A 4-year-old girl was referred for binocular misalignment. She had previously been given glasses for high myopia. Her father incidentally noted that her nostrils flared every time she blinked. There was no history of head trauma, systemic infection, or facial surgery. The family history was negative for strabismus or congenital cranial dysinnervation disorders.
On examination, corrected visual acuity was 20/50 in the right eye and 20/40 in the left eye with a refraction of −18.25 +1.00 × 90 in both eyes. Pupillary responses were normal. Prism and alternate cover testing showed an intermittent exotropia of 20 prism diopters at distance and near that was well-controlled when wearing her glasses. No photophobia, nystagmus, or paradoxical pupillary constriction to light was noted. Physical examination confirmed that her nostrils flared every time she blinked (Fig. 1 and see Supplemental Digital Content, Video, http://links.lww.com/WNO/A313). She was also noted to have maxillary hypoplasia. Anterior segment examination was within normal limits, with an intraocular pressure of 19 and 20 mm Hg in right and left eye, respectively. Retinal examination showed healthy optic discs and a prominent choroidal pattern in both eyes.
Congenital oculonasal synkinesis is a rare condition that is often asymptomatic (1,2). It results from misdirection of cranial nerve axon growth in utero, leading to a common innervation by the facial nerve to the orbicularis oculi and the compressor narium minor muscle (3). The orbicularis oculi is a broad flat muscle arranged in concentric bands around the upper and lower eyelids, and is innervated by the temporal and zygomatic branches of the facial nerve. The compressor narium minor muscle is a small, pyramidal muscle oriented across the domes of the lower lateral cartilages, innervated by the superior buccal branches of the facial nerve. The musculus dilator naris anterior (apices nasi) and the musculus compressor narium minor are in close apposition to the lower lateral cartilages and play an important role in compressing the alae (4). Interestingly, all reported patients with oculonasal synkinesis have been female and without any significant family history. In some cases, oculonasal synkinesis can be asymmetrical or even unilateral (1).
Acquired oculonasal synkinesis can develop after trauma or tumor compression (1). It is attributed to the regrowth of anomalous connections between the temporal and zygomatic branches of the facial nerve (1,3). Treatment is rarely requested, but diminution of synkinesis can be achieved with botulinum toxin, chemodenervation, or selective neurectomy in cases of refractory synkinesis (5).
In our patient, the constellation of findings could be related to a variation in the expression of protein coding genes and signal proteins needed to guide axon development and scleral and bone growth. More specifically, developmental perturbations in neurogenesis could account for the association of congenital oculonasal synkinesis with high myopia, maxillary hypoplasia, and intermittent exotropia. The facial nerve contains axons from branchiomotor and visceromotor neurons, which originate in 2 different rhombomeres of the hindbrain (6).
It has been shown in animals, that the transmembrane protein neuropilin 1 (NRP1) is needed for the patterning of the facial nerve, as it binds the secreted Class-3 semaphorin SEMA3A to guide facial branchiomotor axons and the vascular endothelial growth factor isoform (VEGF164) to control the position of the neuron cell bodies within the hindbrain (6). Class-3 semaphorins have been shown to function as factors that guide axon development, and as antiangiogenic agents (6). PLXNA4 and PLXNA3 are involved in the patterning of SEMA3A-responsive sensory and sympathetic axons, as they both synergize to pattern the facial nerve (7). PLXNA1 has been implicated as a SEMA6A receptor in boundary cap patterning at the interface between the central and peripheral nervous systems to assist the ordered exit of axons from the neural tube (7).
VEGF is a well-known regulator of angiogenesis and plays a key role in regulating both scleral angiogenesis and osteogenesis (8). Inhibition of VEGF signal has been shown to reduce scleral vascularization. Low levels of VEGF can also impede the differentiation and expression of preosteoblasts, which can have a long-term effect on bone formation (8).
Misdirection of facial nerve growth may, therefore, be explained by a lack of function of NRP1 and semaphorins. A decrease expression of these proteins could lead to a decrease in the levels of VEGF, resulting in delayed formation of bone and increased avascular zones within the sclera, resulting in high myopia and maxillary hypoplasia, as seen in our patient. Additional studies are needed to confirm this association.
STATEMENT OF AUTHORSHIP
Category 1: a. Conception and design: L. A. Torrado and M. C. Brodsky; b. Acquisition of data: L. A. Torrado and M. C. Brodsky; c. Analysis and interpretation of data: L. A. Torrado, G. S. Hamilton, and M. C. Brodsky; Category 2: a. Drafting the manuscript: L. A. Torrado, G. S. Hamilton, and M. C. Brodsky; b. Revising it for intellectual content: L. A. Torrado and M. C. Brodsky; Category 3: a. Final approval of the completed manuscript: L. A. Torrado, G. S. Hamilton, and M. C. Brodsky.
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