eMedicine Specialties > Ophthalmology > Genetic Disorders

Albinism

Author: Mounir Bashour, MD, CM, FRCS(C), PhD, FACS, Assistant Professor of Ophthalmology, McGill University; Clinical Assistant Professor of Ophthalmology, Sherbrooke University; Medical Director, Cornea Laser and Lasik MD
Coauthor(s): Khalid Hasanee, MD, Glaucoma and Anterior Segment Fellow, Department of Ophthalmology, University of Toronto; Iqbal Ike K Ahmed, MD, FRCSC, Clinical Assistant Professor, Department of Ophthalmology, University of Utah
Contributor Information and Disclosures

Updated: Sep 10, 2007

Introduction

Background

Albinism consists of a group of inherited abnormalities of melanin synthesis typically characterized by a congenital reduction or absence of melanin pigment. This condition results from defective production of melanin from tyrosine through a complex pathway of metabolic reactions.

There are several types of albinism. The phenotypic heterogeneity of this condition is due to the different gene mutations affecting various points along the melanin pathway, resulting in varying degrees of decreased melanin production. Additionally, there also are associated developmental changes in the optic system resulting from this hypopigmentation.

The ophthalmologist plays an important role in detecting albinism since most forms of albinism present with ocular features as the primary morbidity. The changes to the optic system associated with hypopigmentation include decreased visual acuity secondary to foveal hypoplasia and misrouting of the optic nerves at the chiasm. Other features include photophobia, iris transillumination, nystagmus, and pigment deficiency in the peripheral retina. These ocular changes are common to all types of albinism.

Classification of albinism

Traditionally, albinism has been classified according to clinical phenotype with 2 main categories, as follows: oculocutaneous albinism (OCA) and ocular albinism (OA).

Recently, the albinism subtypes have been reclassified. With the availability of new molecular genetic studies, the classification of albinism has shifted emphasis to genotype as opposed to phenotype alone. Hence, this has led to redefining existing phenotypic categories and the addition of new subtypes based on specific genetic mutations. The following is a brief overview of the current classification of albinism.

OCA is characterized by the reduction or absence of melanin in the skin, hair, and optic system (including the eyes and optic nerves). The lack of skin pigment results in not only a pale skin appearance but also increased risk of skin cancer. As shown in Table 1, OCA is divided further into several subtypes based on the distinct genetic mutation.

Table 1. Oculocutaneous Albinism Types

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OA is characterized by changes in the optic system only with no clinical difference in skin and hair color. As shown in Table 2, two major disorders exist in this category, ocular albinism 1 (OA 1) and autosomal recessive ocular albinism (AROA).

Open table in new window

Pathophysiology

Melanin is a photoprotective pigment in the skin that absorbs UV light from the sun, thereby preventing skin damage. With sun exposure, the skin normally tans as a result of increased melanin pigment in the skin. However, many albinos are sensitive to sunlight and develop a sunburn because of the lack of melanin.

In addition to the skin, melanin is important to other areas of the body, such as the eye and brain, although the function in these areas is not currently known.

Melanin in the eye

The eye has 2 origins from which pigmented cells are derived, as follows:

• The neuroectoderm of the primitive forebrain is the origin of melanocytes in the retinal pigment epithelium, iris epithelium (anterior and posterior), and ciliary epithelium (outer pigmented and inner nonpigmented).
• The neural crest is the origin of melanocytes in the iris stroma, ciliary stroma, and choroid. Melanoblasts from the neural crest migrate to the skin, inner ear, and uveal tract.

The presence of melanin during ocular development is important. The fovea fails to develop properly if melanin is absent during development. Other areas of the retina develop normally regardless of the presence of melanin. Additionally, neural connections between the retina and the brain are altered if melanin in the retina is absent during development. The amount of pigment necessary for appropriate ocular development is currently unknown. More research needs to be completed.

Melanin pathway

Melanin is formed in the melanosome organelle of the melanocyte. Melanocytes are found in the skin, hair follicles, and pigmented tissues of the eye. The melanin pathway consists of a series of reactions that converts tyrosine into 2 types of melanin, as follows: black-brown eumelanin and red-blond pheomelanin. Genetic mutations affecting proteins/enzymes along this pathway inevitably result in reduced melanin production.

Tyrosinase is the major enzyme (coded on chromosome 11) involved in the series of conversions to form melanin from tyrosine. It is responsible for converting tyrosine to DOPA and then to dopaquinone. Through a sequence of steps, dopaquinone subsequently is converted to either eumelanin or pheomelanin. Mutation to the tyrosinase enzyme produces either OCA 1 or AROA.

Additionally, 2 other enzymes involved in the formation of eumelanin are tyrosinase-related protein 1 (TRP1; DHICA oxidase) and tyrosinase-related protein 2 (TRP2; dopachrome tautomerase). Both of these enzymes are coded on chromosome 9. Mutation to the TRP 1 gene causes OCA 3. Mutation to the TRP 2 gene does not produce albinism.

Finally, P protein is a melanosomal membrane protein that is believed to be involved in the transport of tyrosine prior to melanin synthesis. Mutation to this P gene produces OCA 2.

Pathogenesis of ocular features

The development of the optic system is highly dependent on the presence of melanin. If melanin is absent or reduced, the ocular features appear. The mechanisms for these changes include the following:

• Abnormal decussation of optic nerve fibers is due to misrouting of the retinogeniculate projections. It is postulated that melanin determines neuronal target specificity in the brain. Therefore, when pigmentation is incomplete, the developing optic tracts almost completely cross at the chiasm. In nonalbinos, 45% of axons originating in the temporal half of the retina remain uncrossed as they pass through the chiasm and project to the ipsilateral lateral geniculate nucleus. Most of these fibers serve the central 20° of the temporal retina. However, in albinos, most of the fibers decussate at the chiasm and synapse in the contralateral lateral geniculate nucleus. This leads to a predominance of monocular vision and decreased binocular depth perception.
• Light scattering within the eye causes the sensation of photophobia and decreased visual acuity. The translucent irides cause increased light to enter the eye, resulting in light scattering. Patients typically have a supernormal electroretinography (ERG) recording.
• Light-induced retinal damage has been postulated as a contributing mechanism to decreased visual acuity. With increased light scattering, it has been proposed that light-generated free radicals are responsible for nonthermal light damage to the retina. Additionally, it is believed that melanin may play a protective role in reducing these free radicals.
• Foveal hypoplasia is the most significant factor causing decreased visual acuity. The macula lutea pigment is believed to be absent. Currently, the etiology of foveal hypoplasia is not completely known; however, it may be due to the decreased melanin in the retinal pigment epithelium (RPE).
• Congenital nystagmus usually occurs in the first 3 months of life and may lead to the misdiagnosis of congenital motor nystagmus.
• Light-induced subclinical damage to the corneal epithelium and its binding to the Bowman membrane have been postulated as a contributing mechanism to the decreased adhesion of the corneal epithelium in LASIK surgery, leading to a very high risk of epithelial abrasion during LASIK in patients with albinism. Possibly, the increased light scattering produces light-generated free radicals that are responsible for nonthermal light damage to the epithelial linking proteins. Additionally, it is believed that melanin may play a protective role in reducing these free radicals.

Frequency

United States

It is estimated that approximately 1 per 17,000 people have one of the types of albinism. Approximately 18,000 people in the United States have albinism.

OCA 1 occurs in approximately 1 per 40,000 individuals in most populations.

OCA 2 is the most common type of albinism and is especially frequent among African Americans and Africans. The estimated frequency in African Americans is 1 per 10,000, while in Caucasians, the frequency is 1 per 36,000. Overall frequency is 1 per 15,000 in all races.

Hermansky-Pudlak syndrome (HPS) is the most common type of albinism in Puerto Rico with a frequency of 1 per 2,700. This disorder is very rare in other parts of the world.

Mortality/Morbidity

• Increased mortality is not associated with albinism. Lifespan is within normal limits. Since the reduction of melanin in the hair, skin, and eyes should have no systemic effects, the general health of a child and an adult with albinism is normal. The growth and intellectual development of a child with albinism should be normal with developmental milestones expected for age.
• The morbidity with albinism pertains to visual impairment, skin photosensitivity, and increased cutaneous cancer risk. Those patients who have syndromes associated with albinism (eg, HPS) may have hearing difficulties or abnormalities of blood clotting. Albinism also has social ramifications because patients may feel alienated because of the different appearance from their families, peers, and other members of their ethnic group.

Race

• Albinism affects all races.
• Parents of most children with albinism have normal eye color for their ethnic background.
• A high incidence of HPS exists among Puerto Ricans.

Sex

Males and females can be affected. However, in OA 1 (X-linked recessive OA), males are affected, while females are only carriers.

Age

All types of albinism are usually congenital.

Clinical

History

Patients with more severe forms of albinism with cutaneous manifestations are easier for a physician to diagnose compared to those with more subtle forms or those with ocular albinism. With respect to ocular complaints, patients typically complain of decreased central vision and photophobia. Skin complaints include skin photosensitivity.

Search for a history of easy bruising, frequent nosebleeds, or bleeding after surgery or dental work. A positive history may point in the direction of HPS. A history of frequent infections may be consistent with Chediak-Higashi syndrome (CHS).

Inquire about a family history of albinism. Children with albinism tend to prefer reading with a head tilt and usually hold reading material up close.

The following is a more detailed description of the different subtypes of albinism:

• Oculocutaneous albinism
• Oculocutaneous albinism 1
• OCA 1 is a disorder that results from mutations to the tyrosinase gene found on chromosome 11 (band 11q14-21). Several different types of mutations to the tyrosinase gene (missense, nonsense, and frameshift) are responsible for producing the 2 types of OCA 1 (OCA 1A and OCA 1B). Mutations can result in either inactive/no tyrosine (null mutations) or in the production of tyrosine enzyme that has reduced activity from normal (leaky mutations). Null mutations produce OCA 1A, while leaky mutations result in OCA 1B.
• An important distinguishing characteristic of OCA 1 is the presence of marked hypopigmentation at birth. Most individuals with OCA 1 (especially OCA 1A) have white hair, milky white skin, and blue irides at birth. The irides can be very light blue and translucent such that the whole iris appears pink or red in ambient or bright light. However, with age, the irides usually become darker blue and may remain translucent or lightly pigmented with reduced translucency.
• Oculocutaneous albinism 1A
• OCA 1A (classic tyrosinase-negative OCA) is the most severe form of OCA. It is caused by nonsense, frameshift, and missense mutations of the tyrosinase gene on chromosome 11 (band 11q24). These null mutations produce completely inactive tyrosinase, resulting in no melanin formation throughout the patient's life.
• The typical phenotype is white hair and skin, and blue and translucent irides. No pigmented lesions develop in the skin, although amelanotic nevi may be present. Because of a lack of pigmentation, these patients have no tanning potential and are at risk for sunburning and skin cancer. This phenotype is the same in all ethnic groups and in all ages. Visual acuity usually is diminished to as low as 20/400. Photophobia and nystagmus tend to be the worst in this subtype. Hair bulb incubation in tyrosinase is usually negative.
• Oculocutaneous albinism 1B
• OCA 1B (yellow mutant OCA, Amish albinism, xanthous albinism) is produced by leaky mutations of the tyrosinase gene that result in reduced/residual enzyme activity. To date, 55 mutations to the tyrosinase gene have been found to cause OCA 1B. These different mutations result in differing amounts of residual tyrosinase activity and are the primary reason for the variation in pigmentation in individuals with OCA 1B.
• The range in pigmentation can vary from very little cutaneous pigment to nearly normal skin pigmentation. Occasionally, a moderate amount of residual activity can lead to near normal skin pigmentation and the wrong diagnosis of ocular albinism. These patients completely lack pigment at birth, which can cause difficulty in distinguishing it from OCA 1A. However, since some tyrosinase activity is still present, individuals may show an increase in skin, hair, and eye pigment with age and tan with sun exposure.
• Patients rapidly develop yellow hair pigment in the first few years of life and then continue to slowly accumulate pigment, principally yellow-red pheomelanin, in the hair, eyes, and skin. Interestingly, patients with OCA 1B tend to develop dark eyelashes, often darker than the scalp hair. The irides can produce hazel or light brown pigment that sometimes is limited to the inner third of the iris. Visual acuity may be 20/90 to 20/400 and may improve with age. Pigmented nevi can develop, although most nevi are amelanotic. Hair bulb testing shows greatly reduced activity of tyrosinase though still present.
• Temperature-sensitive albinism
• Temperature-sensitive albinism is a subtype of OCA 1B. This type of OCA 1B is caused by a mutation of the tyrosinase gene that produces a temperature-sensitive tyrosinase enzyme. Heat-sensitive tyrosinase has approximately 25% the activity of normal tyrosinase at 37°C and improved activity at lower temperatures. The enzyme does not work at regular body temperatures (axillary and scalp region) but functions in cooler areas of the body (arms and legs). Therefore, since melanin synthesis occurs in cooler areas of the body, arm and leg hair pigment is usually dark, while axillary and scalp hair remains white (occasionally developing a yellow tint with time). Individuals are believed to have OCA 1A during the first few years of life with white hair and skin and blue eyes.
• This may be because the temperature of the fetus is high, so the tyrosinase has low activity, resulting in absent pigment. However, postnatally, the skin is cooler, and, with time, body hair in the cooler areas of the body develop pigment, while the eyes remain blue and the skin remains white and does not tan. The eye is warmer than other areas of the skin; therefore, it does not develop additional pigmentation.
• Oculocutaneous albinism 2
• OCA 2 (tyrosine-positive OCA) is the most prevalent type of albinism in all races. This disorder is also autosomal recessive but coded on a different chromosome from OCA 1 (band 15q11-13). This mutated region also is deleted in Prader-Willi syndrome (PWS) and Angelman syndrome (AS), accounting for the close linkage of OCA 2 to these syndromes.
• In OCA 1, the genetic mutation affects the gene coding for tyrosinase; however, the OCA 2 genetic mutation affects the gene coding for the P protein and tyrosinase is normal. The human P gene located on band 15q11.2-q12 is the homologue of the mouse p locus (mutation causes reduction of eumelanin, a black pigment in the mouse, causing the mouse pink-eyed dilution). It is postulated that this human P gene encodes for a melanosomal membrane protein involved in the transport of tyrosine.
• The phenotypic spectrum of OCA 2 varies, ranging from absent pigmentation to almost normal pigmentation. Even though the tyrosinase genes are normal, most type 2 albinos have no black pigment (eumelanin) in the skin, hair, or eyes at birth. As a result, pigment is nearly absent at birth, sometimes making it indistinguishable from OCA 1. However, pigmentation tends to develop with age. The exact mechanism of this delay in albinism is not known. The intensity of pigment accumulation depends on the racial background of the patients. As the child matures, the increased pigmentation also results in improved vision (20/100 to 20/40).
• In Caucasians with OCA 2, the amount of pigment at birth can vary substantially. The hair can have a light yellow-blond color, or it may be darker with a darker blond-red color. The normal delayed maturation of the pigment system can make it difficult to distinguish OCA 2 from OCA 1. The skin is white and does not tan. Iris color is blue-gray, and the degree of iris translucency is proportional to the amount of pigment present. As the child ages, increased pigmentation occurs with pigmented nevi and freckles developing in areas of repeated sun exposure. The hair also may turn darker with age.
• In African Americans and Africans, OCA 2 has a distinct phenotype. At birth, the hair is usually yellow and tends to remain as such through life, although some darkening may occur. The skin is white, and there is no tanning potential. The iris is blue-gray, and pigmented nevi may develop in some individuals.
• Brown OCA is part of the OCA 2 spectrum that is exclusive to Africans and African Americans. It is speculated that this syndrome may arise from leaky mutations to the P protein gene, resulting in reduced P protein activity. The hair and skin are light brown, and the irides are gray. As time passes, the hair and irides may darken, while the skin color remains mainly unchanged. The ocular features are characteristic with punctate and radial iris translucency and retinal hypopigmentation. Visual acuity ranges from 20/60 to 20/150.
• Oculocutaneous albinism 3
• OCA 3 (previously known as red/rufous OCA) is caused by a mutation to the human gene coding for TRP-1. This protein is the product of the brown locus in the mouse. A mutation at this position causes the fur to be brown rather than black. In humans, the formation of TRP-1 is not fully understood. However, it acts as a regulatory protein in the production of black melanin (eumelanin). With mutation, there is subsequent dysregulation of tyrosinase, and brown pigment is synthesized instead of black pigment.
• OCA 3 is autosomal recessive. The clinical phenotype in African patients is light brown or reddish brown skin and hair, and blue-brown irides. The ocular features are not fully consistent with the diagnosis of OCA because some do not have iris translucency, nystagmus, strabismus, or foveal hypoplasia. No misrouting of the optic nerves has been demonstrated by a visual-evoked potential, suggesting either that this is not a true type of albinism or that the hypopigmentation is not sufficient to consistently alter optic nerve development. The phenotype for Caucasians and Asians is not known at this time.
• Ocular albinism
• Ocular albinism 1
• OA 1 (X-linked recessive OA/Nettleshop-Falls type) involves the eyes only. Patients with OA 1 have normal skin; however, it may be paler than first-degree relatives. Ocular findings in OA 1 are similar to OCA, with decreased visual acuity, refractive error, fundus hypopigmentation, absent foveal reflex, strabismus, iris translucency, and posterior embryotoxon in 30% of patients (implying anterior segment dysgenesis). The presence of nystagmus occasionally has led to the misdiagnosis of congenital motor nystagmus.
• The OA 1 locus is Xp22.3. Since this disorder is X-linked recessive, only males manifest the disease and females are carriers. Hence, males show the complete phenotype, while female carriers can show a mud-splattered fundus with hypopigmented streaks in the periphery and marked iris translucency.
• The protein product of the OA 1 gene, named OA 1 (and also identified as GPR143 in GenBank), is a pigment cell specific membrane glycoprotein, displaying structural and functional features of G protein-coupled receptors (GPCRs). However, in contrast to all other previously characterized GPCRs, OA 1 is not localized to the plasma membrane but is targeted to intracellular organelles, namely late endosomes/lysosomes and melanosomes. These unique characteristics suggest that OA 1 represents the first example described so far of an exclusively intracellular GPCR and regulates melanosome biogenesis by transducing signals from the organelle lumen to the cytosol.^1,2
• Skin biopsy in carriers and in individuals with OA 1 usually shows the presence of macromelanosomes, which aids in the diagnosis of OA 1. It has been postulated that the OA 1 gene is a glycoprotein necessary for the maturation of melanosomes, since macromelanosomes are formed when premelanosomes fail to separate from the endoplasmic reticulum–Golgi system.
• Autosomal recessive ocular albinism
• AROA was first described in the 1970s in a series of families in which children of normally pigmented parents had ocular features of albinism but did not have any cutaneous hypopigmentation.
• AROA was classified as autosomal recessive because both males and females were affected. However, it has been shown that AROA is not a distinct entity. In fact, genetic analysis revealed that some of those diagnosed with AROA had either abnormalities of the tyrosinase gene or the P gene. Of those previously diagnosed with AROA, 14% have a mutation of the tyrosinase gene on chromosome 11, making them OCA 1, while 36% have an abnormality of the P gene on chromosome 15, actually making them OCA 2. Fifty percent have neither an abnormality of the tyrosinase gene nor the P gene.
• Conditions with close linkage to albinism
• Close linkage to OCA 2
• PWS and AS are both caused by deletion to band 15q11-13, the same region coding the P protein gene. In OCA 2, the P gene mutation is adjacent to the area commonly deleted in PWS or AS. One percent of patients with PWS or AS has OCA 2. Both PWS and AS are caused by the same chromosomal deletion, but there are 2 separate phenotypes because of genomic imprinting. If the deletion occurs on the paternal band 15q11-13, then PWS results. However, if the same mutation occurs on the maternally derived chromosome, AS occurs. The cause of this is unknown.
• AS is a developmental disorder characterized by developmental delay, severe mental retardation, inappropriate laughter, hyperactivity, tongue protrusion, widely spaced teeth microcephaly, hypotonia, and ataxia. PWS is a systemic disorder characterized with obesity, hypotonia, hypogonadism, short stature, dysmorphic facial features, and intellectual impairment.
• Close linkage to OA 1: X-linked ichthyosis, Kallmann syndrome, X-linked recessive chondrodysplasia punctata, late-onset sensorineural deafness, and microphthalmia and linear skin defects (MLS) have been linked to the OA 1 gene. These contiguous gene syndromes involve the band Xp22.3 region. Albino phenotypes result when the deleted region includes the OA 1 gene.
• Conditions associated with albinism and not because of close linkage
• HPS includes oculocutaneous albinism, platelet granule deficiency, and a lysosomal ceroid storage disorder leading to accumulation of ceroid in tissues throughout the body. It is an autosomal recessive inherited condition first described in Czechoslovakia by Hermansky and Pudlak. This syndrome has a high frequency in Puerto Rico. The HPS gene is localized to band 10q23.1-23.3. Skin pigmentation varies from none to almost normal with ocular features of nystagmus, strabismus, foveal hypoplasia, retinal hypopigmentation, and decreased visual acuity. Late complications of HPS include interstitial pulmonary fibrosis, inflammatory bowel disease, renal failure, and cardiomyopathy secondary to ceroid deposition.
• CHS is an autosomal recessive condition that is characterized by albinism, increased susceptibility to infections, and deficiency in natural killer cell activity. This rare condition is caused by mutation to band 1q42.1-q42.2, but the CHS gene product is unknown. The skin, hair, and eye pigment is reduced in CHS, but the patient usually does not have obvious albinism. Hair color is light brown to blond. The skin is creamy white to slate gray. Iris pigment is present, and nystagmus and photophobia may or may not be present.

Physical

• Begin with an external examination, checking hair and skin color for depigmentation.
• Follow with a complete ocular examination, including a slit lamp evaluation and dilated fundus examination. The ocular features common to all types of albinism include the following:
  • Refractive error and astigmatism
  • Nystagmus (may compensate with a head tilt that may help improve vision)
  • Iris depigmentation (usually blue-gray or light brown color) and iris transillumination
  • Strabismus
  • Fovea hypoplasia
  • Reduced depth perception secondary to abnormal neural connections
  • A positive angle kappa in patients with congenital nystagmus is associated with albinism. The pathophysiology of the positive angle kappa may relate to the anomalous decussation of optic axons that characterizes the albinotic visual system.³
• Once albinism is suspected, the following steps should be taken to ascertain the type of albinism involved:
  • Assess the phenotype. If the patient (newborn or adult) completely lacks pigment in the skin and hair, OCA 1A is the probable diagnosis. The only type of albinism that is associated with white hair at birth is OCA 1. If a minimal amount of melanin is present, the diagnosis is OCA 1B, OCA 2, or OCA 3.
  • CHS should be suspected if the patient has silvery hair and neutrophils with large inclusions on a blood smear. HPS may be the diagnosis if a minimal-to-moderate hypopigmentation is present along with decreased blood clotting.
  • If OCA 1A is suspected, a hair bulb assay may be performed to confirm this diagnosis. A negative result indicates OCA 1A. However, a positive result could indicate OCA 1B, OCA 2, OCA 3, or OA 1.
  • A patient with minimal pigment and a positive hair bulb assay could have OCA 1B, OCA 2, or OCA 3. A patient with only ocular features, presence of hair and skin pigmentation, and a positive hair bulb assay probably has OA 1.
  • To distinguish between OCA 1B, OCA 2, or OCA 3, a sequence analysis of the genes coding for tyrosinase, P protein, and TRP-1 can be completed. Unfortunately, these tests may not be routinely available. Another alternative test (if available) is a shave skin biopsy (5-8 mm). Cultures of melanocytes can be assessed for function of tyrosinase, P protein, and TRP-1.
  • If OA 1 is suspected, a skin biopsy can be taken to check for the presence of macromelanosomes. It may be necessary to assess the ocular status of female family members. Since the disorder is X-linked recessive, females would be carriers. They typically have a mud-splattered fundus.
  • Albinism does not cause a delay in development or mental retardation. Suspect other causes if this is present.

Causes

Albinism is inherited genetically through specific mutations along the melanin pathway.

• Search for CME/CE on This Topic »

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