NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Congenital Fibrosis of the Extraocular Muscles

Synonym: CFEOM. Includes: KIF21A-Related Congenital Fibrosis of the Extraocular Muscles, PHOX2A-Related Congenital Fibrosis of the Extraocular Muscles, TUBB3-Related Congenital Fibrosis of the Extraocular Muscles, Congenital Fibrosis of the Extraocular Muscles 3C, Congenital Fibrosis of the Extraocular Muscles 4, Tukel Syndrome

, MSc, , MD, PhD, and , MD.

Author Information
, MSc
Research Specialist II, Children's Hospital Boston
Department of Neurology, Harvard Medical School
Boston, Massachusetts
Howard Hughes Medical Institute
Chevy Chase, Maryland
, MD, PhD
Ophthalmologist-in-Chief, Children's Hospital Boston
Professor of Ophthalmology, Harvard Medical School
Boston, Massachusetts
, MD
Department of Neurology
Children's Hospital Boston
Professor of Neurology and Ophthalmology, Harvard Medical School
Boston, Massachusetts
Howard Hughes Medical Institute
Chevy Chase, Maryland

Initial Posting: ; Last Revision: December 29, 2011.

Summary

Disease characteristics. Congenital fibrosis of the extraocular muscles (CFEOM) refers to at least seven genetically defined strabismus syndromes: CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, and Tukel syndrome, characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) with or without ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique). In general, affected individuals have severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze. Individuals with CFEOM frequently compensate for the ophthalmoplegia by maintaining abnormal head positions at rest and by moving their heads rather than their eyes to track objects. Individuals with CFEOM3A may also have intellectual disability, social disability, facial weakness, and/or a progressive axonal peripheral neuropathy (a form of Charcot-Marie-Tooth disease). Individuals with CFEOM3C also have intellectual disability and facial dysmorphism reminiscent of Albright hereditary osteodystrophy-like syndrome. Individuals with Tukel syndrome also have postaxial oligodactyly or oligosyndactyly of the hands.

Diagnosis/testing. The diagnosis of CFEOM is based on ophthalmologic findings, and some subtypes depend on the identification of associated findings. Three CFEOM ophthalmic phenotypes are recognized: CFEOM1, CFEOM2, and CFEOM3. KIF21A mutations are associated with most familial CFEOM1, simplex CFEOM1, and CFEOM3B. PHOX2A mutations are associated with CFEOM2. TUBB3 mutations are associated with CFEOM3A and, rarely, CFEOM1B.

Management. Treatment of manifestations: Refractive errors may be managed with glasses or contact lenses. Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Corneal lubrication may be helpful. Corrective eye muscle and/or ptosis surgery may be required.

Prevention of secondary complications: Amblyopia therapy to prevent vision loss in the less-preferred eye.

Surveillance: To prevent and treat amblyopia and to address complications of corneal exposure. Routine ophthalmologic care with visits every three to four months during the first years of life, and annual or biannual examinations in older affected individuals not at risk for amblyopia.

Evaluation of relatives at risk: Early clinical diagnosis can lead to early treatment and prevent secondary complications.

Genetic counseling. CFEOM1A, CFEOM1B, and CFEOM3A, B, and C are inherited in an autosomal dominant manner. Probands may have inherited the disease-causing mutation or have a de novo mutation. Each child of an individual with CFEOM1 or CFEOM3 has a 50% chance of inheriting the condition. CFEOM1 and CFEOM3A can also result from germline mosaicism in one parent, resulting in more than one affected offspring of unaffected parents. CFEOM2 and Tukel syndrome are inherited in an autosomal recessive manner. At conception, each sib of an individual with CFEOM2 or Tukel syndrome has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

The term CFEOM (congenital fibrosis of the extraocular muscles) refers to several syndromes: CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, and Tukel syndrome [Doherty et al 1999, Nakano et al 2001, Yamada et al 2003, Aubourg et al 2005, Tukel et al 2005, Karadeniz et al 2009, Khan et al 2010, Tischfield et al 2010]. They are characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) typically with ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique).

Additional clinical findings accompany Tukel syndrome and can accompany CFEOM3A.

CFEOM1. CFEOM1 is the "classic" form of CFEOM. Affected individuals exhibit the following:

  • Congenital non-progressive bilateral external ophthalmoplegia
  • Congenital non-progressive bilateral ptosis
  • Primary vertical position of each eye: infraducted (downward)
  • Vertical eye movements: inability to elevate the eyes above the horizontal midline
  • Primary horizontal position of each eye: normal (orthotropic), inward (esotropic), or outward (exotropic)
  • Horizontal eye movements: normal to severely restricted
  • Aberrant eye movements: common, especially both eyes turning inward on attempted upgaze
  • Forced duction test (to assess passive movement of the globe to determine if the extraocular muscles are restricted): positive for restriction
  • Binocular vision: usually absent
  • Refractive errors: frequently high astigmatism
  • Amblyopia: may be strabismic or refractive in nature
  • Pupils: normal
  • Family history: consistent with autosomal dominant inheritance; simplex cases (i.e., a single occurrence in a family) are observed. Parental germline mosaicism can mimic autosomal recessive inheritance.

CFEOM1 is divided into CFEOM1A and CFEOM1B based on genetic findings. CFEOM1A is associated with mutations in KIF21A; CFEOM1B is associated with mutations in TUBB3.

CFEOM2. Affected individuals exhibit the following:

  • Congenital non-progressive bilateral external ophthalmoplegia
  • Congenital non-progressive bilateral ptosis
  • Primary vertical position of each eye: normal or positioned slightly above or below the midline
  • Vertical eye movements: severely restricted
  • Primary horizontal position of each eye: typically fixed outward (exotropic) or rarely fixed in a normal straight-ahead position (orthotropic)
  • Horizontal eye movements: severely restricted
  • Aberrant eye movements: small amplitude, if present
  • Forced duction test: positive for restriction
  • Binocular vision: absent
  • Refractive errors: frequent
  • Amblyopia: frequent
  • Pupils: often small and sluggishly reactive to light
  • Family history: consistent with autosomal recessive inheritance

CFEOM3. Affected individuals exhibit the following:

  • Congenital non-progressive bilateral external ophthalmoplegia primarily affecting muscles in the oculomotor distribution (in individuals who do not meet CFEOM1 criteria)

Affected individuals may exhibit the following:

  • Lid position and movement: normal or congenital non-progressive bilateral or unilateral ptosis
  • Primary vertical position of each eye: downward (infraducted) or normal (primary position)
  • Vertical eye movements: variable restriction with presence or absence of upgaze above the midline
  • Primary horizontal position of each eye: normal (orthotropic) or outward (exotropic) may be more common than inward (esotropic)
  • Horizontal eye movements: normal to severely restricted
  • Aberrant eye movements: absent or present
  • Forced duction test: positive for restriction at least in attempted upgaze
  • Refractive errors: absent or present
  • Binocular vision: absent or present
  • Pupils: normal
  • Magnetic resonance imaging of cranial nerves and orbits: hypoplasia of the oculomotor nerve and levator/superior rectus muscles

CFEOM3 is divided into CFEOM3A, CFEOM3B, and CFEOM3C based on a combination of clinical and genetic findings.

CFEOM3A refers to the CFEOM3 phenotype that results from mutations in TUBB3. Affected individuals exhibit CFEOM3 as described above. In addition, a subset of individuals may have associated findings, including:

  • Intellectual disabilities
  • Social disabilities
  • Facial weakness
  • Progressive sensorimotor axonal polyneuropathy
  • Magnetic resonance imaging of the brain that reveals dysgenesis of the corpus callosum, anterior commissure, corticospinal tracts, and basal ganglia
  • Family history consistent with autosomal dominant inheritance.
    Note: The term "CFEOM3 pedigree" refers to a family in which all affected individuals have CFEOM3, as well as to a family in which some affected individuals have CFEOM3 and some have CFEOM1. Simplex cases (i.e., a single occurrence in a family) are observed. Parental germline mosaicism can mimic autosomal recessive inheritance.

CFEOM3B refers to CFEOM3 when it results from mutations in KIF21A.

  • Affected individuals exhibit CFEOM3 as described above.
  • Family history is consistent with autosomal dominant inheritance.

CFEOM3C refers to a single family that cosegregates CFEOM3 with a translocation.

Tukel syndrome. Affected individuals exhibit the following:

Molecular Genetic Testing

Genes. Three genes in which mutations are known to cause CFEOM:

Other loci

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in CFEOM

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Gene and Test Method 3
KIF21A Sequence analysis of select exonsSequence variants in exons 2, 8, 20, 21 4, 588% in CFEOM1 6
20% in CFEOM3 7
Sequence analysisSequence variants 4≥88% in CFEOM1 6
≥20% in CFEOM3 7
TUBB3Sequence analysisSequence variants 427/27 (100%) in isolated CFEOM3 8
13/13 (100%) in CFEOM3 with additional neurologic findings
CFEOM1: unknown
PHOX2A Sequence analysisSequence variants 4~100% in CFEOM2 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5. Exons sequenced may vary by laboratory.

6. Yamada et al [2003], Ali et al [2004], Tiab et al [2004], Traboulsi & Engle [2004], Lin et al [2005], Shimizu et al [2005], Yamada et al [2005], Chan et al [2007], Karadeniz et al [2009], Rudolph et al [2009], Yang et al [2010]

7. Yamada et al [2004], Lin et al [2005], Lu et al [2008]

8. Individuals who only have the eye phenotype, not additional medical conditions

9. Nakano et al [2001], Yazdani et al [2003]

Testing Strategy

To confirm/establish the diagnosis in a proband, perform testing in the order shown. Individuals with a phenotype consistent with:

CFEOM1

1.

‘Hotspot’ exon sequencing of KIF21A

2.

Sequencing of 35 remaining exons of KIF21A

3.

Sequencing of TUBB3

CFEOM3

1.

Sequencing of TUBB3 (if mutations are identified, the diagnosis of CFEOM3A is established)

2.

‘Hotspot’ exon sequencing of KIF21A

3.

Sequencing of 35 remaining exons of KIF21A (if mutations in KIF21A are identified, the diagnosis of CFEOM3B is established)

4.

Linkage analysis of FEOM4 locus (If linkage established, the diagnosis of CFEOM3C is suspected)

5.

Linkage analysis to other CFEOM loci

Tukel syndrome

1.

Linkage analysis of TUKLS locus

2.

Linkage analysis to other CFEOM loci

3.

Sequencing of TUBB3

4.

‘Hotspot’ exon sequencing of KIF21A

5.

Sequencing of 35 remaining exons of KIF21A

CFEOM2

1.

Sequencing of PHOX2A

2.

Linkage to PHOX2A locus

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation(s) in the family.

Clinical Description

Natural History

Congenital fibrosis of the extraocular muscles (CFEOM) refers to complex strabismus (eye misalignment) syndromes characterized by congenital non-progressive ophthalmoplegia (inability to move the eyes) with or without ptosis (droopy eyelids) affecting part or all of the oculomotor nucleus and nerve (cranial nerve III) and its innervated muscles (superior, medial, and inferior recti, inferior oblique, and levator palpabrae superioris) and/or the trochlear nucleus and nerve (cranial nerve IV) and its innervated muscle (the superior oblique). Magnetic resonance imaging suggests that the abducens and optic nerves can also be hypoplastic [Demer et al 2005, Wu et al 2009].

Strabismus is the deviation of the position of one eye relative to the other, resulting in misalignment of the line of site of the two eyes. Individuals with CFEOM typically have incomitant strabismus, in which their misalignment varies with gaze direction. Incomitant strabismus often results from mechanical dysfunction in the orbit or neuromuscular dysfunction at the level of the brain stem, nerve, or muscle. The primary eye position of an individual with CFEOM is often abnormal. In general, hypotropic (downward) and exotropic (outward) positions are more common than hypertropic (upward) and esotropic (inward) positions. Strabismus in individuals with CFEOM can vary within a single family, and this can be particularly remarkable among affected members of families with CFEOM3. Among families with CFEOM1, the vertical strabismus is quite uniform, but the horizontal strabismus can vary.

Congenital non-progressive external ophthalmoplegia. Individuals with CFEOM are born with a severe form of incomitant strabismus referred to as ophthalmoplegia (inability to move the eyes) caused by dysfunction of specific ocular muscles innervated by the oculomotor and trochlear nerves. In general, affected individuals have severe limitation of vertical gaze and variable limitation of horizontal gaze. Individuals with CFEOM compensate for the ophthalmoplegia by maintaining an abnormal head position at rest and by moving their heads rather than their eyes to track objects.

Ptosis is the drooping of the upper eyelid as a result of dysfunction of the levator palpabrae superioris. Individuals with CFEOM often have a compensatory chin-up head posture to both better position their infraducted eyes and to "see under" their droopy lids.

Refractive errors are common.

Amblyopia. Strabismus (with suppression of one eye), refractive error, and ptosis may cause amblyopia, which can lead to permanent loss of vision when untreated.

CNS malformations. Some individuals with CFEOM have been reported to have central nervous system malformations, including agenesis of the corpus callosum, brain stem atrophy, cerebellar hemisphere atrophy, absence of the cerebral peduncle in the midbrain, colpocephaly, hypoplasia of the cerebellar vermis, expansion of the ventricular system, pachygyria, encephalocele and/or hydrancephaly [Pieh et al 2003, Harissi-Dagher et al 2004]. The CFEOM phenotype in most of these cases is atypical and meets the criteria of CFEOM3.

Some individuals with CFEOM and CNS malformations harbor mutations in TUBB3. This spectrum of CNS malformations has been named the “TUBB3 syndromes.” Genotype-phenotype correlations are clear. In addition to ocular motility defects (CFEOM), phenotypes can include facial paralysis, spasticity, cognitive and behavioral impairments, and a later-onset progressive peripheral sensorimotor axonal polyneuropathy. Radiologic findings are hypoplastic oculomotor nerves, dysmorphic basal ganglia with or without internal capsule hypoplasia, and agenesis or hypoplasia of the corpus callosum and anterior commissure [Demer et al 2010, Tischfield & Engle 2010]. See Genetically Related Disorders.

Marcus Gunn phenomenon and other evidence of misinnervation. KIF21A and TUBB3 mutations have been reported in individuals with CFEOM and Marcus Gunn jaw winking phenomenon and/or facial weakness [Pieh et al 2003, Yamada et al 2005]. The Marcus Gunn jaw winking phenomenon manifests as the momentary elevation of a ptotic upper eyelid with specific movements of the jaw. It is also first noted in young infants when they are feeding. It results from aberrant innervation of the levator palpebrae superioris muscle by axons intended to run in the motor branch of the trigeminal nerve and to innervate the pterygoid muscle. The association of this phenomenon with CFEOM provides additional evidence that these syndromes are primarily neurogenic in cause [Brodsky 1998, Pieh et al 2003].

Tukel syndrome. Affected members of the family with CFEOM3 that maps to the Tukel syndrome locus also manifest bilateral postaxial oligodactyly/oligosyndactyly of the hands, more severe on the right.

Genotype-Phenotype Correlations

Each form of CFEOM has a defined phenotype.

KIF21A. The KIF21A mutations underlying CFEOM1 and rare cases of CFEOM3 alter only a few specific amino acids: those in the third coiled-coil domain of the stalk and two amino acids in the motor domain. Clinical examinations and high-resolution orbital MRI of individuals with CFEOM1 resulting from several of these different specific KIF21A mutations, however, did not reveal a correlation between any specific mutation and clinical phenotype [Yamada et al 2003, Demer et al 2005].

PHOX2A. No correlation between specific PHOX2A mutations and the CFEOM2 phenotype has been found. CFEOM2-causing mutations in PHOX2A all likely result in complete loss of function of paired mesoderm homeobox protein 2A [Nakano et al 2001, Bosley et al 2006].

TUBB3. The eight reported heterozygous TUBB3 missense mutations underlying CFEOM3A alter six amino acids in exons 3 and 4 and occur recurrently. Correlations have been found between specific TUBB3A mutations and the clinical phenotype [Tischfield et al 2010]:

  • c.185G>A (p.Arg62Gln): moderate CFEOM3. Brain MRI: normal.
  • c.784C>T (p.Arg262Cys): mild to severe CFEOM3 or CFEOM1B. Brain MRI: anterior commissure hypoplasia, mild corpus callosum hypoplasia, mild basal ganglia dysgenesis.
  • c.785G>A (p.Arg262His): severe CFEOM3, developmental delay, facial weakness, progressive axonal sensorimotor polyneuropathy, congenital joint contractures. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia, basal ganglia dysgenesis.
  • c.904G>A (p.Ala302Thr): variable CFEOM3, developmental delay. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia.
  • c.1138C>T (p.Arg380Cys): moderate CFEOM3, developmental delay. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia, basal ganglia dysgenesis
  • c.1249G>A (p.Asp417Asn): mild to severe CFEOM3 or CFEOM1B, weakness, progressive axonal sensorimotor polyneuropathy. Brain MRI: anterior commissure hypoplasia, mild corpus callosum hypoplasia, mild basal ganglia dysgenesis.
  • c.1249G>C (p.Asp417His): severe CFEOM3, developmental delay, facial weakness, progressive axonal sensorimotor polyneuropathy, congenital joint contractures. Brain MRI: anterior commissure hypoplasia.
  • c.1228G>A (p.Glu410Lys): severe CFEOM3, developmental delay, facial weakness. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia.

Many persons with CFEOM3 who have aTUBB3 mutation also had aberrant eye movements and several had ptotic eyelid elevation associated with synkinetic jaw movements (Marcus Gunn phenomenon).

Penetrance

Penetrance in CFEOM1A, CFEOM1B, CFEOM2, CFEOM3B, CFEOM3C, and Tukel syndrome is complete.

Penetrance in CFEOM3A can be incomplete and is estimated to be 90% in families harboring the c.784C>T (p.Arg262Cys) substitution [Doherty et al 1999].

Nomenclature

Although long felt to result from primary fibrosis of the extraocular muscles, neuroanatomic [Engle et al 1997, Tischfield et al 2010], genetic [Nakano et al 2001, Yamada et al 2003, Tischfield et al 2010], and neuroimaging [Demer et al 2005, Kim & Hwang 2005, Bosley et al 2006, Lim et al 2007, Wu et al 2009, Demer et al 2010] findings suggest that the various forms of CFEOM result from abnormal development of ocular motor neurons and their processes.

Prevalence

A minimum prevalence of CFEOM is one in 230,000 [Reck et al 1998].

CFEOM1 and CFEOM3 familial and simplex cases have been identified worldwide.

The few individuals reported with CFEOM2 have been offspring of consanguineous unions within Saudi, Turkish, and Iranian families [Traboulsi & Engle 2004].

Differential Diagnosis

The term 'congenital cranial dysinnervation disorders (CCDDs)' was coined to refer to disorders of innervation of cranial musculature [Gutowski et al 2003]. The various forms of CFEOM are included in the CCDDs. Other CCDDs include Duane syndrome, Moebius syndrome, and congenital facial palsy.

The following conditions can be confused with CFEOM:

Brown syndrome ('superior oblique tendon sheath syndrome') is characterized by the inability to elevate the adducted eye actively or passively. Most congenital Brown syndrome is simplex (i.e., a single occurrence in a family) and believed to result from anomalies of the tendon or the trochlear apparatus. Rare familial cases have been reported [Iannaccone et al 2002].

Duane syndrome is characterized by horizontal eye movement limitation, narrowing of the palpebral fissure on attempted side gaze (usually adduction), and retraction of the globe on attempted adduction. It is believed to result from abnormal development of the abducens nucleus and nerve (cranial nerve VI).

Although the majority of cases of Duane syndrome are simplex and isolated (i.e., not associated with other malformations), rare families with autosomal dominant or autosomal recessive inheritance of Duane syndrome with or without accompanying anomalies have been reported:

  • An autosomal dominant locus for Duane syndrome was mapped by linkage analysis to 2q31 (DURS2, OMIM 604356). All affected individuals had bilateral Duane syndrome type 1 or type 3; the prevalence of manifest strabismus and amblyopia was high. Heterozygous missense changes in CHN1 were identified that co-segregated with the affected haplotypes [Miyake et al 2008]. All were predicted to alter amino acids that were conserved in eight different species. CHN1 was subsequently found to not be a common cause of sporadic Duane syndrome [Miyake et al 2010].
  • A contiguous gene deletion syndrome with Duane syndrome is located on 8q13 (DURS1, OMIM 126800).
  • SALL4-related disorders. The SALL4-related syndromes include Okihiro syndrome, Duane-radial ray syndrome, acro-renal-ocular syndrome, and IVIC syndrome. These overlapping syndromes are characterized by unilateral or bilateral Duane syndrome and radial ray malformations that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs; hypoplasia or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication of the thumb (preaxial polydactyly). Deafness, renal anomalies, and imperforate anus can be coinherited. Inheritance is autosomal dominant.
    Heterozygous SALL4 mutations are associated with most familial cases of these syndromes [Al-Baradie et al 2002, Kohlhase et al 2002]. Individuals who represent simplex cases of isolated Duane syndrome have not been found to harbor mutations in SALL4 [Wabbels et al 2004]. However, some members of families segregating a SALL4-related disorder have been found to harbor a SALL4 mutation and to manifest isolated Duane syndrome (without hand or other anomalies) [Al-Baradie et al 2002].
  • Athabaskan brain stem dysgenesis syndrome (ABDS) [Holve et al 2003] and Bosley-Salih-Alorainy syndrome (BSAS) [Tischfield et al 2005] (OMIM 601536) are autosomal recessive disorders that result from mutations in HOXA1 [Tischfield et al 2005]. They are characterized by Duane syndrome type III or horizontal gaze palsy and, in most individuals, bilateral sensorineural hearing loss caused by absent cochlea and rudimentary inner ear development. Depending on the specific syndrome (ABDS vs. BSAS), a subset of individuals manifests intellectual disability, autism, moderate to severe central hypoventilation, facial weakness, swallowing difficulties, vocal cord paresis, conotruncal heart defects, and skull and craniofacial abnormalities.

Chronic progressive external ophthalmoplegia (CPEO) is characterized by chronic progressive loss of extraocular eye movements and ptosis.

Mitochondrial DNA deletion syndromes comprise three overlapping phenotypes, which may be observed in different members of the same family or may evolve in a given individual over time. The three phenotypes are: Kearns-Sayre syndrome (KSS), Pearson syndrome, and progressive external ophthalmoplegia (PEO). These syndromes are caused by mtDNA deletions ranging in size from two to ten kilobases.

  • KSS is defined by the triad of onset before age 20 years, pigmentary retinopathy, and PEO. Individuals additionally have at least one of the following: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, or cerebellar ataxia. Approximately 90% of individuals with KSS have a large-scale (i.e., 1.3-10 kb) mtDNA deletion that is usually present in all tissues; however, mutant mtDNA is often undetectable in blood cells, necessitating examination of muscle.
  • Pearson syndrome is characterized by sideroblastic anemia and exocrine pancreas dysfunction. In Pearson syndrome, mtDNA deletions are usually more abundant in blood than in other tissues.
  • PEO is characterized by progressive ptosis, paralysis of the extraocular muscles (ophthalmoplegia), and variably severe proximal limb weakness.

Other disorders associated with ophthalmoplegia include (with distinguishing features):

Cranial nerve III and IV palsy. Few reports of congenital familial third-nerve palsy or fourth-nerve palsy exist. The etiologies of these disorders are unknown.

Horizontal gaze palsy with progressive scoliosis (HGPPS) (OMIM 607313) is characterized by congenital horizontal gaze palsy (no horizontal eye movements) with progressive scoliosis inherited in an autosomal recessive manner and caused by mutations in ROBO3 [Jen et al 2004]. Compound heterozygous ROBO3 mutations have also been identified in children of non-consanguineous parents [Chan et al 2006]. Results of neuroimaging and neurophysiology studies undertaken on individuals with HGPPS found that the axons that make up the major motor and sensory pathways for communication between the brain and the body fail to cross the midline in the hindbrain [Jen et al 2004, Bosley et al 2005].

Moebius syndrome (MBS) (OMIM 157900) is characterized by facial weakness or diplegia with ocular abduction deficit.

  • The vast majority of individuals with Moebius syndrome represent simplex cases and many are associated with developmental defects of additional lower cranial nerves and distal extremities.
  • Moebius sequence has also been reported in association with congenital non-progressive myopathy and Robin sequence (OMIM 254940)
  • A subset of TUBB3 mutations can result in a Moebius-like syndrome.

Hereditary congenital facial paresis, the isolated dysfunction of the facial nerve, maps to chromosome 3q (locus name HCFP1) (OMIM 601471) and chromosome 10q (locus name HCFP2) (OMIM 604185).

Other. CFEOM has been identified in a single case of Noonan syndrome [Elgohary et al 2005].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

CFEOM3

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with congenital fibrosis of the extraocular muscles, the following evaluations are recommended:

  • Family history
  • Ophthalmologic examination
    • Determination of primary gaze position, head position with eyes in primary position, and vertical and horizontal gaze restrictions
    • Evaluation for aberrant movements including synergistic convergence and divergence, globe retraction, Marcus Gunn jaw wink
    • Palpebral fissure size measurement
    • Anterior segment evaluation to detect corneal exposure
    • Levator function testing
    • Optional forced duction testing
  • Photographic documentation for future comparison
  • Strongly recommended if surgery is planned:
    • MRI or scan to determine orbital anatomy (muscles and nerves)
    • Orbital MRI to detect aplasia of extraocular muscle(s) and defects in the size and/or course of the oculomotor and trochlear nerves

Treatment of Manifestations

Nonsurgical treatment of ophthalmologic findings:

  • Refractive errors may be managed with spectacles or contact lenses. Specialist examination is required to detect refractive errors early in life, when affected individuals may be asymptomatic, to prevent amblyopia and avoid compounding the motility problem with a focusing problem.
  • Amblyopia can be treated effectively with occlusion or penalization of the better-seeing eye. Early detection (in the first years of life) maximizes the likelihood of a good response to treatment.
  • Lubrication of ocular surface (particularly cornea) may be required.

Surgical treatment of ophthalmologic findings (extraocular muscle and/or ptosis surgery):

  • Correction of ptosis
  • Eye muscle surgery
    • To correct or improve a compensatory head posture
    • To improve alignment in primary gaze position
    • To improve ambulation and gross motor development in young children
  • Principles of surgical approach:
    • Orbital imaging is recommended before surgery to assess muscle size and position.
    • Resections tend to be ineffective.
    • Surgery may be technically difficult because of tightness of rectus muscles.
    • Recessions need to be larger than indicated by standard tables.
    • Adjustable sutures allow "supramaximal" recession.
    • Profound weakening procedures (such as suturing muscle to orbital rim) may be necessary.
    • Botulinum toxin may be helpful for residual misalignment in some cases.

Prevention of Secondary Complications

  • Amblyopia therapy to prevent vision loss in the less-preferred eye
  • Eye lubrication to avoid dry eyes, particularly following ptosis surgery but also after successful strabismus surgery in some cases
  • Surgical repositioning of the eyes and lids to help correct head position and alleviate secondary musculoskeletal complications from chronic head turn

Surveillance

CFEOM is congenital and is believed to be non-progressive.

Surveillance is important for prevention of amblyopia, and to treat amblyopia and complications of corneal exposure [Yazdani & Traboulsi 2004].

Routine ophthalmologic care is indicated, with visits every three to four months during the first years of life, and annual or biannual examinations in affected individuals not at risk for amblyopia.

Evaluation of Relatives at Risk

CFEOM can often be diagnosed on clinical findings within the first months of life; early diagnosis can result in prevention of secondary complications.

Because of variable expression, examination of family members may provide early diagnosis of risk factors for amblyopia in mild cases that could otherwise go undetected.

Molecular genetic testing is possible if the family-specific mutation has been identified.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Congenital fibrosis of the extraocular muscles (CFEOM) 1A, CFEOM1B, CFEOM3A, CFEOM3B, and CFEOM3C are inherited in an autosomal dominant manner.

CFEOM2 and Tukel syndrome are inherited in an autosomal recessive manner.

Risk to Family Members - Autosomal Dominant Inheritance (CFEOM1, CFEOM3A, CFEOM3B, CFEOM3C)

Parents of a proband

  • Some individuals diagnosed with CFEOM1 or CFEOM3 have an affected parent.
  • A proband with CFEOM1A may have the disorder as the result of a de novo mutation. In a study of 45 families and 13 simplex cases (i.e., a single occurrence of the CFEOM1A in a family), five and seven de novo mutations respectively were identified, suggesting that de novo mutations may be particularly common in simplex cases [Yamada et al 2003].
  • A proband with CFEOM3 may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations has been reported to be 45% (13/29) [Tischfield et al 2010].
  • Recommendations for the evaluation of parents of a proband with CFEOM1A and an apparent de novo mutation include ophthalmologic examinations and consideration of molecular genetic testing for the KIF21A mutation if one has been identified in the proband.
  • Recommendations for the evaluation of parents of a proband with CFEOM3A or CFEOM1B and an apparent de novo mutation include ophthalmologic examinations and consideration of molecular genetic testing for the TUBB3 mutation if one has been identified in the proband.

Note: Although some individuals diagnosed with CFEOM3 have an affected parent, the family history may appear to be negative because of reduced penetrance in CFEOM3.

Sibs of a proband

  • CFEOM1
    • The risk to sibs of a proband with CFEOM1 depends on the genetic status of the proband's parents.
    • If a parent of the proband is affected, the risk to each sib is 50%.
    • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
    • If a disease-causing mutation cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • CFEOM3

Offspring of a proband. Each child of an individual with CFEOM1 or CFEOM3 has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

Risk to Family Members - Autosomal Recessive Inheritance (CFEOM2 and Tukel Syndrome)

Parents of a proband

  • The parents of an individual with CFEOM2 or Tukel syndrome are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.
  • One or two families with two-generation involvement have been reported. Referred to as pseudodominant inheritance, two-generation involvement can occur in autosomal recessive disorders when a parent (who has two disease-causing alleles) is affected and his/her reproductive partner is a carrier.

Sibs of a proband

  • At conception, each sib of an individual with CFEOM2 or Tukel syndrome has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CFEOM2 or Tukel syndrome are obligate heterozygotes (carriers) for a disease-causing mutation.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a disease-causing mutation.

Carrier Detection

Carrier testing using molecular genetic techniques is possible for CFEOM2 if the PHOX2A mutations have been identified in the family.

Carrier testing using molecular genetic techniques is not possible for Tukel syndrome.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk for some forms of CFEOM is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at about ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

If the disease-causing mutation has been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Requests for prenatal testing for conditions such as CFEOM are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • Prevent Blindness America
    211 West Wacker Drive
    Suite 1700
    Chicago IL 60606
    Phone: 800-331-2020 (toll-free)
    Email: info@preventblindness.org
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Congenital Fibrosis of the Extraocular Muscles: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
FEOM1KIF21A12q12Kinesin-like protein KIF21AKIF21A @ LOVDKIF21A
FEOM2PHOX2A11q13​.4Paired mesoderm homeobox protein 2APHOX2A databasePHOX2A
FEOM3TUBB316q24​.3Tubulin beta-3 chain TUBB3
FEOM4Unknown13q12​.12Unknown
TUKLSUnknown21q22Unknown

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Congenital Fibrosis of the Extraocular Muscles (View All in OMIM)

135700FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 1; CFEOM1
600638FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 3A, WITH OR WITHOUT EXTRAOCULAR INVOLVEMENT; CFEOM3A
602078FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 2; CFEOM2
602661TUBULIN, BETA-3; TUBB3
602753ARISTALESS HOMEOBOX, DROSOPHILA, HOMOLOG OF; ARIX
608283KINESIN FAMILY MEMBER 21A; KIF21A
609384FIBROSIS OF EXTRAOCULAR MUSCLES, CONGENITAL, 3C; CFEOM3C
609428TUKEL SYNDROME

Molecular Genetic Pathogenesis

KIF21A. KIF21A protein is a member of the kinesin family of molecular motors and has a predicted structure similar to classic kinesin [Marszalek et al 1999] with an N-terminal motor domain that interacts with the microtubule track, a central coiled-coil stalk, and a C-terminal tail that loads or interacts with transported cargo. Among the 45 human and mouse kinesins, KIF21A is only one of two kinesins that contain a WD40 (tryptophan aspartate 40) domain (known to assemble a stable platform that facilitates several protein interactions) at its C terminal tail. It is hypothesized that CFEOM1 results from mutations in KIF21A that affect either the dynamics of cargo binding or the ability of mutated KIF21A to deliver cargo necessary for oculomotor axonal, extraocular muscle, or neuromuscular junction development [Yamada et al 2003].

PHOX2A (ARIX). PHOX2A is a homeodomain transcription factor protein that plays a primary role in the oculomotor and trochlear alpha motor neuron development in mice and zebrafish [Pattyn et al 1997, Guo et al 1999]. It is predicted that CFEOM2 results from aberrant development of these motor nuclei [Nakano et al 2001]. Morin et al [1997] demonstrated that Phox2a -/- mice completely lacked a locus coeruleus, the main noradrenergic center of the brain. Furthermore, parasympathetic ganglia in the head are missing, and the superior cervical ganglion, as well as cranial sensory ganglia that normally express Phox2a, are severely affected. Pattyn et al [1997] demonstrated that these mice also completely lack oculomotor and trochlear motor neurons. Homologous genes include PHOX2B (PMX2B). Mutations in PHOX2B cause congenital central hypoventilation syndrome (CCHS) [Amiel et al 2003].

TUBB3. Beta-tubulin isotype III (TUBB3) is a component of microtubules. Microtubules are copolymers assembled from tubulin heterodimers, which contain several different

Alpha- and β-tubulin isotypes encoded by separate genes. TUBB3 encodes one of at least six β-tubulins found in mammals, and is distinct because purified microtubules enriched in TUBB3 are considerably more dynamic than those composed from other β-tubulin isotypes [Panda et al 1994], and because its expression is primarily limited to neurons [Katsetos et al 2003].

KIF21A

Normal allelic variants. The normal cDNA comprises 5,022 bp in 38 exons with alternative splicing of exon 12 and exons 29-31. Genomic length is approximately 150 kb [Yamada et al 2003]. Alternative splicing results in cDNAs of varying lengths. Reference sequence NM_017641.3 has 37 exons and encodes 1661 amino acids.

Pathologic allelic variants. Ten different heterozygous missense mutations in four of the 38 exons of KIF21A have been identified in individuals with CFEOM1 [Yamada et al 2003, Ali et al 2004, Tiab et al 2004, Lin et al 2005, Shimizu et al 2005, Chan et al 2007, Lu et al 2008, Rudolph et al 2009, Khan et al 2010] and CFEOM3 [Yamada et al 2004, Lin et al 2005, Lu et al 2008, Yang et al 2010] and an eleventh missense mutation identified in one CFEOM3 pedigree [Yamada et al 2004]. Forty-three per cent of the 127 probands have the identical mutation, c.2860C>T. Seven of these KIF21A mutations alter only three amino-acid residues, each located in the 'a' position of a heptad repeat within an alpha helical coiled-coil region of the KIF21A stalk. The c.84C>G and c.1067T>C mutations are located in the motor domain. Haplotype analysis demonstrated that five de novo mutations found in autosomal dominant CFEOM1 pedigrees all arose exclusively on the paternal allele [Yamada et al 2003].

Table 2. Selected KIF21A Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change Reference Sequences
c.84C>Gp.Cys28TrpNM_017641​.3
NP_060111​.2
c.1067T>Cp.Met356Thr
c.2860C>Tp.Arg954Trp

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. The predicted protein, kinesin family member 21A (KIF21A) is 1661 amino acids (NP_060111.2) and comprises three domains (characteristic of the kinesin superfamily). See Molecular Genetic Pathogenesis

Northern and Western blot analysis of the murine ortholog Kif21a indicates that the mRNA and protein is expressed early during development and first detected around embryonic day E9.5. Expression analysis of Kif21a in adult mouse tissues indicates highest protein expression in the brain and moderate levels in the kidney, testes, and skeletal muscle [Marszalek et al 1999]. Kif21a protein is found in all regions of the adult CNS examined including the cortex, cerebellum, brain stem, olfactory bulb, and spinal cord [Marszalek et al 1999]. Kif21a protein is detected in the neuronal cell body, axon, and dendrites [Marszalek et al 1999]. Biochemical characterization of Kif21a has demonstrated that it can strongly bind microtubules in the presence of nonhydrolyzable ATP analogue and behaves as plus end-directed motor in in vitro mobility assays [Marszalek et al 1999]. In addition, differential centrifugation experiments demonstrated that Kif21a does not associate with membranous vesicles and is thought to interact with the insoluble cytoskeleton or a large protein complex [Marszalek et al 1999].

Brefeldin A-inhibited nucleotide-exchange protein (BIG) 1 and Kank1 have been shown to interact with KIF21A [Shen et al 2008, Kakinuma & Kiyama 2009].

Abnormal gene product. The position and recurrence of KIF21A mutations suggests that the CFEOM1-causing mutations may have a dominant-negative effect by interfering with the interaction between KIF21A and its unidentified binding partners [Yamada et al 2003].

PHOX2A

Normal allelic variants. The gene contains three exons. The genomic length is approximately 5 kb [Nakano et al 2001].

Pathologic allelic variants. Four different homozygous PHOX2A mutations have been identified in five families with CFEOM2. Two mutations are single base substitutions (one missense and one nonsense) and two are splice-site mutations [Nakano et al 2001, Yazdani et al 2003].

Normal gene product. The gene product is a transcription factor protein containing a homeodomain and brachyury-like motif. The protein is essential for development of the oculomotor and trochlear alpha motor neurons in mice and zebrafish.

Abnormal gene product. It is predicted that most mutations in PHOX2A lead to the truncation of the protein and are therefore thought to cause a lack of function.

TUBB3

Normal allelic variants. The normal cDNA (NM_006086.3, transcript variant 1) comprises 1353 bp in four exons; it has four exons and encodes 450 amino acids.

Pathologic allelic variants. Eight heterozygous missense mutations underlying CFEOM3A alter six amino acids in exons 3 and 4 and occur recurrently [Tischfield et al 2010]. Thirty-nine percent of the 28 probands have the identical mutation, c.784C>T. CFEOM1B results primarily either of from the missense mutations c.784C>T or c.1249G>A.

Table 3. Selected TUBB3 Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.185G>Ap.Arg62GlnNM_006086​.3
NP_006077​.2
c.784C>Tp.Arg262Cys
c.785G>Ap.Arg262His
c.904G>Ap.Ala302Thr
c.1138C>Tp.Arg380Cys
c.1228G>Ap.Glu410Lys
c.1249G>Ap.Asp417Asn
c.1249G>Cp.Asp417His

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. This gene encodes a class III member of the beta tubulin protein family. Tubulin is the major constituent of microtubules. The TUBB3 protein is expressed in neurons and thought to be involved in neurogenesis and in axon guidance and maintenance.

Abnormal gene product. Multiple clinical findings and the recurrence of TUBB3 mutations suggest that the mutations underlying CFEOM3 primarily alter microtubule function in a dominant fashion, although partial loss of function may play a role in some [Tischfield et al 2010].

References

Literature Cited

  1. Abdollahi MR, Morrison E, Sirey T, Molnar Z, Hayward BE, Carr IM, Springell K, Woods CG, Ahmed M, Hattingh L, Corry P, Pilz DT, Stoodley N, Crow Y, Taylor GR, Bonthron DT, Sheridan E. Mutation of the variant alpha-tubulin TUBA8 results in polymicrogyria with optic nerve hypoplasia. Am J Hum Genet. 2009;85:737–44. [PMC free article: PMC2775839] [PubMed: 19896110]
  2. Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet. 2002;71:1195–9. [PMC free article: PMC385096] [PubMed: 12395297]
  3. Ali M, Venkatesh C, Ragunath A, Kumar A. Mutation analysis of the KIF21A gene in an Indian family with CFEOM1: implication of CpG methylation for most frequent mutations. Ophthalmic Genet. 2004;25:247–55. [PubMed: 15621877]
  4. Amiel J, Laudier B, Attie-Bitach T, Trang H, de Pontual L, Gener B, Trochet D, Etchevers H, Ray P, Simonneau M, Vekemans M, Munnich A, Gaultier C, Lyonnet S. Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome. Nat Genet. 2003;33:459–61. [PubMed: 12640453]
  5. Aubourg P, Krahn M, Bernard R, Nguyen K, Forzano O, Boccaccio I, Delague V, De Sandre-Giovannoli A, Pouget J, Depetris D, Mattei MG, Philip N, Levy 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;42:253–9. [PMC free article: PMC1736008] [PubMed: 15744040]
  6. 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;129:2363–74. [PubMed: 16815872]
  7. Bosley TM, Salih MA, Jen JC, Lin DD, Oystreck D, Abu-Amero KK, MacDonald DB, al Zayed Z, al Dhalaan H, Kansu T, Stigsby B, Baloh RW. Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology. 2005;64:1196–203. [PubMed: 15824346]
  8. Brodsky MC. Hereditary external ophthalmoplegia synergistic divergence, jaw winking, and oculocutaneous hypopigmentation: a congenital fibrosis syndrome caused by deficient innervation to extraocular muscles. Ophthalmology. 1998;105:717–25. [PubMed: 9544647]
  9. Chan WM, Andrews C, Dragan L, Fredrick D, Armstrong L, Lyons C, Geraghty MT, Hunter DG, Yazdani A, Traboulsi EI, Pott JW, Gutowski NJ, Ellard S, Young E, Hanisch F, Koc F, Schnall B, Engle EC. Three novel mutations in KIF21A highlight the importance of the third coiled-coil stalk domain in the etiology of CFEOM1. BMC Genet. 2007;8:26. [PMC free article: PMC1888713] [PubMed: 17511870]
  10. Chan WM, Traboulsi EI, Arthur B, Friedman N, Andrews C, Engle EC. Horizontal gaze palsy with progressive scoliosis can result from compound heterozygous mutations in ROBO3. J Med Genet. 2006;43:e11. [PMC free article: PMC2563249] [PubMed: 16525029]
  11. 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;46:530–9. [PubMed: 15671279]
  12. Demer JL, Clark RA, Tischfield MA, Engle EC. Evidence of an asymmetrical endophenotype in congenital fibrosis of extraocular muscles type 3 resulting from TUBB3 mutations. Invest Ophthalmol Vis Sci. 2010;51:4600–11. [PMC free article: PMC2941178] [PubMed: 20393110]
  13. 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;40:1687–94. [PubMed: 10393037]
  14. Elgohary MA, Bradshaw P, Ahmad N. Anterior uveitis and congenital fibrosis of the extraocular muscles in a patient with Noonan syndrome. J Postgrad Med. 2005;51:319–21. [PubMed: 16388177]
  15. Engle EC, Goumnerov BC, McKeown CA, Schatz M, Johns DR, Porter JD, Beggs AH. Oculomotor nerve and muscle abnormalities in congenital fibrosis of the extraocular muscles. Ann Neurol. 1997;41:314–25. [PubMed: 9066352]
  16. 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;24:555–66. [PubMed: 10595509]
  17. Gutowski NJ, Bosley TM, Engle EC. 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25-27 October, 2002. Neuromuscul Disord. 2003;13:573–8. [PubMed: 12921795]
  18. Harissi-Dagher M, Dagher JH, Aroichane M. Congenital fibrosis of the extraocular muscles with brain-stem abnormalities: a novel finding. Can J Ophthalmol. 2004;39:540–5. [PubMed: 15491041]
  19. Holve S, Friedman B, Hoyme HE, Tarby TJ, Johnstone SJ, Erickson RP, Clericuzio CL, Cunniff C. Athabascan brainstem dysgenesis syndrome. Am J Med Genet A. 2003;120A:169–73. [PubMed: 12833395]
  20. Iannaccone A, McIntosh N, Ciccarelli ML, Baldi A, Mutolo PA, Tedesco SA, Engle EC. Familial unilateral Brown syndrome. Ophthalmic Genet. 2002;23:175–84. [PubMed: 12324876]
  21. Jaglin XH, Poirier K, Saillour Y, Buhler E, Tian G, Bahi-Buisson N, Fallet-Bianco C, Phan-Dinh-Tuy F, Kong XP, Bomont P, Castelnau-Ptakhine L, Odent S, Loget P, Kossorotoff M, Snoeck I, Plessis G, Parent P, Beldjord C, Cardoso C, Represa A, Flint J, Keays DA, Cowan NJ, Chelly J. Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria. Nat Genet. 2009;41:746–52. [PMC free article: PMC2883584] [PubMed: 19465910]
  22. Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rub U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004;304:1509–13. [PMC free article: PMC1618874] [PubMed: 15105459]
  23. Kakinuma N, Kiyama R. A major mutation of KIF21A associated with congenital fibrosis of the extraocular muscles type 1 (CFEOM1) enhances translocation of Kank1 to the membrane. Biochem Biophys Res Commun. 2009;386:639–44. [PubMed: 19559006]
  24. Karadeniz N, Erkek E, Taner P. Unexpected clinical involvement of hereditary total leuconychia with congenital fibrosis of the extraocular muscles in three generations. Clin Exp Dermatol. 2009;34:e570–2. [PubMed: 19489868]
  25. Katsetos CD, Legido A, Perentes E, Mörk SJ. Class III beta-tubulin isotype: a key cytoskeletal protein at the crossroads of developmental neurobiology and tumor neuropathology. J Child Neurol. 2003;18:851–66. [PubMed: 14736079]
  26. Khan AO, Khalil DS, Al Sharif LJ, Al-Ghadhfan FE, Al Tassan NA. Germline Mosaicism for KIF21A Mutation (p.R954L) Mimicking Recessive Inheritance for Congenital Fibrosis of the Extraocular Muscles. Ophthalmology. 2010;117:154–8. [PubMed: 19896199]
  27. Kim JH, Hwang JM. Hypoplastic oculomotor nerve and absent abducens nerve in congenital fibrosis syndrome and synergistic divergence with magnetic resonance imaging. Ophthalmology. 2005;112:728–32. [PubMed: 15808269]
  28. Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W. Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet. 2002;11:2979–87. [PubMed: 12393809]
  29. Lim KH, Engle EC, Demer JL. Abnormalities of the oculomotor nerve in congenital fibrosis of the extraocular muscles and congenital oculomotor palsy. Invest Ophthalmol Vis Sci. 2007;48:1601–6. [PMC free article: PMC2262868] [PubMed: 17389489]
  30. Lin LK, Chien YH, Wu JY, Wang AH, Chiang SC, Hwu WL. KIF21A gene c.2860C>T mutation in congenital fibrosis of extraocular muscles type 1 and 3. Mol Vis. 2005;11:245–8. [PubMed: 15827546]
  31. 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;126:388–94. [PubMed: 18332320]
  32. Marszalek JR, Weiner JA, Farlow SJ, Chun J, Goldstein LS. Novel dendritic kinesin sorting identified by different process targeting of two related kinesins: KIF21A and KIF21B. J Cell Biol. 1999;145:469–79. [PMC free article: PMC2185086] [PubMed: 10225949]
  33. Miyake N, Andrews C, Fan W, He W, Chan WM, Engle EC. CHN1 mutations are not a common cause of sporadic Duane's retraction syndrome. Am J Med Genet A. 2010;152A:215–7. [PMC free article: PMC2801889] [PubMed: 20034095]
  34. Miyake N, Chilton J, Psatha M, Cheng L, Andrews C, Chan WM, Law K, Crosier M, Lindsay S, Cheung M, Allen J, Gutowski NJ, Ellard S, Young E, Iannaccone A, Appukuttan B, Stout JT, Christiansen S, Ciccarelli ML, Baldi A, Campioni M, Zenteno JC, Davenport D, Mariani LE, Sahin M, Guthrie S, Engle EC. Human CHN1 mutations hyperactivate alpha2-chimaerin and cause Duane's retraction syndrome. Science. 2008;321:839–43. [PMC free article: PMC2593867] [PubMed: 18653847]
  35. 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;18:411–23. [PubMed: 9115735]
  36. 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;29:315–20. [PubMed: 11600883]
  37. Panda D, Miller HP, Banerjee A, Ludueña RF, Wilson L. Microtubule dynamics in vitro are regulated by the tubulin isotype composition. Proc Natl Acad Sci U S A. 1994;91:11358–62. [PMC free article: PMC45230] [PubMed: 7972064]
  38. 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;124:4065–75. [PubMed: 9374403]
  39. Pieh C, Goebel HH, Engle EC, Gottlob I. Congenital fibrosis syndrome associated with central nervous system abnormalities. Graefes Arch Clin Exp Ophthalmol. 2003;241:546–53. [PubMed: 12819981]
  40. Poirier K, Keays DA, Francis F, Saillour Y, Bahi N, Manouvrier S, Fallet-Bianco C, Pasquier L, Toutain A, Tuy FP, Bienvenu T, Joriot S, Odent S, Ville D, Desguerre I, Goldenberg A, Moutard ML, Fryns JP, van Esch H, Harvey RJ, Siebold C, Flint J, Beldjord C, Chelly J. Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A). Hum Mutat. 2007;28:1055–64. [PubMed: 17584854]
  41. Poirier K, Saillour Y, Bahi-Buisson N, Jaglin XH, Fallet-Bianco C, Nabbout R, Castelnau-Ptakhine L, Roubertie A, Attie-Bitach T, Desguerre I, Genevieve D, Barnerias C, Keren B, Lebrun N, Boddaert N, Encha-Razavi F, Chelly J. Mutations in the neuronal ß-tubulin subunit TUBB3 result in malformation of cortical development and neuronal migration defects. Hum Mol Genet. 2010;19:4462–73. [PMC free article: PMC3298850] [PubMed: 20829227]
  42. Reck AC, Manners R, Hatchwell E. Phenotypic heterogeneity may occur in congenital fibrosis of the extraocular muscles. Br J Ophthalmol. 1998;82:676–9. [PMC free article: PMC1722617] [PubMed: 9797671]
  43. Rudolph G, Nentwich M, Hellebrand H, Pollack K, Gordes R, Bau V, Kampik A, Meindl A. KIF21A variant R954W in familial or sporadic cases of CFEOM1. Eur J Ophthalmol. 2009;19:667–74. [PubMed: 19551685]
  44. Shen X, Meza-Carmen V, Puxeddu E, Wang G, Moss J, Vaughan M. Interaction of brefeldin A-inhibited guanine nucleotide-exchange protein (BIG) 1 and kinesin motor protein KIF21A. Proc Natl Acad Sci U S A. 2008;105:18788–93. [PMC free article: PMC2596273] [PubMed: 19020088]
  45. Shimizu S, Okinaga A, Maruo T. Recurrent mutation of the KIF21A gene in Japanese patients with congenital fibrosis of the extraocular muscles. Jpn J Ophthalmol. 2005;49:443–7. [PubMed: 16365788]
  46. Tiab L, d'Alleves Manzi V, Borruat FX, Munier F, Schorderet D. Mutation analysis of KIF21A in congenital fibrosis of the extraocular muscles (CFEOM) patients. Ophthalmic Genet. 2004;25:241–6. [PubMed: 15621876]
  47. Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, He W, Chan WM, Andrews C, Demer JL, Robertson RL, Mackey DA, Ruddle JB, Bird TD, Gottlob I, Pieh C, Traboulsi EI, Pomeroy SL, Hunter DG, Soul JS, Newlin A, Sabol LJ, Doherty EJ, de Uzcátegui CE, de Uzcátegui N, Collins ML, Sener EC, Wabbels B, Hellebrand H, Meitinger T, de Berardinis T, Magli A, Schiavi C, Pastore-Trossello M, Koc F, Wong AM, Levin AV, Geraghty MT, Descartes M, Flaherty M, Jamieson RV, Møller HU, Meuthen I, Callen DF, Kerwin J, Lindsay S, Meindl A, Gupta ML, Pellman D, Engle EC. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell. 2010;140:74–87. [PMC free article: PMC3164117] [PubMed: 20074521]
  48. Tischfield MA, Bosley TM, Salih MA, Alorainy IA, Sener EC, Nester MJ, Oystreck DT, Chan WM, Andrews C, Erickson RP, Engle EC. Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development. Nat Genet. 2005;37:1035–7. [PubMed: 16155570]
  49. Tischfield MA, Engle EC. Distinct alpha- and beta-tubulin isotypes are required for the positioning, differentiation and survival of neurons: new support for the 'multi-tubulin' hypothesis. Biosci Rep. 2010;30:319–30. [PMC free article: PMC3319081] [PubMed: 20406197]
  50. Traboulsi E, Engle E. Mutations in KIF21A are responsible for CFEOM1 worldwide. Ophthalmic Genet. 2004;25:237–9. [PubMed: 15621875]
  51. Traboulsi EI, Lee BA, Mousawi A, Khamis AR, Engle EC. Evidence of genetic heterogeneity in autosomal recessive congenital fibrosis of the extraocular muscles. Am J Ophthalmol. 2000;129:658–62. [PubMed: 10844060]
  52. 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;42:408–15. [PMC free article: PMC1736053] [PubMed: 15863670]
  53. Wabbels BK, Lorenz B, Kohlhase J. No evidence of SALL4-mutations in isolated sporadic duane retraction "syndrome" (DURS). Am J Med Genet A. 2004;131:216–8. [PubMed: 15386473]
  54. Wu L, Zhou LH, Liu CS, Cha YF, Wang J, Xing YQ. Magnetic resonance imaging features in two Chinese family with congenital fibrosis of extraocular muscles. Zhonghua Yan Ke Za Zhi. 2009;45:971–6. [PubMed: 20137413]
  55. 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, Roggenkaemper 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;35:318–21. [PubMed: 14595441]
  56. Yamada K, Chan WM, Andrews C, Bosley TM, Sener EC, Zwaan JT, Mullaney PB, Ozturk BT, Akarsu AN, Sabol LJ, Demer JL, Sullivan TJ, Gottlob I, Roggenkaemper 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, 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;45:2218–23. [PubMed: 15223798]
  57. Yamada K, Hunter DG, Andrews C, Engle EC. A novel KIF21A mutation in a patient with congenital fibrosis of the extraocular muscles and Marcus Gunn jaw-winking phenomenon. Arch Ophthalmol. 2005;123:1254–9. [PubMed: 16157808]
  58. Yang X, Yamada K, Katz B, Guan H, Wang L, Andrews C, Zhao G, Engle EC, Chen H, Tong Z, Kong J, Hu C, Kong Q, Fan G, Wang Z, Ning M, Zhang S, Xu J, Zhang K. KIF21A mutations in two Chinese families with congenital fibrosis of the extraocular muscles (CFEOM). Mol Vis. 2010;16:2062–70. [PMC free article: PMC2965570] [PubMed: 21042561]
  59. 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;136:861–5. [PubMed: 14597037]
  60. Yazdani A, Traboulsi EI. Classification and surgical management of patients with familial and sporadic forms of congenital fibrosis of the extraocular muscles. Ophthalmology. 2004;111:1035–42. [PubMed: 15121385]
  61. Yoshida K, Okano T, Hoshi K, Yahikozawa H, Suzuki K, Banno H, Tamura T, Sobue G, Ikeda S. Congenital fibrosis of the extraocular muscles (CFEOM) syndrome associated with progressive cerebellar ataxia. Am J Med Genet A. 2007;143A:1494–501. [PubMed: 17551929]
  62. Zhao C, Lu SS, Li ND, Chen WY, Zhao KX. Zhonghua Yan Ke Za Zhi. 2005;41:594–9. [PubMed: 16080892]

Suggested Reading

  1. Engle EC, McIntosh N, Yamada K, Lee BA, Johnson R, O'Keefe M, Letson R, London A, Ballard E, Ruttum M, Matsumoto N, Saito N, Collins M, Morris L, Monte M, Magli A, de Berardinis T. CFEOM1, the classic familial form of congenital fibrosis of the extraocular muscles, is genetically heterogeneous but does not result from mutations in ARIX. BMC Genet. 2002;3:3. [PMC free article: PMC100320] [PubMed: 11882252]
  2. 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;110:510–2. [PubMed: 12073023]
  3. Traboulsi EI. Congenital abnormalities of cranial nerve development: overview, molecular mechanisms, and further evidence of heterogeneity and complexity of syndromes with congenital limitation of eye movements. Trans Am Ophthalmol Soc. 2004;102:373–89. [PMC free article: PMC1280110] [PubMed: 15747768]

Chapter Notes

Author Notes

Dr. Engle’s Web sites:
www.hhmi.org
dms.hms.harvard.edu

Engle Laboratory
Division of Genetics, Children's Hospital Boston
Caroline Andrews, Research Study Coordinator
Email: candrews@enders.tch.harvard.edu

Author History

Caroline Andrews, MSc (2004-present)
Jigar Desai, PhD; Children’s Hospital Boston (2006-2011)
Elizabeth C Engle, MD (2004-present)
David G Hunter, MD, PhD (2006-present)
Koki Yamada, MD, PhD; Children's Hospital Boston (2004-2006)

Revision History

  • 29 December 2011 (cd) Revision: sequence analysis available clinically for PHOX2A
  • 28 July 2011 (cd) Revision: sequence analysis available clinically for entire coding region of KIF21A
  • 21 April 2011 (me) Comprehensive update posted live
  • 19 December 2006 (cd) Revision: prenatal diagnosis available for CFEOM1
  • 22 September 2006 (me) Comprehensive update posted to live Web site
  • 27 April 2004 (me) Review posted to live Web site
  • 7 January 2004 (ee) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1348PMID: 20301522
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...