Related Disorders List

Information on the following diseases can be found in the Related Disorders section of this report:

• Strabismus
• Brown syndrome
• Duane syndrome

Symptoms

CFEOM is frequently associated with a droopy eyelid(s) (ptosis), and, depending on the subtype, may affect one (unilateral) or both (bilateral) eyes. Affected eyes are fixed below the horizontal midline, with limited or no ability to move upward. The ability to move the eyes downward or horizontally ranges from normal to severely limited. Individuals with CFEOM often elevate the chin to compensate for the downward fixation of their eyes, so they can see. The disorder is not progressive: It does not worsen over time.

Prior to genetic studies of CFEOM, this group of conditions was defined clinically, and each variation on its presentation was thought to be a distinct disorder. It is now clear that, in some cases, there can be variable expression of CFEOM within the same family, suggesting that there may be a range of possible clinical presentations for the same genetic defect. For this reason, subclassification of CFEOM based on clinical criteria is being replaced by a combination of gene location and clinical information, as the molecular basis of these conditions becomes known.

Causes

Theories suggest that congenital fibrosis of the extraocular muscles may stem from a disorder of cranial nerve III (oculomotor nerve) and/or the muscles it supplies. Genetics, and possibly environmental factors, are known to play a role. MRI and other studies of individuals with classic CFEOM have shown irregularities in the oculomotor nerve, which normally branches into superior and inferior divisions. The superior division innervates the eyelid muscle and the muscle that moves the eyeball upward, both of which are dysfunctional in individuals with classic CFEOM. These studies suggest a nerve-related (neurogenic) rather than muscle-related (myopathic) cause for CFEOM.

To date, three genetic locations (CFEOM 1-3) have been identified that contain a gene for CFEOM, and others are anticipated. All individuals affected with CFEOM are born with a non-progressive eye movement disorder characterized by variable expression of droopy eyelids (ptosis) and restrictive ability to move the eyes.

CFEOM1 is found on chromosome 12. The medical literature lists nine families that map to this location, seven of whom exhibit the classic form of CFEOM. Affected individuals are born with bilateral ptosis with both eyes partially or completely fixed in a downward position. There is an inability to raise the eyes above the horizontal midline, and horizontal movement ranges from normal to severely limited. Classic CFEOM is inherited in a dominant fashion, does not skip generations (it is "fully penetrant"), and is thought to be the most prevalent type of CFEOM. However, there are two families whose CFEOM gene maps to the chromosome 12 location (CFEOM1 locus) but who do not have a classic CFEOM presentation. One shows a recessive mode of inheritance and a presentation similar to CFEOM2, and the other shows variable expression of CFEOM ranging from very mild to classic, and possibly incomplete penetrance. (CFEOM may skip generations.)

CFEOM2 is found on chromosome 11 and has been identified in three families, each the result of interfamily marriage (consanguinity). Affected individuals in these families are born with bilateral ptosis (both eyes have droopy lids) and with their eyes partially or completed fixed in an outward (exotropic) position. Eye movements are severely limited or absent in all directions. CFEOM2 is inherited in a recessive fashion.

CFEOM3 is found on chromosome 16 and has been identified in one large Canadian kindred. In this CFEOM3 family, there is a marked variability of clinical presentation. Severely affected individuals are born with bilateral ptosis, with eyes fixed in a downward and outward position, and with marked restriction of movement in both eyes. Mildly affected individuals have normally positioned eyes but a limitation of vertical (upward) gaze. Moderately affected individuals have asymmetrical involvement with one eye severely and one eye mildly affected. The disorder in this family exhibits dominant inheritance, but is variably expressed in affected individuals and may skip a generation. (It may show incomplete penetrance.)

Affected Populations

CFEOM is a very rare disorder that has been seen in a range of diverse ethnic populations. It affects both males and females.

Related Disorders

Strabismus is a common group of eye movement disorders in which the eyes are not properly yoked together and one or both eyes are misaligned and cannot be voluntarily controlled. Strabismus is either concomitant or incomitant. Concomitant strabismus occurs when the misalignment, or the angle of deviation between the two eyes, remains constant and independent of the direction of gaze. Strabismus is incomitant when the misalignment varies with gaze direction. Extraocular (outside of the eye) fibrosis syndromes are grouped under incomitant strabismus and include Duane syndrome, Brown Syndrome, and the congenital fibrosis of the extraocular muscles (CFEOM) syndromes. There are many causes of strabismus, and treatments may include surgery, injections that paralyse the eye muscle, and eye patching. Strabismus may be an isolated finding or found in association with other birth defects.

Brown syndrome is a condition that falls under the heading of extraocular fibrosis syndromes. It is a rare eye movement disorder in which the affected eye is unable to look inward towards the nose (adduction) and up, may be out of alignment with the unaffected eye, and may show a downshoot. Symptoms may also include a widening of the eye opening (palpebral fissure) when the eye is directed inward and up. When the individual is looking straight ahead, the affected eye may face downward. (For more information on this disorder, choose "Brown Syndrome" as your search term in the Rare Disease Database.)

Duane syndrome (DS) is an eye movement disorder present at birth that is characterized by a limited ability to move the eye inward toward the nose, outward toward the ear, or in both directions. In addition, when the affected eye(s) move inward toward the nose, the eyeball retracts (pulls in) and the eye opening narrows. In some cases, when the eye attempts to look inward, it moves upward or downward. (For more information on this disorder, choose "Duane Syndrome" as your search term in the Rare Disease Database.

Standard Therapies

Diagnosis
The diagnosis of CFEOM is made by a thorough eye examination, with special attention to the presence of other eye or systemic malformations. Measurements of the ocular (eye) misalignment, ocular range of motion, head turn, glove (eyeball) retraction, palpebral fissure (eye opening) size, and upward and downward movement of the eye are taken. Forced duction (the rotation of the eye by its extraocular muscles) and vision tests are also recommended.

Treatment
The standard management of CFEOM may involve surgery. The goal of surgery is the elimination or improvement of an unacceptable head position, the reduction of ptosis (eyelid droop), and the elimination or reduction of significant misalignment of the eyes. Successful surgery at a young age may avoid loss of vision (amblyopia) in one or both eyes. However, surgery does not eliminate the fundamental abnormality, and no surgical technique has been completely successful in eliminating the abnormal eye movements. The choice of procedure must be individualized.

Investigational Therapies

Genetic research studies are in progress at the Engle Laboratory at Boston's Children's Hospital to identify and characterize the gene(s) involved in CFEOM. With funding from the National Institutes of Health (NIH), Dr. Elizabeth Engle, a pediatric neurologist and genetic researcher, is leading a research team conducting family linkage studies to identify genes involved in rare eye movement disorders that are present at birth. The research team is interested in enrolling families in which there are two or more family members with the same eye disorder, all of whom are willing to participate. Participation requires giving the laboratory access to eye examination records and donating a small sample of blood. For information, contact:

Nathalie McIntosh
Division of Genetics, Enders 5
Children's Hospital
300 Longwood Avenue
Boston, MA 02115
(617) 355-7311
mcintosh@rascal.med.harvard.edu

NORD does not promote, endorse, or encourage participation in any specific medical research study. This information is presented to further scientific understanding that could lead to the prevention, treatment, and/or cure of rare disorders.

This disease entry is based upon medical information available through June 2000. Since NORD's resources are limited, it is not possible to keep every entry in the Rare Disease Database current and accurate. Please check with the agencies listed in the Resources section for the most current information about this disorder.

References

Engle E, The Genetics of Strabismus: Duane, Moebius, and Fibrosis Syndromes. In: Traboulsi E , ed., Genetic Diseases of the Eye: A Textbook and Atlas. New York: Oxford University Press; 1998:477-512.

Sener EC, Lee BA, Turgu B, Akarsu AN, Engle EC, New clinical variation of a fibrosis syndrome in a Turkish family maps to the CFEOM1 locus on chromosome 12. Archives Ophthal (in press):2000.

Traboulsi E, Lee B, Mousawi A, Khamis A, Engle E, Evidence of genetic heterogeneity in autosomal recessive Congenital Fibrosis of the Extraocular Muscles (CFEOM). Am J Ophthal (in press):2000.

Doherty E, Macy M, Wang S, Dykeman C, Melanson M, Engle E, CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3. Investi Ophthal and Visual Sci. 1999;40:1687-94.

Sang S, Zwaan J, Mullaney P, Jabak M, Al-Awad A, Beggs A, Engle E, Congenital fibrosis of the extraocular muscles type 2 (CFEOM2), an inherited exotropic strabismus fixus, maps to distal 11q13. Am J Human Genet. 1998;63:517-25.

Engle EC, Marondel I, Houtman WA, de Vries B, Lowenstein A, Lazar M, Ward DC, et al, Congenital fibrosis of the extraocular muscles (autosomal dominant congenital external ophthalmoplegia): genetic homogeneity, linkage refinement, and physical mapping on chromosome 12. Am J Human Genet. 1995;57:1086-94.

Laughlin RC, Congenital fibrosis of the extraocular muscles; a report of six cases, Am J Ophthal 1956;41:432-38.