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Congenital fibrosis of the extraocular muscles

Reviewed March 2009

What is congenital fibrosis of the extraocular muscles?

Congenital fibrosis of the extraocular muscles is a disorder that affects the muscles that surround the eyes. These muscles control eye movement and the position of the eyes (for example, looking straight ahead). Congenital fibrosis of the extraocular muscles prevents the normal development and function of these muscles. As a result, affected individuals are unable to move their eyes normally. Most people with this condition have difficulty looking upward, and their side-to-side eye movement may also be limited. The eyes may be misaligned such that they look in different directions (strabismus). Instead of moving their eyes, affected individuals may need to turn their head to track moving objects. Additionally, many people with congenital fibrosis of the extraocular muscles have droopy eyelids (ptosis), which further limits their vision.

Researchers have identified at least four forms of congenital fibrosis of the extraocular muscles, designated CFEOM1, CFEOM2, CFEOM3, and Tukel syndrome. The specific problems with eye movement vary among the types. Tukel syndrome is characterized by missing fingers (oligodactyly) and other hand abnormalities in addition to problems with eye movement.

How common is congenital fibrosis of the extraocular muscles?

CFEOM1 is the most common form of congenital fibrosis of the extraocular muscles, affecting at least 1 in 230,000 people. CFEOM1 and CFEOM3 have been reported worldwide, whereas CFEOM2 has been seen in only a few families of Turkish, Saudi Arabian, and Iranian descent. Tukel syndrome appears to be very rare; it has been diagnosed in only one large Turkish family.

What genes are related to congenital fibrosis of the extraocular muscles?

CFEOM1 and rare cases of CFEOM3 result from mutations in the KIF21A gene. This gene provides instructions for making a protein called a kinesin, which is essential for the transport of materials within cells. Researchers believe that this protein plays an important role in the normal development and function of nerves in the head and face. In particular, this protein plays a critical role in the development of a particular branch of cranial nerve III, which emerges from the brain and controls muscles that raise the eyes and eyelids. Mutations in the KIF21A gene likely alter the protein's ability to transport materials within nerve cells, preventing the normal development of these cranial nerves and the extraocular muscles they control. Abnormal function of the extraocular muscles leads to restricted eye movement and related problems with vision.

Mutations in the PHOX2A gene cause CFEOM2. This gene provides instructions for making a protein that is found in the developing nervous system. Studies suggest that the PHOX2A protein plays a critical role in the development of cranial nerves III and IV, which are necessary for normal eye movement. Mutations likely eliminate the function of the PHOX2A protein, which prevents the normal development of these cranial nerves and the extraocular muscles they control.

In most cases of CFEOM3, the genetic cause of the condition is unknown. Studies suggest that a gene associated with CFEOM3 may be located near one end of chromosome 16. The gene associated with Tukel syndrome has not been identified either, although researchers think that it may be located near one end of chromosome 21.

Related Gene(s)

Changes in these genes are associated with congenital fibrosis of the extraocular muscles.

  • KIF21A
  • PHOX2A

How do people inherit congenital fibrosis of the extraocular muscles?

The different types of congenital fibrosis of the extraocular muscles have different patterns of inheritance. CFEOM1 and CFEOM3 are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

CFEOM2 is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. Tukel syndrome also appears to have an autosomal recessive pattern of inheritance, although the genetic change responsible for this disorder is unknown.

Where can I find information about diagnosis or management of congenital fibrosis of the extraocular muscles?

These resources address the diagnosis or management of congenital fibrosis of the extraocular muscles and may include treatment providers.

  • Gene Review: Congenital Fibrosis of the Extraocular Muscles (http://www.ncbi.nlm.nih.gov/books/NBK1348)
  • Genetic Testing Registry: congenital fibrosis of the extraocular muscles (http://www.ncbi.nlm.nih.gov/gtr/conditions/CN043677)
  • Genetic Testing Registry: Fibrosis of extraocular muscles, congenital, 1 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1851102)
  • Genetic Testing Registry: Fibrosis of extraocular muscles, congenital, 2 (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1865915)
  • Genetic Testing Registry: Fibrosis of extraocular muscles, congenital, 3a, with or without extraocular involvement (http://www.ncbi.nlm.nih.gov/gtr/conditions/C2748801)
  • Genetic Testing Registry: Tukel syndrome (http://www.ncbi.nlm.nih.gov/gtr/conditions/C1836217)
  • MedlinePlus Encyclopedia: Extraocular Muscle Function Testing (http://www.nlm.nih.gov/medlineplus/ency/article/003397.htm)
  • MedlinePlus Encyclopedia: Strabismus (http://www.nlm.nih.gov/medlineplus/ency/article/001004.htm)

You might also find information on the diagnosis or management of congenital fibrosis of the extraocular muscles in Educational resources (http://ghr.nlm.nih.gov/condition/congenital-fibrosis-of-the-extraocular-muscles/show/Educational+resources) and Patient support (http://ghr.nlm.nih.gov/condition/congenital-fibrosis-of-the-extraocular-muscles/show/Patient+support).

General information about the diagnosis (http://ghr.nlm.nih.gov/handbook/consult/diagnosis) and management (http://ghr.nlm.nih.gov/handbook/consult/treatment) of genetic conditions is available in the Handbook. Read more about genetic testing (http://ghr.nlm.nih.gov/handbook/testing), particularly the difference between clinical tests and research tests (http://ghr.nlm.nih.gov/handbook/testing/researchtesting).

To locate a healthcare provider, see How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

Where can I find additional information about congenital fibrosis of the extraocular muscles?

You may find the following resources about congenital fibrosis of the extraocular muscles helpful. These materials are written for the general public.

You may also be interested in these resources, which are designed for healthcare professionals and researchers.

What other names do people use for congenital fibrosis of the extraocular muscles?

  • CFEOM
  • congenital external ophthalmoplegia
  • congenital fibrosis of extraocular muscles
  • congenital fibrosis syndrome
  • general fibrosis syndrome

For more information about naming genetic conditions, see the Genetics Home Reference Condition Naming Guidelines (http://ghr.nlm.nih.gov/ConditionNameGuide) and How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What if I still have specific questions about congenital fibrosis of the extraocular muscles?

Ask the Genetic and Rare Diseases Information Center (http://rarediseases.info.nih.gov/GARD/).

What glossary definitions help with understanding congenital fibrosis of the extraocular muscles?

autosomal ; autosomal dominant ; autosomal recessive ; cell ; chromosome ; congenital ; cranial nerves ; extraocular muscles ; fibrosis ; gene ; inheritance ; inherited ; mutation ; nervous system ; oligodactyly ; ophthalmoplegia ; pattern of inheritance ; protein ; ptosis ; recessive ; strabismus ; syndrome

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://ghr.nlm.nih.gov/glossary).

References

  • Aubourg P, Krahn M, Bernard R, Nguyen K, Forzano O, Boccaccio I, Delague V, De Sandre-Giovannoli A, Pouget J, Depétris D, Mattei MG, Philip N, Lévy N. 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 Mar;42(3):253-9. (http://www.ncbi.nlm.nih.gov/pubmed/15744040?dopt=Abstract)
  • Bosley TM, Oystreck DT, Robertson RL, al Awad A, Abu-Amero K, Engle EC. Neurological features of congenital fibrosis of the extraocular muscles type 2 with mutations in PHOX2A. Brain. 2006 Sep;129(Pt 9):2363-74. Epub 2006 Jun 30. (http://www.ncbi.nlm.nih.gov/pubmed/16815872?dopt=Abstract)
  • 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. Invest Ophthalmol Vis Sci. 2005 Feb;46(2):530-9. (http://www.ncbi.nlm.nih.gov/pubmed/15671279?dopt=Abstract)
  • Doherty EJ, Macy ME, Wang SM, Dykeman CP, Melanson MT, Engle EC. CFEOM3: a new extraocular congenital fibrosis syndrome that maps to 16q24.2-q24.3. Invest Ophthalmol Vis Sci. 1999 Jul;40(8):1687-94. (http://www.ncbi.nlm.nih.gov/pubmed/10393037?dopt=Abstract)
  • Heidary G, Engle EC, Hunter DG. Congenital fibrosis of the extraocular muscles. Semin Ophthalmol. 2008 Jan-Feb;23(1):3-8. doi: 10.1080/08820530701745181. Review. (http://www.ncbi.nlm.nih.gov/pubmed/18214786?dopt=Abstract)
  • Lu S, Zhao C, Zhao K, Li N, Larsson C. Novel and recurrent KIF21A mutations in congenital fibrosis of the extraocular muscles type 1 and 3. Arch Ophthalmol. 2008 Mar;126(3):388-94. doi: 10.1001/archopht.126.3.388. (http://www.ncbi.nlm.nih.gov/pubmed/18332320?dopt=Abstract)
  • Mackey DA, Chan WM, Chan C, Gillies WE, Brooks AM, O'Day J, Engle EC. Congenital fibrosis of the vertically acting extraocular muscles maps to the FEOM3 locus. Hum Genet. 2002 May;110(5):510-2. Epub 2002 Mar 23. (http://www.ncbi.nlm.nih.gov/pubmed/12073023?dopt=Abstract)
  • 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. (http://www.ncbi.nlm.nih.gov/pubmed/11600883?dopt=Abstract)
  • Sener EC, Lee BA, Turgut B, Akarsu AN, Engle EC. A clinically variant fibrosis syndrome in a Turkish family maps to the CFEOM1 locus on chromosome 12. Arch Ophthalmol. 2000 Aug;118(8):1090-7. (http://www.ncbi.nlm.nih.gov/pubmed/10922204?dopt=Abstract)
  • Tiab L, d'Allèves Manzi V, Borruat FX, Munier F, Schorderet D. Mutation analysis of KIF21A in congenital fibrosis of the extraocular muscles (CFEOM) patients. Ophthalmic Genet. 2004 Dec;25(4):241-6. (http://www.ncbi.nlm.nih.gov/pubmed/15621876?dopt=Abstract)
  • Tukel T, Uzumcu A, Gezer A, Kayserili H, Yuksel-Apak M, Uyguner O, Gultekin SH, Hennies HC, Nurnberg P, Desnick RJ, Wollnik B. A new syndrome, congenital extraocular muscle fibrosis with ulnar hand anomalies, maps to chromosome 21qter. J Med Genet. 2005 May;42(5):408-15. Erratum in: J Med Genet. 2005 Nov;42(11):862. (http://www.ncbi.nlm.nih.gov/pubmed/15863670?dopt=Abstract)
  • Yamada K, Andrews C, Chan WM, McKeown CA, Magli A, de Berardinis T, Loewenstein A, Lazar M, O'Keefe M, Letson R, London A, Ruttum M, Matsumoto N, Saito N, Morris L, Del Monte M, Johnson RH, Uyama E, Houtman WA, de Vries B, Carlow TJ, Hart BL, Krawiecki N, Shoffner J, Vogel MC, Katowitz J, Goldstein SM, Levin AV, Sener EC, Ozturk BT, Akarsu AN, Brodsky MC, Hanisch F, Cruse RP, Zubcov AA, Robb RM, Roggenkäemper P, Gottlob I, Kowal L, Battu R, Traboulsi EI, Franceschini P, Newlin A, Demer JL, Engle EC. Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1). Nat Genet. 2003 Dec;35(4):318-21. Epub 2003 Nov 2. (http://www.ncbi.nlm.nih.gov/pubmed/14595441?dopt=Abstract)
  • Yamada K, Chan WM, Andrews C, Bosley TM, Sener EC, Zwaan JT, Mullaney PB, Oztürk BT, Akarsu AN, Sabol LJ, Demer JL, Sullivan TJ, Gottlob I, Roggenkäemper P, Mackey DA, De Uzcategui CE, Uzcategui N, Ben-Zeev B, Traboulsi EI, Magli A, de Berardinis T, Gagliardi V, Awasthi-Patney S, Vogel MC, Rizzo JF 3rd, Engle EC. Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3). Invest Ophthalmol Vis Sci. 2004 Jul;45(7):2218-23. (http://www.ncbi.nlm.nih.gov/pubmed/15223798?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: March 2009
Published: October 27, 2014