Klippel-Feil Syndrome

name: Klippel-Feil Syndrome
creation_date: "2026-06-29T00:00:00Z"
category: Mendelian
description: >-
  Klippel-Feil syndrome (KFS) is a congenital axial-skeleton malformation
  defined by failure of segmentation of the cervical spine, producing fusion of
  two or more cervical vertebrae. The classic clinical triad is a short neck,
  low posterior hairline, and restricted neck mobility, often with scoliosis,
  Sprengel deformity, and cranial-base anomalies. It is an axial serial-homology
  disorder: the cervical vertebrae are serially repeated somite (sclerotome)
  derivatives, and KFS represents a failure of the somite-boundary / resegmentation
  program that normally separates adjacent vertebrae. Autosomal recessive KFS is
  caused by biallelic loss-of-function variants in MEOX1, a homeobox
  transcription factor with a nonredundant role in somite development and
  sclerotome polarity; autosomal dominant forms are caused by GDF6 and GDF3
  (BMP-family) variants. KFS conforms to the axial-skeleton serial-homology
  module at its somite-boundary and vertebral-malsegmentation nodes.
disease_term:
  preferred_term: Klippel-Feil syndrome
  term:
    id: MONDO:0001029
    label: Klippel-Feil syndrome
parents:
- Vertebral Malformation Disorders
inheritance:
- name: Autosomal Recessive
  description: >-
    Autosomal recessive KFS is caused by biallelic truncating variants in MEOX1.
    Autosomal dominant forms caused by GDF6 and GDF3 variants also occur.
  evidence:
  - reference: PMID:24073994
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait.
    explanation: >-
      Documents autosomal recessive inheritance via a truncating MEOX1 variant in
      a consanguineous KFS family.
prevalence:
- population: General
  prevalence_class: UNKNOWN
  percentage: Unknown
  notes: >-
    KFS is rare and mostly sporadic; familial cases (including the autosomal
    recessive MEOX1 subtype) are uncommon and described in consanguineous
    families. Formal population-prevalence estimates are not well established.
pathophysiology:
- name: MEOX1 Somite and Sclerotome Polarity Defect
  conforms_to: "axial_segmentation_serial_homology#Disrupted Somite Boundary Formation"
  description: >-
    Loss of MEOX1, a homeobox transcription factor with a nonredundant role in
    somite development, disrupts sclerotome polarity and the somite-boundary /
    resegmentation program in the paraxial mesoderm. KFS is the human phenotypic
    equivalent of the sclerotome polarity defect seen in Meox1-null mice.
    Autosomal dominant forms perturb the same axial-segmentation program via the
    BMP-family genes GDF6 and GDF3.
  role: central_effector
  genes:
  - preferred_term: MEOX1
    term:
      id: hgnc:7013
      label: MEOX1
  - preferred_term: GDF6
    term:
      id: hgnc:4221
      label: GDF6
  - preferred_term: GDF3
    term:
      id: hgnc:4218
      label: GDF3
  cell_types:
  - preferred_term: Presomitic (Paraxial) Mesoderm Cell
    term:
      id: CL:0011007
      label: paraxial cell
  biological_processes:
  - preferred_term: Somitogenesis
    term:
      id: GO:0001756
      label: somitogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23290072
    supports: SUPPORT
    evidence_source: OTHER
    snippet: This gene encodes a transcription factor with a well-established and nonredundant role in somite development
    explanation: >-
      Establishes MEOX1 as a transcription factor with a nonredundant role in
      somite development, the mechanism disrupted in KFS.
  - reference: PMID:23290072
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: KFS is the human phenotypic equivalent of the sclerotome polarity defect that results from Meox1 deficiency in mice.
    explanation: >-
      Identifies KFS as the human equivalent of the Meox1-null sclerotome
      polarity defect, the somite-boundary mechanism. Evidence source is
      MODEL_ORGANISM (mouse).
  downstream:
  - target: Cervical Vertebral Fusion
    description: Failure of the somite-boundary / resegmentation program leaves adjacent cervical vertebrae fused.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - failure of sclerotome resegmentation between adjacent somites
- name: Cervical Vertebral Fusion
  conforms_to: "axial_segmentation_serial_homology#Vertebral and Costal Malsegmentation"
  description: >-
    The somite-boundary defect manifests as a segmentation malformation of the
    cervical spine: two or more cervical vertebrae fail to separate and remain
    fused, frequently accompanied by scoliosis, Sprengel deformity, and
    cranial-base malformations. Because the vertebrae are serially homologous
    somite derivatives, the malsegmentation typically involves multiple
    contiguous segments.
  role: consequence
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  - preferred_term: Osteoblast
    term:
      id: CL:0000062
      label: osteoblast
  biological_processes:
  - preferred_term: Embryonic Skeletal System Morphogenesis
    term:
      id: GO:0048704
      label: embryonic skeletal system morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23290072
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine
    explanation: >-
      Defines KFS as a segmentation malformation of the cervical spine, the
      consequence of the somite-boundary defect.
  - reference: PMID:24073994
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel's deformity
    explanation: >-
      Documents the multi-segment axial malformation bundle — cervical fusion,
      scoliosis, cranial-base anomalies, and Sprengel deformity.
phenotypes:
- name: Cervical Vertebral Fusion
  description: Fusion of two or more cervical vertebrae from failed segmentation.
  phenotype_term:
    preferred_term: Cervical segmentation defect
    term:
      id: HP:0004632
      label: Cervical segmentation defect
  evidence:
  - reference: PMID:24073994
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: fusion defects and numerical abnormalities in the cervical spine
    explanation: KFS is characterized by cervical vertebral fusion defects.
- name: Short Neck
  description: A short neck with reduced mobility, part of the classic KFS triad.
  phenotype_term:
    preferred_term: Short neck
    term:
      id: HP:0000470
      label: Short neck
  evidence:
  - reference: PMID:23290072
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: short neck with reduced mobility
    explanation: Short neck with reduced mobility is a defining feature of KFS.
- name: Low Posterior Hairline
  description: A low posterior hairline, part of the classic KFS triad.
  phenotype_term:
    preferred_term: Low posterior hairline
    term:
      id: HP:0002162
      label: Low posterior hairline
  evidence:
  - reference: PMID:23290072
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: low posterior hairline
    explanation: A low posterior hairline is part of the classic KFS clinical triad.
- name: Scoliosis
  description: Scoliosis frequently accompanies the cervical segmentation defect.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:24073994
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: fusion defects and numerical abnormalities in the cervical spine, scoliosis
    explanation: Scoliosis is documented among the axial malformations in KFS.
- name: Sprengel Anomaly
  description: Congenital elevation of the scapula (Sprengel deformity) is a recognized association.
  phenotype_term:
    preferred_term: Sprengel anomaly
    term:
      id: HP:0000912
      label: Sprengel anomaly
  evidence:
  - reference: PMID:24073994
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: malformations of the cranial base, and Sprengel's deformity
    explanation: Sprengel deformity is documented in the KFS phenotype.
treatments:
- name: Physical Therapy
  description: >-
    Symptomatic management with physical therapy to maintain mobility and manage
    neck and back pain; the mainstay of KFS care is symptomatic.
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Cervical Spine Surgical Stabilization
  description: >-
    Surgical stabilization or decompression for cervical instability, neurologic
    compromise, or significant scoliosis.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure