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X-linked myotubular (centronuclear) myopathy is a severe muscle disorder mainly affecting newborn boys, but sometimes it can also affect girls. Diagnostic
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This article includes discussion of Klippel-Feil syndrome, Klippel-Feil anomaly, Klippel-Feil deformity, and Klippel-Feil sequence. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
The author reviews the basic biological issues surrounding the pathogenesis, clinical manifestations, and progression of Klippel-Feil syndrome, a condition involving fusion of cervical vertebrae and associated changes in neck length and mobility and low hairline posteriorly; the condition is usually sporadic, but may be autosomal dominant or recessive. Genes associated with dominant forms are GDF3 and GDF6. 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.
• Klippel-Feil syndrome is a condition involving fusion of cervical vertebrae and associated changes in neck length and mobility, with low hairline posteriorly.
• The condition is usually sporadic but may be autosomal dominant or recessive. Several genes (GDF3, GDF6, MEOX1, 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.
Klippel-Feil syndrome is a clinical triad consisting of fusion of cervical (and sometimes other) vertebrae, with associated shortening of the neck, limited head motion, and a low posterior hairline. Most cases are sporadic, although autosomal dominant and autosomal recessive cases are recognized.
The characteristic changes have been recognized in an Egyptian mummy from 500 BC and in descriptions dating from the 13th to 16th centuries (120; 61; 46). Klippel and Feil published the description on which the syndrome is based (90); Feil later defined 3 subtypes (44). Since that time, many papers have been published; 2 classic reviews are by Gunderson and colleagues (61), and Helmi and Pruzansky (68).
Affected patients manifest a wide variety of anomalies. Cervical anomalies have a variable influence on the shape of the neck. Butterfly vertebrae are observed only rarely (82). Shortening of the neck is variable but may be extreme, giving the suggestion that the head rests on the shoulders. Enhancing this impression are the trapezius muscles, which are prominently flared laterally (between mastoid process and acromion), giving a web neck appearance (“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 (129). Neck pain can radiate into the back, shoulders, and arms (ie, cervicalgia) (Palacios et al 2013) and can be long-lasting (22). Sprengel anomaly may be unilateral, bilateral (present in up to 30% of individuals), or familial (146; 94) and does not appear to be related to the severity of cervical change (139). 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 (99). The association of Sprengel anomaly and Klippel-Feil syndrome with an omovertebral bone (anomalous bony extension of scapula) may result in cervical myelopathy, which can present in old age (48; 108). Other axial anomalies include cervical or fused ribs, cleft or hemivertebrae, kyphosis, scoliosis, spina bifida occulta, and sacral agenesis (54; 173). One case of Klippel-Feil syndrome with neuroschisis was initially diagnosed as syringomyelia; another was encountered with sacral agenesis, lipomyelomeningocele, split cord malformation, and tethered cord (145; 170). The latter condition can complicate spinal anesthesia in the undiagnosed patient (153). Cervical ribs are recognized clinically but have also been verified in anatomical specimens (163). They may be a cause of nerve compression, with secondary numbness and pain in the arms and hands; the resultant thoracic outlet syndrome may actually lead to the diagnosis of Klippel-Feil syndrome and can be relieved surgically (91). Pneumatocyst has been observed in the cervical rib of a patient with Klippel-Feil syndrome (63). Omovertebrae and cervical ribs may be bilateral, with the latter presenting at multiple levels (144).
Anomalies of the carotid artery (including unilateral agenesis) or the subclavian artery, particularly the latter, are recognized and must be considered when thoracic or cardiovascular surgery is contemplated (130; 134; 19). Likewise, the course of vertebral arteries must be understood with appropriate angiography prior to surgery involving cervical vertebrae (72). A variety of upper limb defects or deficiencies involving the humerus, ulna, or radius are recognized (158). Radial anomalies may manifest as Fanconi anemia (with radial aplasia) and Klippel-Feil syndrome (104) or involve the first metacarpal and thumb (118). Kyphoscoliosis with deformations of the thoracic cage may be a cause of pulmonary hypertension and respiratory failure (154). Lumbar fusion has been reported in one patient (100). Patellar hypoplasia has been associated with Klippel-Feil syndrome (133).
Hearing deficits occur in 20% to 50% of patients and may be conductive, sensorineural, or mixed (146). 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 (175). Preauricular skin tags are reported (32). Eye anomalies such as strabismus, nystagmus, or chorioretinal atrophy occur in 20% of patients. Abnormalities in eyelids have been recognized (32). The spinal cord may have a significantly reduced diameter (11), although this has not been observed in other samples (27). The cord may be altered by a neurenteric cyst (25). Other neurologic impairments manifest in approximately one-half of patients and include synkinesia, facial nerve palsy, spasticity, lower extremity mirror movements, hemiplegia, paraplegia, triplegia, or quadriplegia (113; 164). Quadriplegia may be transient in affected patients and mimic cervical cord neurapraxia (62; 14). 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 (68; Online Mendelian Inheritance in Man, OMIM 1997; 05; 09; 70; 34; 124; 13; 83; 21; 50). Cerebral angiolipoma has been reported in a patient with Klippel-Feil syndrome, bifid thumb, and tracheoesophageal fistula (168). Arachnoid or dermoid cysts may also involve the fourth ventricle or craniocervico-thoracic spine (87; 107; 138). It has been suggested that squamous cell carcinoma may develop secondary to dedifferentiation of a dermoid cyst (122). Intelligence is normal in about 90% of patients.
Patients manifest short stature. One case of Rothmund-Thomson syndrome (poikiloderma congenitale) and (remote) osteosarcoma has been reported (51), as has been Poland anomaly in a 7-year-old girl (43). Cleft palate or submucous cleft palate is recognized in about 17% of affected patients. An osseous choristoma of oral mucosa has been identified in one adult woman (49). Additional dental problems include oligodontia of both primary and permanent teeth, maxillary constriction, and velopharyngeal insufficiency (15). Given the issues of cervical mobility, oral surgery and other dental work, as well as deep sedation, can be challenging and require careful planning prior to treatment (06; 33; 03). Laryngeal cartilages may be malformed, causing aphonia or other voice impairment (29). Absence of all or part of a lung may occur (102). Congenital heart disease (usually ventricular septal defect) is observed in up to 10% of patients. Transposition of the great vessels and total anomalous pulmonary venous return have been reported (102), and cor triatriatum has been in noted 1 patient (02). Aortic arch anomalies have been recognized, including coarctation in 1 adult (47) and absence of 1 internal carotid artery (19; 137). In the latter condition, headaches, paresthesias, and vertigo may occur (01). Aneurysm of a noncoronary sinus of Valsalva has also been reported (86). Isolated hypokinesia of the left ventricle has been reported in one patient (177). Genital anomalies and conditions include cryptorchidism, hypospadias, absence of vagina, uterus (or unicornuate uterus), or Fallopian tubes (MURCS), and azoospermia (167; 166; 178). Unilateral renal agenesis is the most common renal anomaly (56; 100); crossed fused renal ectopia has been reported in one case (117). Several cases of situs inversus have been reported (77; 26).
Prognosis and complications depend on the severity and extent of anomalies. Individuals with few or mild extraaxial anomalies may not have symptoms during childhood and may reach early adulthood before the onset of more severe neurologic complications (individuals with reduced range of motion of the neck, deafness, and extraaxial defects are obvious exceptions). In patients who are affected mildly, participation in sports or other physical exertion may be possible (see Management) or may exacerbate the condition (103; 141; 71). Cervical instability (possibly with disc prolapse), occipitocervical anomalies, degeneration of discs or joints, and scoliosis may develop over time (ie, second to third decade) and lead to neurologic complications including para- or quadriparesis. However, the report of a 5-year-old girl with cervical disc prolapse indicates that onset of these complications may occur earlier (07). Traumatic fractures may occur in fused cervical segments or the axis, but are infrequent and treatable by surgical means (08; 110; 135). Anomalies of the odontoid process and atlas have been reported (35). Defects in the occipital bone may allow communication of infectious agents from the scalp and may lead to pneumoencephaly (74). Skeletal, renal, or cardiovascular anomalies may require more intensive treatment. In one series, atrial septal defect was prominent and sometimes required corrective surgery (17). Surgical stabilization may be required at any age (07), and the contribution of atlantoaxial stability to morbidity continues to be studied (149; 140). In cases of basilar invagination, an anterior transoral approach has proven successful for decompression and fixation of occipitocervical elements (172). Discectomy, sometimes with odontoidectomy, has also been performed transorally (55) or endoscopically (106). The latter technique, in 4 cases, limited the need for prolonged intubation and risk of dysphagia, reduced hospital stay, and was cosmetically successful. Osteophytes at the sites of cervical pseudoarthroses may lead to myelopathy (155). Although surgery may be necessary, vertebral fusion may also increase disc mobility above or below the level of surgery (136). Patients must be followed, as surgical repairs can fail over time or lead to myelopathy (127; 121). Misalignment of cervical and occipital bones following cervical fusion carries certain complications, chiefly dysphagia and trismus (109). Hypermobility of the cervical spine can also be asymptomatic, even for periods of several decades (116), or associated with disc herniation leading to cord compression (141) or traumatic spinal cord injury (169). Disc herniation may occur intradurally (119). Cord contusion can be an additional complication of disc prolapse following minor trauma (04). Anomalies in the course of vertebral arteries are recognized and must be understood prior to surgery (80; 72). Cervical vertebral anomalies may also be associated with vertebral artery dissection (37), at times with CNS (eg, pontine) infarction (65) or rubral lateropulsion leading to rubrothalamic stroke (84). Osteopoikilosis, a rare and usually asymptomatic disorder of bone, has been reported in Klippel-Feil syndrome, where it was familial (160). Laryngeal malformation can produce voice impairment or aphonia. Mental retardation occurs in approximately 10% of patients. Idiopathic growth hormone deficiency has been reported within the context of Klippel-Feil and Duane syndrome and thought to represent a variant of Wildervanck syndrome (162). Unexpected associations have been reported, including a patient with Klippel-Feil anomaly, Tourette syndrome, and 22q11.2 duplication (30); one with Pierre Robin sequence, mandibular duplication, and occipital clefts (06; 174); and another with Down syndrome (45).
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 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 3 small muscular ventricular septal defects. External genitalia were normal, although the uterus was thought to be absent. Karyotype was 46,XX.
The infant suffered respiratory distress syndrome, which required 5 weeks of mechanical ventilation; subsequently, she developed chronic lung disease complicated by 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). A brainstem auditory evoked response showed absence of all wave forms, including wave 1.
In the ensuing 3 months, the baby did fairly well. However, 1 day prior to 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.
Etiology is heterogeneous. Sporadic cases, as well as autosomal dominant and recessive ones, have been reported. Two genes have been associated with dominant forms (GDF3 and GDF6). Mutations in MEOX1 (a mesenchyme homeobox gene) have been identified in 1 consanguineous family (111). A second study has confirmed the recessive nature of this subtype (16). An additional gene, RIPPLY2, has also been associated with recessive disease (81). This latter gene is important in somitogenesis and patterning; one patient with the mutation had situs inversus. The search for candidate genes continues (101). The identification of several novel genes has raised the potential for oligogenic inheritance (98).
Vascular disruption (involving the subclavian artery) has been put forth as a possible cause of Klippel-Feil syndrome (20; 76), as has persistence of embryologic vessels such as the trigeminal artery, an intersegmental vessel communicating with carotid and vertebral-basilar circuits (125). A teratogenic basis has been postulated for some human cases and has received experimental support (171). One patient, for example, was exposed to cyclophosphamide and prednisone in the first trimester (95). Maternal diabetes, hypoxia, and anticonvulsant therapy have been implicated as well (53).
Four subtypes have been identified for this congenital disorder. Types 1, 2, and 3 were defined by Feil (44). Type 1 is defined as extensive, single fusion of cervical and upper thoracic vertebrae. Type 2 is defined as limited, noncontiguous fusion, accompanied by other axial anomalies such as hemivertebrae (occipitoatlantal fusion possible). Type 3 is defined as multiple contiguous areas of vertebral fusion, for example, cervical and lower thoracic or lumbar fusion (142); scoliosis may occur and ribs may be fused or bifid (117). Type 4, cervical fusion with sacral agenesis, was described by Raas-Rothschild and colleagues (132).
In addition to morphologic heterogeneity, genetic differences are recognized (58). Type 1 is mostly sporadic, though a few families have been reported (61). Discordance for Klippel-Feil syndrome in female monozygotic twins with type I disease suggests that postzygotic somatic mutation or environmental factors may also play a role in pathogenesis (161). Type 2 is mostly dominant but with some recessive cases reported; type 3 is likely to be recessive; type 4 is known only through a few reports thus far. Classification schemes continue to be reexamined (28). Abnormal karyotypes have been reported: inv(8)(q22.2q23.3) (31), t(5; 17)(q13; q25) (75), and t(5; 8)(q35.1; p21.1) (59). Mutations in GDF6 have been identified in both sporadic and familial cases of Klippel-Feil syndrome (156). The association of mutations in BMP-13 and Klippel-Feil syndrome is also recognized (148). Mutations in PAX1, a family of developmental control genes, have been found in mice with vertebral segmentation defects as well as a significant subset of patients (8/63) with Klippel-Feil syndrome (104). One patient has been reported with Turner (45,X0) syndrome (128). A father and 2 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 (52).
Much remains to be learned about the pathogenesis of Klippel-Feil syndrome. Normal segmentation of the vertebral column takes place between the fourth and eighth weeks of embryonic life. Mesenchymal cells appear in the fourth week and migrate, surrounding the notochord. Vertebral bodies develop from the lower half of one somite and the upper half of the adjacent (lower) somite. Chondrification begins in the sixth week and spreads until the entire vertebral column is cartilaginous. Primary ossification centers appear in the seventh week of gestation, but secondary ossification centers appear during puberty and continue to develop until the 25th year (112). 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 extraaxial anomalies (131; 146). The association of Klippel-Feil with upper limb deficiency suggests an embryologic onset at 4 weeks to 5 weeks (158), whereas the appearance of dermoid cysts implies a mesodermal disturbance at 4 weeks (70). The occurrence of Klippel-Feil syndrome with split cord malformation suggests that occult spinal dysraphism may play a role in at least some cases (165). Some patients with such malformations can remain asymptomatic for several decades (10). Much remains to be learned about possible teratogenic effects, but it is known that congenital vertebral malformations develop as a result of maternal diabetes, hypoxia, or anticonvulsant drug therapy during pregnancy (53).
The incidence of Klippel-Feil syndrome is estimated to be between 1 in 30,000 and 1 in 40,000 live births; cases with minor changes may go undiagnosed (146; Durmus et al 2013). In a review of 831 children undergoing radiography for suspected trauma to the cervical spine, Klippel-Feil syndrome was diagnosed in 1.2% (114). In a similar review of 2917 patients, Klippel-Feil syndrome was diagnosed in 0.58% (60).
Sporadic cases cannot be predicted or prevented. Prevention in affected families is only possible by avoiding pregnancy.
As with any genetic disease, genetics specialists can provide information regarding risk. This will most likely involve acquiring a family pedigree, which in itself carries a risk of invasion of privacy (23).
Gorlin and colleagues and Scott and colleagues provided thorough lists of diagnoses that must be differentiated from Klippel-Feil syndrome (58; 146). These are summarized in Table 1.
Affected region or system
Morquio syndrome; tuberculosis of cervical spine
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
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
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
MURCS association (Müllerian duct aplasia, renal aplasia, cervicothoracic somite dysplasia)
Blackfan-Diamond syndrome (congenital erythroid hypoplastic anemia with webbed neck, cleft palate, abnormal thumbs, and other bony anomalies)
Patients suspected of having Klippel-Feil syndrome are worked up like those with other axial anomalies, with additional examinations or tests for abnormalities in other organ systems as indicated. Because the spine is slow to ossify, vertebral fusion or other axial anomalies may not be evident in early life, so physicians can expect to make these diagnoses at various times between infancy and early adulthood. A careful physical examination including complete neurologic examination and a thorough family history comprise a necessary beginning. Spine abnormalities may be associated with the hair collar sign, a ring of hair surrounding a midline scalp nodule usually associated with neural tube defects (64). Radiography of the cranium, entire spinal axis, and thorax follows; computerized tomography and cineradiography will provide additional delineation of abnormalities. Previously undiagnosed Klippel-Feil syndrome has been identified in an older child by means of orthodontic examination (176). Cardiac workup may involve ECG, echocardiography, or cardiac catheterization. Renal and pelvic ultrasonography will be required for patients suspected of having anomalies of the urinary system (146).
Management depends on the severity of anomalies and onset of symptoms; these can be highly diverse, so careful and thorough imaging is necessary for identification (93). Cervical immobility may preclude certain physical activities; limited voice or aphonia will affect lifestyle as well. Athletic participation may be possible depending on the severity of the condition, and return-to-play guidelines continue to be developed for younger patients (40; 71). Neck pain can be treated with exercises to strengthen cervical deep muscles (12). Kyphosis and scoliosis will require treatment when severe (eg, surgery or other orthopedic intervention). Radiographic monitoring is necessary, as the anomalies lead to progressive involvement or deterioration of vertebrae. Skull traction may help align cervical vertebrae, diminish or eliminate associated spasticity, and clarify the reducibility of cervical deformities (36). Artificial cervical disc arthroplasty has been performed in one patient (97). Cervical dislocation has been associated with anoxic encephalopathy and death in one case (151). Audiometric assessment is necessary. Plastic surgery has been employed to correct nuchal webbing (69). Positioning or moving the patient in preparation for or during surgical procedures is not at all trivial. One report describes aspiration, tachycardia, hypotension, and ECG changes that occurred when a patient was placed in a prone position for surgery (157). Another reports the development of massive macroglossia following surgery performed in a sitting position. 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. Intubation and possible glossectomy are likely to be required in this context (92) and require very careful preoperative planning and intraoperative coordination to maintain airway patency (88). The association of other anomalies, including those of the CNS, adds to the complexity of care; reports of patients with Chiari type III or anterior cervical myelomeningocele are examples (42; 78). A teratoma involving the cranial base has been successfully resected endoscopically (39). Electrophysiological monitoring (neuromonitoring) in the form of transcranial motor-evoked or somatosensory-evoked potential may be efficacious during surgery (89). One case of duplication of the mandible illustrates how varied the anomalies can be (Durmus et al 2013). Care, including novel surgical approaches such as 3-dimensional navigation, continues to evolve (18; 159). One case of complete heart block in a 36-year-old man with Klippel-Feil syndrome has been reported (41).
Elective cesarean section has been successful in cases complicated by cervical, thoracic, and lumbar instability and distortion (85). Urgent cesarean section has also been performed using a combination of spinal and local anesthesia (143). Airway management during cesarean section can be demanding (152). Genital anomalies may complicate or preclude reproduction. Because of the heritable nature of the condition, affected women may give birth to affected offspring. It is possible that cervical anomalies predispose the fetus to a degree of intrauterine constraint – one 6 month old presented with erosive pustular dermatosis of the scalp without pertinent postnatal history and required significant treatment (150).
The severity of cervical anomalies and mobility and consequences for intubation and use of muscle relaxants must be considered by the anesthesiologist. The presence of atlantoaxial instability and other anomalies (ie, Chiari malformation) increases the challenges of anesthesia (24; 45) and may call for a multidisciplinary approach (73). Fiberoptic intubation through a laryngeal mask has been successful in 2 patients with severely limited range of motion (96). Likewise, fiberoptic intubation has been used successfully for airway management in childbirth and in a patient with micrognathia (66; 115). Video-guided laryngoscopy has proven valuable in this context as well (147; 79). In the young patient, hypertrophic tonsils may complicate intubation (57); tracheal stenosis has been a complicating factor in an affected adult (67).
No information is available as to appropriateness of anesthetic agents or other drugs.
Joseph R Siebert PhD
Dr. Siebert of the University of Washington has no relevant financial relationships to disclose.See Profile
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