Albinism

Updated: Jan 23, 2024
  • Author: Osama Al Deyabat, MD; Chief Editor: Donny W Suh, MD, MBA, FAAP, FACS  more...
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Overview

Background

The term albinism originates from the word, albus (Latin for white), and it is an inherited disorder characterized by reduced pigmentation. [1] Albinism is caused by pathogenic variants in genes important for melanin synthesis. The phenotypic heterogeneity of albinism is associated with pathogenic variants in genes affecting different parts of the melanin pathway, and in such resulting in reduction at a different level of melanin production.

Clinical presentation and classification of albinism

This genetically heterogeneous disorder is characterized by hypopigmentation of the eyes, skin, and hair. Traditionally, albinism has been classified according to clinical phenotype, and the two main categories are oculocutaneous albinism (OCA) and ocular albinism (OA). Ocular involvement (decreased visual acuity secondary to foveal hypoplasia; misrouting of the optic nerves at the chiasm; photophobia and iris transillumination defects; nystagmus; and pigment deficiency in the peripheral retina) is significant in the disease presentation; thus, an ophthalmologist plays an important role in diagnosing this condition. [2]  Albinism can present as a syndromic condition, such as Hermansky-Pudlak syndrome (HPS) or Chediak-Higashi syndrome (CHS), and this should not be forgotten as it has implications in patients care and management.

With advances in genetics, the classification of albinism has shifted emphasis by genotype as opposed to phenotype alone. Nevertheless, in the past it was known that albinism is an autosomal recessive genetically heterogeneous disorder; however, since progress has been made in the genetics/genomics era, an autosomal dominant form of albinism has been reported. [3]

Below is a brief overview of the current classification of albinism by gene (Table 1). [4]

OCA type 1A (OCA1A), due to mutation in the tyrosinase gene (TYR) on chromosome 11q14 with complete lack of tyrosinase activity (it was formerly known as a tyrosinase negative albinism). It is characterized by absence of all pigmentation, thus the affected individuals have the most severe phenotype of all OCAs with marked hypopigmentation at birth. 

OCA type 1B (OCA1B), due to mutation in the tyrosinase gene (TYR) on chromosome 11q14 with reduce activity of tyrosinase (it was formerly known as a yellow variant albinism). It presents with a moderate to severe phenotype.

OCA type 2 (OCA2), due to mutation in the OCA2 gene on chromosome 15q12-q13, which affects the production of P protein (melanocyte specific transport protein). [5]  It usually has less severe presentation than in OCA1, and most patients acquire small amounts of pigment with age. Brown OCA is one clinical variant of OCA2; it has been described in African and African-American populations and is characterized by light brown hair and skin color and gray to tan irides.

OCA type 3 (OCA3), due to mutation in tyrosinase related protein-1 (TYRP1) on chromosome 9q23. It was referred to as rufous oculocutaneous albinism (ROCA), as it usually affects dark-skinned persons, and affected individuals have bright copper-red coloration of the skin and hair and dilution color of iris. It usually associated with milder vision abnormalities than other forms.

OCA type 4 (OCA4), due to mutation in membrane associated transport protein gene (MATP) on chromosome 5p13. The degree of hypopigmentation varies from mild to severe with characteristic ocular findings of albinism.

OCA type 5 (OCA5), due to mutation in the OCA5 gene on chromosome 4q24. Patients have been reported in a consanguineous Pakistani family. The affected individual had golden colored hair, white skin, nystagmus, photophobia, foveal hypoplasia, and impaired visual acuity.

OCA type 6 (OCA6), due to mutation in the SLC24A5 gene on chromosome 15q21. This gene mutation initially was described in a Chinese family, then it was seen in different ethnic groups.

OCA type 7 (OCA7), due to mutation in the C10ORF11 gene (LRMDA) on chromosome 10q22. Affected individuals had predominate eye involvement with a light complexion.

OCA type 8 (OCA8), due to mutation in the DCT gene on chromosome 13q32. It is characterized by mild hair and skin hypopigmentation,, with associated ocular features.

OA type 1 (OA1, Nettleship-falls type), due to mutation in the GPR143 gene on chromosome Xp22. It is the most common form of OA and characterized by ocular findings and normally pigmented skin and hair. Black patients often have brown irides with little or no translucency and varying degrees of fundus hypopigmentation. Carrier females usually have punctate iris translucency and a mottled pattern of fundus pigmentation.

Table 1. Classification of albinism (Open Table in a new window)

Phenotype

Gene

location

Inheritance

OCA type 1A

TYR

11q14.3

AR

OCA type 1B

TYR

11q14.3

AR

OCA type 2

OCA2

15q12-q13.1

AR

OCA type 3

TYRP1

9q23

AR

OCA type 4

SLC45A2 (MATP)

5p13.2

AR

OCA type 5

OCA5

4q24

AR

OCA type 6

SLC24A5

15q21.1

AR

OCA type 7

LRMDA

10q22.2-q22.3

AR

OCA type 8

DCT

13q32.1

AR

OA type 1, Nettleship-falls

GPR143

Xp22.2

XL

As mentioned above, OCA can have extra-ocular features and be associated with syndromic features. Hermansky-Pudlak syndrome is characterized by a bleeding disorder (due to abnormality in the formation of the dens bodies in platelets), lung disease, renal failure, and colitis. Chediak-Higashi syndrome results in recurrent bacterial infections (due to abnormality in the formation of white blood cell giant peroxidase lysosome granules) easy bruising, and peripheral neuropathy.

 

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Pathophysiology

Melanin is a photoprotective pigment in the skin that absorbs ultraviolet (UV) light from the sun, thereby preventing skin and eye damage. With sun exposure, the skin normally tans as a result of increased melanin pigment in the skin. However, many albino individuals are sensitive to sunlight and can develop UV skin damage (ie, a sunburn) easily because of the lack of melanin. In addition to the skin, melanin is important to other areas of the body, such as the eyes and brain.

Melanin in the eye

The eye has 2 origins from which pigmented cells are derived: 1) 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) and 2) the neural crest is the origin of melanocytes in the iris stroma, ciliary stroma, and choroid (uveal melanocytes). 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.

Melanin pathway

Melanin is formed in the melanosome organelle of the melanocyte (intracellular vesicles with the specific purpose of manufacturing and holding this pigment). Melanocytes are found in the skin, hair follicles, and pigmented tissues of the eye. Thus disruption in any part of the melanin synthesis pathway may affect part or all of these organs.

The melanin pathway consists of a series of reactions that converts tyrosine into 2 types of melanin: 1) black-brown eumelanin and 2) red-blond pheomelanin. Genetic variants 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.

Pathogenesis of ocular features

The development of the ocular system is highly dependent on the presence of melanin. Absent or decreased melanin can cause abnormal crisscrossing of optic nerve fibers as a result of misdirected retinogeniculate projections. Melanin is believed to control neuronal target specificity in the brain. In cases of incomplete pigmentation, the developing optic tracts almost entirely intersect at the chiasm, whereas in individuals without albinism, almost half (45%) of axons beginning in the temporal half of the retina pass through the chiasm uncrossed and project to the same-sided lateral geniculate nucleus. In individuals with healthy eyes, the majority of these fibers function in the central 20° of the temporal retina, but in those with albinism, almost all of the fibers crisscross at the chiasm and form a synapse in the opposite-sided lateral geniculate nucleus. This results in predominantly monocular vision and reduced binocular depth perception.

In addition to abnormal chiasmal decussation, albinism can produce a number of other visual symptoms and signs, including the following [6] :

  • Reduced visual acuity (20/60 to 20/400) and color impairment
  • Photophobia, due to light scattering within the eye
  • High refractive errors
  • Positive angle kappa
  • Strabismus and related anomalous head tilt
  • Congenital pendular nystagmus, starting at 2-3 months of age due to loss of visual function
  • Iris hypopigmentation, and iris transillumination defects
  • Fovea hypoplasia (absence of a fovea pit): it is the most significant factor causing decrease visual acuity
  • Decrease retinal pigmentation
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Epidemiology

Frequency

The incidence of albinism is 1 in 20,000 persons worldwide, compared with a rate of 1 in 37,000 in the United States. OCA1 is the most commonly found subtype in Caucasians, and accounting for 50% of all cases worldwide. OCA2 is responsible for 30% of cases worldwide and is more common in Africa. OCA3 affects 3% and OCA4 affects 17% of all cases globally.6 OCA5-8 are rare forms. HPS is a common type of albinism in Puerto Rico, but the disorder is rare in other parts of the world

Mortality/Morbidity

Albinism usually is not linked to mortality, and individuals with the disorder have a normal lifespan; the overall health of children and adults with albinism usually does not suffer from the decreased melanin in the hair, skin, and eyes, and this reduction causes no additional systemic effects. [7]  

Normal growth and intellectual development should progress in a child with albinism, and they should accomplish developmental milestones on par with other children their age.

The bulk of morbidity linked to albinism is related to visual impairment, photosensitivity of the skin, and increased risk for cutaneous cancer.

Those with syndromes related to albinism, such as HPS or CHS, may experience hearing impairment or abnormal blood clotting. Individuals with albinism may have difficulty socially due to alienation because their appearance may differ from that of their families, peers, and others in their ethnic group.

Race

Individuals of all races can be affected by albinism, and it is common for parents of children with albinism to have eye and skin color typical of their ethnic background.

Sex

Albinism can occur in males and females alike; however, only males are affected in OA 1 (X-linked recessive OA), whereas females are carriers only.

Age

Albinism is always congenital.

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Prognosis

Patients with albinism have a normal lifespan but there is an increased risk for skin cancer, and preventive measures are recommended for UV exposure. Genetic counseling is recommended for patients with albinism.

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Patient Education

The main goals of patient education are to determine which type of albinism is present; to exclude systemic syndromes (eg, HPS, CHS); to avoid excess sun exposure; and to provide genetic counseling for the family.

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