Klippel-Feil syndrome (KFS) firstly described by Klippel and Feil and is characterized by the presence of congenital synostosis of some or all cervical vertebrae. This congenital vertebral fusion of the cervical spine results from faulty segmentation along the embryo’s developing axis during the first 3 to 8 weeks of gestation. The prevalence of KFS is about every 40 000 newborns worldwide; mainly in females (60% of cases) (Pizzutillo et al., 1994). The diagnosis is based on clinical triad associating short neck, low posterior hairline, and limited neck movement. Fewer than 50% of patients demonstrate this clinical triad and a wide spectrum of associated anomalies may be present. This heterogeneity has complicated clarification of the genetic etiology and management of the syndrome.
Recently, it has been reported that the prevalence of KFS was high (1 in 172 births) since clinical diagnosis may not be reliable, and most sporadic cases were found incidentally on imaging (Gruber et al., 2018).
In this review, we focused on clinical heterogeneity; radiographic abnormalities and genetic etiology in Klippel-Feil syndrome. We recommend comprehensive evaluation and delineation of diagnostic and prognostic classes for clinical management of patients.
Clinical and radiographic features
KFS manifests with a short neck with reduced mobility and a low posterior hairline. This clinical triad occurs only in 40–50% of patients. Decreased range of neck movements is the most frequent clinical finding. Patients usually present at a younger age when the upper cervical spine is involved.
Three morphological subtypes of this anomaly were described in 1919 by Feil. Type I involves a single congenitally fused cervical segment; type II includes multiple noncontiguous, congenitally fused segments, and type III comprises multiple contiguous, congenitally fused cervical segments (Samartzis et al., 2006). Female patients were predominantly type I, while males were largely type III (Samartzis et al., 2006).
Based on the position of cervical vertebra fusion, the status of familial trait and its characteristics; 4 classes (KF 1, 2, 3, and 4) were identified (Gunderson et al., 1967; Raas-Rothschild et al., 1988; Clarke et al., 1998). When C1 fusion and marked autosomal recessive trait in KF1; there is absolutely a fusion of C2-3 and an autosomal dominant trait; in KF2. C3 fusion is marked in KF3, and trait is reduced penetration type or autosomal recessive. In KF4, an X-linked trait; eye anomalies were associated with cervical fusion (Clarke et al., 1998).
Though this clinical and genetic heterogeneity, it has been reported that the most commonly cervical fusion was C5-C6 and C2-C3 (Gruber et al., 2018). However, patients with Klippel-Feil syndrome are often asymptomatic, nevertheless; they may develop a number of spontaneous neurologic squeal as a result of their bony anomalies. Axial neck symptoms were highly associated with type I patients, whereas predominant radicular and myelopathic symptoms occurred in type II and type III patients. Thus, this classification system was helpful since it promises for early detection for cervical spine-related symptoms.
Furthermore, a wide spectrum of associated anomalies may be present (Mahirogullari et al., 2006) (Table 1). According to many studies, the most commonly associated anomalies in patient with KFS are scoliosis (60% of cases), spina bifida occulta (45%), renal abnormalities (35–55%), rib deformity (20–30%), deafness (30–40%), synkinesia (20%), and congenital heart disease (8–14%) (Jovankovicova et al., 2012). A further anomaly which is quite frequent in KFS is a Sprengel anomaly, which occurs in 20–30% of the patients. It is a complex anomaly that is associated with congenital elevation and dysplasia of the scapula. Less commonly associated anomalies with KFS include congenital limb deficiencies, intestinal malformation, craniofacial, and ear deformities. Thus, clinical heterogeneity requires a comprehensive evaluation of symptoms. This also has made delineation of diagnostic and prognostic classes difficult and has complicated elucidation of the genetic etiology of the syndrome.
KFS may result from mutations or disruptions in genes regulating segmentation and resegmentation. Although most cases of KFS are sporadic, there are at least four genetic forms of KFS with both dominant or recessive inheritance listed at Online Mendelian Inheritance in Man: KFS1, KFS2, KFS3, and KFS4 namely with myopathy and facial dysmorphology (Table 2). At cytogenetic level, a number of chromosome abnormalities have been associated with KFS, for example, a translocation t(5;17) (q11.2;q23) in a sporadic KFS patient with associated brachydactyly (Fukushima et al., 1995), an inversion involving chromosome 2; inv(2)(p12q34); in a KFS patient with hypodontia (Papagrigorakis et al., 2003) and a paracentric inversion of chromosome 8; inv(8)(q22.2q23.3); in a large autosomal dominant KFS family (Clarke et al., 1995). Moreover, it has been reported three-generation family in which a dominant form of type I Klippel-Feil anomaly is cosegregating with t(5;8) (q35.1;p21.1) translocation (Goto et al., 2006). In addition, it has been documented the association of Turner’s and KFS (Hillemand et al., 1973; Suchkova et al., 1987; Park et al., 2012; Park et al., 2013). Besides, several genes involved in proper bone development have been proposed as candidates for KFS. Mutations in the GDF6, GDF3, or MEOX1 gene can cause KFS1 (Tassabehji et al., 2008), 2 (Mohamed et al., 2013), and 3 (Ye et al., 2010), respectively. These proteins, respectively encoded by the GDF6 gene and GDF3 gene, are essential for the formation and the development of bones and joints, including those in the spine. However, the protein produced from the MEOX1 gene, called homeobox protein MOX-1, regulates the process that begins separating vertebrae from one another during early development. Recently, a null mutation in MYO18B was correlated with a novel syndrome of Klippel-Feil anomaly, myopathy, and characteristic faces (Alazami et al., 2015). Moreover, delineation of genetic causes of KFS when it is present with other associated anomalies evident, as a mutation in the FGFR3 gene (Lowry et al., 2001), but the genetics of isolated KFS have been difficult to study because of the syndrome’s mostly sporadic occurrence. Pedigree analysis has identified a human genetic locus for the disease. Mouse models suggest members of the PAX gene family and Notch signaling pathway as possible etiologic candidates (Tracy et al., 2004).
Thus, assessment of the correlation between the genetic etiology and the phenotypic path-anatomy of KFS would rationalize the heterogeneity of the syndrome.
KFS is usually diagnosed in patients during childhood. However, the associated anomalies may delay the diagnosis. The challenge of the specialist is to recognize the concomitant anomalies and to perform the appropriate workup for diagnosis of KFS. Key considerations in the management of KFS include radiographic evaluation for hypermobile cervical segments, recognition of high-risk patterns of skeletal anomalies, and proper referral of the associated anomalies. Awareness of these congenital anomalies is significant for several reasons. First, ascertaining young patients should lead to a vigilant investigation for spinal cord syndromes that are else more common in older individuals. Second, this awareness should also prompt patient education concerning their risks for spinal injury even after mild traumatic events. Last, the potential for other abnormalities should be carefully assessed through appropriate referral. Often, the prognosis for most patients with KFS is good if the disorder is treated early and appropriately. Activities that can injure the neck should be avoided.
Several diagnoses for the fused appearances of the cervical spine should be distinguished to KFS. These include ankylosing spondylitis, juvenile idiopathic arthritis, a chronic complication of discitis, surgical fusion…etc. Multiple biological candidates genes were analyzed and suggesting a shared genetic etiology between KFS and several anomalies as Chiari Type I Malformation (Markunas et al., 2013). Moreover, Klippel-Feil anomaly may be a part of other syndromes, including MURCS (601076), Sprengel deformity (184400), and Wildervanck syndrome (314600).
The variations in patho-anatomy and associated abnormalities in KFS require comprehensive evaluation for treatment managements that can vary from modification of activities to extensive spinal surgeries.
We are grateful for Taoufik Frikha for English revision.
Conflicts of interest
There are no conflicts of interest.
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