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congenital_fibrosis_extraocular_muscles [2026/09/08 12:59] – [Main Features] Scott Larsoncongenital_fibrosis_extraocular_muscles [2026/09/08 14:33] (current) – Scott Larson
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 ====Main Features==== ====Main Features====
  
-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. +  * 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.  
  
-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==== ====Eye Findings====
  
-Congenital non-progressive external ophthalmoplegia with severe limitation of vertical gaze (usually upgaze) and variable limitation of horizontal gaze.  +  * 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;  
-Fixed infraduction (eyes fixed downward) in classic CFEOM1; CFEOM2 characteristically shows bilateral large-angle exotropia; CFEOM3 often unilateral/asymmetric involvement.  +    * 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.  +  * 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 
-Incomitant strabismus (hypotropic/exotropic positions more common), absent binocular vision/poor stereopsis, refractive errors, amblyopia, and poor visual acuity.  +  * 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.  
-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. 
- +
-Neuroimaging (MRI): hypoplasia of extraocular muscles and hypoplastic oculomotor nerves; trochlear, abducens, and optic nerves may also be hypoplastic. +
  
 ====Other Findings==== ====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.  +  * Predominantly in CFEOM3 
- +    * facial paralysis and dysmorphism, vocal cord paralysis, intellectual/social disability, 
-Microcephaly and intellectual disability, particularly in CFEOM3 with polymicrogyria. +    *  Kallmann syndrome (hypogonadotropic hypogonadism with anosmia) 
- +      * progressive peripheral sensorimotor axonal polyneuropathy 
-Marcus Gunn jaw-winking phenomenon and other signs of aberrant dysinnervation, supporting a neurogenic etiology.  +      * congenital joint contractures, gait anomalies 
- +      * cyclic vomiting 
-Tukel syndrome: bilateral postaxial oligodactyly/oligosyndactyly of the hands.  +      * epilepsy.  
- +    * CFEOM3 with polymicrogyria 
-CFEOM has also been reported with progressive cerebellar ataxia and, via COL25A1 variants, with arthrogryposis multiplex congenita. +      * Microcephaly and intellectual disability 
 +  * **Tukel syndrome**: bilateral postaxial oligodactyly/oligosyndactyly of the hands.  
 +  * Progressive cerebellar ataxia 
 +  * Arthrogryposis multiplex congenita. 
  
 ====Etiology==== ====Etiology====
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 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.  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. +  * 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. 
  
-CFEOM2: homozygous PHOX2A/ARIX mutations (11q13; homeodomain transcription factor required for CN III/IV development) — autosomal recessive. +Germline mosaicism is common in apparently sporadic CFEOM1 (presumed rate ~38%), which can mimic recessive inheritance and is important for genetic counseling. 
  
-CFEOM3: KIF21A or β-/α-tubulin isotype genes TUBB3 (16q24), TUBB2B (6p25), or TUBA1A — autosomal dominant, with variable expressivity. +====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|
  
-Germline mosaicism is common in apparently sporadic CFEOM1 (presumed rate ~38%), which can mimic recessive inheritance and is important for genetic counseling.  
  
 ====Resources==== ====Resources====
  
-[[https://www.ncbi.nlm.nih.gov/books/NBK1348/|GeneReviews: Congenital Fibrosis of the Extraocular Muscles Overview]] +  * [[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://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]]
  
-[[https://rarediseases.info.nih.gov/diseases/6094/congenital-fibrosis-of-the-extraocular-muscles|GARD: Congenital Fibrosis of the Extraocular Muscles]]+{{tag>syndrome}}