Retinal Dysfunction in Patients with Congenital Fibrosis of the Extraocular Muscles Type 2

Abstract

Introduction: Congenital fibrosis of the extraocular muscles type 2 (CFEOM2) is a distinct non-syndromic form of congenital incomitant strabismus secondary to orbital dysinnervation from recessive mutations in the gene PHOX2A. The phenotype includes bilateral ptosis, very large angle exotropia, ophthalmoplegia, and poorly-reactive pupils. Other than amblyopia, afferent visual dysfunction has not been considered part of CFEOM2; however, we have repeatedly observed non-amblyopic subnormal vision in affected patients. The purpose of this study was to document this recurrent feature of the phenotype.

Methods: A retrospective case series (2002-2012).

Results: Eighteen patients (four families) were identified; all affected individuals had confirmed homozygous recessive PHOX2A mutations except one individual for whom genetic testing was not done because of multiple genetically confirmed family members. Age at assessment ranged from 5-62 years old (median 10 years old). All patients had decreased best-corrected visual acuity not completely explainable by amblyopia in both the preferred and non-preferred eye. In those patients who had further ancillary testing, visual fields (five patients) and electroretinography (10 patients) confirmed abnormalities not ascribable to amblyopia.

Conclusions: In addition to a distinct form of congenital incomitant strabismus, the phenotype of CFEOM2 includes subnormal vision consistent with retinal dysfunction. This could be the direct result of PHOX2A mutations or a secondary effect of orbital dysinnervation.

Keywords: Congenital cranial dysinnervation disorder; PHOX2A; congenital fibrosis of the extraocular muscles; retina.

Figure 1. Clinical examples

A (patient 2): The typical ptosis and very large angle exotropia can be appreciated in primary position; (B,C: patient 9): Irregular pupils (not pharmacologically dilated) can be appreciated in both the right (B) and left (C) eyes; (D,E: patient 1): (D) The typical ptosis and very large angle exotropia can be appreciated in primary position; (E) The patient uses a finger to lift a ptotic lid and better visualize an object of regard, which is not an uncommon maneuver.

Figure 2. Goldmann visual field examples): (A,B: patient 9

A: The preferred right eye has a slightly constricted field that is otherwise normal; B: The non-preferred left eye has only an inferotemporal island of vision. (C,D; patient 16): C: The non-preferred right eye has only a superior arcuate island of vision; D: The preferred left eye has a slightly constricted field that is otherwise normal.

Figure 3. Scotopic electroretinography [ERG] example, patient 9

(A,B) The abnormal left eye (OS) of patient 9 and a normal control for comparison. (A) For the left eye of patient 9, the white flash a-wave (combined rod-cone response) implicit time was delayed (21 ms vs normal mean[range] 14 [11–17]) and its amplitude is at the low range of normal (169 millivolts [mv] vs 271 [164–378]). Responses to blue (rod isolated) and red (cone isolated) stimuli under scotopic conditions are also depicted, and both also show delayed implicit times (blue 118 ms vs 92 [69–115]; red 56 ms vs 47 [42–53]). In addition, the amplitude of the response to red is depressed (red 36mv vs 124 [51–197]). (B) A normal control is shown for comparison. The white flash a-wave implicit time was 14 ms. Each box corresponds to 100 mv and 20 ms and normal means (ranges) are as follows: a-wave implicit time 14 (11–17) ms; a-wave amplitude 271 (164–378) mv; b-wave implicit time 51 (42–60) ms; b-wave amplitude 242 (103–380) mv.