Any relationship between strabismus and heredity is subject to the dense camouflage caused by the broad heterogeneous nature of the myriad disorders that comprise strabismus and the various factors that can influence its development.⁵ Despite that, strong relationships do exist, although the majority of those tight relationships are with less common strabismus syndromes that are less a true “syndrome” and closer to a unique disorder.⁴

Many of the early studies of the inheritance patterns in strabismus concentrated on the pedigrees of families with strabismus. Various modes of inheritance were proposed for strabismus. Francois⁶ and Waardenburg⁷ postulated a single dominant gene with irregular penetrance; Schlossman⁸ and Czellitzer⁹ thought one and two recessive gene models were more probable. Dahlberg and Nordlow¹⁰ incorporated both these theories in their observation that strabismus may be “caused by different genes of different kinds and with a different type of inheritance in the separate families.” Richter¹¹ theorized separate multifactorial modes of inheritance for sensory and motor functions. The multifactorial model as embraced by Cross¹² and Mash and associates³ is now a commonly held theory of inheritance of strabismus, although at least with congenital esotropia a mendelian codominant model may also explain the inheritance pattern.¹³ In the multifactorial model of inheritance, several gene loci contribute to the expression of a deviation of the extraocular muscles. Multiple loci can be affected by multiple environmental factors, thus leading to variations in the expression of the phenotypic strabismus. It is postulated that a certain degree of interaction may be necessary among the various factors involved to produce a strabismus—the “threshold effect.” When the threshold is reached, the strabismus becomes manifest.

Several characteristics of the multifactorial model of inheritance distinguish it from single gene modes of inheritance:¹⁴

Thus, the risk of recurrence of strabismus in an affected family with a multifactorial mode of inheritance is based on the frequency of that strabismus in the general population and the number of family members affected in the pedigree under study. Various systems for calculating this risk have been proposed. The reader is referred to Curnow and Smith¹⁵ for a discussion of one such system of calculating risk of recurrence in a condition with a multifactorial pattern of inheritance.

The study of a large population with multiple affected families is therefore of utmost importance in investigating conditions with a multifactorial mode of genetic transmission. The risk of recurrence of strabismus in a sibling or offspring of an affected individual can be more correctly calculated by using a large population. Also, the effect of environmental factors on the transmission of the trait can be more accurately assessed. Movement in this direction has been taken in more recent work that implicates a susceptibility locus on chromosome 7p.¹⁶

In recent years, there has been a great deal of epidemiologic research regarding the prevalence of strabismus in school-age children in various countries.^{17,18,19,20,21,22,23,24,25,26,27} The prevalence of strabismus in this group of children is reported to be higher in the countries with predominately white, Hispanic, and African populations and lower in countries from Asia, India, and the Middle East. The reported prevalence rates for strabismus in the countries with higher prevalence rates range from 2.3% to 3.1%. In 1996, the Baltimore Vision Screening Project in the United States found a prevalence of strabismus of 3.1%.¹⁷ In 2006, a study from Sydney, Australia, found a prevalence of strabismus of 2.8%.¹⁸ Two different studies in Sweden, both published in 2001, found a prevalence rate of 2.7% and 3.1%.^19,20 In a study from northern Mexico, the prevalence of strabismus was found to be 2.3%.²¹ In countries with lower prevalence rates for strabismus, the reported prevalence ranges from 0.30% to 1.62%. In 1996, the Taoyaun Republic of China found a prevalence of manifest strabismus of 1.6%.²² In 2005 in Okayama, Japan, the prevalence of strabismus was reported as 1.28%.²³ In 2003 in Nepal, the prevalence of strabismus was found to be 1.60%, while in the same year in southern India, the rate was 0.43%.^24,25 In 2003, a study from southern Jordan reported a prevalence of strabismus of 0.5%, and in 1998 in the Sultanate of Oman, the reported prevalence of strabismus was 0.9%.^26,27

Olmsted County, Minnesota, home to the Mayo Clinic, provides us with many recent epidemiologic studies regarding the prevalence of various types of strabismus in the United States. Congenital esotropia was found to have a birth prevalence of 27 per 10,000 (0.27%).²⁸ Childhood exotropia was found to have an annual age- and gender-adjusted incidence of 64.1 per 100,000 patients younger than 19 years, which corresponded to a prevalence of approximately 1% of all children younger than 11 years.²⁹ A gender difference was seen in another study in Olmsted County, with girls accounting for 64% of the patients with intermittent exotropia and boys accounting for 36%.³⁰ The last study to be published from the Mayo Clinic found vertical strabismus in 12.9 per 100,000 patients younger than 19 years of age for a prevalence of 0.26% or 1 in 391 of all children younger than 19 years of age.³¹

A difference exists between the prevalence of esotropia and exotropia among different countries. This is most likely secondary to racial differences and not those of an environmental nature. Esotropia appears to be more common in white populations and exotropia more common in all other nonwhite populations.^{18,23,24,32,33} A recent study from Sydney, Australia, with a predominately white population, reports esotropia in 54% and exotropia in 29% of all strabismus cases.¹⁸ In Nepal, 1.4% of the schoolchildren studied had exotropia, and 0.2% had esotropia.²⁴ In Japan, 0.60% of schoolchildren had exotropia, and only 0.25% had esotropia.²³ A study from Hong Kong found that esotropia consisted of 24.7% of all strabismus cases and exotropia 65.3%.³² Lambert³³ suggests that these differences seen in the Asian population may reflect a high incidence of moderate to high hyperopia in the white population as compared with that found in the Asian population and therefore a decreased incidence of accommodative esotropes.³³

Hohm³⁴ studied the incidence of esotropia and exotropia in the African population. In examining 931 African individuals in Gabon, he found that the incidence of exotropia was quite similar to that previously reported for white populations. However, the incidence of esotropia was only 0.52%, which was markedly decreased from previous reports of white populations.

To eliminate some of the possible environmental factors encountered when determining rates of strabismus in different racial groups, Eustace³⁵ examined second-generation West Indian children born in Birmingham, England. The prevalence of strabismus and refractive error in this population was then compared with previous data collected on white children from the same region. Exotropia was found to be four times more frequent in the West Indian population of children. In addition, myopia was significantly more frequent in the West Indian children, especially among the exotropes.

Ing and Pang³⁶ studied the incidence of strabismus in individuals of white, Asian, and mixed descent from the Honolulu area. Esotropia was noted to be more common in whites, whereas Asians more frequently manifested exotropia. Mixed-descent individuals were fairly evenly divided between divergent and convergent strabismus. In examining the interracial incidences of nonaccommodative and accommodative esotropia, it was found that Asians and individuals of mixed descent manifested equal incidences of both subtypes. However, the incidence of accommodative esotropia found in whites was nearly four times that of nonaccommodative esotropia.

Several studies have investigated the incidence of strabismus in families with strabismic members. Considerable differences have been encountered in these studies. Schlossman and Priestley³⁷ found that 47.5% of the patients with strabismus in their study belonged to families with two or more affected members. They further broke this down to show an incidence of 48.9% in esotropes and 36.8% in exotropes. Worth³⁸ had similar findings, whereas Scobee³⁹ reported an incidence of 41%. Several studies have reported the familial incidence of strabismus to be as high as 65%.^40,41,42

Such wide variations in reported findings are attributable to several factors. Many studies dealt with strabismus as the phenotype and did not distinguish specific subtypes of strabismus, such as accommodative or congenital esotropia, exotropia, or the different phorias. Sample sizes varied, as did target populations, thus adding to the heterogeneity of the studies. The underlying incidence of strabismus in the population under study was not always determined. Data-gathering methods also varied. Some studies relied on patient histories; others examined all subjects. The extent of investigation of different pedigrees varied considerably.

The difficulties encountered when conducting a population study of strabismus were underscored by Kornder and colleagues⁴³ in their study of the prevalence of strabismus in school-age children in British Columbia. Screening personnel with varied training backgrounds were employed. In addition, a self-administered questionnaire was used to determine familial history of strabismus. The results obtained via examination varied significantly with the level of training of the examiner. In addition, subjective methods of evaluation were found to be inferior to evaluation by both subjective and objective methods. The most frequently “missed” group was children with intermittent exotropia.

In a carefully studied population from Greece, Chimonidou and coworkers⁴⁴ found the overall familial incidence of a history of strabismus to be 55%. In an effort to refine the data, the authors limited their subsequent investigation to the 345 patients who were long-standing patients of the Athens University Eye Clinic. In this group, they found that 97% of affected siblings had the same type of strabismus as the proband. Eighty-three percent of the patients had a significant refractive error. Of the 148 patients with congenital strabismus (defined as onset within the first year of life), 42% had siblings who developed strabismus at a more advanced age. The remaining 58% had siblings who developed strabismus at the same age, within 1 year. Type of strabismus and refractive error were also noted to be the same for each pair.

In many familial cases, the relative with strabismus has the same type of strabismus as the patient. This was shown in a study in from the Cameroons of 275 patients with strabismus.⁴⁵ Seventy-nine cases (29%) were familial, and 23% of these patients had more than one relative with strabismus. In this study, 75% of the patients had the same type of strabismus as their relative.

Twin studies have been used in an effort to delineate the influence of multiple factors on the heredity of strabismus. In classic twin research, monozygotic twins share identical genetic material and, if raised together, the same environment. Dizygotic twins, on the other hand, share only one quarter of their genetic material but do share the same environment if raised together.

Concordance rates in both groups are analyzed for the trait under study. If the concordance rate of a trait in monozygotic twins approaches 100% while the same rate in dizygotic twins is significantly less, then genetic transmission is likely. When the concordance rates between monozygotic and dizygotic twins do not differ significantly, environmental influences and other random factors assume greater importance in the etiology of the trait under study.

Rubin and associates⁴⁶ surveyed ophthalmologists from 50 countries for data on twins with ocular motor anomalies and calculated the heritability of various eye conditions and factors involved in the development of fixation and fusion reflexes. Ophthalmic conditions rated high for genetic influence were exotropia, hyperopia, and myopia. Moderate genetic influences were seen in astigmatism, eccentric fixation, amblyopia, and esotropia.

Waardenburg⁷ analyzed the presence of strabismus in 69 pairs of monozygotic twins, 58 pairs from the literature, and 11 pairs from his own practice. Concordance was found in 81.2%, thus demonstrating some environmental effect. Seven pairs of monozygotic twins were identified with 100% concordance for exotropia. Fifty-one pairs of dizygotic twins were then considered. This included 15 pairs from his own practice. Concordance for strabismus was found in 8.9%. He postulated that this eliminated the possibility that environmental factors alone were responsible for strabismus, since the concordance of strabismus in dizygotic twins was significantly higher than that of the general population and nearly equal to that of siblings from unaffected parents.^9,47

Richter⁴⁷ corroborated Waardenburg’s findings when she found concordance for strabismus in 11 of 12 monozygotic twin pairs (92%) and in only 7 of 27 dizygotic twin pairs (26%). Concordance in amblyopia and retinal correspondence was found to be about 44% in monozygous twins but only 17% in dizygous twins.

Somewhat different results were found in two smaller studies. Weekers and colleagues⁴⁸ found only three of seven pairs (43%) of monozygotic twins concordant for strabismus. However, six of seven pairs (86%) showed identical ametropia. From this, they concluded that strabismus is not hereditary but only secondary to other abnormalities. DeVries and Houtman⁴⁹ found 8 of 17 pairs (47%) of monozygotic twins concordant for strabismus. Several of the concordant pairs were noted to have large variations in the expression of their strabismus. This was thought to represent a common predisposition to strabismus, modified by heredity.

Kvapilikova⁵⁰ compared the sensory status of 34 pairs of monozygous twins to that of 34 pairs of dizygous twins. A high degree of concordance (81%) was found for foveolar fusion in the monozygous twins. The dizygous twins demonstrated moderate concordance (58%) for this characteristic. The author concluded that variability of fusion did have some hereditary component.

The study of differences encountered in monozygotic twins has also yielded other interesting insights. Shippman and coworkers⁵¹ reported a pair of esotropic monozygotic twins. One twin demonstrated a V-pattern esotropia; the other twin demonstrated an A-pattern esotropia. At the time of surgery, twin 2 was found to have anomalous insertions of both medial rectus muscles. The medial rectus insertions of twin 1 were entirely normal. The authors believed that the abnormal medial rectus insertions in one twin were responsible for the difference in pattern of strabismus.

Bucci and associates⁵² reported on two sets of monozygotic twins, each raised in the same environment. One twin of each set had accommodative esotropia. Both esotropic twins manifested greater hyperopia on cycloplegic refractions. Spectacle correction was not given to the orthophoric twins, and neither manifested a subsequent strabismus. The authors concluded that “the greater hyperopia in the strabismic twins advanced these predisposed children beyond the threshold required to express this particular defect.”

Identical twins reared apart give important information on the genetic versus environmental influence of a disease. Two studies report identical cases of strabismus in identical twins reared apart. Knobloch and associates⁵³ examined 26 pairs of twins reared apart ophthalmologically. Included were 18 monozygotic and 8 same-sex dizygotic pairs of twins. Although reared apart, three pairs of monozygotic twins had almost simultaneous onsets of diagnosis and treatment of esotropia, indicating a strong genetic influence. In the previously mentioned study by Chimonidou⁴⁴ from Greece, they encounter one pair of monozygous twins separated at 3 months of age and raised under vastly different socioeconomic conditions. Both developed esotropia at 3 years of age.

The theory of a threshold effect in the multifactorial inheritance of strabismus has prompted several investigators to search for risk factors that play a part in modifying the expression of strabismus in the affected individual. The role of various factors (ametropia, amblyopia, stereopsis, etc.)^54,55,56 in the development of strabismus can be shown but remains unsettled. Many investigators believe that refractive error (magnitude and/or asymmetry) plays an important role in accommodative esotropia.^{11,47,48,57,58,59,60} Conversely, heredity can be more of a factor in hypermetropic accommodative esotropia than in other forms of horizontal strabismus.⁶¹ Francois,⁶ on the other hand, has stated that the hereditary transmission of exotropia is often independent of refraction. However, the incidence of myopia in exotropia has been found to be twice that of myopia in esotropia.³⁵

Some twin studies have suggested that refractive errors are inherited.⁶² A multigenic mode of inheritance has been demonstrated in the refractive range between +6 and -4 diopters,¹⁴ but the extremes of the refractive curve show a strong monogenic influence.⁶³ Keiner,⁶⁴ who believed that a patient’s refraction was determined by the presence and degree of amblyopia, proposed a contrasting theory. He based this theory on the observation that amblyopia has been noted to prevent emmetropization of the affected eye and pointed to the large percentage of hypermetropes found among strabismic patients as proof of this relationship.

Francois,⁶ on the other hand, observed that not all family members with strabismus demonstrate amblyopia. Only 67% to 73% of strabismic patients have some degree of amblyopia. Francois went on to find similar percentages of amblyopia in monozygotic twins (73.6%), dizygotic twins (63.1%), and siblings of strabismic persons (68.3% to 71.3%). Using the same data, he concluded that impairment of binocular vision, anomalous retinal correspondence, and false projection are secondary, nonhereditary characteristics. Finally, no genetic difference was observed between alternating and monocular strabismus.

Using quantitative genetic methods, Spivey⁶⁵ identified spherical refractive error as a key variable in strabismus. He further noted vergence ability to be a primary biologic difference between strabismic and nonstrabismic families with refractive errors. Spivey identified three conditions highly correlated with esotropia in offspring or younger siblings: (a) when a parent has esotropia; (b) when the parents are normal but there is a family history of esotropia; and (c) when the parents are normal but there is, between them, very low vergence ability and a significant hyperopia. The accommodative convergence to accommodation (AC/A) ratio was also noted to be a variable in this process, which has been repeated in collaboration with other researchers.⁶⁶ Its exact role, however, was not delineated.

The role of the AC/A ratio in the inheritance of esotropia was explored by Maumenee and colleagues.¹³ They found that members of a family with an esotropic propositus have a higher ratio than a random population. This suggests that the AC/A ratio may be a factor in the inheritance of esotropia. Hofstetter⁶⁷ found a high correlation of AC/A ratio in monozygotic twins, suggesting a genetic basis.

Chew and coworkers⁶⁸ followed a large cohort of children from gestation to age 7 years. They identified several risk factors for esotropia and exotropia that confound the hereditary study of strabismus. Maternal cigarette smoking and low birth weight were both found to be important and independent risk factors for both forms of horizontal strabismus. The strabismus risk was noted to increase with increasing number of cigarettes smoked by the mother. Other risk factors for both forms of horizontal strabismus were nonspecific uterine bleeding during the third trimester, gestational age, and duration of the second stage of labor. Race, mother’s age, and number of prior pregnancies were significant risk factors for esotropia. The 1-minute Apgar score was noted to be a significant factor for exotropia.