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.

Design: Prospective, observational study.

Participants: 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.

Main outcome measures: 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.

Conflict of interest statement

Conflict of Interest: No conflicting relationship exists for any of the authors.

Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Participant diagnostic categories for Moebius syndrome. A: Currently accepted minimum diagnostic criteria. B: New proposed minimum diagnostic criteria. MDC = minimum diagnostic criteria. *Two brothers within this group were identified with HOXB1 mutations (facial nerve palsy and comitant esotropia). **Two participants (mother and son) were diagnosed with hereditary congenital facial nerve palsy (HCFP). *** All participants were molecularly diagnosed with a TUBB3 mutation causing congenital fibrosis of the extraocular muscles.

Figure 2

Eye alignment, horizontal ocular motility patterns, and facial strength in participants not meeting the minimum diagnostic criteria for Moebius syndrome. Images A, C, D, and E are from an 8 year old boy with a unilateral facial palsy (A) who also demonstrates full abduction of both the right eye (C) and left eye (E) as well as an esotropia in straight ahead gaze (D). Images B, F, G, and H are from an adult woman who does not have facial weakness (B), but does have a severe abduction deficit of the right eye (F) and left eye (H) with a small angle esotropia in straight ahead gaze (G).

Figure 3

Exotropia, limited vertical movement, and ptosis in individuals with genetically confirmed congenital fibrosis of the extraocular muscles type 3. Images A, B, and C are from a 7 year old boy with a heterozygous E410V TUBB3 amino acid substitution. He has a marked exotropia of his right eye in straight ahead position (B) with nearly full abduction and markedly reduced adduction of both eyes (A and C). Aberrant innervation was also present, with left ptosis in right gaze (A). Vertical ductions were absent. Image D is a 7 year old girl with a heterozygous R262H TUBB3 substitution showing exotropia of the right eye and marked bilateral ptosis for which she has already had previous lid surgery with limited success. Image E shows an 8 year old girl with a heterozygous E410K TUBB3 substitution. There is exotropia with both eyes anchored below the vertical midline, and both pupils are small and irregular.

Figure 4

Eye alignment and horizontal ocular motility patterns in two participants with classic Moebius syndrome. Images B and E are in straight ahead gaze, while images A and D are right gaze and images C and F are left gaze. Images A, B, and C show an 18 month old with a large esotropia, marked abduction deficit of each eye with good adduction. Images D, E, and F show an adult with relatively straight eyes (orthotropia) with limited horizontal gaze in both directions.

Figure 5

Volitional Bell’s phenomenon. A, patient fixating on camera; B, volitional Bell’s phenomenon forces upgaze. Corneas are lubricated when they bury under the immobile upper lid. See also Video 2.