title: Diagnostic distinctions and genetic analysis of patients diagnosed with moebius syndrome.
abstract: OBJECTIVE
  To improve diagnostic assessment in Moebius syndrome by (1) creating more selective diagnostic subgroups and (2) conducting genetic evaluation in a large patient cohort.
  
  
  METHODS
  Prospective, observational study.
  
  
  METHODS
  Attendees of 3 consecutive Moebius syndrome conferences held in the United States, with a prior diagnosis of Moebius syndrome, were invited to participate.
  
  
  METHODS
  Participants underwent standardized ophthalmologic examination for Moebius syndrome minimum diagnostic criteria (MDC) (congenital, nonprogressive facial palsy, and abduction deficit) and genetic testing for HOXA1, HOXB1, and TUBB3 mutations.
  
  
  METHODS
  The number of patients meeting MDC and the number of patients with confirmed genetic mutation.
  
  
  RESULTS
  A total of 112 participants from 107 families enrolled. Nineteen percent of participants (21/112) did not meet accepted MDC for Moebius syndrome because they had abduction deficits without facial palsy or facial palsy with full ocular motility. All 5 families with 2 affected individuals had at least 1 family member in this category, including 2 siblings with comitant strabismus who harbored a HOXB1 mutation. Four unrelated participants, also not meeting MDC, had large-angle exotropia, vertical gaze deficiency, and ptosis consistent with congenital fibrosis of the extraocular muscles type 3 (CFEOM3); 1 patient harbored a novel TUBB3 mutation, and 3 patients harbored previously reported de novo TUBB3 mutations. Three percent of participants (3/112) met MDC but also had restricted vertical gaze. The remaining 88 participants (79%) met MDC and had full vertical gaze. This group had relatively homogeneous findings, and none had a family history of Moebius syndrome. Two previously undescribed phenomena were observed in this category: (1) volitional Bell's phenomenon and (2) intorsion with fixation.
  
  
  CONCLUSIONS
  Although the genetic contributors to classic Moebius syndrome remain elusive, accuracy in clinical evaluation will properly subdivide patients to facilitate genetic testing as new candidate genes are identified. Failure to test ocular motility may lead to misdiagnosis of Moebius syndrome, especially in patients who have facial palsy with full ductions. Patients with exotropia, vertical gaze limitation, and ptosis do not have classic Moebius syndrome and may have TUBB3 mutations associated with CFEOM3. To optimize genetic analysis, we propose adding "full vertical motility" to the MDC for Moebius syndrome.
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Sarah
authors.initials: S
authors.lastname: MacKinnon
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts; Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Division of Ophthalmology, Faculty of Health Sciences, University of Stellenbosch, Tygerberg, South Africa.
authors.forename: Darren T
authors.initials: DT
authors.lastname: Oystreck
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts; Department of Neurology, Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Caroline
authors.initials: C
authors.lastname: Andrews
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, Massachusetts; Department of Neurology, Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts. Electronic address: david.hunter@childrens.harvard.edu.
authors.forename: David G
authors.initials: DG
authors.lastname: Hunter
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Boston, Massachusetts; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts; F. B. Kirby Neurobiology Center, Boston Children's Hospital, Boston, Massachusetts; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts; Department of Neurology, Harvard Medical School, Boston, Massachusetts; Howard Hughes Medical Institute, Chevy Chase, Maryland. Electronic address: elizabeth.engle@childrens.harvard.edu.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D000293:Adolescent; D000328:Adult; D001763:Blepharoptosis / Q000175:diagnosis; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005099:Exotropia / Q000175:diagnosis; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D005133:Eye Movements; D005260:Female; D005355:Fibrosis / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020331:Mobius Syndrome / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D015835:Ocular Motility Disorders / Q000175:diagnosis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D014157:Transcription Factors / Q000235:genetics; D014404:Tubulin / Q000235:genetics*; D055815:Young Adult; D000099261:Homeobox A1 Protein
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D014404:Tubulin; D000099261:Homeobox A1 Protein; C101121:HOXB1 homeodomain protein; C498585:TUBB3 protein, human