Congenital fibrosis of the extraocular muscles (CFEOM) is a disease characterized by strabismus and ptosis due to congenital, bilateral, non-progressive extraocular muscle palsy. It was formerly called general fibrosis syndrome. It is classified as one of the congenital cranial dysinnervation disorders (CCDDs).
The prevalence is extremely rare, approximately 1/230,000 to 1/250,000 (Whitman 2021 GeneReviews; Xia 2022). CFEOM1 has been reported in diverse ethnic groups and is most common in the United States and Western countries. CFEOM2 is more frequently reported in families of Turkish, Saudi Arabian, and Iranian descent.
CFEOM is classified into subtypes CFEOM1 to 5 based on clinical features and genotype. All subtypes share the common feature of restricted eye movement due to fibrosis of the extraocular muscles.
The prevalence is estimated to be about 1/230,000 to 1/250,000. It is a rare disease among congenital disorders that cause eye movement impairment.
The main subjective symptoms of CFEOM are as follows:
Since infants and young children have difficulty expressing subjective symptoms, parents often notice a chin-up posture or abnormal eye position and bring them for examination.
The clinical findings of CFEOM vary by subtype. A comparison of the three major subtypes is shown below.
CFEOM1
Ptosis: Bilateral. Always present.
Eye movement: Unable to elevate above the horizontal midline. Often fixed in a downward gaze. Horizontal movement is normal to moderately restricted.
Eye position: Variable, including orthophoria, esotropia, and exotropia.
Pupils: Normal pupil size and light reflex.
Forced duction test: Positive.
CFEOM2
Ptosis: Bilateral, similar to CFEOM1.
Eye movements: More restricted than CFEOM1 in both vertical and horizontal directions. Fixed downgaze is also severe.
Eye position: Often accompanied by exotropia.
Pupil: Small pupil diameter with delayed light reflex. This is an important distinguishing feature from CFEOM1.
Forced duction test: Strongly positive.
CFEOM3
Ptosis: Bilateral or unilateral. Some cases may not have ptosis.
Eye movement: Vertical limitation is present, but elevation beyond the horizontal midline is possible. Horizontal limitation is often absent.
Eye position: Orthophoria or exotropia.
Pupil: Both pupil size and light reflex are normal.
Forced duction test: Positive only in the upward direction.
In CFEOM1 and CFEOM2, eye movement restriction is severe, and abnormal convergence movements or, rarely, Marcus Gunn jaw-winking phenomenon may be present. High refractive errors (especially astigmatism) are also frequently observed, and attention must be paid to the complication of refractive amblyopia.
Other ocular findings include optic nerve hypoplasia and thinning of the ganglion cell layer and photoreceptor layer.
The most important distinguishing feature is the pupillary findings. In CFEOM1, both pupil size and light reflex are normal, whereas in CFEOM2, the pupil is small and the light reflex is delayed. Additionally, CFEOM2 has more severe restriction of eye movement and is more likely to be associated with exotropia.
CFEOM is caused by fibrosis of the extraocular muscles due to developmental abnormalities of the oculomotor and trochlear nuclei, which innervate these muscles. The causative genes and inheritance patterns differ by subtype.
The correspondence between each subtype and its associated gene is shown below.
| Subtype | Inheritance Pattern | Main Causative Gene |
|---|---|---|
| CFEOM1 | Autosomal dominant | KIF21A (12q12) |
| CFEOM2 | Autosomal recessive | PHOX2A (11q13) |
| CFEOM3 | Autosomal dominant | TUBB3 (16q24) |
| CFEOM4 | Autosomal recessive | Unknown (chromosome 21) |
| CFEOM5 | Autosomal recessive | COL25A1 |
In CFEOM3, mutations in TUBA1A, TUBB2B, and KIF21A have also been rarely reported. Additionally, sporadic cases without a family history exist.
CFEOM3 includes an isolated type presenting only with ocular motility disorders and a syndromic type with various neurological abnormalities. Depending on the mutation type, the syndromic type may be associated with intellectual disability, facial nerve palsy, peripheral neuropathy, Kallmann syndrome, corpus callosum hypoplasia, and basal ganglia malformation. CFEOM4 (Tukel syndrome) involves limb abnormalities such as postaxial oligodactyly and oligosyndactyly.
In many cases, it is inherited in an autosomal dominant or autosomal recessive pattern. However, sporadic cases without a family history have also been reported, so it can occur without a genetic history.
The diagnosis of CFEOM is primarily based on clinical findings. Genetic testing is useful for confirming the diagnosis and identifying subtypes.
MRI or CT confirms atrophy of the extraocular muscles. MRI may depict hypoplasia or misdirection of the oculomotor and trochlear nerves.
There are two methods:
The following diseases should be considered in the differential diagnosis of CFEOM.
There is no curative treatment for CFEOM. The goals of treatment are improvement of compensatory head posture, prevention and treatment of amblyopia, and cosmetic improvement.
Indications for surgery are as follows.
Surgical precautions are as follows.
Strabismus surgery is performed first, followed by staged correction. Due to hypoplasia of the levator palpebrae superioris muscle, levator resection often does not provide sufficient effect, and frontalis suspension may be necessary.
Complete functional recovery of the extraocular muscles is not achieved. The goal of surgery is to reduce compensatory head posture and improve cosmesis. Since standard surgical dosage charts do not apply, surgical techniques must be tailored to each individual case.
The understanding of CFEOM pathophysiology has evolved through two historical hypotheses.
Early studies suggested that CFEOM results from primary myopathy of the extraocular muscles, with fibrosis being the primary change.
It is now widely accepted that fibrosis of the extraocular muscles is a secondary change following congenital abnormalities of the cranial nerves. Autopsy and high-resolution MRI studies have demonstrated congenital absence, hypoplasia, and aberrant innervation of the oculomotor nerves (CN III, IV, VI) in affected patients (Whitman 2021 Annu Rev Vis Sci; Demer 2010).
The pathological mechanisms of each genetic mutation are as follows.
Basic research is underway to elucidate the molecular mechanisms of CFEOM.
Studies using yeast models have shown that introducing CFEOM-causing mutations into beta-tubulin impairs microtubule function and induces resistance to depolymerization. Depending on the mutation type, effects on microtubule dynamics vary, with both stabilizing (e.g., A302T, R62Q, R380C) and destabilizing patterns reported.
Attempts to restore axonal growth deficits caused by CFEOM mutations through engineering modifications at the kinesin-microtubule interface have also been reported. Additionally, TUBB3 has been found to be non-essential for normal neuronal function but indispensable for axonal regeneration, raising expectations for future application in nerve regeneration therapy.
