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 4.
Provide an evaluation strategy to identify the genetic cause of CFEOM in a proband (when possible).
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.
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
2. Genetic Causes of CFEOM
Table 2a.
View in own window
| Gene 1 | % of All CFEOM | Associated CFEOM Phenotypes |
|---|
| CFEOM1 | CFEOM2 | CFEOM3 | CFEOM5 |
|---|
|
COL25A1
| <1% | | | | + |
|
KIF21A
| ~55% | +++ | | + | |
|
PHOX2A
| ~10% | | + | | |
|
TUBA1A
| <1% | + | | + | |
|
TUBB2B
| <1% | | | + | |
|
TUBB3
| ~35% | + | | +++ | |
- 1.
Genes are listed alphabetically.
Table 2b.
CFEOM: Gene-Phenotype Correlations
View in own window
| Gene 1 | Phenotype |
|---|
| ID/DD | MRI Findings | Other Features |
|---|
|
COL25A1
| | Small extraocular muscles | Aberrant eye movements incl Duane retraction syndrome or synergistic divergence |
| KIF21A 2 | Rarely + | 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 bodies | Ptotic 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 muscles | Reported 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 stem | Aberrant 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 malformations | Aberrant 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 pathogenic variants most commonly result in ptosis and/or CFEOM without syndromic findings. Very rare specific pathogenic 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 pathogenic 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
View in own window
| Gene (Genetic Mechanism) | Disorder | MOI | Clinical Characteristics |
|---|
| Chromosome 8 anomalies | See Duane syndrome. | | Duane syndrome w/various assoc congenital abnormalities incl other cranial nerve deficits, facial dysmorphisms, ID, cardiac defects |
|
CHN1
| CHN1-related Duane syndrome 1 | AD | Bilateral 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) | AR | Duane 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) | AR | Isolated dysfunction of facial nerve, comitant esotropia |
|
MAFB
| MAFB -related Duane syndrome 1 | AD | Bilateral Duane syndrome ± mild-to-severe SNHL |
|
MYMK
| Carey-Fineman-Ziter syndrome (OMIM 254940) | AR | Facial weakness w/congenital non-progressive myopathy, Pierre Robin sequence |
| mtDNA deletions ranging in size from 2-10 kb | Chronic progressive external ophthalmoplegia caused by mtDNA deletions (See Mitochondrial DNA Deletion Syndromes.) | Mat | Progressive ptosis, paralysis of extraocular muscles (ophthalmoplegia), variably severe proximal limb weakness |
|
PABPN1
|
Oculopharyngeal muscular dystrophy
| AD | Late-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) | AR | Congenital 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
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 pathogenic variants in KIF21A or TUBB3.
Unilateral CFEOM or CFEOM without ptosis is most often caused by pathogenic 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 pathogenic 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 (see Option 1), whereas genomic testing does not (see 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. 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.
Surgical treatment of ophthalmologic findings (extraocular muscle and/or ptosis surgery):
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 pathogenic variants, surveillance for endocrine abnormalities and facial or vocal cord weakness and interventions for developmental delays are indicated as per treating specialists.
6. 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
Some individuals diagnosed with autosomal dominant CFEOM have an affected parent.
A proband with autosomal dominant CFEOM may have the disorder as the result of a de novo pathogenic variant.
The frequency of
de novo pathogenic variants in individuals with
TUBB3-related isolated CFEOM (no other neurologic deficits) is 25% (in 4/16 pedigrees) [
Tischfield et al 2010].
If the proband appears to be the only affected family member (i.e., a simplex case), ophthalmologic examination and/or molecular genetic testing (for the KIF21A, TUBA1A, TUBB2B, or TUBB3 pathogenic variant identified in the proband) are recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
The proband has a de novo pathogenic variant.
The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
The family history of some individuals diagnosed with autosomal dominant CFEOM 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 clinical/genetic status of the proband's parents:
If a parent has clinical characteristics consistent with CFEOM and/or a known KIF21A, TUBA1A, TUBB2B, or TUBB3 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [
Khan et al 2010,
Tischfield et al 2010,
Liu et al 2014].
If the parents of a proband with autosomal dominant CFEOM are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for CFEOM because of the possibility of reduced penetrance in a heterozygous parent or of parental germline mosaicism.
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, the parent's 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 the parent's 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.
Prenatal Testing and Preimplantation Genetic Testing
Once the CFEOM-causing pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for CFEOM are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic 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.
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
Email: info@preventblindness.org
eyeGENE – National Ophthalmic Disease Genotyping Network Registry
Phone: 301-435-3032
Email: eyeGENEinfo@nei.nih.gov
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
21 April 2011 (me) Comprehensive update posted live
22 September 2006 (me) Comprehensive update posted live
27 April 2004 (me) Review posted live
7 January 2004 (ee) Original submission
References
Literature Cited
Balasubramanian
R, Chew
S, MacKinnon
SE, Kang
PB, Andrews
C, Chan
WM, Engle
EC. Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome.
J Clin Endocrinol Metab.
2015;100:E473–7.
[
PMC free article: PMC4333039] [
PubMed: 25559402]
Cederquist
GY, Luchniak
A, Tischfield
MA, Peeva
M, Song
Y, Menezes
MP, Chan
WM, Andrews
C, Chew
S, Jamieson
RV, Gomes
L, Flaherty
M, Grant
PE, Gupta
ML
Jr, Engle
EC. An inherited TUBB2B mutation alters a kinesin-binding site and causes polymicrogyria, CFEOM and axon dysinnervation.
Hum Mol Genet.
2012;21:5484–99.
[
PMC free article: PMC3516133] [
PubMed: 23001566]
Chew
S, Balasubramanian
R, Chan
WM, Kang
PB, Andrews
C, Webb
BD, MacKinnon
SE, Oystreck
DT, Rankin
J, Crawford
TO, Geraghty
M, Pomeroy
SL, Crowley
WF
Jr, Jabs
EW, Hunter
DG, Grant
PE, Engle
EC. A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3.
Brain.
2013;136:522–35.
[
PMC free article: PMC3572929] [
PubMed: 23378218]
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]
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]
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]
Heidary
G, Mackinnon
S, Elliott
A, Barry
BJ, Engle
EC, Hunter
DG. Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles.
J AAPOS.
2019;23:253.e1–253.e6.
[
PMC free article: PMC7075702] [
PubMed: 31541710]
Jónsson
H, Sulem
P, Kehr
B, Kristmundsdottir
S, Zink
F, Hjartarson
E, Hardarson
MT, Hjorleifsson
KE, Eggertsson
HP, Gudjonsson
SA, Ward
LD, Arnadottir
GA, Helgason
EA, Helgason
H, Gylfason
A, Jonasdottir
A, Jonasdottir
A, Rafnar
T, Frigge
M, Stacey
SN, Th Magnusson
O, Thorsteinsdottir
U, Masson
G, Kong
A, Halldorsson
BV, Helgason
A, Gudbjartsson
DF, Stefansson
K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland.
Nature.
2017;549:519–22.
[
PubMed: 28959963]
Jurgens
JA, Barry
BJ, Lemire
G, Chan
WM, Whitman
MC, Shaaban
S, Robson
CD, MacKinnon
S, England
EM, McMillan
HJ, Kelly
C, Pratt
BM, O’Donnell-Luria
A, MacArthur
DG, Boycott
KM, Hunter
DG, Engle
EC, et al.
Novel variants in TUBA1A cause congenital fibrosis of the extraocular muscles with or without malformations of cortical brain development.
Eur J Hum Genet.
2021;29:816–26.
[
PMC free article: PMC8110841] [
PubMed: 33649541]
Kaçar Bayram
A, Per
H, Quon
J, Canpolat
M, Ülgen
E, Doğan
H, Gumus
H, Kumandas
S, Bayram
N, Bilguvar
K, Çağlayan
AO. A rare case of congenital fibrosis of extraocular muscle type 1A due to KIF21A mutation with Marcus Gunn jaw-winking phenomenon.
Eur J Paediatr Neurol.
2015;19:743–6.
[
PubMed: 26190014]
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]
Liu
G, Chen
X, Sun
X, Liu
H, Zhao
K, Chang
Q, Pan
X, Wang
X, Yuan
S, Liu
Q, Zhao
C. Maternal germline mosaicism of kinesin family member 21A (KIF21A) mutation causes complex phenotypes in a Chinese family with congenital fibrosis of the extraocular muscles.
Mol Vis.
2014;20:15–23.
[
PMC free article: PMC3888497] [
PubMed: 24426772]
MacKinnon
S, Oystreck
DT, Andrews
C, Chan
WM, Hunter
DG, Engle
EC. Diagnostic distinctions and genetic analysis of patients diagnosed with Moebius syndrome.
Ophthalmology.
2014;121:1461–8.
[
PMC free article: PMC4082742] [
PubMed: 24612975]
Papakostas
TD, Le
HG, Chodosh
J, Jacobs
DS. Prosthetic replacement of the ocular surface ecosystem as treatment for ocular surface disease in patients with a history of Stevens-Johnson syndrome/toxic epidermal necrolysis.
Ophthalmology.
2015;122:248–53.
[
PubMed: 25282251]
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]
Romaniello
R, Tonelli
A, Arrigoni
F, Baschirotto
C, Triulzi
F, Bresolin
N, Bassi
MT, Borgatti
R. A novel mutation in the β-tubulin gene TUBB2B associated with complex malformation of cortical development and deficits in axonal guidance.
Dev Med Child Neurol.
2012;54:765–9.
[
PubMed: 22591407]
Shoshany
TN, Robson
CD, Hunter
DG. Anomalous superior oblique muscles and tendons in congenital fibrosis of the extraocular muscles.
J AAPOS.
2019;23:325.e1–325.e6.
[
PubMed: 31689500]
Soliani
L, Spagnoli
C, Salerno
G, Mehine
M, Rizzi
S, Frattini
D, Koskenvuo
J, Fusco
C.
A novel de novo KIF21A variant in a patient with congenital fibrosis of the extraocular muscles with a syndromic CFEOM phenotype.
J Neuroophthalmol.
2021;41:e85–e88.
[
PubMed: 32141982]
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
Jr, 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]
Wang
SM, Zwaan
J, Mullaney
PB, Jabak
MH, Al-Awad
A, Beggs
AH, Engle
EC. Congenital fibrosis of the extraocular muscles type 2, an inherited exotropic strabismus fixus, maps to distal 11q13.
Am J Hum Genet.
1998;63:517–25.
[
PMC free article: PMC1377321] [
PubMed: 9683611]
Whitman
MC, Andrews
C, Chan
WM, Tischfield
MA, Stasheff
SF, Brancati
F, Ortiz-Gonzalez
X, Nuovo
S, Garaci
F, MacKinnon
SE, Hunter
DG, Grant
PE, Engle
EC. Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development.
Am J Med Genet A.
2016;170A:297–305.
[
PMC free article: PMC4770801] [
PubMed: 26639658]
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]
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]
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]
