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REVIEW

Albinism: Classification, Clinical Characteristics,and Recent Findings

C. Gail Summers*

ABSTRACTPurpose. To describe the clinical characteristics and recent findings in the heterogeneous group of inherited disorders ofmelanin biosynthesis grouped as albinism.Methods. The current classification of albinism, and the cutaneous, ocular, and central nervous system characteristics are

presented. Recent clinical findings are summarized.Results. Albinism is now classified based on genes known to be responsible for albinism. Foveal hypoplasia is invariablypresent and individuals with albinism often have delayed visual development, reduced vision, nystagmus, a positive anglekappa, strabismus, iris transillumination, and absent or reduced melanin pigment in the fundi. A visual-evoked potentialcan document the excessive retinostriate decussation seen in albinism. Grating acuity can be used to document delayedvisual development in preverbal children. Glasses are often needed to improve visual acuity and binocular alignment.Conclusions. Albinism is caused by several different genes. Heterogeneity in clinical phenotype indicates that expressivityis variable.(Optom Vis Sci 2009;86:659662)

Key Words: albinism, vision, genes

Albinism, derived from the Latin, albus, meaning white, is agroup of inherited disorders in which melanin biosynthesisis reduced or absent. Several genes have been found to be

responsible for albinism. The current classification of albinism isdetermined by the affected gene, making the previously usedterms, partial or complete and tyrosinase-positive or tyrosinase-negative obsolete.1,2 The gene for tyrosinase on chromosome11q14-21 and the Pgene on chromosome 15q11.2 are the mostcommonly affected genes, mutations on these genes cause oculo-cutaneous albinism type 1 (OCA1; OMIM 203100) and oculocu-taneous albinism type 2 (OCA2; OMIM 203200), respectively.

These types of albinism are inherited in an autosomal recessivemanner and are expressed in males and females. Another type ofalbinism caused by mutations on Xp22.3, ocular albinism (OA1;OMIM 300500), affects males because of X-linked inheritance; 85to 90% of obligate carriers show pigmentary mosaicism in thefundi, representing the lyonization effect (X-inactivation), al-though there are no functional sequelae for them. Other types ofalbinism occur more infrequently, including those associated withsystemic manifestations, such as Hermansky-Pudlak syndrome(OMIM 203300; bleeding disorder due to absence of dense bodies

in platelets) and Chediak Higashi syndrome (OMIM 214500;immunodeficiency and neurologic problems). The prevalence ofalbinism in the United States is estimated to be 1 in 18,000.2 Table1 summarizes the genes responsible for albinism. For availabletesting for mutations, the reader is referred to www.genetests.org.

CLINICAL FEATURES OF ALBINISMCutaneous Findings

The cutaneous phenotype often permits the clinical diagnosis tobe made, although gene testing is sometimes required to specify thetype of albinism.1,3 However, foveal hypoplasia is common to alltypes of albinism, even though a rudimentary annular reflex hasbeen described in a few patients with better visual acuity.4,5 Sib-lings with albinism can show variable expression in visual functionand clinical phenotype,68 suggesting that other genes modify theclassical phenotype.9 Ocular findings do not allow one to deter-mine the type of albinism.

Individuals with OCA1 typically have white hair at birth. Some with a leaky mutation (OCA1B) will develop some melaninpigment in their lashes and hair over time, whereas others withOCA1A will fail to show any melanin pigment in their hair, skin,or eyes during their lifetimes.2 Those with OCA2 are typically

born with blond or red hair.2 Individuals with OCA1 and individ-

*MD

Departments of Ophthalmology and Pediatrics, University of Minnesota,

Minneapolis, Minnesota.

1040-5488/09/8606-0659/0 VOL. 86, NO. 6, PP. 659662

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Copyright 2009 American Academy of Optometry

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uals with OCA2 both have pale skin at birth. The phenotype andthe normal presence of an immature fovea at birth can delay diag-nosis, particularly, in families of European descent in whom re-duced melanin pigment in the skin, hair, and eyes is common.However, examination with the slit lamp biomicroscope will showtransillumination of the irides in those with albinism, and rarely isany pigment found at the level of the retinal pigment epithelium withcareful examination of the fundi in an individual with albinism.

Delayed Visual MaturationDelayed visual maturation has been reported in albinism.1015

It is not unusual for parents of an infant with albinism to note poorfixation on faces and objects and a delay in visual develop-ment.15,16 Nystagmus typically develops by 6 to 8 weeks of age. Ifthe phenotype of albinism is not recognized, patients may un-dergo neurologic examination, including magnetic resonanceimaging of the brain, before the diagnosis of albinism, with noabnormalities being detected.16 In fact, neurodevelopment wascarefully measured in 78 children with albinism from ages 4 to 18years and was generally felt to be normal, despite reduced visualacuity.17 However, an increased prevalence of attention deficit and

hyperactivity disorder was found in this prospective study.

Ocular Findings

As infants with albinism develop a fixation response, additionalfindings may be noted. Nystagmus is initially slow and has a largeamplitude, but the amplitude typically decreases within the firstyear of life. One study found that, with monocular fixation on alight, 99.6% of patients had a corneal light reflex deviated nasal tothe center of the pupil, known as a positive angle kappa.18 Prismand alternate cover test at a more rapid rate than usual (to diminisheffect of increased nystagmus amplitude with monocular occlu-sion) often discloses strabismus. Because of the positive anglekappa, an esotropia may be masked or appear diminished inamount on causal gaze, compared with the measured deviation,whereas an exotropia may appear larger than measured. Even in-dividuals with albinism who are orthophoric seem to have a smallexotropia, causing parents to report that the child does not lookdirectly at them. A study of 178 individuals with albinism showeda mean exoshift of 17.11 prism diopters because of the presence ofa positive angle kappa when prism and alternate cover measure-ments were compared with Krimsky assessment of binocularalignment.18

Other ocular findings in albinism are iris transillumination andabsent or poor foveal development. Iris transillumination is bestperformed in a dark room after the examiner has become adaptedto the darkness. The tonometer platform is rotated 90 to avoidhaving it touchthe childs chest, and a small, bright light is directedthrough the pupil while the examiner fixates on the iris. Theamount of iris transillumination can vary and a grading scheme hasbeen described: grade 1, punctate areas of transillumination, indi-cating that a marked amount of pigment is present in the posterioriris epithelium; grade 2, moderate iris pigment; grade 3, minimaliris pigment; and grade 4, full transillumination of the iris becauseof the absence of melanin pigment.19 Examination of the fundi

typically shows that foveal development is absent. A few patientswith albinism, who have vision 20/50 or better, have some rudi-mentary foveal development, and some thinning of the retina inthe foveal area has been demonstrated with optical coherence to-mography.4,5,20 The appearance of the macula has been graded asfollows: grade 1, choroidal vessels easily seen in macula; grade 2,choroidal vessels less distinctly seen because of translucent retinalpigment epithelium; and grade 3, opaque macula so that choroidalvessels are not visible.19 These grading scales forthe iris and maculacan be useful in clinical studies to more precisely describe the studypopulation because these characteristically persist over time. Inaddition, careful inspection can show granular melanin pigment in

the macula in a few patients with albinism and occasionally finelygranular pigment has been identified beyond the macula. Thepresence of melanin pigment in the macula correlates with bettervisual acuity.15

Central Nervous System Findings

Pattern visual-evoked potentials performed with monocularvisual stimulation demonstrate the excessive retinostriate decussa-tion that is characteristic of albinism.21 In individuals with a ques-tionable phenotype for albinism, the visual-evoked potentials canbe useful in identifying those with the disorder before proceeding

with more expensive gene testing. This abnormal decussation may

TABLE 1.Molecular classification of albinism

Responsible gene Gene location

Oculocutaneousalbinism (OCA)

OCA1 Tyrosinase 11q14-q21OCA2 Pgene 15q

OCA3 TYRP1a 9q23OCA4 SLC45A2b 5p

Hermansky-Pudlaksyndrome (HPS)

HPS1 HPS1 10q23.1-q23.3HPS2 AP3B1 5q14.1HPS3 HPS3 3q24HPS4 HPS4 22q11.2-q12.2HPS5 HPS5 11p15-p13HPS6 HPS6 10q24.3HPS7 DTNBP1c 6p22.3HPS 8 BLOC1S3 19q13

Chdiak Higashisyndrome (CHS)

CHS LYSTd 1q42.1-q42.2

Ocular albinism(OA)e

OA1 GPR143 Xp22.3

aTyrosinase-related protein 1.bAlso known as MATP gene, encoding membrane-associated

transporter protein.cDysbindin protein.dLysosomal trafficking regulator.e

Other types of OA have been shown to represent OCA.

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account for absent stereoacuity that is often found in albinism. Astudy of 45 individuals with albinism and strabismus 10 prismdiopters identified 19 with stereoacuity measured with the Titmusvectrograph (Stereo Optical Co., Chicago, IL).22 These individu-als had significantly better visual acuity, more pigment in their iris,reduced or absent nystagmus, and more frequently had melaninpigment identified in their maculae and the development of arudimentary foveal reflex when compared with those without mea-

surable stereoacuity.

TREATMENT OF ALBINISMNystagmus

Nystagmus in albinism is typically pendular in nature. The am-plitude of nystagmus diminishes as the child matures and in somecases may be detected clinically only as latent nystagmus withmonocular occlusion in older children and adults. Patients typi-cally report that nystagmus becomes more noticeable with fatigueand illness. These factors often confound the results of any treat-ment for nystagmus in albinism. Often patients develop an anom-

alous head posture to damp the nystagmus, referred to as the nullpoint, where visual acuity is usually improved. When the headposture is sufficiently large and stable in amount, consideration canbe given to extraocular muscle surgery in an attempt to transfer thenull point to a position closer to primary gaze (Kestenbaum-Anderson procedure).23,24Another surgical procedure, retroequa-torial recession of the horizontal rectus muscles, has been describedto improve visual acuity in patients with nystagmus due to manyetiologies.25,26 Most recently, tenotomy of the horizontal rectusmuscles with reattachment at the original insertion has been intro-duced to improve visual acuity and calculated acuity functionbased on the proposal that the dynamics of the proprioceptive loop

are altered.

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A similar mechanism might exist for the previouslydescribed surgeries in which the muscles are either recessed orresected. Based on cumulative results in the literature, slightlymore than half of individuals with albinism undergoing any ofthese procedures will experience up to one line of improvement inmeasured visual acuity, in addition to alterations in the nystagmuswaveform.27,28 The reason for not recording better postsurgicalvisual acuity in those with albinism is likely due to the associatedanatomic abnormalities. However, even one line improvement invisual acuity may be sufficient to allow some individuals with al-binism to obtain a drivers license so surgery should at least bediscussed with the patient, in addition to other potential methodsto improve visual function.

RECENT FINDINGS IN ALBINISM

Before the clinical use of the Teller Acuity Cards14,29 (TAC;Vistech Consultants, Dayton, OH), measurement of visual acuityin a child with albinism was often limited to the ability to fix andfollow a moving target. With the TAC, resolution acuity could bemeasured. When 14 adults with albinism had resolution acuitymeasured with the TAC presented horizontally and vertically, it was found that vertical presentation (horizontal orientation ofgrating) yielded significantly better vision than when measuredwith standard horizontal presentation of the cards, likely due to the

predominantly horizontal character of the nystagmus.30 Infants

with albinism who are beginning to learn to fixate will typicallyrespond more readily to vertical presentation of the cards. How-ever, as children mature, standard horizontal presentation of theTAC is most often used. Because of the presence of increasednystagmus amplitude with monocular occlusion, monocular grat-ing acuity is frequently worse than binocular grating acuity.

Parents often ask how impaired their childs vision is whenvision is measured with the TAC and what their childs vision will

be when the children are older. A cross-sectional study of 64 chil-dren with albinism showed that visual acuity measured with theTAC was 2.3, 2.1, and 1.7 octaves lower than norms at ages 1, 2,and 3 years, respectively.31 Another study of children with albi-nism compared grating acuity measured with the TAC at ages 1(n 30),2 (n 29), and 3 years (n 19) with recognition acuitymeasured at ages 4 to 6 years.32 In this study, the mean binoculargrating acuity was 2.0, 1.9, and 1.5 octaves below norms at ages 1,2, and 3 years, respectively. Grating acuity at ages 1, 2, and 3 yearscorrelated moderately with recognition acuity at ages 4 to 6. Thiscorrelation improved when grating and recognition acuities wereanalyzed in a subgroup of nine patients who were followed up

longitudinally. Binocular grating acuity in both the subgroup andthe larger group at ages 1 and 2 was significantly worse than rec-ognition acuity, but was not significantly different from binocularletter acuity at age 3.

Recognition visual acuity among persons with albinism variesfrom 20/20 to 20/400, but is commonly close to 20/80. Fovealhypoplasia, nystagmus, and refractive errors contribute to reducedacuity.33A prospective evaluation of 35 individuals with albinism(median age 9.5 years) who had received glasses (spherical equiva-lent from 9.75 D to 8.88 D) had a mean uncorrected visualacuity of 20/107.6 at 6 m, improving to 20/80.9 with glasses.34

Mean uncorrected near acuity was 20/41, improving to 20/28.4

with correction. In addition, with glasses, mean strabismus im-proved from 10 to 7.2 prism diopters at distance, and from 14 to10.8 prism diopters at near. Compliance with wearing refractivecorrection was generally good, despite the absence of normal cor-rected visual acuity. Guidelines for prescribing glasses in childrenwith albinism are given in Table 2.

TABLE 2.Guidelines for prescribing glasses in young childrenwith albinisma34

Children 6 months to 2 yr of ageMyopia 3.50 DHyperopia 3.00 DAstigmatism 3.00 D

Children older than 2 yr

Myopia 2.50 DHyperopia 2.00 DAstigmatism 2.00 D

aRefraction is made after cycloplegia appropriate for age.Please note that these are minimal guidelines for glasses forrefractive error meeting the above criteria in at least one eye, andthat, in some cases, glasses may be prescribed for a lesser amount

of ametropia.

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SUMMARY

In summary, patients with albinism have delayed visual devel-opment that can be monitored by measuring grating acuity. Cy-cloplegic refraction can determine refractive errors that shouldprompt consideration of glasses. A spectrum of structure and func-tion exists in albinism. Examination may disclose absence of nys-tagmus, measurable stereopsis, melanin pigment in the macula,and presence of a rudimentary annular reflex in the macula thattend to be associated with better vision than when these findingsare absent. As research progresses, other methods of improvingvisual acuity in children and adults may emerge.

ACKNOWLEDGMENTS

I gratefully acknowledge the constant encouragement and support of my friendand colleague, Dr. Velma Dobson, during this study of visual development inalbinism.

This work was supported, in part, by an unrestricted grant from Researchfor the Prevention of Blindness, New York, NY.

Received September 3, 2008; accepted December 11, 2008.

REFERENCES

1. Summers CG, Oetting WS, King RA. Diagnosis of oculocutaneousalbinism with molecular analysis. Am J Ophthalmol 1996;121:7246.

2. King RA, Oetting WS, Summers CG, Creel DJ, Hearing VJ. Abnor-malities of pigmentation. In: Rimoin DL, Connor JM, Pyeritz RE,Korf BR, eds. Emery and Rimoins Principles and Practice of MedicalGenetics, 5th ed. Philadelphia: Churchill Livingstone Elsevier; 2007:3380427.

3. King RA, Pietsch J, Fryer JP, Savage S, Brott MJ, Russell-Eggitt I,Summers CG, Oetting WS. Tyrosinase gene mutations in oculocu-taneous albinism 1 (OCA1): definition of the phenotype. Hum

Genet 2003;113:50213.4. Harvey PS, King RA,Summers CG.Spectrum of foveal development

in albinism detected with optical coherence tomography. J AAPOS2006;10:23742.

5. Seo JH, Yu YS, Kim JH, Choung HK, Heo JW, Kim SJ. Correlationof visual acuity with foveal hypoplasia grading by optical coherencetomography in albinism. Ophthalmology 2007;114:154751.

6. Summers CG, Creel D, Townsend D, King RA. Variable expressionof vision in sibs with albinism. Am J Med Genet 1991;40:32731.

7. Castronuovo S, Simon JW, Kandel GL, Morier A, Wolf B, WitkopCJ, Jenkins PL. Variable expression of albinism within a single kin-dred. Am J Ophthalmol 1991;111:41926.

8. Cheong PY, King RA, Bateman JB. Oculocutaneous albinism: vari-

able expressivity of nystagmus in a sibship. J Pediatr OphthalmolStrabismus 1992;29:1858.

9. King RA, Willaert RK, Schmidt RM, Pietsch J, Savage S, Brott MJ,Fryer JP, Summers CG, Oetting WS. MC1R mutations modify theclassic phenotype of oculocutaneous albinism type 2 (OCA2). Am JHum Genet 2003;73:63845.

10. Jacobson SG, Mohindra I, Held R, Dryja TP, Albert DM. Visualacuity development in tyrosinase negative oculocutaneous albinism.Doc Ophthalmol 1984;56:33744.

11. Fielder AR, Russell-Eggitt IR, Dodd KL, Mellor DH. Delayed visualmaturation. Trans Ophthalmol Soc UK 1985;104(Pt 6):65361.

12. Birch E, Hale L, Stager D, Fuller D, Birch D. Operant acuity oftoddlers and developmentally delayed children with low vision.

J Pediatr Ophthalmol Strabismus 1987;24:649.

13. Tresidder J, Fielder AR, Nicholson J. Delayed visual maturation:ophthalmic and neurodevelopmental aspects. Dev Med ChildNeurol1990;32:87281.

14. Fielder AR,Dobson V, Moseley MJ, Mayer DL. Preferential looking:clinical lessons. Ophthalmic Paediatr Genet 1992;13:10110.

15. Summers CG. Vision in albinism. Trans Am Ophthalmol Soc 1996;94:1095155.

16. Oetting WS, Summers CG, King RA. Albinism and the associatedocular defects. Metab Pediatr Syst Ophthalmol 1994;17:59.

17. Kutzbach BR, Summers CG, Holleschau AM, MacDonald JT. Neu-rodevelopment in children with albinism. Ophthalmology 2008;115:18058.

18. Merrill KS, Lavoie JD, King RA, Summers CG. Positive angle kappain albinism. J AAPOS 2004;8:2379.

19. Summers CG, Knobloch WH, Witkop CJ Jr, King RA. Hermansky-Pudlak syndrome. Ophthalmic findings. Ophthalmology 1988;95:54554.

20. Izquierdo NJ, Emanuelli A, Izquierdo JC, Garcia M, Cadilla C,Berrocal MH. Foveal thickness and macular volume in patients withoculocutaneous albinism. Retina 2007;27:122730.

21. Creel DJ, Summers CG, King RA. Visual anomalies associated withalbinism. Ophthalmic Paediatr Genet 1990;11:193200.

22. LeeKA, King RA,Summers CG.Stereopsis in patients with albinism:clinical correlates. J AAPOS 2001;5:98104.

23. Kestenbaum A. [New operation for nystagmus]. Bull Soc OphtalmolFr 1953;6:599602.

24. Anderson JR. Causes and treatment of congenital eccentric nystag-mus. Br J Ophthalmol 1953;37:26781.

25. Helveston EM,Ellis FD, Plager DA. Large recession of the horizontalrecti for treatment of nystagmus. Ophthalmology 1991;98:13025.

26. von Noorden GK, Sprunger DT. Large rectus muscle recessions forthe treatment of congenital nystagmus. Arch Ophthalmol 1991;109:2214.

27. Hertle RW, Anninger W, Yang D, Shatnawi R, Hill VM. Effects ofextraocular muscle surgery on 15 patients with oculo-cutaneous albi-nism (OCA) and infantile nystagmus syndrome (INS). Am J Oph-thalmol 2004;138:97887.

28. Egbert JE, Anderson JH, Summers CG. Increased duration of lowretinal slip velocities following retroequatorial placement of horizon-tal recti. J Pediatr Ophthalmol Strabismus 1995;32:35963.

29. Sebris SL, Dobson V, MacDonald MA, Teller DY. Acuity cards forvisual acuity assessment of infants and children in clinical settings.Clin Vision Sci 1987;2:4558.

30. Meiusi RS, Lavoie JD, Summers CG. The effect of grating orienta-tion on resolution acuity in patients with nystagmus. J Pediatr Oph-thalmol Strabismus 1993;30:25961.

31. Whang SJ, King RA, Summers CG. Grating acuity in albinism in thefirst three years of life. J AAPOS 2002;6:3936.

32. Louwagie CR, Jensen AA, Christoff A, Holleschau AM, King RA,

Summers CG. Correlation of grating acuity with letter recognitionacuity in children with albinism. J AAPOS 2006;10:16872.

33. Summers CG. Causes of abnormal refractive errors in children. AmOrthop J 2006;56:10815.

34. Anderson J, Lavoie J, Merrill K, King RA, Summers CG. Efficacy ofspectacles in persons with albinism. J AAPOS 2004;8:51520.

C. Gail Summers

University of MinnesotaDepartment of Ophthalmology, MMC 493

420 Delaware St. SEMinneapolis, MN 55455

e-mail: [email protected]

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