Arch Dis Child 1999;80:565–569 565

CURRENT TOPIC Arch Dis Child: first published as 10.1136/adc.80.6.565 on 1 June 1999. Downloaded from

Oculocutaneous

S Biswas, I C Lloyd

Oculocutaneous albinism (OCA) is a heterog- OCA1a,12 where enzyme activity is reduced enous group of autosomal recessive disorders rather than abolished. Similarly, OCA1-MP aVecting synthesis, characterised by may be caused by a that reduces congenital of the skin, , expression of the .13 Individuals and eyes. Reduced visual acuity, , aVected by OCA1b and OCA1-MP accumu- iris transillumination, foveal hypoplasia, nys- late some pigment in the hair and irides with tagmus, and an abnormal decussation of nerve time. Pigment accumulation occurs to a lesser fibres at the optic chiasm are common extent in OCA1-MP than in OCA1b. Many features.1 (OA) shares the individuals with OCA1 are compound hetero- ocular features of OCA including the increased zygotes inheriting diVerent allelic for nerve fibre decussation at the optic chiasm. the tyrosinase gene from each parent. The ocu- Patients aVected by OA are often fairer in lar phenotypes among these individuals with complexion than their unaVected siblings and OCA1 are similar. have macromelanosomes present in the skin. In general, the skin hypopigmentation seen in OA Type II OCA (OCA2) is not as marked as that seen in OCA. Tyrosinase positive OCA (OCA2) is caused by mutations at the P on Melanogenesis 15q11.2–q12.14 However, the role of the P pro- The tyrosinase gene regulates ocular and cuta- tein in humans is unknown. The phenotypic neous melanin synthesis. Tyrosinase catalyses expression of this disorder varies according to the first two steps in melanin synthesis. These the racial background of the individual. Pig- are the oxidation of 1- to 3,4- mentation increases with age, resulting in the dihydroxyphenylalanine (DOPA) and its sub- appearance of pigmented naevi, , or http://adc.bmj.com/ sequent conversion to dopaquinone. Later lentigenes. Although hair colour may darken, steps in the melanin pathway, resulting in the formation of insoluble eumelanin, also involve tyrosinase. Phaeomelanin, a red-yellow pig- ment, is produced via an alternative pathway entered into by dopaquinone. Tyrosinase

contains two copper atom binding sites form- on September 29, 2021 by guest. Protected copyright. ing a coupled, binuclear complex.2 Two related , tyrosinase related proteins 1 and 2 (TRP-1 and TRP-2),34both contain structures similar to tyrosinase and form a tyrosinase enzyme “superfamily” involved in eumelanin production. TRP-1 regulates eumelanin pro- duction and has catalytic activity.56 The tyrosinase gene is located on chromo- some 11q14–q21.78 The TRP-1 and TRP-2 map to 9p239 and to 13q32,10 respec- tively.

Type I OCA (OCA1) Lesions aVecting the tyrosinase gene can result in complete or partial inhibition of tyrosinase. These give rise to the various subtypes of tyro- Department of Ophthalmology, sinase negative OCA (OCA1) that have been 11 Manchester Royal Eye characterised. These include OCA1a (fig 1), Hospital, Oxford Road, OCA1b (yellow OCA), minimal pigment albi- Manchester M13, UK nism (OCA1-MP) and temperature dependent S Biswas albinism (OCA1-TP). Where there is no I C Lloyd residual function within tyrosinase, as in Figure 1 An infant with type-1a. The infant has a “snowy-white” appearance with complete Correspondence to: OCA1a, full expression of the albino pheno- absence of skin and hair pigmentation. (Photograph Dr Lloyd. type occurs.11 OCA1b is an allelic variant of reproduced with the permission of the child’s parents.) 566 Biswas, Lloyd

the skin does not tan. OCA1 can be diYcult to studied. Midline chiasmal cells influence the distinguish from OCA2 when there is partial diVerential growth of crossed and uncrossed Arch Dis Child: first published as 10.1136/adc.80.6.565 on 1 June 1999. Downloaded from tyrosinase enzyme activity. A positive hairbulb retinal ganglion cells.19 Cues present within incubation test can help diagnose OCA2,15 chiasmal cells are involved in the pathway although high false negative rates make this test choice of retinofugal fibres. However, no unreliable. Some cases of autosomal recessive diVerence has been observed in the ability of ocular albinism may in fact be individuals with chiasmal cells to influence the growth of OCA2 who are compound heterozygotes for P ipsilateral retinal ganglion cell axons of albino gene mutations.16 compared with pigmented mice.20 In the Prader-Willi and Angelman syn- The site of influence of the albino mutation dromes the incidence of OCA2 is 1%. This on the fate of retinal ganglion cell axons is likely high incidence may be the result of hemizygos- to be the retina. There are decreased numbers 16 ity for inherited mutant of the P gene. of ipsilaterally projecting retinal ganglion cells in albino retinas. In animals with a sharp verti- Type III OCA (OCA3) cal naso-temporal divide in retinal ganglion cell Brown OCA (OCA3) arises from a defect in projections, there is a shift in the line of retinal 11 TRP-1. The phenotype, described only in decussation 20° temporal to its normal midline African and African-American individuals, is position in albino retinas.21 It has been characterised by light brown skin and hair, suggested that lack of melanin, or a related moderate tanning ability, blue-grey irides, and agent, alters the normal spatio-temporal se- transilluminable irides. Tyrosinase is found in quence of retinal ganglion cell production. The normal amounts in intact cells, but it exhibits influence of retinal pigment epithelium over reduced tyrosine hydroxylase activity, which retinal development was reviewed by JeVery.22 appears to be the consequence of absent He suggested that normal development of the TRP-1.17 Rufous oculocutaneous albinism neural retina occurs via a series of overlapping (ROCA), also ascribed to TRP-1 mutations, is waves operating over a roughly “centre to characterised by bright copper red skin and peripheral” gradient. In albinos, the normal hair and iris pigment dilution. Visual pathway spatio-temporal sequences of cell generation anomalies (vide infra) are not described in within the ganglion cell layer are delayed. The ROCA. time scale of this delay (in the order of two days) could result in decreased generation of Hermansky-Pudlak and Chediak-Higashi ipsilaterally projecting ganglion cells. syndromes Both of these syndromes are multisystemic dis- Similarly, a disturbance in the spatio- orders associated with albinism and are an temporal sequence of retinal development important part of the diVerential diagnosis. might disrupt the normal gradient of matura- Abnormal synthesis of the pigmented melano- tion of the retina. Consequently, this might result in underdevelopment of the central

some as well as abnormal organellogenesis http://adc.bmj.com/ underscores these disorders. Hermansky- retina and thinning of the inner and outer 22 Pudlak syndrome (chromosome 10q23.1– nuclear layers within this region. Melanin is q23.3) has a variable pigment phenotype, but normally absent in the retinal pigment epithe- aVected individuals do not tan. The triad of lium during these early developmental stages, albinism, abnormal platelet aggregation, and although tyrosinase is present. DOPA or its abnormal tissue ceroid accumulation charac- breakdown product seems the likely active terises the disorder.17 Chediak-Higashi syn- agent capable of influencing retinal develop-

drome (chromosome 1q43) is characterised by ment. Lack of DOPA in the albino retina might on September 29, 2021 by guest. Protected copyright. albinism, increased susceptibility to infection result in excessive mitosis. Excessive cell death as a result of dysfunctional leucocyte degranu- is a sequela of this and results in a thinner lation, and large eosinophilic, peroxidase posi- retina with a reduced number of rod photore- tive inclusion bodies in peripheral blood.17 ceptors. Cone photoreceptor numbers are Patients with both of these disorders have ocu- unaVected, but because they are generated at lar features that fit the diagnostic criteria for about the same time as the aVected retinal albinism. ganglion cells, and at an earlier stage than rods, this suggests that the albino mutation is Ocular features operating in a cell specific manner rather than The ocular features of albinism are similar in a particular time frame.22 The influence of among the subgroups but may vary in degree. DOPA, and lack of it, on spatio-temporal Recent research has focused on developmental events in retinal development awaits further retinal abnormalities that include underdevel- investigation. opment of the central retina, reduction in rod Misrouting of retinofugal fibres, detected by photoreceptor and ganglion cell numbers, and visual evoked potential (VEP) studies,23 con- a relatively small uncrossed retinofugal path- firms the diagnosis of albinism. In albinism the way. VEP detected at the occiput is of the opposite Melanin is transiently present in the retinal polarity when comparing each eye (crossed part of the developing optic stalk in many asymmetry). Crossed asymmetry is a universal mammals. However, the possibility that it finding in all forms of albinism (except influences the decussation pattern of develop- ROCA). Various test paradigms are used ing retinofugal fibres has been discounted.18 according to age.24 VEPs can distinguish The influence of the optic chiasm on retinofu- albinoid individuals and other equivocal cases gal fibre decussation patterns has also been from true albinos. Oculocutaneous albinism 567

Reported VEP crossed asymmetry in cases of Prader-Willi syndrome has been disputed.25 Key messages Arch Dis Child: first published as 10.1136/adc.80.6.565 on 1 June 1999. Downloaded from It has been argued that these patients may have + Oculocutaneous albinism comprises a had albinism.26 Asymmetric VEPs have also heterogenous group of disorders of mela- been reported in conditions other than albi- nin metabolism resulting in a variable nism such as congenital idiopathic cutaneous phenotype that ranges from ,27 dissociated vertical deviation,28 mild to severe . Similarly, and congenital stationary night blindness type the ocular features generally vary in II.29 This would reduce the value of the VEP as severity with degree of depigmentation. a diagnostic tool, but other VEP studies have Visual evoked potential crossed asymme- not confirmed the presence of crossed asym- try signifies an abnormal decussation of metry in these conditions.30 31 In addition, no nerve fibres at the optic chiasm that is the histological verification of visual pathway hallmark of the disorder misrouting has ever been provided. Moreover, + Molecular analysis of gene sequences VEP asymmetry reported in dissociated verti- may be an accurate tool for diagnosis and cal deviation and congenital idiopathic nystag- reveals that compound heterozygosity is mus might just be revealing a variation in common in all forms of oculocutaneous hemispheric lateralisation rather than specific albinism crossed asymmetry. The contrasting language, + Developmental events in the albino retina diVerent recording techniques, diVerent re- might be aVected by abnormal melanin sponse criteria, and diVerent stimuli used in metabolism and could underlie the in- various studies could also lead to confusion creased decussation at the optic chiasm, regarding the specificity of VEP asymmetry.32 as well as the underdevelopment of the Foveal hypoplasia (fig 2), like visual pathway central retina misrouting, is said to be a consistent diagnostic + Abnormal melanin metabolism might be feature of albinism.24 Other disorders that may responsible for other neurodevelopmen- feature foveal hypoplasia include aniridia, tal defects that underlie delayed visual achromatopsia, and isolated foveal maturation and nystagmus commonly hypoplasia.33 The underlying cause of albinism seen in albinism may arise from the same events that result in the visual pathway anomaly. Histopathological is reached in albinism where acuity fails to studies of foveal hypoplasia in albinism demon- improve further because of factors such as strate an absent foveal pit on light microscopy.34 foveal hypoplasia and increased light scatter.40 Although abnormal vessels have been noted Surgical attempts to reduce nystagmus, such coursing over the central macula these may not as the Kestenbaum-Anderson procedure and aVect vision.35 In general, visual acuity follows its variants, have been warned against in the degree of pigmentation. More than 60% of albinism because of the higher prevalence of

patients with OCA2 have a visual acuity better http://adc.bmj.com/ periodic alternating nystagmus, with its accom- than 6/60, whereas less than 40% of patients panying shifting null zone. A more successful with OCA1 have a best visual acuity better than approach involves large retroequatorial reces- 6/60.36 Visual acuity ranges from 6/18 to 6/48 sions of the horizontal recti muscles that stabi- in brown OCA,37 but acuities of 6/9 or better lise the eye position and increase foveation are seen in ROCA, despite the presence of nys- times.41 tagmus. Because 14% of all albinos have Visual pathway anomaly might also be refractive errors greater than 10 dioptres,36 cor- responsible for the increased incidence of stra- rection of this might result in a modest on September 29, 2021 by guest. Protected copyright. bismus seen in albinism. It is aggravated by improvement in vision. decreased visual acuity and increased light Nystagmus is a consistent finding in all scattering. Although fine grade stereoscopic forms of albinism although, occasionally, indi- vision is absent, gross random dot stereopsis viduals exist with albinism but without has been demonstrated in some albinos.42 The nystagmus.24 It usually appears in the first 2 or anatomical substrate for this is uncertain, but 3 months of life and often lessens with age. gross stereopsis might be supported by either Nystagmus has been well characterised in albi- nos and factors that might be responsible for it include anomalous visual pathways and foveal hypoplasia.38 It is usually in the horizontal plane but mixed patterns also exist (torsional or vertical). A rare form of nystagmus, periodic alternating nystagmus, is a conjugate horizon- tal jerk nystagmus that periodically reverses its direction. It might have a higher prevalence among albinos.39 Here, the “null zone”, the position of reduced amplitude of nystagmus, may shift periodically and unpredictably. Near vision is generally better in albinism, as a result of dampening of nystagmus on conver- gence. In general, visual acuity improves with increasing percentage of time during the Figure 2 Fundus photograph of an albino retina demonstrating pallor of the retinal pigment epithelium with nystagmus cycle, where the eye movement prominence of the choroidal vasculature, fovea hypoplasia, velocity is < 10°/second. However, a threshold and retinal vessels coursing over the central macula. 568 Biswas, Lloyd

projections from the temporal retinal periph- for delayed visual maturation. Delay in estab- ery, whose fibres remain correctly routed, or via lishment of synapses in the visual cortex seems Arch Dis Child: first published as 10.1136/adc.80.6.565 on 1 June 1999. Downloaded from intercortical and intracortical communications unlikely because pattern VEP results in pa- via the corpus callosum.42 Whether this serves tients with delayed visual maturation are age any useful function is debatable. “Size con- appropriate, reflecting appropriate cortical stancy” is an attribute of stereopsis that enables function. Delay in the development of visual an individual, under binocular viewing condi- association areas that mediate visual attention tions, to perceive an object to be of constant has also been proposed as a possible cause.45 size despite varying distances between object OCA remains a much stigmatised condition, and subject. By assessing whether stereopsis particularly in countries with a high incidence. can support “size constancy” in albinos, three However, with appropriate ophthalmic care, groups of albinos have been classified: (1) those including refractive correction and the provi- with no stereopsis, (2) those with measurable sion of tinted spectacles and low vision aids, stereopsis in whom it serves no function, and individuals may attain reasonable visual func- (3) those with stereopsis in whom it is tion. Albinos perform equally well compared 43 functional. with control subjects in intelligence tests. This Infants with albinism commonly display might mean that with improved parental and visual inattention for the first few months after teacher understanding, and early recognition birth, often followed by an improvement at of any specific educational problems, these about 3–8 months of age. This form of delayed children might achieve the same performance visual maturation has been classified as type 44 levels as their unaVected counterparts, often III. This distinguishes it from type Ia delayed within mainstream schooling.49 visual maturation where no ocular or neuro- logical abnormality exists, type Ib where a perinatal intercurrent illness occurs, and type 1 Guillery RW, Okoro AN, Witkop CJ. Abnormal visual path- II where widespread neurological abnormali- ways in the brain of a human albino. Brain Res 1975;96:373–7. ties are present. The subtypes of delayed visual 2 Kwon BS, Haq AK Pomerantz SH, Halaban R. Isolation maturation behave diVerently in terms of the and sequence of a cDNA clone for human tyrosinase that maps at the mouse c-albino locus. Proc Natl Acad Sci USA onset and rate of visual recovery. Type III 1987;84:7473–7. delayed visual maturation behaves intermedi- 3 Cohen T, Muller RM, Tomita Y, Shibahara S. Nucleotide sequence of the cDNA encoding human tyrosinase-related ately between types I and II. In type III delayed . Nucleic Acids Res 1990;18:2807–8. visual maturation the final visual acuity is dic- 4 Jackson IJ, Chambers DM, Tsukamoto K, et al. A second tyrosinase-related protein, TRP-2, maps to and is mutated tated by the severity of the underlying ocular at the mouse slaty locus. EMBO J 1992;11:527–35. disease.44 Lambert et al found no significant 5 Halaban R, Moellmann G. Murine and human b locus pig- mentation genes encode a glycoprotein (gp75) with diVerence between flash and pattern VEPs in catalase activity. Proc Natl Acad Sci USA 1990;87:4809–13. infants with type I delayed visual maturation 6 Winder A, Kobayashi T, Tsukamoto K, et al. The tyrosinase gene family: interactions of melanogenic proteins to and age matched normal controls. This sug- regulate melanogenesis. Cell Mol Biol Res 1994;40:613–26. 7 Giebel LB, Strunk KM, Spritz RA. Organisation and nucle-

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