Comparison of Clinical Characteristics of Familial and Sporadic Acquired Accommodative Esotropia Michelle Z. Seeley, MD,a T. Otis Paul, MD,b Sue Crowe, COT,a Gabrielle Dahms, MA,b Susan Lichterman, RN,a and Elias I. Traboulsi, MDa Purpose: To compare the clinical characteristics of patients with familial and nonfamilial acquired accommodative esotropia. Methods: We recruited 48 patients from 33 families with acquired accommodative esotropia (an inward deviation of the eyes of 10 PD or more, a hypermetropia greater than or equal to +1.50 D, and an onset of esotropia at, or later than, 1 year of age). Our control group consisted of 20 patients with no known family history. Spherical error of refraction, stereoacuity, and need for strabismus surgery were determined and the 2 groups were compared. Results: No statistically significant difference was found between the spherical equivalent error of refraction in familial cases (mean = +4.50 OD, +4.63 OS; range = +1.50 to +10.30 OD, +2.00 to +9.38 OS) versus those with nonfamilial disease (mean = +4.93 OD, +5.02 OS; range = +2.50 to +11.00 OD, +2.50 to +10.90 OS) (P = .47 OD; P = .47 OS). There also was no difference between the percentage of patients with familial disease who had some degree of stereoacuity (58%) and those without a family history (59%) (P > .99). Patients with familial acquired accommodative esotropia did not require more surgical interventions (26%) than those with nonfamilial acquired accommodative esotropia (30%) (P = .79). Conclusions: The general clinical characteristics of familial and nonfamilial acquired accommodative esotropia are very similar. (J AAPOS 2001;5:18-20)
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ccommodative esotropia is a familial disorder and a leading cause of amblyopia in the pediatric population. The average age of onset of strabismus in acquired accommodative esotropia is 21⁄2 years.1 Patients are hypermetropic and some have a larger angle of esotropia at near than at distance (high accommodative convergence/accommodation [AC/A] ratio). Correction of the full refractive error eliminates the ocular deviation in some patients, while in others the angle of the esotropia is reduced but strabismus surgery is necessary to correct the residual deviation. It is estimated that up to 30% of patients with accommodative esotropia have other family members with the disease.2 Although there are no published studies of the mode(s) of inheritance of this disorder, we have found that the pedigrees of about 80% of families with accommodative esotropia that are enrolled in our studies of the genetics of strabismus are compatible From the Cleveland Clinic Eye Institute, Cleveland, Ohio,a and the Smith-Kettlewell Institute, San Francisco, California.b Poster presented at the 25th Annual Meeting of the American Association for Pediatric Ophthalmology and Strabismus, Toronto, Ontario, Canada, April 15-18, 1999. Submitted October 18, 1999. Revision accepted September 5, 2000. Reprint requests: Elias I. Traboulsi, MD, Cole Eye Institute, i33, 9500 Euclid Ave, Cleveland, OH 44195 (e-mail:
[email protected]). Copyright © 2001 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/2001/$35.00 + 0 75/1/111784 doi:10.1067/mpa.2001.111784
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with autosomal recessive inheritance.3 The purpose of the present study is to compare the clinical characteristics of familial and sporadic acquired accommodative esotropia.
SUBJECTS AND METHODS Eligible families were identified in the practices of pediatric ophthalmology and strabismus at the Cleveland Clinic Eye Institute and at the Smith-Kettlewell Institute. Informed consent was obtained from parents of affected children or from adults with the disease. Permission was requested to contact blood relatives of all patients with familial disease. Affected and non-affected relatives underwent a clinical ophthalmologic examination that included ocular motility testing, cycloplegic retinoscopy, and determination of stereoacuity. Pedigrees were drawn with use of the program Cyrillic. Acquired accommodative esotropia was defined as familial if the proband had at least one first-degree relative with acquired accommodative esotropia (Figure). Patients with acquired accommodative esotropia and no known family history of the disease were used as the control group. All study patients were, with the exception of the esotropia, healthy and had normal growth and development. Acquired accommodative esotropia was defined as an inward deviation of the eyes of 10 PD or more, a hypermetropia greater than or equal to +1.50 D, and an onset of esotropia at, or later than, 1 year of age. Patients had either Journal of AAPOS
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TABLE. A comparison of the clinical characteristics of familial and sporadic acquired accommodative esotropia Familial acquired accommodative esotropia (D)
Nonfamilial acquired accommodative esotropia (D)
Significant difference between familial and nonfamilial disease
Mean spherical equivalent error of refraction, OD Mean spherical equivalent error of refraction, OS Percentage of patients with stereoacuity ≥ 3000 seconds of arc Percentage of patients requiring surgical intervention
4.50 4.63 58% 26%
4.93 5.02 59% 30%
No No No No
pure refractive accommodative esotropia, defined as an esotropia that is restored to orthotropia at all fixation distances and in all gaze positions by optical correction of the underlying hypermetropic refractive error with or without bifocals, or partially accommodative esotropia, in which a residual esotropia persisted despite the full correction of the hypermetropic error or the prescription of bifocal lenses.4 The mean age of onset of the patient’s acquired accommodative esotropia was determined. χ2 statistical analysis was used to determine whether there was a difference in the mean age of onset between familial and nonfamilial cases. The spherical error of refraction of the right and left eyes of the control and study groups were evaluated separately. The spherical error of refraction was calculated as the algebraic sum of the spherical component + 1⁄2 the cylindrical component. χ2 statistical tests were used to compare the magnitude of errors of refraction in the control and experimental groups. Patients in the experimental and control groups were divided into those with and without stereoperception, defined as stereoacuity better than or equal to 3000 seconds of arc. χ2 analysis was used to compare the proportion of patients with stereoperception in the 2 groups. Finally, we divided patients in the 2 groups into those who required surgical intervention and those who did not. We used χ2 statistical analysis to compare the proportions between the 2 groups. A comparison of the 2 groups with respect to the prevalence of an abnormal AC/A ratio could not be performed because this information was not available on all patients. Pedigrees of the families in whom an adequate number of individuals were personally examined by the authors were analyzed for best fit into different modes of mendelian inheritance. Those pedigrees with unaffected parents and affected offspring were considered to have an autosomal recessive inheritance pattern. Pedigrees which demonstrated vertical transmission of the disease from generation to generation were classified as autosomal dominant.
The mean age of onset of familial acquired accommodative esotropia was 36 months and of nonfamilial disease was 34 months. The difference between these 2 groups was not statistically significant (P > .10). There was no statistically significant difference between the spherical component of the error of refraction in familial acquired accommodative esotropia (mean = +4.30 OD, +4.40 OS) and nonfamilial disease (mean = +4.10 OD, +4.20 OS) (P = .76 OD; P = .68 OS), between the cylindrical component of the error of refraction in familial (mean = +0.94 OD, +0.95 OS) versus nonfamilial disease (mean = +0.81 OD, +0.83 OS) (P = .65 OD; P = .67 OS), and between the spherical equivalent error of refraction in familial (mean = +4.50 OD, +4.63 OS; range = +1.50 to +10.30 OD, +2.00 to +9.38 OS) versus nonfamilial disease (mean = +4.93 OD, +5.02 OS; range = +2.50 to +11.00 OD, +2.50 to +10.90 OS) (P = .47 OD; P = .47 OS). An equal proportion of patients with (58%) and without (59%) familial disease had at least 3000 seconds of arc of stereoacuity (P > .99). Patients with familial acquired accommodative esotropia did not require more surgical interventions (26%) than those with nonfamilial acquired accommodative esotropia (30%; P = .79; Table). Sufficient data from personal examinations by the authors were available on members of 8 of the 33 families to allow reliable classification of the pedigrees by mode of mendelian inheritance. Six of the 8 pedigrees (75%) were compatible with autosomal recessive and 25% with autosomal dominant inheritance.
Clinical characteristic
RESULTS Forty-eight patients from 33 families with familial acquired accommodative esotropia were recruited. There were 27 males and 21 females. The control group consisted of 20 patients (9 males and 11 females) with no known family history of acquired accommodative esotropia.
DISCUSSION The earliest recorded statement that strabismus is a familial disease is attributed to Hippocrates who stated that “…children of parents having disturbed eyes squint also for the most part.”5 In 1903, Worth6 suggested that a “hereditary factor” was present in 51.8% of patients with strabismus. Czelliter7 found that 14% of siblings of patients with strabismus were affected and proposed an autosomal recessive mode of inheritance. Schlossman and Priestley8 found a positive family history for strabismus in 49% of patients with esotropia and 37% with exotropia.8 Twin studies of strabismus demonstrated that concordance averages 73% (33%100%) in monozygotic twins and 35% (4%-47%) in dizygotic twins,2 further supporting the importance of genetic factors in the pathogenesis of this group of disorders.
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FIGURE. Pedigree demonstrating an autosomal recessive inheritance pattern of familial acquired accommodative esotropia. Full circles and squares, Affected; half-full circles and squares, presumed carriers of the gene.
The Collaborative Perinatal Project studied over 5000 families. Evaluation of separate birth data revealed that the odds of having esotropia for one sibling doubled if another sibling had esotropia, whereas the odds for exotropia were not significantly increased. Examination of the multiple birth data revealed that the odds greatly increased for esotropia and exotropia if another sibling had strabismus.9 More is known about the inheritance of infantile or congenital esotropia than accommodative esotropia. In 1986, Maumenee et al10 examined 173 pedigrees of families with a history of congenital esotropia that included 1589 individuals. Pedigree analysis was compatible with an autosomal recessive inheritance pattern, but segregation analysis with the use of the Pedigree Analysis Package computer program was most compatible with codominant genes. The authors concluded that although the majority of cases of congenital esotropia are autosomal recessive, some are autosomal dominant, and others are nongenetic.10 Paul and Hardage2 estimated that up to 30% of patients with accommodative esotropia have a family history of the disease. There have been no published systematic studies that have analyzed the mode of inheritance of this disorder or mapped the responsible gene(s). We compared 48 patients with familial accommodative esotropia to a sex- and age-matched group of 20 patients with nonfamilial disease. All patients had onset of esotropia at, or later than, 1 year of age. The esotropia measured more than 10 PD, and there was a hypermetropia greater than, or equal to, +1.50 D.
We found no significant difference between the clinical characteristics (error of refraction, stereoacuity, and need for strabismus surgery) of patients with familial and nonfamilial acquired accommodative esotropia. These findings suggest that some of the isolated cases may have similar underlying genetic mechanisms (eg, autosomal recessive genes) to familial cases. However, it is also possible that other genes, as well as epigenetic factors, are involved in the pathogenesis of acquired accommodative esotropia. From our limited pedigree analysis, familial acquired accommodative esotropia seems most commonly to demonstrate an autosomal recessive inheritance pattern. However, more families need to be collected and evaluated for these results to be statistically significant. Our data suggest clinical homogeneity among patients with familial and nonfamilial accommodative esotropia with onset after the first year of life. This information should be helpful if sib-pair linkage analysis of families with one or more affected individuals is used to map the loci of the major determining genes of these diseases. References 1. Baker JD, Parks MM. Early-onset accommodative esotropia. Am J Ophthalmol 1980;90;11-8. 2. Paul TO, Hardage LK. The heritability of strabismus. Opthalmic Genet 1994;15:1-18. 3. Seeley MZ, Fakhry CA, Crowe S, Lichterman S, Traboulsi EI. The inheritance of accommodative esotropia [abstract No. 4075]. Invest Opthalmol Vis Sci 1999;40(4):146. 4. von Noorden GK. Binocular vision and ocular motility, St Louis: Mosby; 1996. p. 299-340. 5. Hippocrates. Airs, waters, and places. In: The Genuine works of Hippocrates. New York: William and Wood & Co; 1886. p. 171. 6. Worth C. Squint, its causes, pathology, and treatment. Philadelphia: P Blakiston’s Son & Co; 1903. 7. Czellitzer A. Wie vererbt sich Schielen? Arch Rassen Gessellsch Biol 1923;14:377-94. 8. Schlossman A, Priestly BS. Role of heredity in etiology and treatment of strabismus. Arch Opthalmol 1952;47:1-20. 9. Podgor MJ, Remaley NA, Chew E. Associations between siblings for esotropia and exotropia. Arch Opthalmol 1996;114:739-44. 10. Maumenee IH, Alston A, Mets MB, Flynn JT, Mitchell TN, Beaty TH. Inheritance of congenital esotropia. Trans Am Ophthalmol Soc 1986;vol LXXXIV:85-93.
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