Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and Chiari malformation Type I in patients with hereditary disorders of connective tissue

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  • 1 Department of Neurosurgery, The Chiari Institute, North Shore-Long Island Jewish Health System, Manhasset, New York;
  • 2 Medical Genetics, NIH National Institute on Aging; and
  • 3 Harvey Institute for Medical Genetics, Greater Baltimore Medical Center, Baltimore, Maryland
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Object

Chiari malformation Type I (CM-I) is generally regarded as a disorder of the paraxial mesoderm. The authors report an association between CM-I and hereditary disorders of connective tissue (HDCT) that can present with lower brainstem symptoms attributable to occipitoatlantoaxial hypermobility and cranial settling.

Methods

The prevalence of HDCT was determined in a prospectively accrued cohort of 2813 patients with CM-I. All patients underwent a detailed medical and neuroradiological workup that included an assessment of articular mobility. Osseous structures composing the craniocervical junction were investigated morphometrically using reconstructed 3D computed tomography and plain x-ray images in 114 patients with HDCT/CM-I, and the results were compared with those obtained in patients with CM-I (55 cases) and healthy control individuals (55 cases).

Results

The diagnostic criteria for Ehlers–Danlos syndrome and related HDCT were met in 357 (12.7%) of the 2813 cases. Hereditability was generally compatible with a pattern of autosomal dominant transmission with variable expressivity. The diagnostic features of HDCT/CM-I were distinguished from those of CM-I by clinical stigmata of connective tissue disease, a greater female preponderance (8:1 compared with 3:1, p < 0.001), and a greater incidence of lower brainstem symptoms (0.41 compared with 0.11, p < 0.001), retroodontoid pannus formation (0.71 compared with 0.11, p < 0.001), and hypoplasia of the oropharynx (0.44 compared with 0.02, p < 0.001). Measurements of the basion–dens interval, basion–atlas interval, atlas–dens interval, dens–atlas interval, clivus–atlas angle, clivus–axis angle, and atlas–axis angle were the same in the supine and upright positions in healthy control individuals and patients with CM-I. In patients with HDCT/CM-I, there was a reduction of the basion–dens interval (3.6 mm, p < 0.001), an enlargement of the basion–atlas interval (3.0 mm, p < 0.001), and a reduction of the clivus–axis angle (10.8°, p < 0.001), clivus–atlas angle (5.8°, p < 0.001), and atlas–axis angle (5.3°, p < 0.001) on assumption of the upright position. These changes were reducible by cervical traction or returning to the supine position.

Conclusions

The identification of HDCT in 357 patients with CM-I establishes an association between two presumably unrelated mesodermal disorders. Morphometric evidence in this cohort—cranial settling, posterior gliding of the occipital condyles, and reduction of the clivus–axis angle, clivus–atlas angle, and atlas–axis angle in the upright position—suggests that hypermobility of the occipitoatlantal and atlantoaxial joints contributes to retroodontoid pannus formation and symptoms referable to basilar impression.

Abbreviations used in this paper:CCJ = craniocervical junction; CM-I = Chiari malformation Type I; CT = computed tomography; EDS = Ehlers–Danlos syndrome; HDCT = hereditary disorders of connective tissue; KPS = Karnofsky Performance Scale; MASS = mitral valve, aorta, skeleton, and skin; MR = magnetic resonance; POTS = postural orthostatic tachycardia syndrome; SD = standard deviation; TGFβ = transforming growth factor–β.

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Contributor Notes

Address correspondence to: Thomas H. Milhorat, M.D., Department of Neurosurgery, The Chiari Institute, Harvey Cushing Institutes of Neuroscience, North Shore–LIJ Health System, 300 Community Drive, Manhasset, New York 11030. email: Milhorat@nshs.edu.
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