Albinism refers to a heterogeneous group of hypopigmentation disorders that share an absolute or relative inherited deficiency of the pigment melanin that leads to characteristic changes in the skin, hair, and visual system (eyes and optic tracts). Melanin is produced and contained within melanosomes, intracellular organelles that are present in the stratum basale of the epidermis, hair bulbs, and intraocular epithelia. Most individuals with albinism have a simple, or nonsyndromic, form that affects the visual system, hair, and skin (oculocutaneous albinism, OCA) or mainly the visual system (ocular albinism, OA). Less commonly, individuals may have a complex, or syndromic, form of albinism that includes a distinctive pattern of organ involvement in addition to OCA. In recent years, much progress has been made in understanding the clinical features, pathophysiology, and molecular basis of albinism ( Box 60.1 ).
Albinism is a heterogeneous group of disorders
Melanin pigment is deficient in all forms of albinism
Hypopigmentation affects the eyes, skin, and hair to varying degrees
Identification of ocular features is essential for the diagnosis of albinism
Individuals with albinism are typically fair of skin and hair and have hypopigmentation of ocular structures ( Figure 60.1 ). The degree of cutaneous hypopigmentation can vary greatly, ranging from the classic image of the albino with white hair, white skin, and pink-red irides to one in which no apparent cutaneous hypopigmentation is present. More constant are the effects that albinism has on the eye and visual pathways. Consequently, examination of the eyes remains an essential step for the diagnosis of albinism.
The key ocular symptoms and signs are intimately related ( Table 60.1 ). Deficits in iris pigmentation typically impart a gray or blue color to the irides, which transilluminate light ( Figure 60.2A and B ). Foveal hypoplasia and mild optic nerve hypoplasia are typical ( Figure 60.2C ), as is nystagmus. The foveal reflex is almost always absent. The ocular fundi appear pale with the choroidal vasculature visible through the neurosensory retina and retinal pigment epithelium ( Figure 60.2D ). Strabismus and high refractive errors are common ( Box 60.2 ).
|High refractive errors
|Irides that transilluminate light
Low visual acuity
Iris sites that transilluminate light
High refractive errors
Acuity is low, ranging from a legal blind level to only mild acuity deficits; median acuity is often cited as approximately 20/60. The low acuity is secondary to foveal hypoplasia ; nystagmus may also degrade acuity. Anomalous head posture is used to counteract the effects of the nystagmus. Depth perception may be poor; typically no stereopsis is demonstrated. Strabismus is common, with esotropia more frequent that exotropia. High refractive errors are common in albinism, apparently from failure of emmetropization. In children with albinism, the ophthalmologist must be alert to amblyopia superimposed on the acuity deficit directly related to the foveal hypoplasia. In a child with albinism, as in other children, asymmetric acuity should alert the ophthalmologist to possible amblyopia associated with strabismus or with difference in refractive error between right and left eye, anisometropia.
The lack of the protective effect of melanin in the eye underlies photophobia. The individual with albinism is also at risk for sunburn rather than tanning, and for malignancies of the skin, especially if exposed unprotected to intense tropical sun.
From biblical times albinism has been recognized; it has been argued that Noah was an albino ( Box 60.3 ). There is a long, anecdotal history of albinism throughout the animal kingdom with notable ocular features. Foveal hypoplasia was recognized and documented histologically by Elschnig and a paucity of nondecussated fibers at the chiasm was reported in classical studies of the visual system in albino animals. In human subjects with albinism, electrophysiological and, more recently, functional magnetic resonance imaging studies have demonstrated anomalous organization of the visual pathways.
Albinism has been recognized since biblical times
Structural and functional anomalies of the visual pathways have been substantiated
Molecular genetic basis for simple and complex forms of albinism has been delineated
For many years albinism was classified on a biochemical basis as tyrosinase-positive or tyrosinase-negative in the hair bulb incubation test. However, this test is seldom performed today because of its lack of sensitivity and specificity, giving rise to many false negatives and false positives; for example, patients with OCA1B and OCA2 have different genetic bases for their albinism, but both yield tyrosinase-positive results in the hair bulb test. Conversely, OCA1A and OCA1B are caused by the same gene but give rise to tyrosinase-negative and tyrosinase-positive results, respectively.
Gradually the genetic foundation for the simple forms of albinism has been established. Four autosomal-recessive genes for OCA and one gene for X-linked OA have been identified ( Table 60.2 ). OCA types 1–4 are inherited with equal frequency in males and females. The recurrence risk to couples with an affected child is 25% with each pregnancy. The ophthalmic characteristics of OCA1–4 are listed in Table 60.1 . OA1 follows an X-linked pattern of inheritance with affected hemizygous males, and female carriers who have healthy eyes, normal vision, and uneven fundus pigmentation ( Figure 60.2E ). Males with OA share essentially the same ophthalmic characteristics of those with OCA. All daughters of fathers with X-linked OA are obligate carriers, and carriers have a 50% chance of having an affected son (or carrier daughter) with each pregnancy.
|Melanosome membrane protein involved in processing and transport of tyrosinase and other melanosomal proteins in small vesicles immediately post-Golgi
|Cream skin and yellow-tinged hair; some progressive pigmentation over time; improved visual acuity over time. High prevalence in Africa
|Tyrosinase- related protein
|Binds to tyrosinase, function unclear. Retention in endoplasmic reticulum
|Red hair and red-brown skin. High prevalence in sub-Sahara Africa and New Guinea
|Rare outside Japan
|Processing and transport of tyrosinase to melanosomes
|Similar to OCA2
|OA, type 1
|Regulation of melanosome number and size
|1/1800 among Puerto Ricans
|Biogenesis of specialized organelles of endosomal lysosomal system, including melanosomes and platelet-dense bodies
|Bleeding diathesis, restrictive lung disease, pulmonary fibrosis, inflammatory bowel disease
|Lysosomal trafficking regulator
|Immunodeficiency, neutropenia, malignant lymphoma, large lysosomal granules
|Absence of paternally expressed genes at 15q11-13, including SNRPN, Necdin, P-gene
|SNRPN, Necdin, P-protein, possibly others
|1/15 000 (1% have albinism)
|P-gene-related and possibly other pigmentary genes
|Obesity, hypotonia, mental retardation, short stature, hypogonadotrophic hypogonadism, almond-shaped eyes, narrow bifrontal diameter of skull, small hands and feet, food obsession, skin-picking behavior, sleep apnea
|Happy puppet syndrome
|UBE3A, P-protein, possibly others
|1/15 000 (1% have albinism)
|P-gene-related and possibly other pigmentary genes
|Ataxia, mental retardation, absent speech, inappropriate laughter, seizures, microcephaly, prognathism, widely spaced teeth, poor sleep
The genetic basis has also been determined for a number of complex forms of albinism that have systemic comorbidities ( Table 60.2 ). In contrast, the simple forms of albinism ( Table 60.2 ) do not lead to systemic comorbidities.
The overall frequency of albinism in the general population is estimated to be 1 in 17 000, and about 1 in 65 individuals is a carrier for OCA. The frequency varies with specific type ( Table 60.2 ) and with ethnicity. An estimated 18 000 individuals in the USA have a form of albinism. OCA1 and OCA2 are the two most common forms of albinism and occur with similar frequencies.
A history of nystagmus, decreased visual acuity, and fair skin and hair within the family group raises the suspicion for albinism ( Box 60.4 ). Inspection of the ocular structures adds diagnostic information. Typically, the irides transilluminate light ( Figure 60.2A and 60.2B ). Foveal hypoplasia and albinotic fundi ( Figure 60.2c and 60.2D ) are the main fundus features; mild optic nerve hypoplasia may also be present. The optic nerve head in children with albinism is significantly smaller than in normally pigmented, age-similar children, being about 80% of the normal mean diameter (AB Fulton, personal observation).