Strabismus, Susceptibility To

Description

Strabismus, a misalignment of the eyes also referred to as 'squint,' is one of the most common ocular disorders in humans, affecting 1 to 4% of the population. It is frequently associated with amblyopia (uniocular visual neglect) (Parikh et al., 2003).

Strabismus is also a feature of several syndromes, including congenital fibrosis of extraocular muscles (see, e.g., CFEOM1; 135700), Duane retraction syndrome (126800), and chronic progressive external ophthalmoplegia with myopathy (530000).

Clinical Features

Michaelides and Moore (2004) noted that incomitant strabismus is characterized by a degree of ocular misalignment which differs depending upon the direction of gaze or according to which eye is fixing an object, and is associated with defective ocular movement. Concomitant strabismus is characterized by an angle of deviation (magnitude of ocular misalignment) that remains the same in all directions of gaze, whichever eye is fixing. Concomitant strabismus is one of the most common problems in pediatric ophthalmology, affecting 3 to 5% of the childhood population. Overall, esotropia is more common than exotropia.

Inheritance

The familial nature of isolated or nonsyndromic strabismus has been recognized in the medical literature since Hippocrates (see Cantolino and Von Noorden, 1969). Cantolino and Von Noorden (1969) reported that there may be a hereditary component to microtropia, the minor form of strabismus. Richter (1967) found lower risk in first-degree relatives of a proband with divergent strabismus than with convergent strabismus. When 2 first-degree relatives (e.g., 2 parents, 1 parent and a child, or 2 children) were affected, the risk was about 1 in 4 and 1 in 2 for the 2 forms, respectively.

Richter (1968) and Friendly et al. (1973) reported a syndrome of cyclic strabismus (periodic esotrophia) in which the eyes are alternately straight for 24 hours and crossed for 24 hours. Friendly et al. (1973) observed that strabismus appeared to be unusually frequent in the families of these patients.

Assuming that strabismus is a multifactorial and polygenic trait, Hegmann et al. (1974) measured interpupillary distance, 'kappa' angle (the angle formed by the visual axis and the pupillary axis), spherical refractive error, and cylindrical refractive error in various populations affected with strabismus. Significant differences, particularly in refractive errors, suggested that the individual parameters reflect underlying continuous variables that may contribute to the development of strabismus.

Data compiled from multiple studies indicated that 73% of monozygotic (MZ) twin pairs and 35% of dizygotic twin (DZ) pairs were concordant for strabismus (Lorenz, 2002; Parikh et al., 2003). As noted by Parikh et al. (2003), ocular alignment relies on complex sensory and motor pathways in the retina, thalamus, visual cortex, and brainstem, and on the proper development and functioning of the extraocular muscles and orbit, suggesting that a multiplicity of components, and perhaps loci, are involved in the development of the disorder.

In a study of 173 pedigrees with infantile nonaccommodative esotropia, Maumenee et al. (1986) found that the disease best fit a model with either 2 autosomal dominant genes with incomplete penetrance or multifactorial inheritance. However, Parikh et al. (2003) noted that precise analysis is complicated by the observation that uncorrected refractive error is a risk factor for strabismus, that anisometropia is a general risk factor for strabismus, and that hypermetropia is a risk factor specifically for esotropia. As refractive error has a significant heritability, genes affecting refraction per se may act as strabismus susceptibility loci.

Michaelides and Moore (2004) pointed out that most progress in the understanding of the genetics of strabismus had been made in incomitant strabismus. Family studies suggest that there is a strong genetic component to the etiology of concomitant strabismus, with approximately 30% of probands with strabismus having a family member or close relative with strabismus (Paul and Hardage, 1994).

Mapping

In a large family with nonsyndromic strabismus, Parikh et al. (2003) found linkage of a presumptive strabismus susceptibility locus to chromosome 7p22.1 with a multipoint lod score of 4.51 at marker 1911/1912 under a model of recessive inheritance. In 6 other multiplex families, linkage to 7p was not observed, consistent with genetic heterogeneity.

Population Genetics

Studies by Holm (1939) and Gover and Yaukey (1944) documented a lower incidence of all types of strabismus among Africans and African Americans, 0.5% and 0.6%, respectively, compared to Americans of European ancestry (2.5%). In addition, the majority of African, African American, and Asian strabismics are exotropes, whereas the majority of Caucasian strabismics are esotropes.