August 12, 2020
Years published: 2000, 2010, 2013
NORD gratefully acknowledges Elizabeth C. Engle, MD, Professor of Neurology and Ophthalmology, Harvard Medical School and Children’s Hospital Boston; Investigator, Howard Hughes Medical Institute, for assistance in the preparation of this report.
Congenital fibrosis of the extraocular muscles (CFEOM) includes at least five rare genetic eye movement disorders present at birth that are characterized by incomitant strabismus. Specifically, there is an inability to move the eyes in certain directions (opthalmoplegia), droopy eyelids (ptosis) and eyes that are fixed in an abnormal position. The oculomotor nucleus and nerve (cranial nerve III) and the muscles it serves and, in some cases the trochlear nucleus and nerve (cranial nerve IV) and/or the abducens nucleus and nerve (cranial nerve VI) and the muscles they serve are affected.
Affected individuals have limited ability to move their eyes vertically (upward and downward) and can have variable limitations in moving their eyes horizontally. CFEOM is also frequently associated with droopy eyelids (ptosis) and eyes that are fixed in an abnormal position. Individuals with CFEOM often have their eyes fixed in a downward position, and elevate the chin so they can see. These disorders have been classified as CFEOM1, CFEOM2, and CFEOM3 based on ophthalmologic findings and molecular genetic testing. CFEOM3 can be characterized by additional involvement of the peripheral and central nervous system in addition to the eye findings. Tukel syndrome is characterized by missing and webbed fingers and toes in addition to the eye findings. These disorders do not worsen over time.
CFEOM 1 and CFEOM 3 are inherited as autosomal dominant genetic conditions. CFEOM 2 and Tukel syndrome are inherited as autosomal recessive genetic conditions.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
Several genes have been found to be associated with the CFEOM syndromes:
KIF21A gene – CFEOM 1 and rarely CFEOM 3
PHOX2A gene – CFEOM 2
TUBB3 gene – CFEOM3 and rarely CFEOM1, and can be associated with additional findings, referred to as the TUBB3 syndromes.
TUBB2B gene – CFEOM3 in association with polymicrogyria
FEOM4 locus on chromosome 13 – CFEOM 3
TUKLS locus on chromosome 21 – Tukel syndrome
CFEOM are rare disorders that have been seen in a range of diverse ethnic populations and affect males and females. A minimum prevalence has been estimated to be 1 in 230,000.
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.
Molecular genetic testing is available to identify mutations in the KIF21A, PHOX2A, TUBB3, and TUBB2B genes and confirms the diagnosis.
Eyeglasses and contact lenses are used to treat focusing problems (refractive errors). Reduced vision that is not correctable by these devices (amblyopia) can be treated by making the child use the eye with the reduced vision. This can be done by inserting a drop of atropine in the stronger eye once a day to temporarily blur the vision so that the child will prefer to use the eye with amblyopia or by placing a patch over the stronger eye.
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, and the elimination or reduction of significant misalignment of the eyes. Successful surgery at a young age may avoid loss of vision 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.
Genetic research studies are in progress at the Engle Laboratory at Boston 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 genetic studies to identify genes involved in rare eye movement disorders that are present at birth. The research team is interested in enrolling individuals who would like to participate. Participation requires giving the laboratory access to pertinent medical records and donating a small sample of blood. Contact Caroline Andrews ([email protected] or 617- 919-2168) to obtain further information about these studies or if you are interested in enrolling a patient or participating yourself. Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov.
All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact:
Contact for additional information about congenital fibrosis of the extraocular muscles:
Elizabeth C. Engle, MD
Professor of Neurology and Ophthalmology
Children’s Hospital Boston, CLS14075
300 Longwood Ave
Boston, MA 02115
e-mail: [email protected]
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Nugent AA, Kolpak LA, Engle EC. Human disorders of axon guidance. Curr Opin Neurobiol. 2012 Mar 5. [Epub ahead of print]. PubMed # 22398400 NIHMSID #363464
Tischfield MA, Cederquist GY, Gupta ML Jr, Engle EC. Phenotypic spectrum of the tubulin-related disorders and functional implications of disease-causing mutations. Curr Opin Genet Dev. 2011 Jun;21(3):286-94. Epub 2011 Feb 1. PMCID: PMC3100401
Engle EC. Human genetic disorders of axon guidance. Cold Spring Harbor Perspect. Biol. 2010 Mar;2(3):a001784. PMCID: PMC2829956
Cederquist GY, Luchniak A, Tischfield MA, et al. An inherited TUBB2B mutation alters a kinesin binding site and causes polymicrogyria, CFEOM, and axon dysinnervation. Human Molecular Genetics. 2012, Sept 21 (epub ahead of print) in press.
Tischfield, M.A., Baris, H.N., Wu, C., et al. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell. 2010 Jan 8;140(1):74-87. PMCID: PMC3164117
Yamada K, Chan W-M, Andrews C, et al. Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A. Brain. 2006;129(9):2363-74. Epub 2006 Jun 30.
Aubourg P, Krahn M, Bernard R, et al. Assignment of a new congenital fibrosis of extraocular muscles type 3 (CFEOM3) locus, FEOM4, based on a balanced translocation t(2;13) (q37.3;q12.11) and identification of candidate genes. J Med Genet. 2005; 42: 253-9.
Demer JL, Clark RA, Engle EC. Magnetic resonance imaging evidence for widespread orbital dysinnervation in congenital fibrosis of extraocular muscles due to mutations in KIF21A. Investigative Ophthalmology & Visual Science. 2005 Feb;46(2):530-9.
Tukel T, Uzumcu A, Gezer A, et al. A new syndrome, congenital extraocular muscle fibrosis with ulnar hand anomalies, maps to chromosome 21qter. J Med Genet. 2005; 42: 408-15.
Engle EC. KIF21A mutations are a rare cause of congenital fibrosis of the extraocular muscles type 3. Investigative Ophthalmology & Visual Science. 2004;45:2218-2223.
Yamada K, Andrews C, Chan W-M, et al. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nature Genetics. 2003;35:318-321.
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;29:315-320.
Traboulsi EI, Lee BA, Mousawi A et al. Evidence of genetic heterogeneity in autosomal recessive congenital fibrosis of the extraocular muscles. Am J Ophthalmol. 2000;129: 658-62.
Engle EC, Goumernov BC, McKeown CA, Schatz M, Johns DR, Porter JD, Beggs AH. Oculomotor Nerve and Muscle Abnormalities in Congenital Fibrosis of the Extraocular Muscles. Annals of Neurology. 1997;41:314-25.
Andrews, CV, Desai J, Hunter DG, and Engle EC. (Updated:December 29, 2011). Congenital Fibrosis of the Extraocular Muscles. In: GeneReveiws at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2013. Available at http://www.genetests.org Accessed:March 21, 2013.
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