AAPOS Workshop

Albinism for the busy clinician

Alex V. Levin, MD, MHSc, and Eliza Stroh, MS, CGC
SUMMARY Albinism is a group of disorders characterized principally by its ophthalmic features with or without systemic manifestations. Persons with albinism manifest a wide variety of phenotypes and limited number of genotypes. Modern molecular genetics has encouraged a new classication and understanding of the subtypes of these disorders. In addition to the ocular and systemic manifestations, ophthalmologists must be familiar with the specic visual needs and psychological challenges of these individuals as well as those of their families. ( J AAPOS 2011;15:59-66)

he term albinism refers to disorders of reduced pigmentation compared with others of the same ethnic and racial backgrounds with characteristic ocular involvement. If there is little or no detectable loss of pigmentation of the skin and hair, the disorder is usually referred to as ocular albinism (OA). If there is hypopigmentation of the skin and hair, the condition is referred to as oculocutaneous albinism (OCA). Melanin is found in both the uveal melanocytes, derived from neural crest, and the retinal pigmented epithelium (RPE), derived from neuroectoderm. In both locations, melanin is found in the melanosomes, which are intracellular vesicles with the specic purpose of manufacturing and holding this pigment; therefore, appropriate pigmentation requires the presence of the host cell, proper formation of the melanosomes, and an adequate amount of melanin within the melanosomes. Both skin and iris color are caused by the number and size of melanosomes rather than the number of melanocytes. Melanin can also be found in the iris-pigmented posterior epithelium and phagocytic clump cells in the iris stroma. The retina is not pigmented except for the macular lutein, which is unrelated to albinism disorders. When viewing the fundus, one can see that pigmentation derives from the RPE as well as the underlying choroidal melanocytes. Albinism is widely distributed throughout the animal kingdom, affecting virtually every genus. Likewise, all races of Homo sapiens can be affected by albinism, although the phenotype may be more recognizable in more darkly pigmented races. Some ethnic groups (for example, those from Finland and Sweden) are so lightly pigmented that their appearance is distinctive, but the determination that albinism is present rests on the crossing of a threshold
See editorial on page 1.

that impairs ocular development. Some forms of albinism may be so mild that they appear to straddle this threshold between normal appearance and visual function and frank albinism.

Clinical Features
Perhaps the most common feature for persons with albinism is iris transillumination, which may range from a few specks to diffuse transillumination that is so great that one can easily see the outline of the lens edge behind the iris (Figure 1). Detection of subtle iris transillumination may require completely darkening the room, using a slit beam just wide enough to t into the patients pupil, and setting the slit lamp on high power. Although it has been our preference to keep the beam coaxial with the view of the examiner, who then scans the peripheral iris for transillumination, others may nd it easier to rotate and decenter the illumination so that it is no longer parfocal with the viewing portion of the slit lamp. Iris transillumination can occur in the presence of iris malformations unrelated to albinism and in neonates. Pathologic causes of iris transillumination in adults also include pseudoexfoliation and pigment dispersion syndrome. Other causes include X-linked recessive megalocornea, trauma, iris atrophy (eg, after herpes infection or uveitis) and Axenfeld-Rieger spectrum. Otherwise, iris transillumination, even in lightly pigmented ethnic groups, is usually abnormal. When present, in an otherwise-normal individual, the transillumination may indicate that the patient is a carrier of a hypomelanotic gene mutation. Albinoidism is a hypopigmentary disorder in which patients have iris transillumination and distinct oculocutaneous hypopigmentation. Albinoidism is an autosomaldominant condition, because a mutation in only 1 of the 2 gene copies is sufcient to cause disease. These patients have normal vision, normal retinal development, and no nystagmus. Albinoidism is rarely associated with other syndromes but is most often isolated. This might be considered a disorder that bridges the gap between lightly pigmented individuals and true albinism with macular hypoplasia.

Author afliations: Wills Eye Institute, Philadelphia, Pennsylvania Submitted March 6, 2010. Revision accepted October 3, 2010. Reprint requests: Alex V. Levin, MD, MHSc, Wills Eye Institute, Pediatric Ophthalmology and Ocular Genetics, 840 Walnut Street Philadelphia, Pennsylvania, 19107 (email: alevin@willseye.org). Copyright 2011 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 doi:10.1016/j.jaapos.2010.10.012

Journal of AAPOS

59

60

Levin and Stroh

Volume 15 Number 1 / February 2011

FIG 1. Marked iris transillumination.

Nystagmus is almost always present in persons with albinism, although rare cases do occur in which patients have other signs and symptoms of albinism without nystagmus. In early infancy, nystagmus has a large-amplitude, lowfrequency (triangular wave form) pattern that sometimes causes parents to think their infant is unable to xate on visual targets. With age, the nystagmus eventually matures into a pendular form followed later by a typical jerk nystagmus. Virtually any type of nystagmus is possible, including vertical and rotatory. Anomalous head positions may be observed. Although eye muscle surgery may be useful in reducing the nystagmus, the surgeon must inform the family that visual improvement will likely be limited by the degree of macular hypoplasia. Persons with albinism also have increased frequency of strabismus, refractive error, and amblyopia. Therefore, periodic screening (perhaps every 6 months for the rst 2 years of life and every year thereafter) should be encouraged. Macular hypoplasia (Figure 2) is the most vision limiting abnormality in patients with albinism. In the normal developing eye, pigmentation in the RPE is required for the induction of appropriate macular development. With increasing degrees of RPE hypopigmentation and corresponding macular hypoplasia, the vascular pattern of the posterior pole becomes less respectful of the distribution of the normal arcade. Anomalous vessels may be seen coursing near or through the location where the fovea should have been (Figure 2). Optical coherence tomography may be useful in documenting the presence of macular hypoplasia and will demonstrate an absence of the foveal pit and loss of the usual thinning of the retina in this area, although the nystagmus of albinism may prevent adequate optical coherence tomography imaging. Hypopigmentation of the fundus is particularly prominent in the midperipheral and peripheral retina where the examiner can see through the retina to the underline white sclera. Lutein pigments in the macula can be present because they are not related to the melanogenic pathways.

FIG 2. Macular hypoplasia. Note the multitude of retinal vessels coursing into what should be the foveal avascular zone. The fovea pit is absent. Note also the presence of optic nerve hypoplasia.

Macular hypoplasia can occur without albinism either as an isolated genetic disorder or in the presence of other syndromes such as aniridia. Another important ocular feature of albinism is the abnormal decussation of the visual pathways.1 In normal individuals, approximately 55% of optic nerve bers from each eye decussate to the contralateral side of the brain. In patients with albinism, there is abnormal decussation in which up to 75% to 85% of nerve bers decussate to the contralateral side. Although early studies claim that this pattern of abnormal decussation, detected by 3-lead visual evoked potential,2 was required for a diagnosis of albinism, it has since been recognized that patients with albinism may have normal visual pathway decussation.3 Presence of asymmetric decussation may be an important risk factor for the development of strabismus as stereopsis is usually moderately reduced. Knowing that a person has abnormal decussation by 3-lead visual-evoked potential may be useful in counseling patients and parents that the chance of achieving stable alignment after strabismus surgery may be lower than that in those individuals without abnormal decussation. The occurrence of abnormal decussation is illustrative of an important principle in developmental genetics: Certain genes are expressed only at certain times during development. There are groups of genes in humans that attract growing neurons and other genes that repel these growing neurons. Such developmental genes are important in the distribution of neurons throughout the brain and at the chiasm. Because of the hypopigmentation of RPE and ensuing macular hypoplasia, retinal ganglion cells are delayed in their development and growth to the chiasm. In patients with albinism, visual pathway neurons do not reach the chiasm until after the appropriate gene expression has ceased. As a result, abnormal decussation occurs.

Journal of AAPOS

Volume 15 Number 1 / February 2011

Levin and Stroh

61

Multiple intermediates tyrosinase tyrosinase

Pheomelanins

Tyrosine

DOPA

DOPAquinone

DOPAchrome

Multiple intermediates

Quinones

Eumelanins
FIG 3. The melanogenesis pathway.

Most patients with albinism have reduced visual acuity. The degree of visual compromise is worse in those patients with severe macular hypoplasia. Nystagmus, amblyopia, and uncorrected refractive error can also contribute to low vision. Photodysphoria can also be difcult for some patients in large part because of the scattering of light within the eye where it is not properly absorbed by melanin. This is the same phenomenon that results in the supranormal electroretinogram that is usually found in albinism. The optic nerves of patients with albinism may be small (Figure 2) or have a visually insignicant grayish appearance, particularly in infancy.

Pathophysiology
Although the intricacies of the biochemistry of melanogenesis are beyond the scope of this article, it should be noted that melanin can be subcategorized as either eumelanin or pheomelanin. Eumelanin pigments are the darker pigments (browns and blacks) that are also responsible for tanning. Pheomelanins are responsible for the blonde, orange, and reddish colorations we see in humans and animals. Eumelanins serve a protective function with regards to the ultraviolet rays of the sun. When pheomelanins are exposed to ultraviolet rays, free radicals are produced, which contribute to the development of cancer. In Africa, where albinism is not uncommon, skin cancer results in signicant morbidity for these patients. The bottleneck step in human melanogenesis is the conversion of tyrosine to dopa and Dopaquinone by tyrosinase (Figure 3). Tyrosinase is also responsible for the increase in iris pigmentation, which occurs during the rst 6 months

of life, when there is a physiologic up-regulation of tyrosinase activity. Multiple other enzymes are subsequently involved in forming eumelanin and pheomelanin. Impairment of any particular enzyme will potentially result in albinism phenotypes. If tyrosinase is decreased, but not completely inactive, the bottleneck step is closed and no eumelanin or pheomelanin are produced. If tyrosinase is downregulated but not completely inactive, there will be a preferential shunting to the pheomelanin pathway, giving the patient a yellow, orange, or reddish pigmentation rather than the stark white pigmentation seen in the skin and hair of patients who have no tyrosinase activity. As the disorder is autosomal recessive, pathologic mutation in one copy of a persons tyrosinase gene usually does not result in albinism. These patients may have small amounts of iris transillumination allowing the detection of the carrier state or they may have some degree of hypopigmentation. When both copies of the gene are affected, albinism may occur. Different mutations have a different effect on tyrosinase activity. If a patient has the same mutation in each copy of their gene, they are said to be homozygous. If each copy of the tyrosinase gene is mutated but the mutation in each copy is different, the patient is said to be compound heterozygous. It is the combination of mutations and their effect on the overall tyrosinase activity that lead to particular phenotypes.

Nomenclature
Historically, patients with albinism were divided into tyrosinase-negative OCA, tyrosinase-positive OCA, and ocular albinism in part based simply on their external

Journal of AAPOS

62

Levin and Stroh

Volume 15 Number 1 / February 2011

Table 1. Nomenclature for albinism (digenic disorders not included) Full name Tyrosine negative Yellow variant Minimal pigment Temperature sensitive Type 2 OCA Brown albinism Type 3 OCA Type 4 OCA Hermansky-Pudlak syndrome Chediak-Higashi syndrome X-linked ocular albinism Piebald trait Abbreviation OC1A OCA1B OCA1MP OCA1TS OCA2 BOCA OCA3 OCA4 HPS CHS OA1 PBT Type Gene/protein Locus OMIM* Inheritance AR AR AR AR AR AR AR AR XLr AD

OCA Tyrosinase 11q14-q21 203100 OCA Tyrosinase 11q14-q21 606952 OCA Tyrosinase 11q14-q21 606952 OCA Tyrosinase 11q14-q21 606952 OCA P gene 15q11.2-q12 203200 OCA P gene 15q11.2-q12 203200 OCA Tyrosinase related protein 9p23 203290 OCA Membrane associated transport protein 5p13.3 606574 OA, OCA multiple multiple 203300 OCA LYST 1q42.1-q42.2 214500 OA GPR143 Xp22.3 300500 not true albinism c-kit 8q11 172800

AD, autosomal dominant; AR, autosomal recessive; OA, ocular albinism; OCA, oculocutaneous albinism; XLr, X-linked recessive. *OMIM indicates Online Mendelian Inheritance in Man (http://www.ncbi.nlm.nih.gov/omim).

appearance. When a patient appeared to have no pigmentation, they were called tyrosinase negative. If the skin and hair appeared normal but ocular features were present, they were said to have ocular albinism. A small tuft of hair could be plucked from the scalp, including the hair roots, and then incubated with tyrosinase to see if microscopic evidence of pigmentation occurred. If so, the patients were thought to have tyrosinase activity. As molecular genetics evolved, it became clear that there was a very poor correlation between this categorization of phenotypes and the actual genotypes. Molecular genetics has thus led us to a gene based nomenclature for OCA and OA (Table 1).

Type 1 OCA (Tyrosinase-Related OCA)

Tyrosinase-related OCA is one of the most common forms of oculocutaneous albinism, with an incidence of 1 in 16,000-20,000 live births. The tyrosinase gene is located on the long arm of chromosome 11 (11q14.2). Because a mutation is required in each copy of the gene to cause albinism, the disorder is autosomal recessive. Type 1 OCA can be divided into 4 subtypes: type 1A OCA, type 1B OCA, type 1MP OCA, and type 1 TS OCA. Type 1A OCA is a truly tyrosinase-negative form of OCA. There is a null mutation in each copy of the tyrosinase gene, resulting in no melanin production.4 As a result, the phenotype is severe, with very fair complexion, white hair, marked iris transillumination, nystagmus, and poor visual acuity, often in the range of 20/200 to 20/400. These patients are at the greatest risk for skin cancer and have the greatest frequency of visual signs and symptoms. In the type 1B OCA version of tyrosinase-related OCA, the overall tyrosinase activity is decreased to approximately 7%, such that there is a preferential shunting of pigmentation into the pheomelanin pathway.5 This disorder is also known as the yellow variant. Patients may be born with a phenotype that is virtually indistinguishable from type 1A but, with time, the hair grows in with a typical whitetipped hair pattern that can eventually wind up as a blonde or even light brown in appearance.6 Vision is moderately to

severely reduced, and patients almost always have nystagmus and iris transillumination. Type 1MP OCA is the minimal pigment form of type 1 OCA, as a result of decreased but not absent tyrosinase activity. Hair color tends to be blonde. Patients may have skin nevi. Visual acuity is approximately 20/80-20/200, and there is variable iris transillumination.7 Type 1 TS OCA is the temperature-sensitive form of type 1 OCA, resulting from production of a tyrosinase protein with activity that varies according to temperature.8 In areas of the body that are naturally warmer, the tyrosinase activity is reduced, whereas the cooler areas of the body have normal tyrosinase function. As a result, these patients have dark hair on their arms, legs, and chest but white hair in their axilla, pubic area, and scalp (Figure 4). At birth and in infancy, these patients can be indistinguishable from type 1AOCA.

Type 2 OCA
This group of phenotypes is unrelated to tyrosinase activity. Rather, the molecular genetic defect is in the P gene located on the long arm of chromosome 15 (15q11.2-11.3).9 Patients may be compound heterozygotes or homozygotes, resulting in variable autosomal-recessive phenotypes. Autosomal-dominant phenotypes have also been rarely described. Nonpathogenetic polymorphisms in the P gene also play a major role in the determination of iris color in normal individuals. The P gene is important in melanosome function as it helps to regulate the inux of tyrosine as well as the internal environment of the melanosome. A dysfunctional melanosome will lead to hypopigmentation or albinism. There are a wide variety of phenotypes as a result of mutations in the P gene. Skin color can range from white to fair complexion, and hair color can be yellow, red, brown, or even black. The visual acuity is usually better than that seen in type 1A OCA. In some forms of P gene related disease, the vision defect can actually be quite mild. Likewise, nystagmus may be seen less frequently than it is in type 1A OCA. Type 2 OCA

Journal of AAPOS

Volume 15 Number 1 / February 2011

Levin and Stroh

63

FIG 4. Temperature-sensitive oculocutaneous albinism (OCA 1TS). The patient has white axillary hair (warmer) but dark hair on the forearms (cooler). Reprinted with permission from Levin AV, Wilson T, eds. The Hospital for Sick Childrens atlas of pediatric ophthalmology. Philadelphia, PA: Lippincott Williams and Wilkins; 2007.

can be indistinguishable from types 1B and 1MP clinically.10 A few forms of type 2 OCA deserve particular mention. Brown albinism (BOCA) can mimic the phenotype of type 3 OCA. In patients with OCA with ephelides, an unstable intragenic duplication in the P gene can spontaneously revert to normal allowing small areas of pigmentation to occur on the skin. Approximately 1 in 100 patients with Prader-Willi or Angelman syndromes also have type 2 OCA. The P gene is located in the region of chromosome 15 between the genes responsible for these two syndromes. As a result, after a deletion occurs on one chromosome, resulting in the syndrome, a mutation in the other copy of the P gene can lead to albinism.

Waardenburg syndrome type 2, in combination with a mutation in one copy of tyrosinase, can exhibit a phenotype of ocular albinism and deafness. Other forms of digenic inheritance will certainly be identied in the future.

OCA with Systemic Manifestation

In Hermansky-Pudlak syndrome there is an abnormality in the formation of some intracellular vesicles, including melanosomes in melanocytes and the dense bodies of platelets. As a result of the latter, patients have a predisposition to bleeding. The albinism phenotype can range from OA to severe OCA. This disorder is most common in Switzerland and Puerto Rico. On skin biopsy, abnormal large melanosomes, called macromelanosomes, are observed. Approximately 50% of patients with this autosomalrecessive disorder experience problems with ceroid lipofuscin deposition, which increases with age and may result in interstitial lung disease, granulomatous colitis, renal failure, or cardiomyopathy. The bleeding disorder is usually characterized as cutaneous and small vessel bleeding but intracranial hemorrhage may result. Mutations of at least 8 different genes have been associated with HermanskyPudlak syndrome. The diagnosis should be considered in patients with OCA who are of Swiss or Puerto Rican descent or have a history of bleeding problems. Diagnosis can be made by bleeding time (or PFA100), biopsy of affected tissues for ceroid deposition, electron microscopy of platelet morphology, or platelet aggregation studies. Patients with Chediak-Higashi syndrome also have a disorder of vesicle formation, including melanosomes and the white blood cell giant peroxidase lysosome granules resulting in decreased neutrophil chemotaxis and bactericidal capacity. Patients are susceptible to lymphoreticular malignancy and have an intermediate form of OCA characterized by metallic gray sheen to the hair, slate gray patches on the skin, and macromelanosomes on skin biopsy. Other features include optic nerve edema and peripheral

Other Genetic Subtypes

Type 3 OCA is caused by mutations in the tyrosinaserelated protein gene (ie, TRP1; Figure 3) sometimes referred to as the brown gene.11 Phenotypes include BOCA and rufous albinism (ROCA). Type 4 OCA is caused by mutations in the membrane-associated transport protein gene (ie, MATP), which is responsible for protein transport and melanosome function. This form is more common in Japan and has a phenotype very similar to Type 1A OCA. Undoubtedly, with greater than 50 forms of oculocutaneous albinism in mice, more genes will be found to be responsible for other subcategories of OCA. In addition, there are an increasing number of subtypes of OCA as the result of digenic inheritance. In such disorders, a mutation in one copy of one gene alone is insufcient to cause disease. If there is 1 mutation in each of 2 genes, then disease can occur. For example, one mutation in the P gene plus a mutation in the melanocortin 1 receptor results in red hair OCA2.12 This is an intermediate albinism phenotype with red hair present at birth. Patients who have a mutation in the microphthalmia-associated transcription factor (ie, MITF) gene, which is associated with

Journal of AAPOS

64

Levin and Stroh

Volume 15 Number 1 / February 2011

FIG 5. Mud-splattered fundus as a result of Lyonization. Reprinted with permission from Levin AV, Wilson T, eds. The Hospital for Sick Childrens atlas of pediatric ophthalmology Philadelphia, PA: Lippincott Williams and Wilkins; 2007.

neuropathy. Bone marrow transplantation has been curative in some patients with regards to the systemic manifestations, which appear to be most severe in patients with a complete loss of protein function.13 The CHS gene on 1q43 is known to have a role in membrane identication and intravesicular sorting. There are several other syndromes with OCA and systemic manifestations. Disorders such as Griscelli and Elejalde syndromes marry OCA with immune systems abnormalities. Albinism may coexist with deafness due to the need for pigment in the stria vasculosa of the ear.

Dominant OCA
Dominant OCA is uncommon but has been reported. It is characterized by variable expressivity but complete penetrance. The intrafamilial variability can be quite striking.

is viewing patches of RPE cells expressing the X chromosome with a mutation (amelanotic) next to patches of cells expressing the normal X chromosome (melanotic). Other manifestations of the carrier state include iris transillumination seen in 75% of carrier females, hypopigmented macules of the skin, and macromelanosomes when these areas are biopsied.17 Skewed X-inactivation can even lead to frank manifestations of albinism. Therefore, examination of the mother of a boy with albinism, if she has characteristic ndings of the carrier state (other than iris transillumination which may be seen in any form of albinism), may allow for identication of the childs albinism as X-linked recessive OA. This is particularly important in evaluating blonde boys with albinism who may either have autosomal-recessive OCA to account for their phenotype or they are coincidentally blonde boys with OA.

X-linked OA
Perhaps the most common form of albinism is X-linked recessive OA , formerly known as the Nettleship-Falls syndrome, representing 10% of all albinism. Although patients may have a slightly lighter complexion and hair color compared with their family members, black hair is also possible. Mutations in the GPR143 gene at Xp22.3-22.2 are known to be causative.14,15 This protein controls the melanosomes number and size. Therefore it is not surprising that these patients may have macromelanosomes on skin biopsy. The albinism tends to be more severe with poor vision. Because of Lyonization, the process by which all females inactivate one X chromosome in each of their somatic cells, evidence of the carrier state may be available in the mothers of affected boys. A mud-splattered fundus is seen in 80% to 90% of carrier females (Figure 5).16 The ophthalmologist

Melanocyte Disorders
Piebaldism, perhaps the rst described autosomaldominant disorder, is the result of mutations in the c-kit gene that is responsible for proliferation of melanocytes in the skin. Patients have ventral large patches of hypopigmentation (Figure 6) that contain no melanocytes. Although there may be pigmentary manifestations in the eye, the patients do not manifest true albinism. Homozygous mutations in this gene have rarely been reported and resulted in severe OCA, deafness, and death in infancy.

Treatment
Molecular genetics has given us a new insight and nomenclature for the albinism variance. Diagnosis can be made from the basis of pedigree, review of systems, careful clinical examination of the skin, hair, and eyes, as well as, in selected cases, skin biopsy, coagulation study, and 3-lead

Journal of AAPOS

Volume 15 Number 1 / February 2011

Levin and Stroh

65

FIG 6. Piebaldism. Reprinted with permission from Levin AV, Wilson T, eds. The Hospital for Sick Childrens atlas of pediatric ophthalmology Philadelphia, PA: Lippincott Williams and Wilkins; 2007. Courtesy of Dr. Bernice Krafchik, Toronto.

visual evoked potentials. Molecular genetics diagnosis provide the ultimate explanation of the clinical scenario and is available from several laboratories (Table 1), although this test may be quite costly, and one must recognize that falsepositive and false-negative results require careful interpretation by a ocular geneticist or clinical geneticist familiar with these disorders and tests. For more information on the availability of genetic testing for albinism (and other disorders) the reader is referred to GeneTests (http:// www.ncbi.nlm.nih.gov/sites/GeneTests/?db5GeneTests). Genetic counseling is an important part of the care of these families to help improve understanding of the disorder, the risk for recurrence, the genetic basis of its occurrence, the advantages and disadvantages of molecular genetic testing, interpretation of testing results, and the potential for future gene-based treatment. Prenatal diagnosis raises interesting ethical concerns. Initially, prenatal diagnosis was attempted by fetoscopy with or without scalp biopsy. Molecular genetics have raised the possibility of prenatal diagnosis using chorionic villus sampling or amniocentesis. One must weigh the potential psychosocial manifestations of living with albinism versus the ethical concerns about abortion for individuals who only have an ocular disorder. Further discussion of this ethical debate is beyond the scope of this article. Management of patients with albinism should include consideration of Corning spectacles in those patients who experience photophobia. Because most children perform very well at near, interventions are rarely needed. As children go beyond grades 1 and 2 with increasing distance demands, they may benet by small hand-held telescopes for viewing the blackboard. To optimize visual acuity, it is essential to correct refractive error with spectacle correction or contact lenses and initiate patching/penalization for amblyopia. Low vision consultation and individualized education plans with low vision support may also be warranted in more severely affected children. Strabismus surgery may help to reduce nystagmus by eliminating the manifest latent component and eye muscle surgery may also be used to reduce nystagmus amplitude.

Merrill and colleagues18 found that almost all patients had a positive angle kappa attention to which is important when planning strabismus surgery. Eye muscle surgery may also be indicated for anomalous head positions. Patients should be advised to wear appropriate sunblock during periods of prolonged sun exposure. Consultation with a dermatologist may be useful. The possibility of gene therapy has been explored. In vitro transfection of albinotic cells with RNA-DNA oligonucleotides, carrying the appropriate sequence in the tyrosinase gene has resulted in melanization of cells. When this oligonucleotide is transformed into a cream to be massaged onto the coats of clinically affected mice, black hairs grow. Unfortunately, patients with albinism cannot easily dye their hair as the result is often cosmetically unacceptable. One can only imagine the effect such therapy would have on patients with severe hypopigmentation of their hair who have lived their lives being stared at by others. In a mouse model that lacks active tyrosinase, the adult mice have several retinal functional anomalies associated with photoreceptor loss. These anomalies were reversible upon intraocular administration of an adeno-associated virus-based vector, encoding the human tyrosine gene.19 This nding demonstrates that some of the ocular abnormalities of albinism may be partially reversible with gene therapy. Much has been written about the psychosocial impact of this disorder.20,21 As far back as the 1600s, those with albinism were recognized in some African communities as being revered as doctors and prominent people in society. In most instances, patients with albinism were shunned and considered deformed or even contagious. Currently in Tanzania, patients with albinism are being murdered for the use of their body parts in witchcraft and alternate health practices. Safe havens for patients in Tanzania are being developed to protect these individuals. It was not long ago that patients with piebaldism and albinism were featured attractions in circus freak shows. Myths and stigmas surround patients with albinism,22 including their alleged ability to tell the future. The movie industry has exploited albinism by using albinos as evil characters in many lms. For all of these reasons, and many more, the National Organization for Albinisim and Hypopigmentation is available to lend support to affected individuals and their families (http://www. albinism.org/).

References
1. Creel D, ODonnell FE Jr, Witkop CJ Jr. Visual system anomalies in human ocular albinos. Science 1978;201:93931-3. 2. Bouzas EA, Caruso RC, Drews-Bankiewicz MA, Kaiser-Kupfer MI. Evoked potential analysis of visual pathways in human albinism. Ophthalmology 1994;101:309-14. 3. Soong F, Levin AV, Westall CA. Comparison of techniques for detecting visual evoked potential asymmetry in albinism. J AAPOS 2000;4:302-10.

Journal of AAPOS

66

Levin and Stroh

Volume 15 Number 1 / February 2011

13. Karim MA, Sozuki K, Fukai K, Oh J, Nagle DL, Moore KJ, et al. Apparent genotype-phenotype correlation in childhood, adolescent, and adult Chediak-Higashi syndrome. Am J Med Genet 2002;108: 16-22. 14. Bassi MT, Schiafno MV, Renieri A, De Nigris F, Galli L, Bruttini M, et al. Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome. Nature Genetics 1995;10:13-19. 15. Camand O, Boutboul S, Arbogast L, Roche O, Sternberg C, Sutherland J, et al. Mutational analysis of the OA1 gene in ocular albinism. Ophthalmic Genet 2003;24:167-73. 16. Lang GE, Rott HD, Pfeiffer RA. X-linked ocular albinism: Characteristic pattern of affection in female carriers. Ophthalmic Paediatr Genet 1990;11:265-71. 17. Schnur RE, Gao M, Wick PA, Keller M, Benke PJ, Edwards MJ, et al. OA1 mutations and deletions in X-linked ocular albinism. Am J Hum Genet 1998;62:800-809. 18. Merrill KS, Lavoie JD, King RA, Summers CG. Positive angle kappa in albinism. J AAPOS 2004;8:237-9. 19. Gargiulu A, Bonetti C, Montefusco S, Neglia S, Di Vicino U, Marrocco E, et al. AAV-mediated tyrosinase gene transfer restores melanogenesis and retinal function in a model of oculocutaneous albinism type I (OCA1). Mol Ther 2009;178:1347-54. 20. Kromberg J, Zwane E, Jenkins T. The response of black mothers to the birth of an albino infant. Am J Dis Child 1987;141:911-16. 21. Lund P. Health and education of children with albinism in Zimbabwe. Health Educ Res 2001;16:1-7. 22. Haefemeyer J, Knuth J. Albinism. J Ophthalmic Nurs Technol 1991; 10:55-62.

4. Giebel LB, Musarella MA, Spritz RA. A nonsense mutation in the tyrosinase gene of Afghan patients with tyrosinase negative (type IA) oculocutaneous albinism. J Med Genet 1991;28:464-7. 5. Giebel LB, Tripathi RK, Strunk KM, Hanin JM, Jackson CE, King RA, et al. Tyrosinase gene mutations associated with type IB (yellow) oculocutaneous albinism. Am J Hum Genet 1991;48: 1159-67. 6. Camand O, Marchant D, Boutboul S, P equignot M, Odent S, Dollfus H, et al. Mutation analysis of the tyrosinase gene in oculocutaneous albinism. Hum Mutat 2001;17:352-8. 7. Summers CG, King RA. Ophthalmic features of minimal pigment oculocutaneous albinism. Ophthalmology 1994;101:906-14. 8. Giebel LB, Tripathi RK, King RA, Spritz RA. A tyrosinase gene missense mutation in temperature-sensitive type I oculocutaneous albinism: A human homologue to the Siamese cat and the Himalayan mouse. J Clin Invest 1991;87:1119-22. 9. Ramsay M, Colman MA, Stevens G, Zwane E, Kromberg J, Farrall M, et al. The tyrosinase-positive oculocutaneous albinism locus maps to chromosome 15q11.2-q12. Am J Hum Genet 1992;51:879-84. 10. Spritz RA, Oh J, Fukai K, Holmes SA, Ho L, Chitayat D, et al. Novel mutations of the tyrosinase (TYR) gene in type I oculocutaneous albinism (OCA1). Hum Mutat 1997;10:171-4. 11. Manga P, Kromberg JG, Box NF, Sturm RA, Jenkins T, Ramsay M. Rufous oculocutaneous albinism in southern African Blacks is caused by mutations in the TYRP1 gene. Am J Hum Genet 1997;61: 1095-101. 12. King RA, Willaert RK, Schmidt RM, Pietsch J, Savage S, Brott MJ, et al. MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2). Am J Hum Genet 2003;73:638-45.

Journal of AAPOS