====== Congenital Fibrosis of the Extraocular Muscles ======

====Main Features====

  * 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.  


====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. 
  * 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. 

====Other Findings====

  * 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. 

====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. 
    * **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. 

====Compare Chronic Progressive External Ophthalmoplegia (CPEO) with Congenital Fibrosis of EOM (CFEOM)====
^Feature  ^CPEO	^CFEOM ^
|Nature of disorder	|Mitochondrial myopathy of extraocular muscle	|Congenital cranial dysinnervation disorder (neurogenic; abnormal CN III/IV/VI development with secondary muscle fibrosis)|
|Onset	|Adult, typically 18–40 yrs; ptosis first sign	|Congenital / present at birth |
|Course	|Slowly progressive over years	|Non-progressive (rare exceptions)|
|Symmetry / gaze |Generally symmetric, diffuse limitation of all directions; superior rectus often prominently involved |Fixed characteristic pattern — CFEOM1: eyes fixed in infraduction, absent upgaze; CFEOM2: large-angle exotropia|
|Ptosis	|Common, may be uni- or bilateral, progressive	|Congenital, typically bilateral; chin-up head posture|
|Diplopia |Usually absent (<30%) due to gradual symmetric onset|Absent; binocular vision typically never develops|
|Pupils	|Spared	|Spared in CFEOM1; poorly reactive in CFEOM2|
|Inheritance / genetics	|Single large-scale mtDNA deletion (~50%, sporadic); also nuclear mtDNA-maintenance genes (POLG, RRM2B, TWNK) and mtDNA point mutations |Mendelian: CFEOM1 (AD, KIF21A); CFEOM2 (AR, PHOX2A); CFEOM3 (AD, TUBB3/TUBB2B/TUBA1A/KIF21A)|
|Systemic/associated features	|"CPEO-plus": retinopathy, ataxia, neuropathy, deafness, cardiac conduction block, diabetes (Kearns-Sayre) |Usually isolated; CFEOM3 may have developmental/CNS anomalies (e.g., Tukel syndrome)|
|Muscle biopsy	|Ragged-red / COX-negative fibers; mitochondrial abnormalities| Not a mitochondrial biopsy diagnosis; muscle shows fibrosis/denervation changes|
|Orbital MRI	|Mild EOM atrophy with fatty/spongiform T1 signal| EOM hypoplasia + hypoplastic ocular motor nerves|


====Resources====

  * [[https://www.ncbi.nlm.nih.gov/books/NBK1348/|GeneReviews: Congenital Fibrosis of the Extraocular Muscles Overview]]
  * [[https://omim.org/entry/135700|OMIM: Fibrosis of Extraocular Muscles, Congenital, 1 (FEOM1)]]
  * [[https://rarediseases.info.nih.gov/diseases/6094/congenital-fibrosis-of-the-extraocular-muscles|GARD: Congenital Fibrosis of the Extraocular Muscles]]

{{tag>syndrome}}