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Congenital Fibrosis of the Extraocular Muscles

Synonym: CFEOM

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

Author Information
, MD, PhD
Department of Ophthalmology, Boston Children's Hospital
Instructor in Ophthalmology, Harvard Medical School
Boston, Massachusetts
, MD, PhD
Ophthalmologist-in-Chief, Boston Children's Hospital
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 Update: January 14, 2016.

Summary

Clinical characteristics.

Congenital fibrosis of the extraocular muscles (CFEOM) refers to at least eight genetically defined strabismus syndromes (CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, Tukel syndrome, and CFEOM3 with polymicrogyria) 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, Kallmann syndrome, facial weakness, and vocal cord paralysis; and/or may develop a progressive sensorimotor axonal polyneuropathy. Individuals with Tukel syndrome also have postaxial oligodactyly or oligosyndactyly of the hands. Those with CFEOM3 with polymicrogyria also have microcephaly and intellectual disability.

Diagnosis/testing.

The diagnosis of CFEOM is based on ophthalmologic findings, and the subtypes depend on the identification of specific eye findings and associated findings. KIF21A pathogenic variants are associated with CFEOM1A and CFEOM3B. PHOX2A pathogenic variants are associated with CFEOM2. TUBB3 pathogenic variants are associated with CFEOM3A and CFEOM1B. TUBB2B pathogenic variants are associated with CFEOM3A and CFEOM3 with polymicrogyria.

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. In individuals with specific TUBB3 variants, surveillance for endocrine abnormalities, facial or vocal cord weakness, and interventions for developmental delays are indicated.

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

Genetic counseling.

CFEOM is inherited in either an autosomal dominant (CFEOM1, CFEOM3, and CFEOM3 with polymicrogyria) or autosomal recessive (CFEOM2 and Tukel syndrome) manner.

  • CFEOM1, CFEOM3, and CFEOM3 with polymicrogyria. An affected individual may have inherited a pathogenic variant from an affected parent or have the disorder as the result of a de novo pathogenic variant. Each child of an individual with autosomal dominant CFEOM has a 50% chance of inheriting the pathogenic variant.
  • CFEOM2 and Tukel syndrome. The parents of a child with autosomal recessive CFEOM are obligate heterozygotes (i.e., carriers of one pathogenic variant). At conception, each sib of an affected individual 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 if the pathogenic variant(s) have been identified in an affected family member.

Diagnosis

The term congenital fibrosis of the extraocular muscles (CFEOM) refers to several syndromes: CFEOM1A, CFEOM1B, CFEOM2, CFEOM3A, CFEOM3B, CFEOM3C, Tukel syndrome, and CFEOM3 with polymicrogyria [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, Cederquist et al 2012].

Suggestive Findings

Congenital fibrosis of the extraocular muscles (CFEOM) should be suspected in individuals with the following clinical features:

  • Congenital non-progressive ophthalmoplegia (inability to move the eyes) typically with severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze
  • Ptosis (droopy eyelids) that may range from mild to profound, and can be unilateral

The condition affects 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).

Typically binocular vision is absent. Refractive errors are common.

Note: For complete description of the eye findings to aid in establishing the diagnosis of a specific form of CFEOM, see Table 1.

Table 1.

Comparison of Types of CFEOM

CFEOM1CFEOM2CFEOM3Tukel SyndromeCFEOM3 w/Polymicrogyria
External ophthalmo-
plegia
Congenital, non-progressive. bilateral, profound, w/limited upgazeCongenital, non-progressive, bilateral, profound, w/eyes in exotropic (outward deviating) positionCongenital, non-progressive, bilateral OR unilateral; primarily affecting muscles in the oculomotor distribution 1Congenital, non-progressive, bilateral OR unilateral; primarily affecting muscles in the oculomotor distribution 1Congenital, non-progressive, bilateral; limited upgaze
Lid positionCongenital non-progressive bilateral ptosisCongenital non-progressive bilateral ptosisNormal OR congenital non-progressive bilateral or unilateral ptosisNormal OR congenital non-progressive bilateral or unilateral ptosisCongenital non-progressive bilateral ptosis
Primary vertical position of each eyeInfraducted (downward)Normal or positioned slightly above or below midlineInfraducted or normal (primary position)Infraducted or normal (primary position)Infraducted
Vertical eye movementsInability to elevate eyes above horizontal midlineSeverely restrictedVariable restriction w/ or w/out upgaze above midlineVariable restriction w/ or w/out upgaze above midlineSeverely limited
Primary horizontal position of each eyeOrthotropic (normal), esotropic (inward), or exotropic (outward)Typically exotropic; rarely, orthotropicOrthotropic or exotropic more frequent than esotropicOrthotropic or exotropic may be more frequent than esotropicOrthotropic or exotropic
Horizontal eye movementsNormal to severely restrictedSeverely restricted; only abduction preservedNormal to severely restrictedNormal to severely restrictedVariably restricted
Aberrant eye movementsFrequent, especially both eyes turning inward on attempted upgazeSmall amplitude, if presentSometimes presentSometimes presentConvergent nystagmus w/attempted upgaze
Forced duction testPositive for restrictionPositive for restrictionPositive for restriction at least in attempted upgazePositive for restriction at least in attempted upgazePositive for restriction
Binocular visionUsually absentAbsentRarely presentRarely presentUsually absent
Refractive errorsFrequently high astigmatismFrequentCommonCommonFrequent, high astigmatism
AmblyopiaFrequent; may be strabismic or refractive in natureFrequentFrequentFrequentFrequent
PupilsNormalOften small & sluggishly reactive to lightTypically normal, occasionally small & sluggishNormalNormal
Family historyConsistent w/AD inheritance; simplex cases 2 observed; parental germline mosaicism can mimic AR inheritanceConsistent w/AR inheritanceConsistent w/AD inheritance; simplex cases 2 observed; parental germline mosaicism can mimic AR inheritanceConsistent w/AR inheritanceConsistent w/AD inheritance
GeneticsCFEOM1A: associated w/pathogenic variants in KIF21A
CFEOM1B: associated w/path variants in TUBB3
Associated w/path variants in PHOX2ACFEOM3A: associated w/path variants in TUBB3 or TUBB2B
CFEOM3B: associated w/path variants in KIF21A
CFEOM3C: refers to cosegregation of CFEOM3 w/a translocation (in 1 family)
Associated w/path variants in TUBB2B
Additional findingsNoneRetinal dysfunctionVariably present in CFEOM3A:
intellectual & social disability, facial weakness, vocal cord paralysis, Kallmann syndrome, cyclic vomiting, spasticity, progressive sensorimotor axonal polyneuropathy
On brain MRI:
malformations of cortical development; dysgenesis of: corpus callosum, anterior commissure, corticospinal tracts, & basal ganglia
On MRI of cranial nerves & orbits:
hypoplasia of the oculomotor nerve & levator/superior rectus muscles
Postaxial oligodactyly or oligosyndactyly of the hands;
In one affected person w/an unbalanced translocation: facial dysmorphisms, kyphosis, pectus excavatum, developmental delay, & motor regression
Intellectual disability,
polymicrogyria,
microcephaly

AR = autosomal recessive
1. In individuals not meeting CFEOM1 criteria

2.

A single occurrence in a family

Establishing the Diagnosis

The diagnosis of CFEOM is established in a proband with identification of a specific CFEOM phenotype and/or of a heterozygous pathogenic variant in KIF21A, TUBB3, or TUBB2B or biallelic pathogenic variants in PHOX2A by molecular genetic testing (see Table 2).

Molecular testing approaches can include serial single-gene testing, use of a multi-gene panel, and more comprehensive genomic testing.

Serial single-gene testing can be considered if (1) a pathogenic variant in a particular gene accounts for a large proportion of the disease OR (2) additional factors (e.g., clinical findings, laboratory findings, and ancestry) indicate that a pathogenic variant in a particular gene is most likely. Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.

A multi-gene panel that includes KIF21A, TUBB3, TUBB2B, PHOX2A, and other genes of interest (see Differential Diagnosis) may also be considered. Note: The genes included and the sensitivity of multi-gene panels vary by laboratory and over time.

More comprehensive genomic testing – when available – including whole-exome sequencing (WES), whole-genome sequencing (WGS), and whole mitochondrial sequencing (WMitoSeq) may be considered if serial single-gene testing (and/or use of a multi-gene panel that includes KIF21A, TUBB3, TUBB2B, and PHOX2A) fails to confirm a diagnosis in an individual with features of CFEOM. For issues to consider in interpretation of genomic test results, click here.

Table 2.

Molecular Genetic Testing Used in CFEOM

Gene 1Proportion of CFEOM Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
KIF21A~55%81/94 in CFEOM1 5
5/20 in CFEOM3 6
Unknown 7
TUBB3~35%15/15 in isolated CFEOM3 8
27/27 in CFEOM3 with additional neurologic findings 9
Unknown 7
PHOX2A~10%15/15 in CFEOM2 10Unknown 7
TUBB2B<1%3/3 in CFEOM3 with polymicrogyria 11Unknown 7
Unknown 12NANA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

5.
6.
7.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

8.

Individuals who have the eye phenotype only, with no additional medical conditions. TUBB3 pathogenic variants are associated with familial and simplex occurrences of CFEOM3 [Tischfield et al 2010]; this is referred to as CFEOM3A. TUBB3 pathogenic variants are also a rare cause of CFEOM1; this is referred to as CFEOM1B.

9.
10.

Nakano et al [2001], Yazdani et al [2003]. PHOX2A is the only gene in which pathogenic variants are known to cause the CFEOM2 phenotype [Nakano et al 2001, Bosley et al 2006].

11.
12.

A three-generation family that cosegregated CFEOM3 and a balanced/unbalanced reciprocal translocation t(2;13) (q37.3;q12.11) permitted assignment of CFEOM3C, OMIM 609384 to 13q27.3 [Aubourg et al 2005]. A genome-wide linkage screen of a large consanguineous family whose affected members have a CFEOM3 phenotype and postaxial oligodactyly/oligosyndactyly of the hands, referred to as Tukel syndrome (OMIM 609428), mapped the locus to a 1.5-Mb region on chromosome 21qter [Tukel et al 2005]. See also Shinwari et al [2015].

Clinical Characteristics

Clinical Description

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 (MRI) suggests that the abducens and optic nerves can also be hypoplastic [Demer et al 2005, Wu et al 2009, Demer et al 2010].

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 resting 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 but not characteristic.

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 or hypoplasia of the corpus callosum, brain stem hypoplasia, cerebellar hemisphere hypoplasia, absence of the cerebral peduncle in the midbrain, colpocephaly, hypoplasia of the cerebellar vermis, expansion of the ventricular system, pachygyria, polymicrogyria, encephalocele, and/or hydrancephaly [Flaherty et al 2001, Pieh et al 2003, Harissi-Dagher et al 2004]. The CFEOM phenotype in most of these individuals is atypical and meets the criteria of CFEOM3. Other CNS findings include hypoplastic oculomotor nerves, dysmorphic basal ganglia with or without internal capsule hypoplasia, and agenesis or hypoplasia of the anterior commissure [Demer et al 2010, Tischfield et al 2010, Cederquist et al 2012, Chew et al 2013, Balasubramanian et al 2015, Whitman et al 2015].

Non-ocular findings in a subset of individuals with CFEOM3 include facial paralysis, spasticity, cognitive and behavioral impairments, and a later-onset progressive peripheral sensorimotor axonal polyneuropathy, joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism with anosmia), and cyclic vomiting [Tischfield et al 2010, Chew et al 2013].

Marcus Gunn phenomenon and other evidence of misinnervation have been reported in individuals with CFEOM [Pieh et al 2003, Yamada et al 2005, Kaçar Bayram et al 2015]. The Marcus Gunn jaw winking phenomenon manifests as the momentary elevation of a ptotic upper eyelid with specific movements of the jaw. Often first noted in young infants when they are feeding, the phenomenon 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 finding 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 pathogenic variants are associated with CFEOM1 and rare cases of CFEOM3. Clinical examinations and high-resolution orbital MRI of individuals with CFEOM1 resulting from several different specific KIF21A pathogenic variants did not reveal a correlation between any specific pathogenic variant and clinical phenotype [Yamada et al 2003, Demer et al 2005].

PHOX2A pathogenic variants are associated with CFEOM2. No correlation between specific PHOX2A pathogenic variants and specific aspects of the CFEOM2 phenotype has been found.

TUBB3 pathogenic variants are associated with CFEOM1B or CFEOM3. Correlations have been found between specific TUBB3A pathogenic variants and the clinical phenotype [Tischfield et al 2010, Chew et al 2013, Whitman et al 2015]:

  • c.185G>A (p.Arg62Gln): moderate CFEOM3. Brain MRI: normal. No developmental delays or intellectual disability.
  • c.784C>T (p.Arg262Cys): mild to severe CFEOM3 or CFEOM1B. Brain MRI: anterior commissure hypoplasia, mild corpus callosum hypoplasia, mild basal ganglia dysgenesis. No developmental delays or intellectual disability.
  • 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, midface hypoplasia, Kallmann syndrome (hypogonadotropic hypogonadism with anosmia), progressive sensorimotor polyneuropathy, vocal cord paralysis, and cyclic vomiting. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia, basal ganglia dysgenesis, hypoplastic to absent olfactory bulbs, olfactory sulci, and oculomotor and facial nerves.
  • c.211G>A (p.Gly71Arg): moderate CFEOM3, developmental delay, hypotonia, thinning or agenesis of corpus callosum, increased and abnormal cortical gyration, basal ganglia and thalamus dysgenesis, brain stem hypoplasia, incomplete rotation of hippocampus, hypoplasia of optic and oculomotor nerves
  • c.292G>A (p.Gly98Ser): moderate CFEOM3, developmental delay, hypotonia, thinning of corpus callosum, increased and abnormal cortical gyration, basal ganglia and thalamus dysgenesis, brain stem hypoplasia, incomplete rotation of hippocampus, cerebellar vermis hypoplasia with dysmorphic folia, hypoplasia of optic and oculmotor nerves

Many persons with CFEOM3 who have a TUBB3 pathogenic variant also have aberrant eye movements and several have ptotic eyelid elevation associated with synkinetic jaw movements (Marcus Gunn phenomenon). However, the Marcus Gunn phenomenon has also been reported in association with a KIF21A -related CFEOM.

TUBB2B. Only one pathogenic variant (c.1261G>A, p.Glu421Lys) has been associated with both CFEOM and polymicrogyria. Seven other pathogenic variants are associated with polymicrogyria without CFEOM.

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 1:230,000 [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 that cosegregated with the affected haplotypes were identified [Miyake et al 2008]. All were predicted to alter amino acids that were conserved in eight different species. CHN1 was subsequently found not to 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 pathogenic variants 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 pathogenic variants in SALL4 [Wabbels et al 2004]. However, some members of families segregating a SALL4-related disorder have been found to harbor a SALL4 pathogenic variant 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 pathogenic variants 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- to 10-kb) mtDNA deletion that is usually present in all tissues; however, mutated 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) the following:

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 pathogenic variants in ROBO3 [Jen et al 2004]. Compound heterozygous ROBO3 pathogenic variants 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)

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

Other. CFEOM has been identified in one individual with Noonan syndrome [Elgohary et al 2005].

Management

Evaluations Following Initial Diagnosis

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

  • Consultation with a medical geneticist and/or genetic counselor
  • Ophthalmologic examination
    • Determination of resting gaze position, head position with eyes in resting gaze 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
    • Refraction, including cycloplegic refraction in children
    • Photographic documentation for future comparison
  • Neuroimaging suggested if there are any additional neurologic symptoms or developmental delays
  • Strongly recommended if eye muscle surgery is planned:
    • Brain and brain stem MRI scan to determine the size and/or course of the oculomotor and trochlear nerves
    • High-resolution orbital MRI (1- to 3-mm cuts) to detect abnormalities in the size and/or course of the extraocular muscle(s) and atrophy of the superior rectus-levator complex

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. In cases of severe exposure, a PROSE lens can be of significant benefit [Papakostas et al 2015].

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.
    • Extraocular muscles may be found at surgery to be attached in unexpected locations.
    • Resections or plications may be helpful in some cases to provide traction against large recessions during healing.
    • Surgery is likely to be technically difficult because of tightness of rectus muscles.
    • Recessions need to be larger – sometimes considerably larger – than indicated by standard tables, especially recessions of the inferior rectus muscles.
    • Dysinnervation causing esotropia in attempted upgaze may mask an underlying exotropia that will be unmasked after inferior rectus muscle weakening.
    • Inferior rectus muscle weakening may be enhanced by superior oblique weakening.
    • Profound weakening procedures (e.g., suturing muscle to orbital rim, rectus muscle myectomy) may be necessary.
    • Botulinum toxin may be helpful for residual misalignment in some cases.

Prevention of Secondary Complications

The following are appropriate:

  • 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.

In individuals with specific TUBB3 variants, surveillance for endocrine abnormalities, facial or vocal cord weakness, and interventions for developmental delays are indicated.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • If the pathogenic variant(s) in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant(s) in the family are not known, clinical ophthalmologic exam can be used to clarify the disease status of at-risk relatives.

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) 1 (mutation of KIF21A or TUBB3), CFEOM3 (mutation of TUBB3, TUBB2B, or KIF21A), and CFEOM3 with polymicrogyria (mutation of TUBB2B) are inherited in an autosomal dominant manner.

CFEOM2 (mutation of PHOX2A) and Tukel syndrome (molecular basis unknown) are inherited in an autosomal recessive manner.

Risk to Family Members – Autosomal Dominant Inheritance (CFEOM1, CFEOM3, CFEOM3 with Polymicrogyria)

Parents of a proband

  • Some individuals diagnosed with CFEOM1, CFEOM3, or CFEOM3 with polymicrogyria have an affected parent.
  • A proband may have the disorder as the result of a de novo pathogenic variant in KIF21A, TUBB3, or TUBB2B.
    • KIF21A. De novo pathogenic variants have been reported (see Yamada et al [2003]).
    • TUBB3. The proportion of cases caused by a de novo pathogenic variant among patients with isolated CFEOM3 (no other neurologic deficits) has been reported to be 25% (4/16 pedigrees) [Tischfield et al 2010]. Probands with CFEOM3A with additional neurological deficits are usually the result of de novo TUBB3 pathogenic variant (85%, 17/20 pedigrees) [Tischfield et al 2010, Chew et al 2013, Balasubramanian et al 2015, Whitman et al 2015].
    • TUBB2B. The proportion of cases caused by a de novo TUBB2B pathogenic variant is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo KIF21A, TUBB3, or TUBB2B pathogenic variant include ophthalmologic examinations and consideration of molecular genetic testing for the pathogenic variant if one has been identified in the proband.
  • If a KIF21A, TUBB3, or TUBB2B pathogenic variant cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent.
  • The family history of some individuals diagnosed with CFEOM1, CFEOM3, or CFEOM3 with polymicrogyria may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (e.g., ocular examination and/or molecular genetic testing) have been performed on the parents of the proband.

Sibs of a proband

  • The risk to sibs of a proband depends on the genetic status of the proband's parents.
  • If a parent has clinical characteristics consistent with CFEOM and/or a pathogenic variant in KIF21A, TUBB3, or TUBB2B, the risk to the sibs is 50%. The chance that a sib who inherits the pathogenic variant will manifest CFEOM may be less than 50% depending on the penetrance of the variant (see Penetrance).
  • The sibs of a proband with clinically unaffected parents are still at increased risk for CFEOM because of the possibility of reduced penetrance in a parent.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with CFEOM1, CFEOM3, or CFEOM3 with polymicrogyria has a 50% chance of inheriting the pathogenic variant.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected and/or has a pathogenic variant, 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 (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
  • Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) of CFEOM2 has been reported in two consanguineous families [Wang et al 1998] (see Prevalence). Two-generation involvement can occur in autosomal recessive disorders when a parent (who has 2 pathogenic 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with CFEOM2 or Tukel syndrome are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant.

Carrier (Heterozygote) Detection

CFEOM2. Carrier testing for relatives at risk requires prior identification of the PHOX2A pathogenic variants in the family.

Tukel syndrome. Carrier testing using molecular genetic techniques is not possible because the associated gene has not been identified.

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 pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant or clinical evidence of the disorder, it is likely that the proband has a de novo pathogenic variant. However, 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, are carriers, 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the KIF21A, TUBB3, TUBB2B, or PHOX2A pathogenic variant(s) has been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis for a pregnancy at increased risk for CFEOM may be options that a couple may wish to consider.

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.

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.

  • 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

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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
610031POLYMICROGYRIA, SYMMETRIC OR ASYMMETRIC; PMGYSA
612850TUBULIN, BETA-2B; TUBB2B

Molecular Genetic Pathogenesis

CFOEM is a cranial motor neuron disorder caused by pathogenic variants in the genes encoding KIF21A, PHOX2A, TUBB3, and TUBB2B. These proteins are expressed in tissues affected in CFEOM, as well as many other tissues. KIF21A is expressed widely in the cell bodies, axons and dendrites of multiple neuronal populations, as well as extraocular and other skeletal muscles [Yamada et al 2003, Desai et al 2012]. TUBB3 is expressed primarily in neurons [Katsetos et al 2003]. TUBB2B is highly expressed in both neurons and glia.

Microtubules are copolymers assembled from tubulin heterodimers, which contain several different alpha- and β-tubulin isotypes encoded by separate genes. KIF21A, a member of the kinesin family of molecular motors, interacts with the microtubule track to transport cargos in an anterograde direction from the cell body to the developing growth cone [Marszalek et al 1999]. TUBB3 and TUBB2B are components of the microtubules. 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].

KIF21A

Gene structure. 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_001173464.1 (Table 3) is the longest transcript variant. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Ten heterozygous missense KIF21A variants have been associated 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]. One missense variant was identified in one CFEOM3 pedigree [Yamada et al 2004].

In a study of 127 probands, the pathogenic variant c.2860C>T accounted for more than 40% of abnormal alleles. Seven of these KIF21A pathogenic variants occur at 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 pathogenic variants are located in the motor domain. Haplotype analysis demonstrated that five de novo pathogenic variants found in autosomal dominant CFEOM1 pedigrees all arose exclusively on the paternal allele [Yamada et al 2003].

Table 3.

Selected KIF21A Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.84C>Gp.Cys28TrpNM_001173464​.1
NP_001166935​.1
c.1067T>Cp.Met356Thr
c.2860C>Tp.Arg954Trp

Note on variant classification: Variants listed in the table have been provided by the authors. 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, encoded by transcript NM_001173464.1, kinesin family member 21A (KIF21A), is 1674 amino acids and comprises three domains characteristic of the kinesin superfamily: 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 [Marszalek et al 1999]. See Molecular Genetic Pathogenesis.

Kif21a mRNA and protein are expressed early during mouse development highly in the brain and moderately in the kidney, testes, and skeletal muscle [Marszalek et al 1999]. Kif21a is hypothesized to interact with the insoluble cytoskeleton or a large protein complex [Marszalek et al 1999]. In vitro, KIF21A acts as an inhibitor of microtubule dynamics [van der Vaart et al 2013].

Abnormal gene product. In vivo and in vitro, CFEOM-causing pathogenic variants in KIF21A attenuate normal autoinhibition of the protein, leading to a constitutively active molecule, increased microtubule association, and oculomotor axon stalling [Cheng et al 2014].

PHOX2A

Gene structure. The gene contains three exons. The genomic length is approximately 5 kb [Nakano et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Four different homozygous PHOX2A pathogenic variants have been identified in five families with CFEOM2. Two pathogenic variants are single-base substitutions (1 missense and 1 nonsense) and two are splice-site variants [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. See Molecular Genetic Pathogenesis.

Abnormal gene product. It is predicted that most pathogenic variants in PHOX2A lead to the truncation of the protein resulting in complete loss of protein function [Nakano et al 2001, Bosley et al 2006]. It is predicted that CFEOM2 results from aberrant development of the 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.

TUBB3

Gene structure. The normal cDNA (NM_006086.3, transcript variant 1) comprises 1794 bp in four exons and encodes 450 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Ten heterozygous pathogenic missense variants causative of CFEOM3A alter eight amino acids in exons 3 and 4 and occur recurrently [Tischfield et al 2010, Whitman et al 2015]. Thirty-two percent of 34 reported probands have the pathogenic variant c.784C>T (p.Arg262Cys). CFEOM1B is most frequently caused by the missense variants c.784C>T (p.Arg262Cys) or c.1249G>A (p.Asp417Asn).

Table 4.

Selected TUBB3 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.185G>Ap.Arg62GlnNM_006086​.3
NP_006077​.2
c.211G>Ap.Gly91Arg
c.292G>Ap.Gly98Ser
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 authors. 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 pathogenic variants suggest that the pathogenic variants underlying CFEOM3 primarily alter microtubule function in a dominant fashion [Tischfield et al 2010]. CFEOM-causing pathogenic vairants have been associated with increased microtubule stability [Tischfield et al 2010, Tischfield et al 2011].

TUBB2B

Gene structure. The normal cDNA comprises 2019 bp in four exons and encodes 445 amino acids. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. Seven heterozygous variants are associated with polymicrogyria. One heterozygous missense variant, p.Glu421Lys, is associated with CFEOM3 with polymicrogyria.

Table 5.

TUBB2 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1261G>Ap.Glu421LysNM_178012​.4
NP_821080​.1

Note on variant classification: Variants listed in the table have been provided by the authors. 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 445-amino acid protein has an N-terminal domain, an intermediate domain, and a C-terminal domain. This gene encodes a class II member of the beta tubulin protein family, beta-tubulin isotype IIB (TUBB2B). Tubulin is the major constituent of microtubules. The TUBB2B protein is expressed in neurons and glia in the central and peripheral nervous system.

Several pathogenic variants in humans lead to polymicrogyria, and are associated with decreased levels of TUBB2B protein. The p.Glu421Lys pathogenic variant, which is associated with CFEOM3 with polymicrogyria, causes increased microtubule stability in yeast and disrupts kinesin binding sites [Cederquist et al 2012].

Abnormal gene product. Pathogenic variants associated with polymicrogyria fold and incorporate into microtubules poorly, and the phenotype may therefore be caused by haploinsufficiency. The pathogenic variant associated with CFEOM3 with polymicrogyria reduces the formation of alpha-beta heterodimers, and disrupts microtubule dynamics [Cederquist et al 2012].

References

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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

Author History

Caroline Andrews, MSc; Howard Hughes Medical Institute (2004-2016)
Jigar Desai, PhD; Children’s Hospital Boston (2006-2011)
Elizabeth C Engle, MD (2004-present)
David G Hunter, MD, PhD (2006-present)
Mary Whitman, MD, PhD (2016-present)
Koki Yamada, MD, PhD; Children's Hospital Boston (2004-2006)

Revision History

  • 14 January 2016 (me) Comprehensive update posted live
  • 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
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