Klippel-Feil syndrome (KFS) is a congenital anomaly characterized by a defect in the formation or segmentation of the cervical vertebrae, resulting in a fused appearance. The clinical triad consists of short neck, low posterior hairline, and limited neck movement, ...Klippel-Feil syndrome (KFS) is a congenital anomaly characterized by a defect in the formation or segmentation of the cervical vertebrae, resulting in a fused appearance. The clinical triad consists of short neck, low posterior hairline, and limited neck movement, although less than 50% of patients demonstrate all 3 clinical features (Tracy et al., 2004). - Genetic Heterogeneity of Klippel-Feil Syndrome Additional forms of KFS include autosomal recessive KFS2 (214300), caused by mutation in the MEOX1 gene (600147) on chromosome 17q21, and autosomal dominant KFS3 (613702), caused by mutation in the GDF3 gene (606522) on chromosome 12p13. See also MURCS association (601076), in which Klippel-Feil anomaly is associated with urogenital anomalies
Klippel and Feil (1912) first described the disorder in a 46-year-old French man who had a short immobile neck with massive fusion of cervical and upper thoracic vertebrae.
Shaver et al. (1986) reported a family in which ...Klippel and Feil (1912) first described the disorder in a 46-year-old French man who had a short immobile neck with massive fusion of cervical and upper thoracic vertebrae. Shaver et al. (1986) reported a family in which 31 individuals spanning 5 generations had Klippel-Feil syndrome inherited in an autosomal dominant pattern. The proband was a 24-year-old woman with unilateral sensorineural hearing loss since adolescence, head tilt, scoliosis, mild Sprengel anomaly (184400), and facial asymmetry. Radiographic examination showed C2-3 fusion. Five of 12 affected family members examined showed hearing loss, scoliosis with Sprengel anomaly, and facial asymmetry. Shaver et al. (1986) noted that sensorineural hearing impairment had been reported in as many as 30% of patients with KFS. Clarke et al. (1994, 1995) described a 4-generation family with a autosomal dominant form of Klippel-Feil syndrome in association with malformation of laryngeal cartilages and mild to severe vocal impairment. Vertebral fusion was confined to the cervical spine in all affected members at C2-3; C4-5 and C6-7 fusions were less consistently present. Clarke et al. (1994) had demonstrated in the aphonic proband that severe voice impairment was directly related to malformed laryngeal cartilages. All affected members of the family had microtia and some had a history of mild conductive hearing impairment. Most affected individuals also had bilateral restricted supination and elbow flexion of the forearms. Clarke et al. (1998) provided follow-up of the family reported by Clarke et al. (1994, 1995). The new proband showed separation of C2 and C3 vertebrae at 10 weeks of age, with progression to ossification of the C2-3 interspace and complete fusion of the C2-3 vertebral bodies by age 4 years. The authors concluded that in this family, C2-3 fusion is dominant and that fusion is postnatal. In total, 11 family members had radiographically confirmed C2-3 fusion, 70% of whom had C2-3 and C4-5 skipped fusion, and 20% of whom had C2-3, C4-5, and C6-7 skipped fusion. In most cases, vertebral bodies were completely fused while spinous processes were not fused along their entire length. All those with 2 or more fusions were vocally impaired in association with laryngeal cartilage malformations. Most affected patients also had low-set and/or underdeveloped ears and mild conductive hearing loss. Tassabehji et al. (2008) provided further follow-up of this family now expanded to 5 generations. Additional features included scoliosis, fusion of the carpal and tarsal bones, and restricted flexibility of the hands, wrists, elbows, feet, and legs. There was also moderate hearing impairment and severe vocal impairment. About 50% of affected individuals had Sprengel anomaly (184400). Deafness is a well-known feature of KFS and may be of sensorineural, conductive, or mixed type. McGaughran et al. (1998) studied 44 individuals with KFS (18 male, 26 female) and found audiologic abnormalities in 35 (80%) with a slight excess of females (M:F ratio 1:1.5). Sensorineural deafness was the most common (15 cases), followed by mixed (10 cases) and conductive loss (7 cases). No characteristic audiogram profile was noted. Conductive hearing loss was not due to secretory otitis media. The authors commented that several otologic abnormalities have been described in KFS, including external ear malformation, ossicular chain abnormalities, and structural abnormalities of the inner ear. Vestibular abnormalities were not assessed. Clarke et al. (1998) reported a family in which the proband had vertebral fusion at C4-5 and her father had fusion at C5-6. Fusions in both the father and daughter showed complete fusion along the entire length of the spinous processes and lamina up to and including the vertebral bodies. There was also a marked reduction in the rostrocaudal width of the fused vertebrae, suggesting a congenital fusion that would have been apparent prenatally. Both patients had mild neck stiffness without short neck or low hairline. Thompson et al. (1998) reported a family in which 6 individuals had Klippel-Feil anomaly inherited in an autosomal dominant pattern. Four of the 6 had cleft palate. Toyoshima et al. (2006) reported female monozygotic twins who were discordant for Klippel-Feil syndrome. The affected twin had short neck, limited neck movement, and low posterior hairline. CT scan showed C1-4 vertebral fusion. She had no other anomalies and showed normal development. Toyoshima et al. (2006) postulated a postzygotic somatic mutation or intrauterine environmental factors in the etiology of the syndrome. Tassabehji et al. (2008) reported a 3-generation family with autosomal dominant Klippel-Feil syndrome and C2-3 fusion, consistent with type II in the classification system of Clarke et al. (1998). Tassabehji et al. (2008) also reported 2 patients with sporadic KFS. One was an adult male with short neck, mirror movements, relative macrocephaly, and left Sprengel anomaly. The second patient was a female fetus assessed following termination of pregnancy for antenatal diagnosis of multiple segmentation abnormalities affecting the entire spine and ribs. She also had multiple other congenital anomalies, including developmental failure of the lumbar and sacral spine, rocker-bottom feet, Arnold-Chiari type II malrotation, and urologic anomalies. Tassabehji et al. (2008) commented that the 2 sporadic cases were consistent with type I in the classification system of Clarke et al. (1998)
In affected members of a 3-generation family with autosomal dominant Klippel-Feil syndrome, Tassabehji et al. (2008) identified a heterozygous mutation in the GDF6 gene (A249E; 601147.0001). A different heterozygous mutation (L289P; 601147.0002) was identified in 2 unrelated patients with ...In affected members of a 3-generation family with autosomal dominant Klippel-Feil syndrome, Tassabehji et al. (2008) identified a heterozygous mutation in the GDF6 gene (A249E; 601147.0001). A different heterozygous mutation (L289P; 601147.0002) was identified in 2 unrelated patients with sporadic Klippel-Feil syndrome. In the family reported by Clarke et al. (1995), Tassabehji et al. (2008) determined that the proximal breakpoint was located 623 kb 3-prime to the GDF6 gene within a region known to harbor GDF6 long-range enhancer elements. As mutations in the GDF6 gene were identified in other patients with dominant Klippel-Feil syndrome, the authors suggested that the chromosome 8 inversion was responsible for the phenotype in the family of Clarke et al. (1995) by affecting GDF6 expression. However, no GDF6 mutations were identified in the family reported by Clarke et al. (1995). The distal breakpoint was within an intergenic region and not believed to influence the phenotype. Tassabehji et al. (2008) commented that the phenotype was similar to that observed in the Gdf6-null mouse. Asai-Coakwell et al. (2009) screened DNA samples from 489 patients with ocular anomalies (microphthalmia, clinical anophthalmia, and coloboma) and 81 patients with vertebral segmentation anomalies for mutations in the GDF6 gene. They identified heterozygosity for 7 different missense mutations in 9 patients, including 1 with spondylothoracic dysostosis (601147.0003) and 1 with hemivertebra, rib malformations, and horseshoe kidney (601147.0004)