The purpose of this study is to better understand the genetic factors related to the Chiari I
malformation. In people with this abnormality, the lower part of the skull is smaller than
normal. As a result, the lowest part of the brain, called the cerebellar tonsils, protrudes
out of the hole at the bottom of the skull into the spinal canal. This study will try to
discover the location of the genes responsible for the malformation.
Candidates for this study are: 1) Patients with Chiari I malformation who also have a family
member with the abnormality or a family member with syringomyelia (a cyst in the spinal cord
that is often associated with the Chiari I malformation). 2) Family members of patients with
the Chiari I malformation.
Participants will have a medical history and physical and neurologic examinations. They will
undergo magnetic resonance imaging (MRI) of the brain and cervical (neck) spinal cord to
measure the size of the head and determine the presence of the Chiari I malformation and
syringomyelia. A small blood sample (about 2 tablespoons) will be drawn for DNA studies
relating to the Chiari I malformation.
Objectives: The goal of this study is to establish family pedigrees and undertake genetic
linkage analysis that will identify gene loci associated with the Chiari I malformation and
underdevelopment of the bone forming the posterior cranial fossa.
Study Population: Patients and family members of patients with the Chiari I malformation.
Because the research institutions are located in the United States and Russia, subjects will
be recruited predominantly from these countries.
Design: Human subjects will undergo 1) neurologic examinations, 2) head and cervical MRI
scans to evaluate for the Chiari I malformation, syringomyelia, and maldevelopment of the
posterior fossa, and 3) isolation and analysis of genomic DNA from whole blood for linkage
Outcome Measures: Pedigrees will be established based on the MRI findings. The Chiari I
phenotype will be defined as the caudal portion of the cerebellar tonsils lying greater than
or equal to 2 mm below the foramen magnum and underdevelopment of the bone of the posterior
fossa will be defined as 1) obliteration of the CSF pathways in the inferior portion of the
posterior fossa, 2) posterior fossa volume to supratentorial volume ratio of less than or
equal to 15%, or 3) abnormal shortening of the bones of the skull base. Genetic analysis of
the genomic DNA will be performed with DNA polymorphic markers to identify chromosomal loci
linked to the small posterior fossa phenotype. A lod score of 3.0 (equivalent to 1000:1 odds
in favor of linkage) will be taken as proof that the Chiari I gene maps to the same genetic
region of the human genome as a given DNA marker.
- INCLUSION CRITERIA:
To be eligible for entry into the study, a candidate must meet the following criteria:
Patient with the Chiari I malformation who has a family member with syringomyelia or Chiari
I malformation, or
Family member of a patient with the Chiari I malformation, AND
There are at least two family members diagnosed with Chiari I malformation.
If an adult, able to give informed consent; if a minor, has an adult who is legally
responsible for the subject and who is able to give consent.
A candidate will be excluded if he:
Has a contraindication to MRI scanning.
Is unable to comprehend the risks of the testing.
Is less than one year of age.
Cannot undergo MRI scanning without sedation.