Congenital Fibrosis of the Extraocular Muscles

• Non-progressive hereditary strabismus syndrome belonging to the congenital cranial dysinnervation disorders (CCDDs), characterized by congenital restrictive ophthalmoplegia with or without ptosis.
• Prevalence ~1/250,000–1/230,000
• Maldevelopment of the oculomotor (CN III) and trochlear (CN IV) nuclei/nerves and their axons, with secondary changes in the innervated muscles. This leads to a secondary fibrosis.

• 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.
• Aberrant eye movements (e.g., convergent movement on attempted upgaze) and, in CFEOM2, poorly reactive pupils (pupillary involvement is absent in CFEOM1).
• Marcus Gunn jaw-winking phenomenon and other signs of aberrant dysinnervation
• 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.
• Absent binocular vision/poor stereopsis, refractive errors, amblyopia, and poor visual acuity.
• Neuroimaging (MRI): hypoplasia of extraocular muscles and hypoplastic oculomotor nerves; trochlear, abducens, and optic nerves may also be hypoplastic.

• Predominantly in CFEOM3
  • 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
    • epilepsy.
  • CFEOM3 with polymicrogyria
    • Microcephaly and intellectual disability
• Tukel syndrome: bilateral postaxial oligodactyly/oligosyndactyly of the hands.
• Progressive cerebellar ataxia
• Arthrogryposis multiplex congenita.

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.
  • Tukel syndrome is CFEOM3 with ulnar hand anomalies.

Germline mosaicism is common in apparently sporadic CFEOM1 (presumed rate ~38%), which can mimic recessive inheritance and is important for genetic counseling.

• GeneReviews: Congenital Fibrosis of the Extraocular Muscles Overview
• OMIM: Fibrosis of Extraocular Muscles, Congenital, 1 (FEOM1)
• GARD: Congenital Fibrosis of the Extraocular Muscles