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 2016].
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 2016]:
(p.Arg62Gln): moderate CFEOM3. Brain MRI: normal. No developmental delays or intellectual disability.
(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.
(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.
(p.Ala302Thr): variable CFEOM3, developmental delay. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia.
(p.Arg380Cys): moderate CFEOM3, developmental delay. Brain MRI: anterior commissure hypoplasia, corpus callosum hypoplasia, basal ganglia dysgenesis
(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.
(p.Asp417His): severe CFEOM3, developmental delay, facial weakness, progressive axonal sensorimotor polyneuropathy,
congenital joint contractures. Brain MRI: anterior commissure hypoplasia.
(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.
(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
(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.