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Congenital Fibrosis of the Extraocular Muscles
Main Features
Congenital fibrosis of the extraocular muscles (CFEOM) is a rare, non-progressive hereditary strabismus syndrome (prevalence ~1/250,000–1/230,000) belonging to the congenital cranial dysinnervation disorders (CCDDs), characterized by congenital restrictive ophthalmoplegia with or without ptosis.
Despite the historical name, it is not a primary muscle fibrosis but results from maldevelopment of the oculomotor (CN III) and trochlear (CN IV) nuclei/nerves and their axons, with secondary changes in the innervated muscles.
Classified into three main subtypes by inheritance and phenotype: CFEOM1 (most common, autosomal dominant, KIF21A), CFEOM2 (autosomal recessive, PHOX2A), and CFEOM3 (autosomal dominant, KIF21A or tubulin genes); Tukel syndrome is CFEOM3 with ulnar hand anomalies.
Eye Findings
Congenital non-progressive external ophthalmoplegia with severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze.
Fixed infraduction (eyes fixed downward) in classic CFEOM1; CFEOM2 characteristically shows bilateral large-angle exotropia; CFEOM3 often unilateral/asymmetric involvement.
Ptosis (uni- or bilateral) from levator palpebrae superioris dysfunction, with compensatory chin-up head posture to see beneath the lids and better position the infraducted eyes.
Incomitant strabismus (hypotropic/exotropic positions more common), absent binocular vision/poor stereopsis, refractive errors, amblyopia, and poor visual acuity.
Aberrant eye movements (e.g., convergent movement on attempted upgaze) and, in CFEOM2, poorly reactive pupils (pupillary involvement is absent in CFEOM1).
Neuroimaging (MRI): hypoplasia of extraocular muscles and hypoplastic oculomotor nerves; trochlear, abducens, and optic nerves may also be hypoplastic.
Other Findings
Predominantly in CFEOM3, syndromic non-ocular features may occur: facial paralysis and dysmorphism, vocal cord paralysis, intellectual/social disability, Kallmann syndrome (hypogonadotropic hypogonadism with anosmia), progressive peripheral sensorimotor axonal polyneuropathy, congenital joint contractures, gait anomalies, cyclic vomiting, and epilepsy.
Microcephaly and intellectual disability, particularly in CFEOM3 with polymicrogyria.
Marcus Gunn jaw-winking phenomenon and other signs of aberrant dysinnervation, supporting a neurogenic etiology.
Tukel syndrome: bilateral postaxial oligodactyly/oligosyndactyly of the hands.
CFEOM has also been reported with progressive cerebellar ataxia and, via COL25A1 variants, with arthrogryposis multiplex congenita.
Etiology
A congenital cranial dysinnervation disorder caused by abnormal development of ocular motor neurons and their axons, altering either motor neuron specification or nerve growth/guidance.
CFEOM1: heterozygous KIF21A mutations (chromosome 12q12; kinesin motor protein affecting axonal transport) — autosomal dominant.
CFEOM2: homozygous PHOX2A/ARIX mutations (11q13; homeodomain transcription factor required for CN III/IV development) — autosomal recessive.
CFEOM3: KIF21A or β-/α-tubulin isotype genes TUBB3 (16q24), TUBB2B (6p25), or TUBA1A — autosomal dominant, with variable expressivity.
Germline mosaicism is common in apparently sporadic CFEOM1 (presumed rate ~38%), which can mimic recessive inheritance and is important for genetic counseling.