Alternative titles; symbols
ORPHA: 2345; DO: 0080590;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q21.31 | Klippel-Feil syndrome 2 | 214300 | Autosomal recessive | 3 | MEOX1 | 600147 |
A number sign (#) is used with this entry because of evidence that Klippel-Feil syndrome-2 (KFS2) is caused by homozygous mutation in the MEOX1 gene (600147) on chromosome 17q21.
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).
Clarke et al. (1998) proposed a classification system for KFS in which an autosomal recessive form is characterized by the most rostral fusion at C1 and the presence of severe associated anomalies, including short neck, cardiac defects, and craniofacial anomalies.
For a general description and a discussion of genetic heterogeneity of Klippel-Feil syndrome, see KFS1 (118100).
Lubs et al. (1963) reported a family in which 2 of 11 sibs had fusion of vertebrae C5-6; a third sib had narrowing of the interspace. The parents were probably consanguineous.
Juberg and Gershanik (1976) reported a patient with KFS born of consanguineous parents. She had short neck, restricted cervical movement, and low posterior hairline. Radiographic examination showed C1 anomalies and fusion of C2-3 and C3-4. She also had hearing loss.
Chemke et al. (1980) described absent ulna and ulnar ray bilaterally in a female infant with KFS. The parents, Iraqi Jews, were not known to be consanguineous. Congenital absence of the ulna is rare; it may occur with the Cornelia de Lange syndrome (122470).
In a large kindred, da-Silva (1982) reported 4 sibships with a total of 7 females and 5 males with Klippel-Feil syndrome. Each had unaffected, first-cousin parents. The degree of vertebral fusion was variable: 6 patients had massive fusion of several cervical vertebrae and 2 had cervical, upper thoracic, and lumbar fusions.
Fragoso et al. (1982) described an 8-year-old girl who, in addition to KFS, had frontonasal dysplasia, Sprengel deformity (184400), widely spaced nipples, and postaxial polydactyly of the left foot. Facial features included flat facies, low anterior and posterior hairlines, hypertelorism, high-arched palate, and low-set ears. She had a short neck with limited movements.
Clarke et al. (1998) reported a family in which the proband displayed the classic KFS triad of vertebral fusion, very short neck, and low hairline associated with fusion of C1-4 and C5-7. Fusion of spinous processes C1-4 was present at birth and did not progress in the following year to include the vertebral bodies. Other features included cleft palate, large pointed ears, and cardiac ventriculoseptal defect. The maternal grandmother had cleft lip and palate without vertebral fusion and a maternal uncle was reported to have had a very short neck. The authors suggested autosomal recessive inheritance with variable expression.
Erol et al. (2004) reported a 7-year-old girl of Turkish origin with Klippel-Feil syndrome and Poland anomaly (173800). She had the typical triad of KFS, including very short neck, low occipital hairline, and reduced bilateral neck movements. Radiographic examination showed fusion of C1 and C2 vertebrae. She also had absence of the right pectoralis muscle, hypoplastic right breast, hypoplastic costochondral junctions, and hypoplastic sternum consistent with Poland anomaly. She had no cardiac, vascular, or renal anomalies. Erol et al. (2004) noted that a child with features of KFS, Poland anomaly, and Moebius syndrome (157900) had been reported by Issaivanan et al. (2002), who postulated a disruption in the subclavian artery supply.
Bayrakli et al. (2013) studied a consanguineous Turkish family in which 7 members had Klippel-Feil syndrome. All 7 had short neck, low posterior hairline, limited neck movements, and elevated scapula. Computerized tomography revealed anomalies of the foramen magnum, occipitalization of the atlas (C1 vertebrae), fusion of the atlas and axis (C2 vertebrae), fusion of some cervical vertebrae, and omovertebral bone causing Sprengel deformity. Magnetic resonance imaging showed scoliosis.
The occurrence of KFS in sibs and in consanguineous families suggests autosomal recessive inheritance of a form of the disorder (Juberg and Gershanik, 1976; da-Silva, 1982).
Ohashi et al. (1992) described a 6-year-old girl with Klippel-Feil-like phenotype associated with a de novo balanced translocation between chromosomes 5q and 17q with breakpoints at q11.2 and q23, respectively. She had midfacial hypoplasia with a low nasal root, a short nasal septum, a long philtrum, a thin upper lip, micrognathia, a low posterior hairline, a short and broad neck, brachydactyly, hypoplastic nails, and pes planus. Radiologic examination demonstrated fusion of C5-7. Psychosomatic development was normal. Ohashi et al. (1992) suggested that one of the genes responsible for the disorder was located at 5q11.2 or 17q23.
Mohamed et al. (2013) studied a large consanguineous Saudi family with Klippel-Feil syndrome in which the proband was a 10-year-old girl exhibiting the clinical triad of the disorder, with a short neck, low posterior hairline, and inability to flex, extend, or rotate her neck or lift her right hand to touch the back of her neck; full skeletal survey confirmed the C2-C3 fusion and Sprengel deformity but no other skeletal defects. Autozygosity mapping identified only 1 run of homozygosity, on chromosome 17 (chr17:29,323,850-45,448,560; NCBI36), that was exclusively shared by the affected members of the family; it was subsequently confirmed by linkage analysis.
By linkage analysis in a consanguineous Turkish family segregating Klippel-Feil syndrome, Bayrakli et al. (2013) found linkage to chromosome 17q12-q23 with a maximum lod score of 4.2.
In a large consanguineous Saudi family segregating autosomal recessive Klippel-Feil syndrome mapping to chromosome 17q21.31, Mohamed et al. (2013) analyzed the candidate gene MEOX1 and identified a homozygous 1-bp deletion (600147.0001) that segregated fully with the disease and was not found in 210 Saudi controls. Sequencing of the MEOX1 gene in affected sibs from an unrelated consanguineous family revealed homozygosity for a nonsense mutation (600147.0002).
In a consanguineous Turkish family segregating Klippel-Feil syndrome mapping to chromosome 17q12-q23, Bayrakli et al. (2013) identified a homozygous truncating mutation (Q84X; 600147.0003) in the MEOX1 gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
Bayrakli, F., Guclu, B., Yakicier, C., Balaban, H., Kartal, U., Erguner, B., Sagiroglu, M. S., Yuksel, S., Ozturk, A. R., Kazanci, B., Ozum, U., Kars, H. Z. Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype. BMC Genetics 14: 95, 2013. Note: Electronic Article. [PubMed: 24073994] [Full Text: https://doi.org/10.1186/1471-2156-14-95]
Chemke, J., Nisani, R., Fischel, R. E. Absent ulna in the Klippel-Feil syndrome: an unusual associated malformation. Clin. Genet. 17: 167-170, 1980. [PubMed: 7363502] [Full Text: https://doi.org/10.1111/j.1399-0004.1980.tb00127.x]
Clarke, R. A., Catalan, G., Diwan, A. D., Kearsley, J. H. Heterogeneity in Klippel-Feil syndrome: a new classification. Pediatr. Radiol. 28: 967-974, 1998. [PubMed: 9880643] [Full Text: https://doi.org/10.1007/s002470050511]
da-Silva, E. O. Autosomal recessive Klippel-Feil syndrome. J. Med. Genet. 19: 130-134, 1982. [PubMed: 7077623] [Full Text: https://doi.org/10.1136/jmg.19.2.130]
Erol, M., Caksen, H., Tan, O., Atik, B., Unal, O., Odabas, D. Report of a girl with Klippel-Feil syndrome and Poland anomaly. Genet. Counsel. 15: 469-472, 2004. [PubMed: 15658624]
Fragoso, R., Cid-Garcia, A., Hernandez, A., Nazara, Z., Cantu, J. M. Frontonasal dysplasia in the Klippel-Feil syndrome: a new associated malformation. Clin. Genet. 22: 270-273, 1982. [PubMed: 7151311] [Full Text: https://doi.org/10.1111/j.1399-0004.1982.tb01444.x]
Issaivanan, M., Virdi, V. S., Parmar, V. R. Subclavian artery supply disruption sequence-Klippel-Feil and Mobius anomalies. Indian J. Pediat. 69: 441-442, 2002. [PubMed: 12061681] [Full Text: https://doi.org/10.1007/BF02722639]
Juberg, R. C., Gershanik, J. J. Cervical vertebral fusion (Klippel-Feil) syndrome with consanguineous parents. J. Med. Genet. 13: 246-249, 1976. [PubMed: 933127] [Full Text: https://doi.org/10.1136/jmg.13.3.246]
Lubs, H. A., Jr., Gunderson, C. H., Greenspan, R. H. Genetic reevaluation of fused cervical vertebrae (Klippel-Feil anomaly). Clin. Res. 11: 179 only, 1963.
Mohamed, J. Y., Faqeih, E., Alsiddiky, A., Alshammari, M. J., Ibrahim, N. A., Alkuraya, F. S. Mutations in MEOX1, encoding mesenchyme homeobox 1, cause Klippel-Feil anomaly. Am. J. Hum. Genet. 92: 157-161, 2013. [PubMed: 23290072] [Full Text: https://doi.org/10.1016/j.ajhg.2012.11.016]
Ohashi, H., Wakui, K., Nishimoto, H., Sato, M., Aihara, T., Nishida, T., Fukushima, Y. Klippel-Feil syndrome and de novo balanced autosomal translocation [46,XX,t(5,17)(q11.2;q23)]. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A294 only, 1992.
Tracy, M. R., Dormans, J. P., Kusumi, K. Klippel-Feil syndrome: clinical features and current understanding of etiology. Clin. Orthop. Relat. Res. 424: 183-190, 2004. [PubMed: 15241163]