (82; 134). Associated morphologic abnormalities may include frontonasal malformation, hydrocephalus, Chiari or Dandy-Walker malformation, cervical myelomeningocele, anterior or posterior meningocele, encephalocele, syringomyelia, diastematomyelia, intramedullary inflammatory mass, and posterior fossa dermoid cyst (03; 47; 93; 11). Cervical ribs causing thoracic outlet syndrome with the typical symptoms of numbness and pain in the arms can lead to findings of Klippel-Feil syndrome, and the neural compression can be relieved surgically (63; 90). Various upper limb defects or deficiencies involving the humerus, ulna, or radius are recognized (124). Radial aplasia has been reported as Fanconi anemia and Klippel-Feil syndrome (74) or sometimes involvement of the first metacarpal and thumb (84). Short stature can be concomitant for patients with Klippel-Feil syndrome in either syndromic (50) or nonsyndromic presentations. Familial osteopoikilosis, a rare and usually asymptomatic disorder of bone, has been reported in Klippel-Feil syndrome (126).

Vascular and cardiac anomalies. Anomalies of the carotid artery (including unilateral agenesis) or the subclavian artery and, for instance, the vertebral arteries, have been described. Subclavian artery anomalies play a crucial role and must be recognized with angiographic studies and considered when thoracic or cardiovascular surgery is contemplated, and alternative surgical planning may be needed (eg, harvesting free vascular grafts from patients with these anatomical variants) (97; 102; 09). Persistence of a trigeminal artery with Klippel-Feil syndrome has also been reported (91). Congenital heart disease (usually ventricular septal defect) is observed in as many as 10% to 14% of patients (70). Transposition of the great vessels and total anomalous pulmonary venous return have been reported (72; 71), and aortic coarctation has been reported in two adults (29; 33).

Urogenital anomalies. Reported conditions include cryptorchidism, hypospadias, absence of vagina or uterus, unicornuate uterus, absence of Fallopian tubes (MURCS), and azoospermia (129; 149). Unilateral renal agenesis is the most common renal anomaly (70), and fused crossed renal ectopia has been reported in one case with a combination of other anomalies, including craniofacial anomalies (83).

Miscellaneous. Intellectual disability occurs in approximately 10% of patients and has been reported in addition to more genetic syndromes and even oncological pathology in the same patient (35). Idiopathic growth hormone deficiency has been reported within the context of Klippel-Feil and Duane syndrome and is thought to represent a variant of Wildervanck syndrome (128). Unexpected associations have been reported, including a patient with Klippel-Feil anomaly, Tourette syndrome, stereotypies, obsessive-compulsive behavior, and chromosome 22q11.2 duplication (18); one patient with Pierre Robin sequence, mandibular duplication, and occipital clefts (140); and another with Down syndrome (31).

Prognosis and complications

Prognosis and complications depend on the severity and extent of anomalies, and classifying Klippel-Feil syndrome has been helpful. There are multiple classification systems proposed, starting with the original classification from Feil in 1919 (96) that had three different categories depending on the amount and extent of the fusion as well as the segments involved:

	• Subtype I: Extensive fusion of cervical and upper thoracic vertebrae
	• Subtype II: Fusion of cervical or thoracic vertebrae at one or two levels only
	• Subtype III: Any combination of cervical vertebral fusion PLUS lower thoracolumbar involvement

The most widely accepted classification dates from 2006 (110), and it is based only on the spinal fusion pattern:

	• Type I: Single congenitally fused cervical segment
	• Type II: Multiple, noncontiguous fused cervical segment
	• Type III: Multiple, contiguous fused cervical segments

Individuals with few or mild extra-axial anomalies may remain symptom-free during childhood and perhaps even for all of adulthood, but the average age of symptom onset is around 16 years (96). Their participation in sports or other physical exertion may be possible, but physical activity may exacerbate the condition or lead to neurologic deficits of concern, including cervical instability, cervical disc prolapse, Brown-Sequard syndrome (73; 109; 150), or spinal cord contusion with even minor trauma (28; 132; 02). Similarly, occipitocervical anomalies, degeneration of discs or joints, and scoliosis may develop over time (ie, in the second to third decade) and lead to neurologic complications, including para- or quadriparesis, a consequence of cervical compressive myelopathy due to the development of osteophyte formations near the adjacent segments. These formations grow in an attempt to fuse a hypermobile adjacent segment (143; 120).

The axis tends to be affected, being a transitional segment from a hypermobile segment like C1-C2 towards a relatively less mobile segment like C2-C3. In cases with fusion of C2-C3, there is an increased mechanical stress towards the adjacent vertebra, and a bigger leverage is applied to the fused spinal segment that will act as a fulcrum. Traumatic fractures may occur in fused cervical segments or the axis but are infrequent and treatable by surgical and nonsurgical means (41; 04; 103; 147).

Because many anomalies can co-exist with Klippel-Feil syndrome, there is a large potential for complications requiring intervention. Spinal fusion and arthrodesis may be required at any age, and the contribution of atlantoaxial hypermobility to the development of any morbidity and neurologic complications has been studied (116). The way that we assess cranio-vertebral hypermobility in patients with a non-Klippel-Feil syndrome cervical anatomy is different in terms of objective values, and patients with Klippel-Feil syndrome may need a different threshold to define hypermobility. Additionally, the presence of other spinal segmentation pathologies like C0-C1 occipitalization plays a role in the assessment of these patients. Such assessment details are beyond the purpose of this review, but it is important to be aware of these differences.

In cases of basilar invagination, a posterior occipitocervical fixation strategy can be pursued, but sometimes an anterior transoral approach is necessary, depending on the reducibility of the deformity with cervical traction. Both approaches have proven to be successful for the decompression and fixation of occipitocervical elements (152; 136), but the amount of decompression and fusion rates are better when anterior and posterior approaches are done on the same patient regardless of whether the surgery is related to a Klippel-Feil syndrome or not (152). When the anterior approach is necessary, complications are well known, including surgical site infection rates of nearly 3.5%, but strict consideration of surgical indications, adequate preoperative preparation, careful surgical techniques to avoid dural injury, and postoperative oropharyngeal care are important steps for preventing surgical site infection in surgeries that use a transoral approach (136).

Like in any spinal procedure that involves bone hardware and bone grafts with the intention of fusing any spinal segment, patients can have postoperative complications, including hardware failure, dislodgement, and pseudoarthrosis, and patients may develop chronic pain and myelopathy (94; 87). Rarer complications have been reported, including intradural disc herniation (85), postoperative dysphagia, and trismus requiring spinal revision surgery (80; 79); these complications seemed related to the particular spinal biomechanics of patients with Klippel-Feil syndrome. Anomalies in vertebral arteries must be recognized and understood before surgery due to a described association between these vascular anomalies and the concomitant risk of cerebrovascular complications in the Klippel-Feil syndrome population (26; 48). Case reports of vertebral artery dissection, pontine infarction, and rubro-thalamic stroke support the need to pay special attention to the vascular anatomy (45; 56; 26; 138). Additionally, atrial septal defects were prominent in one series, and almost half of the cases with this type of anomaly required corrective surgery (07).

Clinical vignette

This 9-month-old infant girl died of complications of prematurity and Klippel-Feil syndrome. She was born at 28 weeks' gestation (twin A), weighing 861 g. Subsequent examination revealed a short neck, cervical spine abnormalities (splaying of lateral elements), and 11 pairs of ribs. Other anomalies included micrognathia, highly arched palate, widely spaced nipples, single palmar creases and clinodactyly, bilateral hearing loss, cross-fused renal ectopia with vesicoureteral reflux, and three small muscular ventricular septal defects. External genitalia were normal, although the uterus was thought to be absent. Karyotype was 46,XX.

Klippel-Feil syndrome in an infant

Anteroposterior and lateral views of 9-month-old female, showing ocular hypertelorism and shortened neck.

The infant suffered respiratory distress syndrome, which required 5 weeks of mechanical ventilation; subsequently, she developed chronic lung disease complicated by a small thoracic cage and restrictive lung disease. At 4 weeks of age, bilateral subependymal hemorrhages were identified in the cerebrum (resolved by 9 weeks). At 5 weeks of age, she underwent aortopexy for tracheal compression by the innominate artery and had a patent ductus arteriosus ligated. Severe gastroesophageal reflux was treated with gastrostomy tube placement (age 4 months) and later was followed by a Roux-en-Y jejunostomy (age 6 months). Brainstem auditory evoked response showed an absence of all waveforms, including wave 1.

In the ensuing 3 months, the baby did fairly well. However, 1 day before death, she became lethargic, with fever, diarrhea, and leakage around the jejunostomy. She was admitted, rehydrated, given antibiotics, and discharged. She was found unresponsive the next day, and she was taken to hospital by ambulance. She suffered cardiopulmonary arrest but was resuscitated and transferred to a tertiary-level pediatric medical center. There, an abdominal ultrasound showed peritoneal fluid that grew Enterobacter, Klebsiella, Pseudomonas, Enterococcus, and Candida. Exploratory laparotomy revealed perforation of the bowel by the jejunostomy tube. This was repaired, but the infant remained unresponsive during the postoperative period and died a day later.

Autopsy revealed the anomalies described above, as well as pulmonary edema, acute peritonitis, acute tubular necrosis, and widespread ischemic encephalopathy. The thymus showed acute involutional changes, mesenteric lymph nodes were enlarged, and the trachea remained indented. A single muscular ventricular septal defect was identified, and the uterus and other internal genitalia were normal.

Biological basis

Etiology and pathogenesis

Klippel-Feil syndrome is a heterogeneous entity, and the scarcity of cases has created a challenge in trying to elucidate the cause of the condition. The pathophysiology is thought to be due to failed segmentation of the cervical spine during embryological development (127), so the genes involved in spinal segmentation and somitomere formation have been the focus of research.

Each of the subtypes from Feil’s classification was later found to have genetic correlation and inheritance patterns (38; 96) thus:

	• Subtype I: Sporadic (43).
	• Subtype II: Autosomal dominant inheritance.
	• Subtype III: Autosomal recessive inheritance.

Sporadic cases, as well as familial cases with a Mendelian inheritance, have been reported. Two genes, GDF3 and GDF6, have been associated with dominant forms (121; 141). Mutations with an autosomal recessive pattern in the MEOX1 gene (a mesenchyme homeobox gene) have been identified in one consanguineous family (06; 81). Two additional genes, RIPPLY2 and MIYO18B, have also been associated with recessive disease (54). Later, another study in China tried to find if these previously described genes were found in their patient population; interestingly, with whole-exome sequencing methods, they identified a new set of genes, including BAZ1B, as having the highest probability of association with Klippel-Feil syndrome, followed by FREM2, SUFU, VANGL1, and KMT2D (68). The identification of these novel genes has raised the potential for oligogenic inheritance. The GDF3 and GDF6 genes are essential for bone and joint growth and development. MEOX1 plays an important role in somitogenesis. MYO18B is a class-XVIII myosin, primarily expressed in human cardiac and skeletal muscle, and it plays important roles in diverse human syndromes and cellular processes. RIPPLY2 has a well-established role in somitogenesis and vertebral column formation (76; 68; 52). Mutations in PAX 1, a highly conserved family of developmental control genes that encode transcription factors, have been found in mice with vertebral segmentation defects as well as a significant subset of patients (8 of 63) with Klippel-Feil syndrome (74). A father and two daughters have been diagnosed with both Klippel-Feil and Treacher-Collins syndromes, verified by the presence of classic phenotypes and the identification of mutations in POLR1D, which is found in about 5% of patients with Treacher-Collins syndrome (36).

The 14th day after conception, the gastrulation process generates the mesenchymal cells that will form the head and cardiac segments and the paraxial and lateral mesoderm (Sadler 1985). Normal segmentation of the vertebral column occurs between the fourth and eighth weeks of embryonic life. Mesenchymal cells appear in the fourth week and migrate, surrounding the notochord. The ability to form segmental units appears to be a property specific to the paraxial mesoderm (as opposed to lateral or limb mesoderm), and this ability is probably acquired during early development when paraxial mesoderm is specified and emerges from the primitive streak (39). It is presumably during the fourth to eighth weeks of embryogenesis that the segmentation defect responsible for Klippel-Feil syndrome takes place; mechanisms responsible for axial defects remain unclear and do not account for extra-axial anomalies (114), but is known that fibroblast growth factor-8 has been implicated as a main driver in vertebrate segmentation; one pivotal process that FGF signaling controls is the division of vertebrate paraxial mesoderm into repeated segmented units called somites. Somite segmentation occurs periodically and sequentially in a head-to-tail manner and lays down the plan for the compartmentalized development of the vertebrate body axis (15). The Sprengel and Klippel-Feil anomalies have been associated with a unique point mutation (Pro250Arg) in fibroblast growth factor receptor 3 in some, but not all, cases (88).

The first report of an abnormal karyotype dates from 1995, when a paracentric inversion in 8q was reported: inv(8) (q22.2q23.3) (20) produced a vertebral fusion confined to the cervical spine and was present in association with malformation of laryngeal cartilages and mild-to-severe vocal impairment. Reciprocal translocations were also reported (40).

Other than a genetic cause, it has been hypothesized that a vascular disruption involving the subclavian artery is a possible cause of Klippel-Feil syndrome (10; 51). Supporting this theory is the persistence of embryologic vessels such as the trigeminal artery, an intersegmental vessel communicating with carotid and vertebral-basilar circuits (91). Still, it is important to mention that case reports of Klippel-Feil syndrome and vascular abnormalities have been found in patients with a myriad of different congenital defects, not only Klippel-Feil syndrome.

A teratogenic basis has been postulated. There are reports of patients exposed to cyclophosphamide in the first trimester (65; 101), but it is now better recognized that brevicollis or short neck expressed as Klippel-Feil syndrome is part of the cyclophosphamide embryopathy. Maternal medical comorbidities, including alcoholism, diabetes, hypoxia, and anticonvulsant therapy, have been implicated as well (113; 37).

Differential diagnosis

Associated or underlying disorders

The differential diagnosis is:

	• Healing osteomyelitis or discitis
	• Previous fusion without instrumentation
	• Juvenile idiopathic arthritis
	• Juvenile rheumatoid arthritis
	• Ankylosing spondylitis
	• Fibrodysplasia ossificans progressiva
	• Goldenhar syndrome
	• NOG-related syndromes: These include proximal symphalangism; multiple synostoses syndrome 1; stapes ankylosis with broad thumbs and toes; tarsal-carpal coalition syndrome; and brachydactyly type B2.
(99; 52; 77)

Gorlin and colleagues and Scott and colleagues provided thorough lists of diagnoses that must be differentiated from Klippel-Feil syndrome (38; 114). These are summarized in Table 1.

Table 1. Differential Diagnosis in Klippel-Feil Syndrome

Affected region or system	Alternate diagnosis
Head-on-neck appearance	Morquio syndrome; tuberculosis of cervical spine
Prominent trapezius	Turner syndrome; Noonan syndrome
Fusion of basal vertebrae	spondylothoracic dysplasia (Jarcho-Levin syndrome); nevoid cell carcinoma syndrome; fetal alcohol syndrome; Crouzon, Apert, or Binder syndromes
Other vertebral anomalies (eg, hemivertebrae; butterfly vertebrae; scoliosis)	spondylothoracic dysplasia (Jarcho-Levin syndrome); spondylocostal dysplasia (rib anomalies); oculo-auriculo-vertebral syndrome
Face	Goldenhar (facio-auriculo-vertebral) syndrome or hemifacial microsomia (cervical vertebral anomalies common; asymmetric facial anomalies; CNS involvement; cleft lip/palate; features of VATER association); abnormalities of eyelids
Ear	Wildervanck (cervico-auriculo-vertebral) syndrome (conduction deafness; Duane syndrome, abducens palsy with retraction of bulb on lateral gaze; epibulbar dermoid in some patients); preauricular skin tags
Müllerian anomalies	MURCS association (Müllerian duct aplasia, renal aplasia, cervicothoracic somite dysplasia)
Reticulo-endothelial system	Blackfan-Diamond syndrome (congenital erythroid hypoplastic anemia with webbed neck, cleft palate, abnormal thumbs, and other bony anomalies)

Management

Multidisciplinary teams are involved in treating these patients, and surgical teams should assess if intervention is necessary, depending on the severity of anomalies, onset of symptoms, and type of osseous or ligamentous lesion. In general terms, we can divide the treatment options into nonoperative and operative when addressing the spinal condition.

Nonoperative management. Nonoperative management is a reasonable option for asymptomatic patients. The treatment is conservative and directed to address symptoms. Most of the patients in this category are those who were diagnosed incidentally or those with non-disabling symptoms like mechanical mild neck pain or radicular symptoms. Physical therapy and activity modifications are the mainstay. Additionally, pain control with pharmacological options or neck injections can be offered (127; 52).

Operative management. Kyphosis and scoliosis require surgical treatment when there is severe deformity or compression of neural elements or affection to the breathing mechanics. Nonoperative alternatives can be tried, within their limitations, following the general principles of scoliosis management (151). Radiographic monitoring is necessary, as the anomalies from Klippel-Feil syndrome lead to progressive involvement or deterioration of vertebrae. Sometimes, the fused cervical segment is not directly responsible, and attention must be paid to other potential culprits. When cranio-cervical junction anomalies are the focus of treatment, preoperative skull traction is a critical step in assessing whether the craniocervical deformity is reducible or not. When the deformity can be reduced, a pure posterior decompression with fusion will usually give better results and fewer morbidities than anterior transoral approaches that are necessary when the patient’s deformity cannot be reduced with traction (135). Skull traction by itself may help align cervical vertebrae and diminish or eliminate associated spasticity (25). For traumatic lesions, the spectrum of treatment options ranges from a halo vest for axis fracture treatment (103) to anterior or posterior arthrodesis and fusion procedures as needed for subaxial fractures.

For nontraumatic lesions of the subaxial cervical spine, any of the usual surgical options are reasonable and are selected case by case. Anterior cervical discectomy with fusion ACDF or artificial cervical disc arthroplasty has been performed with good results (67; 146). Patients with kyphosis and scoliosis require surgical treatment when there is either severe deformity, compression of neural elements, or affection to the breathing mechanics. Nonoperative alternatives can be tried, with their own limitations, following the general principles of scoliosis management (151). Electrophysiological monitoring (neuromonitoring) in the form of transcranial motor-evoked or somatosensory-evoked potential may be efficacious during surgery to prevent additional transoperative neurologic complications (61; 123), especially for patients who will undergo correction of deformities and procedures under cervical traction. Computer-assisted navigation to insert spinal hardware has become extensively used without increasing surgical times but improving precision and accuracy (particularly when pedicle cervical screws are necessary) and decreasing the chances of neurovascular injury (142).

Treatment outside the spine. Any additional complication in a patient with Klippel-Feil syndrome may need assessment. For example, for those with hearing impairment, otolaryngological evaluation and treatment options such as cochlear implants or other hearing devices may be necessary (77; 100); plastic surgery might needed to treat nuchal webbing (46). A patient with a teratoma involving the cranial base has been successfully resected endoscopically (27). A case of complete heart block in a 36-year-old man with Klippel-Feil syndrome has been reported (142); the patient required the usual treatment with a pacemaker, as might any other patient with a heart block.

Special considerations

Sports

Although cervical immobility or restriction of movement may preclude certain physical activities, no contraindication exists when Klippel-Feil syndrome is found at or below the level of C3, presuming there is no adjacent-level instability or significant stenosis. Absolute contraindications exist when multilevel Klippel-Feil syndrome is found or the syndrome involves the levels of C0, C1, or C2 in any manner (131; 59; 145).

Pregnancy

Elective cesarean section has been successful in cases complicated by cervical, thoracic, and lumbar instability and distortion. Urgent cesarean section has also been performed using a combination of spinal and local anesthesia (57; 111). Genital anomalies may complicate or preclude reproduction. Because of the heritable nature of the condition, affected women may give birth to affected offspring.

Anesthesia

Airway management during cesarean section can be challenging (117; 17), so fiberoptic intubation is the recommended technique for avoiding excessive mobilization or hyperextension of the neck (66; 08).

Positioning or moving the patient in preparation for or during surgical procedures is not trivial for any neurosurgical procedure, and spine procedures are not an exception. One report warns about the care necessary to prevent cardiovascular complications from sternal compression while the patient is under prone positioning (122) or massive macroglossia following surgery performed in a sitting position (64). Possible mechanisms for this complication include prolonged cervical flexion intraoperatively, oropharyngeal shrinkage secondary to surgery-induced craniocervical changes, or obstruction to lymphatic or venous drainage of the tongue, possibly with thrombosis. The severity of cervical anomalies and mobility and the consequences of intubation and the use of muscle relaxants must be considered by the anesthesiologist. The presence of atlantoaxial instability and other anomalies like craniovertebral malformations increases the challenges of anesthesia and requires a multidisciplinary approach (49).

References

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Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Authors

Aparna M Prabhu MD MRCP

Dr. Prabhu of Thomas Jefferson University and Jefferson Einstein Medical Center has no relevant financial relationships to disclose.
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Juan P Solano Romero MD

Dr. Solano Romero of Einstein Healthcare Network and Thomas Jefferson University Hospitals has no relevant financial relationships to disclose.
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Editor

Ganeshwaran H Mochida MD

Dr. Mochida of Boston Children's Hospital and Harvard Medical School has no relevant financial relationships to disclose.
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Former Authors

Joseph R Siebert PhD

Patient Profile

Age range of presentation: 0 month to 44 years
Sex preponderance: female>male, >1:1
Heredity: heredity may be a factor

autosomal dominant

autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Klippel-Feil syndrome: Q76.1
ICD-11: Klippel-Feil anomaly: LB73.20
OMIM: Klippel-Feil deformity, conductive deafness, and absent vagina: 601076

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Klippel-Feil syndrome

Differential Diagnosis

Morquio syndrome
tuberculosis of cervical spine
Turner syndrome
Noonan syndrome
spondylothoracic dysplasia (Jarcho-Levin syndrome)
- nevoid cell carcinoma syndrome
- fetal alcohol syndrome
- Crouzon syndrome
- Apert syndrome
- Binder syndrome
- spondylocostal dysplasia (rib anomalies)
- oculo-auriculo-vertebral syndrome
- Goldenhar (facio-auriculo-vertebral) syndrome
- hemifacial microsomia (cervical vertebral anomalies common)
- asymmetric facial anomalies
- CNS involvement
- cleft lip/palate
- features of VATER association
- abnormalities of eyelids
- Wildervanck (cervico-auriculo-vertebral) syndrome
- conduction deafness
- Duane syndrome
- Abducens palsy with retraction of bulb on lateral gaze
- epibulbar dermoid
- preauricular skin tags
- MURCS association
- Müllerian duct aplasia
- renal aplasia
- cervicothoracic somite dysplasia
- osteopoikilosis
- Blackfan-Diamond syndrome

Also Relevant

Alien hand syndrome
Basilar impression
Chiari malformation
Dermoid and epidermoid tumors
Sacral agenesis
- Tethered spinal cord
- Thoracic outlet syndromes

Klippel-Feil syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Symptoms

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Associated or underlying disorders

Table 1. Differential Diagnosis in Klippel-Feil Syndrome

Diagnostic workup

Management

Special considerations

Sports

Pregnancy

Anesthesia

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

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Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

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