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Congenital Fibrosis of the Extraocular Muscles Overview

Synonym: CFEOM

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

Author Information

Initial Posting: ; Last Update: August 12, 2021.

Estimated reading time: 22 minutes

Summary

The purpose of this overview is to increase the awareness of clinicians regarding the genetic causes and management of congenital fibrosis of the extraocular muscles (CFEOM).

The following are the goals of this overview.

Goal 1.

Describe the clinical characteristics of CFEOM.

Goal 2.

Review the genetic causes of CFEOM.

Goal 3.

Review the disorders to consider the differential diagnosis of CFEOM

Goal 4.

Provide an evaluation strategy to identify the genetic cause of CFEOM in a proband (when possible).

Goal 5.

Inform genetic counseling of family members of an individual with CFEOM.

Goal 6.

Review management of CFEOM.

1. Clinical Characteristics of Congenital Fibrosis of the Extraocular Muscles

Congenital fibrosis of the extraocular muscles (CFEOM) is diagnosed based on characteristic eye findings: 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 sometimes the trochlear and abducens nuclei and nerves (cranial nerves IV and VI) and their innervated muscles (superior oblique muscle and lateral rectus muscle, respectively).

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 (chin up) at rest and by moving their heads rather than their eyes to track objects. Binocular vision is typically absent. Refractive errors are common.

Although once felt to result from primary fibrosis of the extraocular muscles, neuroanatomic, genetic, and neuroimaging findings suggest that the various forms of CFEOM result from abnormal development of oculomotor neurons and their processes [Whitman & Engle 2017]. Magnetic resonance imaging suggests that the trochlear, abducens, and optic nerves can also be hypoplastic [Demer et al 2005, Demer et al 2010].

Phenotypes of CFEOM based on specific eye findings, CNS malformations, and other non-ocular findings are summarized in Table 1.

Table 1.

Congenital Fibrosis of the Extraocular Muscles: Phenotypes

FindingCFEOM Subtype
CFEOM1CFEOM2CFEOM3CFEOM5 1Tukel syndromeCFEOM3 w/
polymicrogyria
Congenital non-progressive external ophthalmoplegia Bilateral, profound; limited upgazeBilateral, profound, w/eyes in exotropic (outward deviating) positionBilateral OR unilateral; primarily affecting muscles in the oculomotor distributionNl OR variable restrictions in vertical &/or horizontal gaze, bilateral OR unilateralBilateral OR unilateral; primarily affecting muscles in the oculomotor distributionBilateral; limited upgaze
Lid position Congenital non-progressive bilateral ptosisCongenital non-progressive bilateral ptosisNl OR congenital non-progressive bilateral or unilateral ptosisNl OR congenital non-progressive bilateral or unilateral ptosisNl OR congenital non-progressive bilateral or unilateral ptosisCongenital non-progressive bilateral ptosis
Primary vertical position of each eye Infraducted (downward)Nl or positioned slightly above or below midlineInfraducted or nl (primary position)Nl (primary position)Infraducted or nl (primary position)Infraducted
Vertical eye movements Inability to elevate eyes above horizontal midlineSeverely restricted (up- & downgaze)Variable restriction w/or w/o upgaze above midlineNl or w/mildly restricted upgazeVariable restriction w/or w/o upgaze above midlineSeverely restricted
Primary horizontal position of each eye Orthotropic (nl), esotropic (inward), or exotropic (outward)Typically exotropic; rarely, orthotropicOrthotropic or exotropic more frequent than esotropicOrthotropic or exotropicOrthotropic or exotropic may be more frequent than esotropic.Orthotropic or exotropic
Horizontal eye movements Nl to severely restrictedSeverely restricted; only abduction preservedNl to severely restrictedNl to severely restrictedNl to severely restrictedVariably restricted
Aberrant eye movements Frequent, esp both eyes turning inward on attempted upgazeSmall amplitude, if presentSometimes presentSometimes present as Duane retraction syndrome w/synergistic divergenceSometimes presentConvergent nystagmus w/attempted upgaze
CFEOM1 CFEOM2 CFEOM3 CFEOM5 1 Tukel syndrome CFEOM3 w/
polymicrogyria
Positive forced duction test for restriction ++At least in attempted upgazeUnreportedAt least in attempted upgaze+
Binocular vision Usually absentAbsentRarely presentUnreportedRarely presentUsually absent
Refractive errors (hyperopia, myopia, or astigmatism) Frequently high astigmatismFrequentCommonRareCommonFrequent, high astigmatism
Amblyopia Frequent; may be strabismic or refractiveFrequentFrequentUnspecifiedFrequentFrequent
Pupils NlOften small & sluggishly reactive to lightTypically nl, occasionally small & sluggishly reactive to lightNlNlNl
CNS malformations NoneNoneSee CNS malformations following this table.None reportedPostaxial oligodactyly/ oligosyndactylyAgenesis or hypoplasia of corpus callosum, schizencephaly, polymicrogyria, basal ganglia dysmorphism, thalamus dysmorphisms, cerebellar dysplasia
Non-ocular findings NoneNoneSee Non-ocular findings following this table.Postaxial oligodactyly or oligosyndactyly of the handsID, microcephaly, &/or progressive sensorimotor axonal polyneuropathy sometimes present

ID = intellectual disability; nl = normal

1.

This phenotype, caused by COL25A1 variants, is described per authors' personal observations. A few clinical phenotyping parameters were not reported in detail.

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 palpebrae 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.

Strabismus is the deviation of the position of one eye relative to the other, resulting in misalignment of the line of sight of the two eyes. Individuals with CFEOM 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.

CNS malformations. Individuals with CFEOM typically have hypoplastic oculomotor nerves on MRI. Some individuals with CFEOM3 have central nervous system malformations, including agenesis or hypoplasia of the corpus callosum and anterior commissure, pachygyria, polymicrogyria, schizencephaly, dysgenesis of the olfactory bulbs and sulci, expansion of the ventricular system, deficiency of the falx cerebri, paucity of white matter, colpocephaly, dysmorphic basal ganglia with or without internal capsule hypoplasia, malformations of the thalamus and hippocampus, hypoplasia of the cerebellar vermis and/or hemispheres, brain stem hypoplasia, facial nerve hypoplasia, absence of the cerebral peduncle in the midbrain, arachnoid cysts, encephalocele, and/or hydrancephaly. The CFEOM phenotype in most of these individuals meets the criteria of CFEOM3 [Demer et al 2010, Tischfield et al 2010, Cederquist et al 2012, Romaniello et al 2012, Chew et al 2013, Balasubramanian et al 2015, Whitman et al 2016, Jurgens et al 2021, Soliani et al 2021]. Some individuals, particularly those with CFEOM3 with polymicrogyria, also have microcephaly and intellectual disability.

Non-ocular findings

  • CFEOM3. In a subset of individuals with CFEOM3 the non-ocular findings comprise distinct syndromes that can include facial paralysis and facial dysmorphisms, vocal cord paralysis, intellectual and/or social disability, Kallmann syndrome (hypogonadotropic hypogonadism with anosmia), progressive peripheral sensorimotor axonal polyneuropathy, congenital joint contractures, gait anomalies, cyclic vomiting, epilepsy, and microcephaly [Tischfield et al 2010, Chew et al 2013, Whitman et al 2016, Jurgens et al 2021].
  • Marcus Gunn phenomenon and other evidence of dysinnervation have been reported in individuals with CFEOM [Pieh et al 2003, Yamada et al 2005, Kaçar Bayram et al 2015, Jurgens et al 2021]. 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 these findings with CFEOM provides additional evidence that these syndromes are primarily neurogenic in cause.
  • 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.

2. Genetic Causes of CFEOM

Table 2A.

CFEOM: Associated Genes

Gene 1% of All CFEOMAssociated CFEOM Phenotypes
CFEOM1CFEOM2CFEOM3CFEOM5
COL25A1 <1%+
KIF21A 2 ~55%++++
PHOX2A ~10%+
TUBA1A <1%++
TUBB2B 3<1%+
TUBB3 4~35%++++
1.

Genes are listed alphabetically

Table 2B.

CFEOM: Gene-Phenotype Correlations

Gene 1Phenotype
ID/DDMRI FindingsOther Features
COL25A1 Small extraocular musclesAberrant eye movements incl Duane retraction syndrome or synergistic divergence
KIF21A 2Rarely +Hypoplastic oculomotor nerve & small extraocular muscles; small optic nerves. Other findings (extremely rare) incl cerebellar hypoplasia, arachnoid cyst, corpus callosal thinning, paucity of white matter, dysmorphic midbrain, small caudate bodiesPtotic eyelid elevation assoc w/synkinetic jaw movements (Marcus Gunn phenomenon). Other syndromic features (extremely rare) incl facial weakness, pes cavus, sensorimotor peripheral neuropathy w/axonal denervation
PHOX2A Absent oculomotor & trochlear nerves, small or absent extraocular musclesReported only in consanguineous families from the Middle East; minimally reactive pupils
TUBA1A ±Hypoplastic oculomotor nerve & small extraocular muscles, ± perisylvian polymicrogyria, ± deficiency of the falx cerebri, asymmetry of caudate heads & lateral ventricles, nl anterior commissure, cerebellum, & brain stemAberrant eye movements w/convergence on attempted upgaze or divergence on attempted downgaze; rarely assoc w/cyclic vomiting, hypotonia, facial dysmorphisms, gait anomalies, &/or gastrointestinal symptoms
TUBB2B 3+Small extraocular muscles; perisylvian polymicrogyria, ± schizencephaly, asymmetric basal ganglia, corpus callosal thinning, cerebellar dysplasia, nl brain stem± epilepsy, microcephaly
TUBB3 4±Hypoplastic oculomotor nerve & small extraocular muscles, agenesis or hypoplasia of corpus callosum & anterior commissure, dysgenesis of olfactory bulbs & sulci, basal ganglia malformationsAberrant eye movements & Marcus Gunn phenomenon; may be assoc w/facial dysmorphisms, Kallmann syndrome, vocal cord paralysis, axonal peripheral neuropathy, cyclic vomiting

DD = developmental delay; ID = intellectual disability; nl = normal

1.

Genes are listed alphabetically.

2.

KIF21A variants most commonly result in ptosis and/or CFEOM without syndromic findings. Very rare specific variants can result in syndromic features resembling those seen in TUBB3-associated CFEOM [Soliani et al 2021].

3.

Allelic w/TUBB2B-related tubulinopathy: malformations of cortical development without CFEOM (See Tubulinopathies Overview.)

4.

Allelic w/TUBB3-related tubulinopathy: microlissencephaly or polymicrogyria, usually accompanied by abnormalities of the corpus callosum and cerebellar, basal ganglia, and brain stem dysplasia, but without CFEOM (See Tubulinopathies Overview.)

Genotype-Phenotype Correlations

KIF21A. 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].

Recently, one specific KIF21A variant was reported to result in a syndromic CFEOM3 phenotype with a progressive peripheral neuropathy, reminiscent of the syndromic findings in TUBB3-CFEOM [Soliani et al 2021].

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

TUBA1A. No correlation between specific TUBA1A pathogenic variants and specific aspects of the CFEOM phenotype has been found [Jurgens et al 2021].

TUBB2B. No correlation between specific TUBB2B pathogenic variants and specific aspects of the CFEOM phenotype has been found [Cederquist et al 2012, Romaniello et al 2012, Romaniello et al 2019].

TUBB3. Suggested correlations (based on data from a limited number of individuals) between specific TUBB3 pathogenic variants and distinctive phenotypes are summarized in Table 3 (pdf) [Tischfield et al 2010, Chew et al 2013, Whitman et al 2016]. Additional data are necessary to determine if these described associations represent true genotype-phenotype correlations.

3. Differential Diagnosis of CFEOM

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.

Genetic disorders with ophthalmoplegia in the differential diagnosis of CFEOM are summarized in Table 4.

Table 4.

Genetic Disorders with Ophthalmoplegia in the Differential Diagnosis of Congenital Fibrosis of the Extraocular Muscles

Gene (Genetic Mechanism)DisorderMOIClinical Characteristics
Chromosome 8 anomaliesSee Duane syndrome.Duane syndrome w/various assoc congenital abnormalities incl other cranial nerve deficits, facial dysmorphisms, ID, cardiac defects
CHN1 CHN1-related Duane syndrome 1ADBilateral involvement, vertical movement abnormalities beyond the upshoot & downshoot often seen in Duane syndrome
DMPK Myotonic dystrophy type 1 AD
HOXA1 Athabaskan brain stem dysgenesis syndrome (ABDS) & Bosley-Salih-Alorainy syndrome (BSAS) (OMIM 601536)ARDuane syndrome type III or horizontal gaze palsy & (in most persons) bilateral SNHL. Depending on specific syndrome (ABDS vs BSAS), a subset manifest ID, autism, moderate-to-severe central hypoventilation, facial weakness, swallowing difficulties, vocal cord paresis, conotruncal heart defects, & skull & craniofacial abnormalities.
HOXB1 Hereditary congenital facial paresis 3 2 (OMIM 614744)ARIsolated dysfunction of facial nerve, comitant esotropia
MAFB MAFB -related Duane syndrome 1ADBilateral Duane syndrome ± mild-to-severe SNHL
MYMK Carey-Fineman-Ziter syndrome (OMIM 254940)ARFacial weakness w/congenital non-progressive myopathy, Robin sequence
mtDNA deletions ranging in size from 2-10 kbChronic progressive external ophthalmoplegia caused by mtDNA deletions (See Mitochondrial DNA Deletion Syndromes.)MatProgressive ptosis, paralysis of extraocular muscles (ophthalmoplegia), variably severe proximal limb weakness
PABPN1 Oculopharyngeal muscular dystrophy ADLate-onset severe dysphagia
POLG
RRM2B
SLC25A4
TK2
TMPO
TWNK
Ophthalmoplegia caused by mtDNA maintenance defects (See Mitochondrial DNA Maintenance Defects Overview.)AD
AR
ROBO3 Horizontal gaze palsy w/progressive scoliosis (OMIM 607313)ARCongenital horizontal gaze palsy (no horizontal eye movements) w/progressive scoliosis
SALL4 SALL4-related disorders incl Duane-radial ray syndrome (DRRS) & acro-renal-ocular syndrome (AROS)AD
  • DRRS: uni- or bilateral Duane anomaly & radial ray malformation
  • AROS: radial ray malformations, renal abnormalities, ocular coloboma, & Duane anomaly

AD = autosomal dominant; AR = autosomal recessive; CFEOM = congenital fibrosis of the extraocular muscles; ID = intellectual disability; Mat = maternal; MOI = mode of inheritance; mtDNA = mitochondrial DNA; SNHL = sensorineural hearing loss

1.

Duane syndrome is characterized by horizontal eye movement limitation, usually of abduction, with retraction of the globe and narrowing of the palpebral fissure 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.

2.

Hereditary congenital facial paresis 1 (HCFP1) maps to chromosome 3q21-q22 (OMIM 601471); HCFP2 maps to chromosome 10q21.3-q22.1 (OMIM 604185).

Other disorders with ophthalmoplegia in the differential diagnosis of CFEOM

  • Brown syndrome (OMIM 616407) – "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 or possibly from aberrant innervation. Rare familial cases have been reported. The genetic cause of Brown syndrome is not known.
  • Myasthenia gravis (fluctuating weakness and diplopia). See Congenital Myasthenic Syndromes.
  • Cranial nerve III palsy. Few reports of congenital familial third-nerve palsy exist and those that do may be misdiagnosed CFEOM.
  • 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 affected individuals also have developmental defects of additional lower cranial nerves and distal extremities. Individuals with MBS have normal vertical eye movements and do not have ptosis [MacKinnon et al 2014].

4. Evaluation Strategy to Identify the Genetic Cause of CFEOM in a Proband (When Possible)

Establishing a specific genetic cause of CFEOM:

  • Can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling;
  • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing.

Medical history. A thorough medical history should be taken, including pre- or perinatal findings, developmental history, and growth trajectory. A history of perinatal distress, developmental delay, and slow growth is most consistent with CFEOM3 and a pathogenic variant in one of the tubulin genes (see also Tubulinopathies Overview).

Physical examination. A thorough physical examination (including of the extremities and genitalia), comprehensive eye examination, and neurologic examination should be performed. See Table 2B and Table 3 (pdf) for more details.

  • Bilateral CFEOM with ptosis and upgaze restriction without other physical findings can be caused by variants in KIF21A or TUBB3.
  • Unilateral CFEOM or CFEOM without ptosis is most often caused by variants in TUBB3.
  • The combination of CFEOM3 with facial weakness, other cranial nerve dysfunction, peripheral neuropathy, microphallus and/or cryptorchidism, or congenital joint contractures strongly suggests specific TUBB3 variants.

Family history. A three-generation family history should be taken, with attention to relatives with manifestations of CFEOM and documentation of relevant findings through direct examination or review of medical records including results of molecular genetic testing.

Molecular Genetic Testing

Testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved (Option 1), whereas genomic testing does not (Option 2).

Option 1

A multigene panel that includes some or all of the genes listed in Table 2A is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

5. Genetic Counseling of Family Members of an Individual with CFEOM

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Congenital fibrosis of the extraocular muscles (CFEOM) caused by pathogenic variants KIF21A, TUBA1A, TUBB2B, or TUBB3 is inherited in an autosomal dominant manner.

CFEOM caused by pathogenic variants in COL25A1 or PHOX2A is inherited in an autosomal recessive manner.

Tukel syndrome (a disorder of unknown genetic cause) is thought to be inherited in an autosomal recessive manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

Sibs of a proband. The risk to sibs of a proband depends on the clinical/genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with autosomal dominant CFEOM has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has a pathogenic variant, his or her family members may be at risk.

Autosomal Recessive – Inheritance Risk to Family Members

Parents of a proband

  • The parents of an individual with autosomal recessive CFEOM are obligate heterozygotes (i.e., presumed to be carriers of one pathogenic variant based on family history).
  • If biallelic COL25A1 or PHOX2A pathogenic variants have been identified in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a COL25A1 or PHOX2A pathogenic variant and to allow reliable recurrence risk assessment.
  • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) of PHOX2A-related CFEOM has been reported in two consanguineous families [Wang et al 1998]. Two-generation involvement can occur in autosomal recessive disorders when a parent (who has biallelic pathogenic variants) is affected and his/her reproductive partner is a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • If both parents are known to be heterozygous for an autosomal recessive CFEOM-related pathogenic variant, each sib of an affected individual has at conception 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 autosomal recessive CFEOM are obligate heterozygotes (carriers) for a pathogenic variant.

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

Carrier Detection

Carrier testing for relatives of a proband with COL25A1-related or PHOX2A-related CFEOM requires prior identification of the COL25A1 or PHOX2A pathogenic variants in the family.

Carrier testing is not possible for relatives of a proband with Tukel syndrome because the associated gene has not been identified.

Related Genetic Counseling Issues

Evaluation of relatives at risk. It is appropriate to evaluate relatives of a proband with CFEOM in order to identify as early as possible those who would benefit from prompt initiation of treatment and prevention of secondary complications.

Prenatal Testing and Preimplantation Genetic Testing

Once the CFEOM-causing pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for CFEOM are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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.

  • Moebius Syndrome Foundation
    Individuals with CFEOM do not have Moebius syndrome, but many individuals with syndromic CFEOM3 that includes facial weakness have found the resources of the Moebius syndrome foundation helpful.
    PO Box 147
    Pilot Grove MO 65276
    Phone: 844-MOEBIUS (844-663-2487)
    Email: info@moebiussyndrome.org
  • National Eye Institute
    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

6. Management of CFEOM

Evaluations Following Initial Diagnosis

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

  • Consultation with a clinical 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
    • Measurement of palpebral fissure size
    • 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
  • 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
  • Referral to relevant specialists regarding evaluation of associated CNS findings/malformations and/or non-ocular findings

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, Heidary et al 2019].

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.
    • Most individuals with CFEOM have abnormally inserted superior oblique tendons and/or tight muscles or abnormally thin tendons [Shoshany et al 2019].
    • 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.

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 and facial or vocal cord weakness and interventions for developmental delays are indicated as per treating specialists.

Chapter Notes

Acknowledgments

We thank the many individuals with these disorders and their family members for participating in these studies. Our work has been supported by NEI R01EY027421 and NHLBI X01HL132377 (ECE); the Broad Institute of MIT and Harvard Center for Mendelian Genomics (NHGRI/NEI/NHLBI UM1HG008900); the Ocular Genomics Institute Genomics Core (Massachusetts Eye and Ear Infirmary/Harvard Medical School, NEI 2P30EY014104); NHGRI R01HG009141, T32GM007748-42, 5T32NS007473-19, 5T32EY007145-16; the William Randolph Hearst Fund, NEI 5K08EY027850; the Boston Children’s Hospital Ophthalmology Foundation Faculty Discovery Award; Children's Hospital Ophthalmology Foundation, Inc, Boston, MA; and Howard Hughes Medical Institute.

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)
Julie A Jurgens, PhD (2021-present)
Mary C Whitman, MD, PhD (2016-present)
Koki Yamada, MD, PhD; Children's Hospital Boston (2004-2006)

Revision History

  • 12 August 2021 (bp) Comprehensive update posted live; scope changed to overview
  • 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 live
  • 27 April 2004 (me) Review posted live
  • 7 January 2004 (ee) Original submission

References

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