Klippel Feil Syndrome

Clinical History:
A 60 year-old woman presented to her physician complaining of upper and lower extremity pain. A (1a) T2-weighted sagittal MR image and (1b) sagittal and (1c) coronal cervical spine CT images are provided. What are the findings? What is your diagnosis?

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Figure 1

Findings:

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Figure 2:

(2a) Congenital fusion of the occiput and C1 is present (long arrows), known as atlantooccipital assimilation. The tip of the dens violates Chamberlain’s line (green dotted line), indicative of basilar invagination, resulting in brainstem compression (short arrow). Associated Chiari 1 malformation is also evident (arrowhead).
(2b) Atlantooccipital assimilation (longs arrows) and basilar invagination (arrowhead) are depicted well on CT. Chamberlain’s line is shown in green.
(2c) Atlantooccipital assimilation involving the lateral masses of C1 and the occipital condyles is apparent (long arrows).

Diagnosis

Klippel Feil Syndrome Type 2, manifested by atlantooccipital assimilation. Associated anomalies include basilar invagination, which results in brainstem compression, and Chiari 1 malformation.

Introduction

Klippel Feil Syndrome (KFS) is a congenital malformation defined by segmentation failure at one or multiple levels of the cervical spine, with or without thoracic and lumbar segmentation anomalies. It is a term applied to many types of congenital fusion anomalies of the cervical spine regardless of extent.¹  The original syndrome described by Klippel and Feil in 1912 consisted of a clinical triad of a short neck, low posterior hairline and restricted cervical motion (Fig. 3). The most commonly involved level is C2-3, followed by C5-6 and the craniovertebral junction. While KFS may be detected on imaging as an incidental finding in patients with unrelated complaints, patients come to clinical and imaging attention because of associated spinal, neural and visceral anomalies, scapular and other deformities, cosmetic complaints, or complications from spinal anomalies, including accelerated degenerative changes adjacent to the level of fusion, which may result in spinal cord compression. Cardiac and genitourinary anomalies may occur and account for much of the morbidity and nearly all of the mortality related to KFS.²

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Figure 3:

Illustration depicting the short neck and low posterior hairline of KFS described as part of the classic clinical triad by Klippel and Feil. These findings and restricted neck motion occur in 33-50% of persons with KFS. Used with permission of Brittanie Marie Marques, OpenPediatrics.org.

Pathogenesis

KFS occurs as the result of a sporadic mutation or as an inherited disorder, with variable expression. Presumed causative factors include teratogens and maternal alcoholism. SGMI is the first KFS gene identified, found on chromosome 8.

The embryonic insult is thought to occur between the 3rd and 8^th gestational weeks and results in a defect of vertebral segmentation.² The vertebrae form by a sequential process consisting of membranous development, chondrification and ossification. The membranous stage of development begins by Day 17 of gestation. Mesodermal cells form a thick mass of paraxial mesenchyme located lateral to the notochord and ventrolateral to the neural plate. The paraxial mesoderm forms bilaterally symmetrical longitudinal columns of solid mesoderm that begin to segment into 42-44 paired blocks called somites by Day 20. The first occipital and the last 5-7 coccygeal pairs later disappear. The ventromedial portion of each somite differentiates into a sclerotome that will form the cartilage, bone and ligament of the vertebral column during the fourth week of development. The dorsolateral portion of each somite differentiates into a dermatomyotome, which forms the skeletal muscle and dermis. Cells from the sclerotomes of the somites migrate to surround the notochord and neural tube to form the membranous anlagen of the vertebrae. Resegmentation of the somites occurs at Day 24.³ In this process, the vertebral body forms from the caudal section of a rostral somite and the cranial section of the corresponding caudal somite. KFS occurs as a result of faulty segmentation of somites. The combined vertebrae may be of normal, decreased or increased height.² The disc space is usually rudimentary or absent.

KFS is classified into three subtypes based on the level and extent of vertebral fusion.

Type 1 is defined by extensive fusion of most of the cervical and upper thoracic spine (three or more levels) ⁴

(Fig. 4). Severe neurologic impairment and associated anomalies are most common in this group. An autosomal recessive pattern of inheritance has been found in Type 1.⁵

Type 2 is characterized by fusions at one or two levels and may include atlantooccipital fusion. Type 2 is the most common of the types.² (Figs. 1 and 2) Fusions at C2-3 show autosomal dominant and fusions at C5-6 autosomal recessive inheritance. In 75% of cases, fusions occur from C3 cephalad. Isolated one level involvement accounts for about 20% of KFS cases.⁶

Type 3 is comprised of type 1 or 2 with coexistent lower thoracic or lumbar fusion. An autosomal recessive pattern of inheritance has been described for this type.³(Fig. 5)

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Figure 4:

Klippel Feil Spectrum Type 1 in a 44 year-old man.
(4a) Sagittal CT reconstruction image demonstrates multilevel fusions, including atlantooccipital assimilation (short arrow), fusions of C4 through C6 and C7-T1. Associated basilar invagination is present (long arrow). Anterolisthesis at C2-3 results in central canal stenosis. Mild anterolisthesis is also noted at C6-7, adjacent to the fused levels.
(4b) Coronal CT reconstruction image additionally demonstrates lower cervical scoliosis (dotted lines).
(4c) Axial CT image depicts anomalies of the neural arch, including spina bifida (arrows).
(4d) Axial CT image at the cervicothoracic junction shows portions of omovertebral bones posteriorly (arrows).

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Figure 5:

Klippel Feil Spectrum Type 3 in a 54 year-old woman presenting with neck pain, upper extremity paresthesias and low back pain.
Sagittal T2-weighted MR images of the cervical spine (a-c) and lumbar spine (d-f)
(5a) Midline sagittal image reveals a segmentation anomaly at C2-3 with rudimentary disk (arrow). Note the disc protrusion at C3-4 (short arrow), adjacent to the level of the segmentation anomaly, a complication of KFS. Unrelated disc extrusion at C5-6 and protrusion at C6-7 (arrowheads) are also noted.
(5b) Image through the right lateral masses reveals fusion of the right lateral masses of C2 and C3 (arrow).
(5c) Image through the left lateral masses reveals fusion of the left lateral masses of C2 and C3 (arrow).
(5d) Image slightly to the left of midline fails to show T12. Note advanced disc degeneration at T11-L1 and L1-2, and retrolisthesis at L1-2, resulting in narrowing of the spinal canal.
(5e and f) Images to the right (e) and far right (f) of midline now reveal T12, a right lateral hemivertebra, which is fused with L1.

Epidemiology

The reported frequency of KFS is variable, from between 1/233 to 1/42,000 births and found in 0.5% of spinal radiographs.^1,3 Occurrence in females is greater than males.^2,5

Clinical Presentation

Patients with mild cases of KFS are often asymptomatic. The classic clinical triad described by Klippel and Feil is present in 33-50% of patients. Limitation of neck motion is the most common clinical finding. Cosmetic problems include webbed neck and external ear anomalies. Sensorineural hearing loss may occur. Neurologic problems in infancy and childhood are usually due to craniovertebral junction abnormalities. Neurologic symptoms developing later in life are due to development of degenerative disc disease, instability and spinal stenosis at adjacent segments.² Patients may present with neck or radicular pain, slowly progressive or acute myelopathy, ataxia, hyperreflexia, and upper and lower motor neuron dysfunction.⁴ Mirror movements may occur in patients with KFS who have associated cervicomedullary neuroschisis. This phenomenon is characterized by voluntary movements in one extremity mimicked by involuntary movements in the other with a central plane of symmetry.⁷ Brainstem compression from basilar invagination may result in obstructive hydrocephalus, autonomic dysfunction, with labile blood pressure, arrhythmias, respiratory depression and sudden death, and vascular compromise, with resultant neurologic deficits, vertebrobasilar insufficiency or transient ischemic attacks.⁸

Imaging

Imaging establishes the diagnosis of KFS and its associated complications and anomalies.

Cervical vertebral fusion: The cervical vertebral fusion of KFS may be partial or complete and involve the vertebral bodies, pedicles, laminae and/or spinous processes.¹ A rudimentary intervertebral disc may or may not be apparent. The anteroposterior diameter of the vertebral bodies at the level of the fusion may be narrower than at the superior and inferior margins adjacent to the normal discs, resulting in a trapezoidal shape of the vertebral bodies, anterior vertebral concavity and the “wasp waist” sign (Figs. 6, 11a). The combination of impaired vertebral growth at the level of the fusion and continued growth at the unaffected portions of the vertebral bodies creates this characteristic appearance.  When segmentation failure occurs between the skull base and the atlas, it is referred to as atlantooccipital assimilation or C1 assimilation (Figs. 1, 2).

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Figure 6:

80 year-old woman with neck pain radiating to left shoulder. Klippel Feil Syndrome demonstrating the “wasp waist” sign.

Complications of vertebral fusion: The fused segments of the spine result in altered mechanical force transfer to and excessive mobility and overloading of the adjacent unfused segments (Fig. 7a-c), which undergo accelerated degenerative disc disease (Fig. 8). Hypermobility and disc bulges or herniations predispose to cord or vertebral artery injuries following even relatively minor trauma, especially with a narrowed spinal canal.^4,9 Acquired spinal stenosis may result from disc bulges and herniations, osteophytes and ligamentum flavum buckling at the adjacent levels (Fig. 8). Odontoid fracture has been associated with atlantooccipital or upper cervical fusion.¹⁰ Limited upper cervical flexion and extension caused by fusion of the upper cervical spine allows extension forces to exert increased strain on the atlantooccipital stabilizing ligaments, placing the odontoid process at increased risk for fracture.

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Figure 7:

28 year-old woman with KFS complaining of neck pain and stiffness and left upper extremity tingling. Flexion, extension and neutral lateral views of the cervical spine (a-c). T2-weighted coronal image through the cervical and upper thoracic spine (d) and axial image at the T2 level (e).
(7a) The C2 and C3 vertebrae are fused (arrowheads). Note mild anterolisthesis at the adjacent C3-4 level in flexion (arrow).
(7b) Retrolisthesis is present on extension at C3-4 (arrow). The increased mobility of the spine between flexion and extension is indicative of instability.
(7c) The cervical spine has a kyphotic deformity in neutral position.
(7d) Note the sagittal cleft (arrow) within the T2 vertebral body forming a butterfly vertebra. The left component is fused to the T1 vertebral body (asterisk). Associated dextroscoliosis is present.
(7e) The butterfly vertebra is manifested by a sagittal cleft on the axial image (arrow).

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Figure 8:

67 year-old woman with KFS presenting with neck pain and hand numbness. Sagittal T2-weighted image reveals fusion of the C2 and C3 vertebrae (arrowheads), which is associated with advanced degenerative disc disease and accompanying osteophytes at the adjacent level, C3-4. The osteophytes result in severe central canal stenosis and cord compression (arrow). Note also atlantooccipital assimilation (short arrows) and basilar invagination associated with narrowing of the foramen magnum and mass effect on the cervicomedullary junction (asterisk).

Associated anomalies: Myriad anomalies may occur in association with KFS. Early diagnosis of KFS is important because of the high incidence of associated disorders. 3D CT is useful in delineating the skeletal abnormalities associated with KFS. MRI detects anomalies of the cord and brain, and compression and injury of the brainstem or cord.

Spine, rib and shoulder anomalies: KFS may be associated with failure of vertebral formation, resulting in hemivertebrae and cleft vertebrae.² The chondral stage of vertebral development begins after the membranous stage. The newly formed primitive membranous vertebrae chondrify at this time. Paired paramedian foci of chondrification develop to the right and left of the midline within the primitive vertebral body.³ In contrast, during the later ossification stage, each vertebral body has two ossification centers, one ventral and the other dorsal. The lateral hemivertebra results from failure of one chondral center (Fig. 9). The posterior hemivertebra results from failure during the ossification stage. The sagittal cleft (“butterfly”) vertebra occurs when separate ossification centers form in each of the chondrification centers but fail to unite (Fig 7 d, e). A coronal cleft vertebra results from formation and persistence of separate ventral and dorsal ossification centers. Scoliosis with or without kyphosis occurs in 60% (Figs. 4b, 7c and d, 9, 10). Rib anomalies are present in 10-15% and include fused, absent or deformed ribs.¹(Fig. 10 b,c; 11 b,c)

Sprengel’s deformity is characterized by congenital elevation of the scapula (Figs. 12, 13), with or without an omovertebral bone (Figs. 4d, 13b), and occurs in 15 to 30% of patients with KFS. The scapula develops from the paraxial mesoderm and is therefore closely associated with the development of the cervical spine.⁵ Failure of caudal descent of the scapula results in the Sprengel’s deformity. It is associated with restricted motion of the scapula and glenohumeral joint.  The omovertebral bone connects the scapula and vertebrae and may be ossified or composed of cartilaginous or fibrous tissue. ¹

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Figure 9:

15 year-old boy with KFS and congenital scoliosis. Coronal T2-weighted image at the cervicothoracic junction reveals C7 right lateral hemivertebra and left interbody fusion of C6 and T1 resulting in dextroscoliosis.

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Figure 10:

53 year-old woman with scoliosis and chronic neck, right shoulder and arm pain. KFS associated with rib anomalies.
(10a) Sagittal T2-weighted image revealing interbody fusions at C2-3 and C7-T1, basilar invagination and kyphosis. Basilar invagination in KFS is usually associated with atlantooccipital fusion, which was absent in this patient. Advanced degenerative disc disease is also present at C4-5 through C6-7.
(10b) Coronal T2-weighted image showing absence of ribs at T1 and levoscoliosis.
(10c) Axial T1-weighted image demonstrating absence of T1 ribs.

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Figure 11:

55 year-old woman with KFS presenting with neck pain and bilateral arm numbness, low back and left leg pain and bilateral lower extremity paresthesias.
(11a) Sagittal T2-weighted MR image through the cervical and upper thoracic spine. Note the C6 through T1 vertebral body fusions and fusions of the lateral masses of C2 and C3, and C4 and C5 (arrows). A small C7 vertebral body forming a “wasp waist” sign results from growth disturbance created by the fusions.
(11b) Far right sagittal T2-weighted image shows fusion of the right first and second ribs (arrow).
(11c) Axial T2-weighted image at T1. Note the fusion of the right first and second ribs (arrow).
(11d) Sagittal T2-weighted image through the lumbar spine. Note the partial absence of the sacrum (arrow).

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Figure 12:

Sprengel’s deformity. (Photographs used by permission of Charles Goldfarb, M.D., Washington University School of Medicine, Department of orthopaedic Surgery, Congenital Hand and Arm Differences Blog.)
(Left) Left scapular Sprengel’s deformity in a young boy. Note the elevated, rotated left scapula.
(Right) The Sprengel’s deformity limits motion of the scapula and shoulder joint.

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Figure 13:

39 year-old woman with chronic neck pain and KFS associated with a left Sprengel’s deformity.
(13a) Frontal radiograph of the chest shows elevation and rotation of the left scapula (asterisk).
(13b) Axial T1-weighted image in the same patient at the T1 level demonstrating an omovertebral bone (arrow) fused to the left scapula (short arrow).
(13c) Sagittal T2-weighted image showing multilevel vertebral body fusions, sparing C3-4 (arrow).
(13d) Sagittal T2-weighted image revealing fusions of the T2, T3 and T4 vertebral bodies.

Craniovertebral junction abnormalities

Basilar Invagination:  Atlantooccipital assimilation invariably results in basilar invagination (Figs. 1, 2, 4a, 10a, 17b). Basilar invagination is a primary developmental anomaly characterized by an abnormally high position of the spine which protrudes into the skull base.¹¹ Detection of basilar invagination is important because of potential cervicomedullary compression. The skull moves caudally and anteriorly with respect to the odontoid, forcing the cervicomedullary junction against the odontoid.¹²

The relationship between the tip of the dens and McRae’s, Chamberlain’s or McGregor’s lines are used to determine basilar invagination (Figure 14). The tip of basion and the tip of the opisthion define the endpoints of McRae’s line. The dens should lie below this line.^8,13 McRae’s line is useful because it is easy to remember, does not differ between radiographs and CT and does not require localization of the hard palate, which is sometimes not included in the field of view of cross sectional studies of the cervical spine.  Anomalies of the basion preclude this method, however, and Chamberlain’s and McGregor’s lines are used instead. Normal CT values of Chamberlain’s and McGregor’s lines differ slightly from radiographic values. Chamberlain’s line extends from the posterior pole of the hard palate to the tip of the opisthion. Projection of the dens greater than 6 mm above Chamberlain’s line on CT is indicative of basilar invagination. McGregor’s line is a modification of Chamberlain’s line, extending from the posterior hard palate to the lowest point on the midline occipital curve. Protrusion of the dens greater than 7 mm above this line on CT is abnormal.⁸

Atlantoaxial subluxation: Atlantoaxial subluxation is a potential complication caused by atlantooccipital assimilation in association with fusion of C2 and C3. In this situation, gradual loosening of the atlantodental joint resulting in atlantoaxial subluxation occurs in 50% of cases.¹¹ (Fig. 15)

Platybasia: Platybasia is a term applied to flattening of the skull base, resulting in an increase in the Welcher basal angle. This angle is formed by the intersection of a line from the nasion to the tuberculum sella and a line from the tuberculum to basion. Welcher’s basal angle is abnormal if greater than 140 degrees.¹¹

Odontoid anomalies: Anomalies of the odontoid occur in less than 5% of patients with KFS.³ (Figs. 6, 16)

Neural and facial abnormalities: Potential associated neural disorders and anomalies are syringomyelia (Fig. 17), spinal dysraphisms, including diastematomyelia in 20%, neuroschisis, meningocele, meningomyelocele, spina bifida in 45% (Fig 4c), occipital cephalocele, and Chiari 1 malformation, present in 8%.^2,3,14

(Figs 1, 2). Associated neurenteric cysts or dermoids are rare. Facial anomalies, including cleft palate, occur in 10-13%.¹⁵

Visceral anomalies: Genitourinary tract anomalies occur in 35%, with unilateral renal agenesis most common. Cardiovascular anomalies occur in 14%, with ventricular septal defect most common.¹⁵

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Figure 14:

Chamberlain’s (green) and McRae’s lines (yellow). Chamberlain’s line extends from the posterior hard palate to the tip of the opisthion. The tip of the dens should not project more than 6 mm above Chamberlain’s line. The endpoints of McRae’s line are the tip of the basion and the tip of the opisthion. The tip of the dens should lie below this line.

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Figure 15:

31 year-old woman presenting with left upper extremity paresthesias. MR imaging showed KFS complicated by atlantoaxial subluxation.

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Figure 16:

49 year-old man with neck pain radiating to right hand. KFS manifested by fusion of C2 and C3. Note the associated persistent C2 synchondrosis (arrow).

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Figure 17:

31 year-old man complaining of left shoulder pain and arm and hand numbness, due to a disc protrusion at C6-7, not shown. KFS was also detected, with an associated cord syrinx.
(17a) T2-weighted sagittal image revealing partial atlantooccipital assimilation (arrows).
(17b) T2-weighted sagittal image shows basilar invagination (short arrow) and syringomyelia (long arrow). Chamberlain’s line is depicted (dotted red line).

Treatment

In order to prevent spinal injuries, persons with congenital or operative cervical fusion should avoid contact sports and occupations and recreational activities associated with increased risk of head or neck trauma.^2,9 Spinal decompression and fusion are indicated for patients with neurological lesions, significant pain despite conservative therapy or progressive instability. Treatment for basilar invagination is craniocervical fusion; odontoid resection may be required for significant brainstem compromise. ¹⁶

Differential Diagnosis

Spinal fusion: Congenital fusion of the spine needs to be distinguished from acquired causes of fusion, including surgery, ankylosing spondylitis, discitis and juvenile idiopathic arthritis. ² Fusion caused by surgery, ankylosing spondylitis and discitis does not show the narrowing or “waist” at the disc space seen in congenital fusion (Fig. 18). In operative ankylosis, the facets are infrequently involved. The vertebral body fusion in ankylosing spondylitis is characterized by thin, contiguous syndesmophytes (Fig. 19), lack of rudimentary discs and is associated with symmetric sacroilliitis and HLA-B27 positivity. Discitis-related ankylosis shows irregular endplates and may be associated with kyphosis. History of prior spinal infection is confirmatory. Juvenile idiopathic arthritis (JIA) may lead to fused vertebrae. If fusion occurs early in childhood, the vertebrae are narrow in anteroposterior dimension, similar to KFS. Involvement of other joints and clinical history allow differentiation of JIA from KFS.

Basilar invagination: In addition to the C1 assimilation of KFS, basilar invagination may be caused by the reduced height of the occiput caused by congenital anomalies of the occiput. There is confusion surrounding the terms “basilar invagination”, “basilar impression”, and “cranial settling.” Basilar impression is the secondary, or acquired form of basilar invagination caused by softening of the skull base from Paget disease, osteomalacia, hyperparathyroidism, osteogenesis imperfecta, Hurler syndrome, rickets or skull base infection.¹¹ Cranial settling refers to descent of the cranium on the spine caused by destructive changes of the craniovertebral joint due to rheumatoid arthritis (Fig. 19 from MR Imaging of Rheumatoid Arthritis, MRI Web Clinic, June 2016). Like basilar invagination and basilar impression, cranial settling results in protrusion of the odontoid into the foramen magnum. If rheumatoid arthritis causes erosion of the odontoid tip, the Redlund-Johnell and modified Ranawat methods are used as alternatives to Chamberlain’s, McGregor’s and McRae’s lines.⁸

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Figure 18:

54 year-old woman who underwent multilevel cervical fusion. Note the lack of vertebral body narrowing in the anteroposterior plane at the level of fusion at C5-6 and C6-7, in contrast to the “wasp waist” sign of congenital fusions of KFS.

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Figure 19:

72 year-old man with chronic ankylosing spondylitis and severe neck pain. Note multilevel vertebral body fusion by thin, bridging anterior and posterior syndesmophytes (arrows).

Conclusion

Klippel Feil Syndrome (KFS) is a complex disorder that is quite variable in its manifestations, ranging from fusion of one level of the cervical spine detected incidentally on imaging studies to extensive fusion of most of the cervical and upper thoracic spine in patients who are symptomatic. Regardless of its extent, KFS is an important malformation to recognize for several reasons. First, abnormal forces created by the spinal fusion may lead to hypermobility and accelerated degenerative disease of the spine at adjacent levels with development of disc herniations, spinal stenosis, instability and cord compression. Second, early diagnosis is valuable because of the numerous possible associated anomalies and their complications, such as basilar invagination, neural dysgenesis, and skeletal and visceral anomalies. Finally, since KFS predisposes to spinal and neural injury, awareness of the disorder is important so that activities associated with increased risk of head and neck trauma can be avoided.

References