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.)
CFEOM2 Proposed Pathology
The surgical observations and examination of biopsy specimens taken at the time of strabismus surgery, as well as the results of CT and MRI scans of the brain and orbit, support our hypothesis that CFEOM2 results from maldevelopment of the entire motor division of cranial nerves III and IV.
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, last updated 6/13/2002 (entry number #602078). Home page: http://www3.ncbi.nlm.nih.gov/Omim/.
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.
Homozygous mutations in ARIX(PHOX2A) result in congenital fibrosis of the extraocular muscles type 2.
Yazdani A, Chung DC, Abbaszadegan MR, Al-Khayer K, Chan WM, Yazdani M, Ghodsi K, Engle EC, Traboulsi EI. A novel PHOX2A/ARIX mutation in an Iranian family with congenital fibrosis of extraocular muscles type 2 (CFEOM2). Am J Ophthalmol. 2003 Nov;136(5):861-5.
Learn about PHOX2A
In 2001, we identified PHOX2A as the gene mutated in CFEOM2.
PHOX2A is a homeodomain transcription factor protein has a primary role in the generation and survival of adrenergic neurons and a population of brainstem motor neurons, as well as in the determination of the noradrenergic neurotransmitter phenotype. In mice, Phox2a and its paralog Phox2b are co-expressed in the developing locus coeruleus, in parasympathetic, cranial sensory, sympathetic and enteric ganglia, in hindbrain branchiomotor and visceral motor neurons, and in midbrain nIII and nIV somatic motor nerons. Morin et al (1997) demonstrated that Phox2a -/- mice lack the oculomotor and trochlear nuclei, the locus coeruleus, parasympathetic ganglia in the head, and the superior cervical ganglion. In addition, cranial sensory ganglia that normally express Phox2a are severely affected.
Of these structures, only nIII/nIV are absent in Phox2a-/- mice but present in Phox2b-/-, indicating that nIII/nIV are the only Phox2a-dependent neurons that do not also require Phox2b for normal development.
The absence of nIII/nIV in the Phox2a-/- mice corresponds to the predicted neuropathology of CFEOM2, as the absence of these nuceli would account for the bilateral ptosis and restrictive exotropia in these affected individuals. We predict that CFEOM2 results from aberrant development of these motor nuclei [Nakano et al 2001].
Online Mendelian Inheritance in Man (OMIM). Victor A. McKusick, Editor, Johns Hopkins University, creation date 11/12/2003 (entry number *602753). Home page: http://www3.ncbi.nlm.nih.gov/Omim/.
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. Nat Genet. 2001 Nov;29(3):315-20.
Morin X, Cremer H, Hirsch MR, Kapur RP, Goridis C, Brunet JF. Defects in sensory and autonomic ganglia and absence of locus coeruleus in mice deficient for the homeobox gene Phox2a. Neuron. 1997 Mar;18(3):411-23.
Pattyn A, Morin X, Cremer H, Goridis C, Brunet JF. Expression and interactions of the two closely related homeobox genes Phox2a and Phox2b during neurogenesis. Development. 1997 Oct;124(20):4065-75
Guo S, Brush J, Teraoka H, Goddard A, Wilson SW, Mullins MC, Rosenthal A.. Development of noradrenergic neurons in the zebrafish hindbrain requires BMP, FGF8, and the homeodomain protein soulless/Phox2a. Neuron. 1999 Nov;24(3):555-66.