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
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.
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.
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
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 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%.
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
Sibs of a proband
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.
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
