Congenital Fibrosis of the Extraocular Muscles (CFEOM)

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Congenital fibrosis of the extraocular muscles (CFEOM)

Congenital fibrosis of the extraocular muscles (CFEOM) is a rare congenital syndrome characterized by non-progressive unilateral or bilateral restrictive strabismus with or without ptosis. Various phenotypes of CFEOM have been described, which all result from fibrosis of the extraocular muscles causing restricted ocular motility, especially restricted ocular elevation. Patients classically present with a chin up head position to compensate for poor ocular elevation and ptosis, although presentations may vary.

Common ocular findings include:

  • Ocular motility restriction, usually upgaze
  • Orthophoria, hypotropia, esotropia, or exotropia in primary gaze
  • Unilateral or bilateral ptosis
  • Compensatory head position, usually chin up
  • Generally poor visual acuity due to deprivation amblyopia from congenital ptosis

Other ocular findings may include:

  • Optic nerve hypoplasia[1]
  • Ganglion cell and photoreceptor layer thinning[1]
  • Marcus Gunn jaw-winking phenomenon and other forms of aberrant innervation[2]
  •  High refractive error, especially astigmatism[3]

Non-ocular findings may include include:

  • Central nervous system abnormalities (in CFEOM3)
  • Limb abnormalities (in CFEOM4)

Etiology

The following genes have been implicated in CFEOM: COL25A1, KIF21A, PHOX2A, TUBA1A, TUBB2B, TUBB3.[4] These mutations are most commonly inherited in an autosomal document or autosomal recessive fashion, although sporadic mutations also occur.

Summary of CFEOM subtypes[4]

Subtype Inheritance Clinical Characteristics Associated Genes
CFEOM1 Autosomal Dominant

(full penetrance, variable expressivity)[5]

  • Bilateral ptosis
  • Hypotropia
  • Restricted vertical gaze, no farther than midline
  • Variably restricted horizontal gaze
  • Normal pupils
  • Absence of superior division of oculomotor nerve
KIF21A gene encoding kinesin protein

TUBA1A

Rarely TUBB3 gene

CFEOM2 Autosomal Recessive
  • Bilateral ptosis
  • Exotropia
  • Restricted vertical and horizontal gaze
  • Pupils small and sluggishly reactive to light
  • Absence of motor neurons CNIII and CNIV
PHOX2A gene encoding homeodomain transcription factor
CFEOM3 Autosomal Dominant

(full penetrance, variable expressivity)[5]

  • Unilateral or bilateral ptosis
  • Less severe unilateral or bilateral restricted vertical gaze that may extend past midline
  • Neurologic abnormalities, developmental delay, and body dysmorphism
TUBB3 encoding neuron-specific β-tubulin isotype III

Rarely TUBA1A,

TUBB2B, KIF21A[6]

CFEOM4 (Tukel Syndrome)9 Autosomal Recessive
  • CFEOM3 phenotype with postaxial oligodactyly or oligosyndactyly
  • More severe on the right side [cite
Unknown, suspected to be on chromosome 21
CFEOM5 Autosomal Recessive
  • Bilateral or unilateral ptosis
  • Restricted vertical and/or horizontal gaze
  • Orthotropic or exotropic
COL25A1 gene encoding a transmembrane protein10
CFEOM3 with polymicrogyria Autosomal dominant
  • Bilateral ptosis
  • Restricted vertical gaze
  • Orthotropic or exotropic
  • Hypoplasia or agenesis of brain structures (e.g. basal ganglia, thalamus, corpus callosum)
TUBB2B11 encoding a beta isoform of tubulin

Risk Factors

CFEOM is a rare disorder with a minimum prevalence of 1/250,000[7]

  • CFEOM1: has been described in diverse ethnic populations and is the most commonly encountered in the United States and other Western countries[8]
  • CFEOM2: has been described most commonly in families of Turkish, Saudi Arabian, and Iran descent.[8]

General Pathology

The abnormal innervation of the extraocular muscles results in fibrosis and atrophy of the associated extraocular muscles.

Pathophysiology

  • The Myogenic Theory: supported by earlier studies, this theory postulated that CFEOM is due to a primary myopathy with fibrosis of the extraocular muscles.
  • The Neurogenic Theory: now more commonly accepted, this theory postulates that fibrosis of the extraocular muscles in CFEOM is due to the congenital absence, hypoplasia, or misrouting of cranial nerves, most commonly the oculomotor nerve.[9] This theory is supported by autopsy[10] and high-resolution MRI studies[11], which have demonstrated the congenital absence, hypoplasia, and/or misrouting of orbital motor nerves (cranial nerves III, IV, VI) to their corresponding extraocular muscles in affected patients.

Diagnosis

The diagnosis of CFEOM is made clinically. However, identifying the specific form of CFEOM through genetic testing may be important for counseling and prognosis.

  • Medical History: should include prenatal and perinatal developmental history, with history of developmental delay being suggestive of CFEOM3.
  • Physical Examination: should include a neurological exam and examination of the extremities. Examiners should be mindful that due to the limited ability to examine infants, findings may be falsely considered new or progressive if they were challenging to identify during infancy. The physical exam should include measurements of the following:
    • Visual acuity
    • Anomalous head position
    • Levator function
    • Ocular alignment
    • Ductions and versions
    • Cycloplegic refraction
    • Dilated fundus exam
  • Genetic Testing: can be taken by one of two approaches:[4]
    • A multigene panel: is a targeted approach wherein the physician hypothesizes potentially involved genes. The panel should include COL25A1, KIF21A2, PHOX2A, TUBA1A, TUBB2B, & TUBB3
    • Exome sequencing or genome sequencing: this form of testing does not does not require the physician to hypothesize a priori which genes are most likely involved. This is often used as a last resort which bypasses the hypothesis driven approach.[12]

Differential diagnosis

The differential diagnosis of CFEOM includes other causes of ophthalmoplegia, including but not limited to  Monocular Elevation Deficit, Congenital Third Nerve Palsy, Brown Syndrome, Congenital Myasthenic Syndrome, and Chronic Progressive External Ophthalmoplegia (CPEO).

Management

General treatment

Non-surgical management includes close monitoring of refractive error and treatment of amblyopia. It should be kept in mind that patients can have high degrees of astigmatism and that refractive error may change significantly following strabismus or ptosis surgery.

Surgery

Surgical management includes strabismus surgery and ptosis repair in order to achieve more acceptable appearance and to relieve highly anomalous head postures. However, surgery poses a challenge as full functionality of the extraocular muscles cannot be restored and typical surgical dose charts do not apply to these cases. Stepwise correction of strabismus should occur before ptosis surgery.[5]

Indications for surgery may include:

  1. Unacceptable degree of compensatory head tilt
  2. Strabismus either causing amblyopia or interfering with daily function
  3. Ptosis that is either aesthetically unacceptable or interferes with daily function

General surgical considerations in CFEOM:

  • Strabismus surgery:
    • Forced duction testing should be performed at the beginning of surgery and be repeated throughout the surgery.[5]
    • Large recessions to relieve restriction are often required. When restriction remains after a large recession, a conjunctival recession or traction suture to the orbital wall may be helpful.[13]
    • Resections may be required, especially in the cases of poor elevation to achieve proper alignment.[13]
    • Hangback sutures have not been found to be helpful, especially in cases with absence counteracting forces by the antagonist muscle.[5]
  • Ptosis surgery:
    • If ptosis surgery is necessary, a frontalis sling may be required due to levator palpebrae hypoplasia. [5]
    • Caution must be taken to prevent overcorrection in ptosis surgery, as CFEOM patients may be at increased risk for exposure keratopathy.[5]

References

  1. 1.0 1.1 Thomas MG, Maconachie GDE, Kuht HJ, et al. Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles. Int J Mol Sci. 2021;22(5):2575. doi:10.3390/ijms22052575
  2. 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(9):1254–1259. doi:10.1001/archopht.123.9.1254
  3. Heidary G, Engle E, Hunter DG. Congenital Fibrosis of the Extraocular Muscles. Semin Ophthalmol. 2009;23:3-8. doi:10.1080/08820530701745181
  4. 4.0 4.1 4.2 Whitman MC, Jurgens JA, Hunter DG, et al. Congenital Fibrosis of the Extraocular Muscles Overview. 2004 Apr 27 [Updated 2021 Aug 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022.
  5. 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Tawfik HA, Rashad MA. Surgical management of hypotropia in congenital fibrosis of extraocular muscles (CFEOM) presented by pseudoptosis. Clin Ophthalmol. 2013;7:1-6.
  6. Yamada K, Chan WM, Andrews C, et al. Identification of KIF21A Mutations as a Rare Cause of Congenital Fibrosis of the Extraocular Muscles Type 3 (CFEOM3). Invest Ophthalmol Vis Sci. 2004;45(7):2218-2223.
  7. Vivian AJ. Congenital fibrosis of the extra-ocular muscles (CFEOM) and the cranial dysinnervation disorders. Eye Lond Engl. 2020;34(2):251-255.
  8. 8.0 8.1 Yazdani A, Traboulsi EI. Classification and surgical management of patients with familial and sporadic forms of congenital fibrosis of the extraocular muscles. Ophthalmology. 2004 May;111(5):1035-42.
  9. Whitman MC, Engle EC. Ocular congenital cranial dysinnervation disorders (CCDDs): insights into axon growth and guidance. Hum Mol Genet. 2017;26(R1):R37-R44. doi:10.1093/hmg/ddx168
  10. Engle EC, Goumnerov BC, McKeown CA, Schatz M, Johns DR, Porter JD, Beggs AH. Oculomotor nerve and muscle abnormalities in congenital fibrosis of the extraocular muscles. Ann Neurol. 1997 Mar;41(3):314-25.
  11. Merino P, Gómez de Liaño P, Fukumitsu H, Franco G, Ruiz Y. Congenital fibrosis of the extraocular muscles: magnetic resonance imaging findings and surgical treatment. Strabismus. 2013 Sep;21(3):183-9.
  12. Xue Y, Ankala A, Wilcox WR, Hegde MR. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet Med. 2015;17(6):444-451.
  13. 13.0 13.1 Rosenbaum AL, Santiago AP. Clinical Strabismus Management: Principles and Surgical Techniques. David Hunter; 1999.
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