Individuals with CFEOM2 share a non-classic CFEOM phenotype. Affected individuals are born with bilateral ptosis (droopy lids), with their eyes partially or completely fixed in an outward (exotropic) position. Eye movements are severely limited or absent in all directions, and forced duction testing is positive for restriction. In addition, pupils are often small and non-reactive.

The clinical characterization and enrollment of CFEOM2 families involved much work by our collaborators in the Middle East. In total, we have identified four Saudi Arabian and one Iranian pedigree with CFEOM2. The families are consanguineous (contain interfamily marriages) and the CFEOM phenotype is inherited in an autosomal recessive fashion.

We mapped CFEOM2 to the FEOM2 locus on chromosome 11q13. This was identified using the technique of linkage analysis. After defining the critical region of the FEOM2 disease gene, we evaluated candidate genes within the FEOM2 region and in 2001 reported PHOX2A (previously known as ARIX) to be the gene mutated in this form of CFEOM. Thus far, we have identified four unique homozygous mutations in PHOX2A, two splice site mutations, one missense mutation, and one nonsense mutation.

CFEOM2 PROPOSED PATHOLOGY:
The diagram below details the proposed pathology for CFEOM2. It shows an absence of the motoneurons in all of the oculomotor and trochlear nuclei, with corresponding absence of cranial nerves III and IV and abnormalities of the innervated muscles. (Refer to eye muscle and nerve anatomy to review the normal lateral eye.)

Please contact Caroline Andrews to obtain further information on the genetic studies that we are undertaking and if you are interested in enrolling a patient or participating yourself.

Nakano M, Yamada K, Fain J, Sener EC, Selleck CJ, Awad AH, Zwaan J, Mullaney PB, Bosley TM, Engle EC. Homozygous mutations in ARIX (PHOX2A) result in congenital fibrosis of the extraocular muscles type 2 (CFEOM2). Nature Genetics, 2001 Nov;29(3):315-20.