The extraocular muscles (EOMs) form from paraxial and prechordal mesoderm, following cues from the developing eye as well as from surrounding neural crest–derived mesenchyme. Indeed, the interactions among the optic cup, mesoderm, and neural crest cells are crucial to the proper development and organization of the EOMs. If the optic cup fails to form and the eye vesicle turns into a cyst (microphthalmia spectrum), the EOMs often develop anomalously, an outcome that is likely because signals from the optic cup are necessary for proper migration of neural crest cells into the eye and surrounding tissues, and subsequent signals from these neural crest–derived cells are required for proper development and organization of the EOMs. Interestingly, eyeless blind cave fish have embryonic eyes, likely because the developing eyes serve as important organizers of facial and head development (possibly through the morphogenic actions of retinoic acid).
Congenital cranial dysinnervation disorders involving the EOMs include Duane retraction syndrome, Marcus Gunn jaw-winking syndrome, Möbius syndrome, and congenital fibrosis of the extraocular muscles (see BCSC Section 6, Pediatric Ophthalmology and Strabismus). Genetic studies have identified mutations in genes for neuron biology and axon guidance (eg, KIF21A, PHOX2A, TUBB3) that cause these EOM syndromes.
By extrapolation, congenital ptosis and other congenital EOM disorders probably result from delays in muscle innervation. Current models suggest that as the muscle mesenchyme and associated nerve jointly develop, a delay in innervation of the muscle mesenchyme can cause premature differentiation of that mesenchyme into connective tissue (ie, fibrosis). The extent of delay may correlate with the severity of fibrosis (eg, severity of the congenital ptosis and levator muscle dysfunction). Furthermore, the delay in, or absence of, innervation may provide a window for inappropriate innervation by another cranial nerve, such as trigeminal innervation of the levator muscle (Marcus Gunn jawwinking syndrome) or oculomotor innervation of the lateral rectus muscle (Duane retraction syndrome).
Bohnsack BL, Gallina D, Thompson H, et al. Development of extraocular muscles requires early signals from periocular neural crest and the developing eye. Arch Ophthalmol. 2011;129(8):1030–1041.
Engle EC. Human genetic disorders of axon guidance. Cold Spring Harb Perspect Biol. 2010;2(3):a001784.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.