Klippel-Feil Syndrome 1, Autosomal Dominant
A number sign (#) is used with this entry because Klippel-Feil syndrome-1 is caused by heterozygous mutation in the GDF6 gene (601147) on chromosome 8q22.
DescriptionKlippel-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, autosomal dominant KFS3 (613702), caused by mutation in the GDF3 gene (606522) on chromosome 12p13, and autosomal recessive KFS4 (616549), caused by mutation in the MYO18B gene (607295) on chromosome 22q12.
See also MURCS association (601076), in which Klippel-Feil anomaly is associated with urogenital anomalies.
Clinical FeaturesKlippel 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).
HeterogeneityClassification Systems
Gunderson et al. (1967) recognized 3 morphologic types of cervical vertebral fusion in Klippel-Feil syndrome. Type I consists of massive fusion of many cervical and upper thoracic vertebrae into bony blocks; type II has fusion at only one or two interspaces (although hemivertebrae, occipitoatlantal fusion, and other anomalies might be associated); and type III comprises both cervical fusion and lower thoracic or lumbar fusion. By observation of affected families, Gunderson et al. (1967) suggested that C2-3 fusion, a subtype of type II, may be a simple dominant trait, whereas C5-6 fusion, may be recessive. The authors noted that C2-3 fusion is the most common form of congenital fused cervical vertebrae. Raas-Rothschild et al. (1988) suggested the existence of a fourth type of Klippel-Feil anomaly, that associated with sacral agenesis.
Based on the findings in 3 unrelated families with KFS demonstrating different modes of inheritance and different rostral vertebral involvement, Clarke et al. (1998) proposed a revised classification system. Type 1 is characterized by the most rostral fusion at C1 and severe associated anomalies with autosomal recessive inheritance. Type 2 is characterized by dominant C2-3 fusion which develops postnatally. Type 3 shows a singular isolated fusion, most rostral at C3, and shows reduced penetrance. Type 4 shows vertebral fusion and ocular anomalies associated with Wildervanck syndrome (314600) and shows possible X-linked inheritance. Thoracic and lumbar fusions have no bearing on class in this system.
InheritanceAlthough most cases of KFS are sporadic, both autosomal dominant (Bauman, 1932; Bizarro, 1938; Clemmesen, 1936; Erskine, 1946) and autosomal recessive (see 214300) forms have been reported. KFS1 is an autosomal dominant disorder (Tassabehji et al., 2008).
PathogenesisBavinck and Weaver (1986) hypothesized that Poland syndrome (173800), Klippel-Feil anomaly, Moebius syndrome (157900), isolated absence of pectoralis major with breast hypoplasia, isolated transverse limb defects, and Sprengel anomaly are all the result of interruption of the early embryonic blood supply in the subclavian arteries, the vertebral arteries and/or their branches. The term subclavian artery supply disruption sequence (SASDS) was suggested for this group of birth defects. They discussed causative mechanisms such as pressure on the vessel by edema.
Matsuoka et al. (2005) identified Klippel-Feil syndrome, Sprengel deformity, and Arnold-Chiari I/II malformation (207950) as defects of post-otic neural crest (PONC) cells. Matsuoka et al. (2005) mapped the destinations of embryonic neural crest and mesodermal stem cells using Cre-recombinase-mediated transgenesis. The single-cell resolution of this genetic labeling revealed cryptic cell boundaries traversing the seemingly homogeneous skeleton of the neck and shoulders. Within this assembly of bones and muscles they discerned a precise code of connectivity that mesenchymal stem cells of both neural crest and mesodermal origin obey as they form muscle scaffolds. The neural crest anchors the head onto the anterior lining of the shoulder girdle, while a Hox gene-controlled mesoderm links trunk muscles to the posterior neck and shoulder skeleton. The skeleton that Matsuoka et al. (2005) identified as neural crest-derived is specifically affected in human Klippel-Feil syndrome, Sprengel deformity, and Arnold-Chiari I/II malformation. In Sprengel deformity a large fibrous, sometimes endochondral, so-called omo-vertebral bone replaces all dorsal neural crest-derived endochondral elements of the occipital region, cervical spinous processes, spina scapulae, and trapezius inside the PONC trapezius territory. On this basis, Matsuoka et al. (2005) identified Sprengel deformity, which is one of the phenotypic facets of Klippel-Feil syndrome, as primarily affecting PONC fate choices and not cervical segmentation as had been thought. Moreover, the authors suggested that the cervical hypomobility of Klippel-Feil patients can also be understood as caused by defects in PONC fate choices: ectopic ossifications of PONC (trapezius) connective tissues around the somitic mesodermal neck vertebrae and an ectopic ossification of the PONC prevertebral ligaments of pharyngeal muscles. Similarly, loss or dysplasia of PONC-derived basicranial (clivus) bone attachments for the internal pharynx and larynx constrictors and ensuing widening of the foramen magnum are the primary mechanical cause of the Arnold-Chiari I/II malformation, a serious human congenital malformation associated with swallowing problems and sudden infant death syndrome (SIDS; 272120). In this case PONC respecification from endochondral attachment bone to connective tissue is the likely cause of cryptic basicranial instability and early death.
CytogeneticsIn affected members of a family with Klippel-Feil syndrome and laryngeal malformation, Clarke et al. (1995) demonstrated a pericentric inversion of chromosome 8: inv(8)(q22.2q23.3). Clarke et al. (1995) suggested that a gene, symbolized SGM1 (presumably for 'segmental-1'), is located at one of the breakpoints of the inversion and was responsible for Klippel-Feil syndrome. Whether the laryngeal manifestations were due to disruption of the same gene or of a gene at the other breakpoint could not be determined.
In a 9-year-old girl with short stature, microcephaly, short neck, low posterior hairline, and limited cervical movement, who was found to have C2-C7 fusion on x-ray, Goto et al. (2006) identified a t(5;8)(q35.1;p21.1) translocation. Screening of family members revealed 4 other affected individuals in 3 generations, all of whom had the translocation; 3 unaffected individuals did not.
Molecular GeneticsIn 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).
Animal ModelSettle et al. (2003) found that Gdf5 (601146)/Gdf6-double mutant mice survived to birth in normal mendelian ratios, but only a small percentage survived to adulthood. The double-mutant mice had skeletal defects not seen in either Gdf5 or Gdf6 single mutants. Many limb bones were severely reduced or absent, several limb joints failed to form, and the vertebral column of 2 of 7 mice showed severe scoliosis.