title: The ECEL1-related strabismus phenotype is consistent with congenital cranial dysinnervation disorder.
abstract: BACKGROUND
  Congenital cranial dysinnervation disorders (CCDDs) are phenotypes of congenital incomitant strabismus and/or ptosis related to orbital dysinnervation. CCDDs have been associated with dominant or recessive monogenic mutations in at least 7 different genes (CHN1, SALL4, HOXA1, KIF21A, PHOX2A, TUBB3, ROBO3) that cause phenotypes such as Duane retraction syndrome, congenital fibrosis of the extraocular muscles, and horizontal gaze palsy with progressive scoliosis. Recently, arthrogryposis with or without strabismus has been shown to be caused by recessive mutations in ECEL1, a gene likely involved in neuromuscular junction formation. The strabismus phenotype in ECEL1-related cases has not always been detailed but may be a form of CCDD. To better define the ECEL1-related ophthalmic phenotype, we detail ophthalmic findings in 4 affected siblings from a consanguineous family and review documented ophthalmic findings for other reported mutation-positive cases.
  
  
  METHODS
  Affected family members were prospectively examined and the relevant literature was reviewed.
  
  
  RESULTS
  Ophthalmic findings were present in 3 of the 4 siblings with ECEL1-related distal arthrogryposis: bilateral ptosis with bilateral congenital fibrosis of the extraocular muscles, right ptosis with ipsilateral Y exotropia (exotropia increasing in upgaze), and right ptosis with ipsilateral Duane retraction syndrome. The fourth affected sibling, who had the mildest arthrogryposis, had no ophthalmic abnormalities. Of 26 other reported recessive ECEL1 mutation cases (14 families), all had arthrogryposis, 19 had documented ptosis, and 4 had documented complex strabismus. One of these cases had both documented ptosis and complex strabismus.
  
  
  CONCLUSIONS
  Our clinical findings are consistent with recessive ECEL1 mutations causing variably penetrant orbital dysinnervation phenotypes (ptosis and/or complex strabismus with abnormal synkinesis) in the context of arthrogryposisis, that is, with the ECEL1-related ophthalmic phenotype being a form of CCDD.
authors.affiliation: Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. Electronic address: arif.khan@mssm.edu.
authors.forename: Arif O
authors.initials: AO
authors.lastname: Khan
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
mesh_terms: D000293:Adolescent; D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics*; D001763:Blepharoptosis / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003241:Consanguinity; D003391:Cranial Nerves / Q000002:abnormalities*; D004370:Duane Retraction Syndrome / Q000175:diagnosis / Q000235:genetics*; D005099:Exotropia / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011446:Prospective Studies; D014792:Visual Acuity; D055815:Young Adult
chemical_list: C492359:ECEL1 protein, human; D008666:Metalloendopeptidases