Oculocutaneous albinism

INTRODUCTION — 

Oculocutaneous albinism (OCA) is a group of rare genetic disorders of melanin biosynthesis that disrupt melanosomal proteins; each is inherited in an autosomal recessive pattern [1]. Eight types of OCA caused by variants in different genes have been recognized (table 1). All types share reduced to absent pigmentation of skin, hair, and eyes, but the clinical phenotypes vary along a broad spectrum of disease severity.

The ocular manifestations, including reduced vision, photophobia, nystagmus, and strabismus, are the most debilitating aspect of OCA [2]. They are associated with a reduction in melanin within the iris and retina and misrouting of the optic nerve fibers from the eye to the brain during development.

Reduced skin pigmentation leads to photosensitivity, increased skin cancer risk, and social consequences of appearing different than others. Discrimination against individuals with albinism is more prominent in some parts of the world and may be severe [3-8].

This topic will review the pathogenesis, clinical manifestations, diagnosis, and management of nonsyndromic OCA. Hermansky-Pudlak syndrome and Chediak-Higashi syndrome are discussed separately. (See "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome".)

EPIDEMIOLOGY — 

The overall prevalence of albinism in the Western world is estimated to be 1 in 17,000 to 1 in 20,000, with ample variations across ethnic groups and geographic regions. One in 70 individuals is estimated to carry an OCA-mutated allele [9-11].

In Africa, prevalence is estimated at 1 in 5000 to 1 in 15,000 [12]. In rare autosomal recessive disorders, parental consanguinity is more frequent. This phenomenon is well documented in certain populations with albinism [13].

Oculocutaneous albinism type 2 (OCA2) is the most common type of albinism worldwide due to its high prevalence in sub-Saharan Africa, where prevalence ranges from as low as 1 in 15,000 in Nigeria to as high as 1 in 1000 in selected Zimbabwean populations [12,14,15]. In persons from sub-Saharan Africa, OCA2 is primarily due to a common 2.7 kb interstitial deletion in the OCA2 gene, related to a founder effect [16]. The estimated OCA2 prevalence in the United States is 1 in 36,000 [17,18].

Oculocutaneous albinism type 1 (OCA1) has an overall prevalence of approximately 1 in 40,000; it is extremely uncommon in Africa, while more common among African Americans [19]. OCA1 and OCA2 are the most common types of albinism in the United States. Oculocutaneous albinism type 3 (OCA3) occurs in approximately 1 in 8500 African individuals [20]. Oculocutaneous albinism type 4 (OCA4), first described in a Turkish individual, occurs in 5 to 8 percent of German and in 18 to 30 percent of Japanese individuals with albinism [21-24].

Among Chinese individuals with albinism, approximately 70 percent have OCA1, 10 percent have OCA2, 13 percent have OCA4, and 2 percent have Hermansky-Pudlak syndrome type 1 [25]. A Danish study of 62 patients with OCA identified 26 percent with OCA1, 15 percent with OCA2, and 3 percent with OCA4 [26].

Oculocutaneous albinism type 5 (OCA5), oculocutaneous albinism type 6 (OCA6), oculocutaneous albinism type 7 (OCA7), and oculocutaneous albinism type 8 (OCA8) are rare. Their phenotypic spectrum and prevalence are largely unknown. OCA5 has been reported in a Pakistani family [27]. OCA6 has been described in a Chinese cohort [28]. OCA7 has been described in a family from the Faroe Islands, a Lithuanian individual, and Kurdish and Dutch patients and is mostly limited to the common ocular phenotypes [27-30]. OCA8 has been described in a French female child and a North African female [31].

CLASSIFICATION AND TERMINOLOGY — 

All forms of albinism involve reduced eye pigment and some degree of vision impairment. OCA is additionally associated with varying degrees of hypopigmentation of the hair and skin. Thus, OCA is distinct from ocular albinism type 1 (OA1), which only involves the eyes. (See "The genodermatoses: An overview", section on 'Ocular albinism'.)

The classification of albinism by causative gene is preferred over older terms such as "partial" or "complete" albinism, "perfect" or "imperfect" albinism, "tyrosinase-positive" or "tyrosinase-negative" albinism, and "yellow mutant" or "rufous" albinism. Eight nonsyndromic types of albinism, numbered as oculocutaneous albinism type 1 (OCA1) to oculocutaneous albinism type 8 (OCA8), have been recognized (table 1) [32].

Syndromic OCA includes 11 types of Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. In syndromic OCAs, pathogenic variants that affect melanosomes also affect similar organelles in other tissues. For example, impairment of delta granules within platelets leads to a bleeding disorder in Hermansky-Pudlak syndrome, and lysosomal impairment leads to increased pyogenic infection in Chediak-Higashi syndrome. (See "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome".)

PATHOGENESIS

Defective melanin biosynthesis — Melanin (a complex pigment that absorbs ultraviolet [UV] radiation and protects against sun-related damage) is synthetized by melanocytes (specialized cells derived from neural crest ectoderm) in the basal layer of the skin and in the retinal pigment epithelium (a neuroepithelial cell layer located over the choroid in the back of the eye), which are both affected in OCA [33]. The pigmentation of the hair, skin, and eye depends on enzymatic biosynthesis of melanin. Iris color is determined, in part, by the stromal melanocytes derived from the neural crest. Other pigments, such as lutein and xanthophylls, are present in the retina and are not impaired in albinism but may appear more prominent in the absence of melanin.

OCA is caused by variants in genes encoding proteins involved in the melanin biosynthesis pathway, which include melanogenic enzymes (ie, tyrosinase [TYR], tyrosinase-related protein 1 [TYRP1]) and specific transport proteins found in melanosomes [34]. The TYR enzyme catalyzes the first step in melanin biosynthesis by oxidizing L-tyrosine to L-DOPA (dihydroxy-L-phenylalanine) and catalyzes the second step by oxidizing L-DOPA to dopaquinone.

Melanin comprises two main types: the brown/black eumelanin and the red/yellow pheomelanin [35]. Individuals with albinism typically have reduced eumelanin but may have normal levels of pheomelanin in hair [36].

Melanin biosynthesis is compartmentalized in the melanosomes, lysosome-related organelles within melanocytes and retinal pigment epithelium. Melanosomes mature through four stages; premelanosomes in stages 1 and 2 do not yet contain melanin, whereas stages 3 and 4 are melanized [37]. Mature, pigment-filled melanosomes are transferred from melanocytes to keratinocytes or other epithelial cells by a poorly understood intercellular transfer process.

Syndromic forms of albinism (ie, Hermansky-Pudlak syndrome and Chediak-Higashi syndrome) with extracutaneous and extraocular features result from gene variants that disrupt the process of pigment transfer by interfering with the biogenesis of melanosomes and melanosome-related critical organelles in other tissues, such as platelet dense bodies in Hermansky-Pudlak syndrome or lysosomes in Chediak-Higashi syndrome. (See "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome".)

In humans, binocular vision requires some nerve fibers from each eye to cross to the opposite side of the brain at the optic chiasm. During embryogenesis, several signaling pathways, including the retinal pigmentation pathway, guide the development of retinal and vascular structures and the routing of ganglion cell axons in the retina to the lateral geniculate nucleus and on to the occipital cortex. Melanin deficiency results in misrouting of the nerve fibers, abnormal foveal development (foveal hypoplasia), and abnormal foveal cone specialization, all of which contribute to reduced visual acuity in albinism [38-40].

Genetics — Most types of OCA display autosomal recessive inheritance. There are eight known types of OCA, seven of which are associated with pathogenic variants in distinct genes that affect melanin synthesis and transportation (table 1) [34,41].

●OCA1 – Oculocutaneous albinism type 1 (OCA1) is caused by variants in TYR on chromosome 11q14.3, encoding the TYR enzyme. OCA1 is further subdivided into two subtypes: oculocutaneous albinism type 1A (OCA1A; MIM #203100) and oculocutaneous albinism type 1B (OCA1B; MIM #606952).

•OCA1A – Individuals with OCA1A carry two null (severe) variants resulting in the complete absence of TYR activity, which causes complete, lifelong absence of melanin pigment in the skin, hair, and eyes (picture 1A). Therefore, OCA1A is considered to be the most severe type of OCA.

•OCA1B – In contrast, individuals with OCA1B, who carry milder mutations that allow some residual function of TYR, are able to develop some hair and skin pigment with time (picture 1B).

●OCA2 – Oculocutaneous albinism type 2 (OCA2; MIM #203200) is caused by variants in OCA2 (previously called P gene), which encodes a melanosome membrane pH-regulating protein essential for TYR function and melanogenesis.

●OCA3 – Oculocutaneous albinism type 3 (OCA3; MIM #203290) is caused by variants in TYRP1 at 9p23, encoding a membrane-bound protein thought to stabilize TYR and support the structure of melanosomes [42].

●OCA4 – Oculocutaneous albinism type 4 (OCA4; MIM #606574) is caused by variants in the solute carrier protein gene SLC45A2 (formerly termed MATP [membrane-associated transporter protein]). It regulates pH and osmolarity of the melanosome [43].

●OCA5 – Oculocutaneous albinism type 5 (OCA5; MIM #615312), described in a Pakistani family, has been linked to a locus on chromosome 4q24, but the mutated gene has not been identified [27].

●OCA6 – Oculocutaneous albinism type 6 (OCA6; MIM #113750) is caused by variants in SLC24A5, encoding another solute carrier protein involved in sodium/calcium exchange [28].

●OCA7 – Oculocutaneous albinism type 7 (OCA7; MIM #615179), described in individuals from the Faroe Islands, is associated with variants in LRMDA (formerly known as C10orf11), a gene involved in melanocyte differentiation [29,44]. A comprehensive study of patients with OCA7 describes phenotypes restricted to the eyes and similar to that of X-linked ocular albinism type 1 (OA1), and based on that assessment, it has been proposed to rename OCA7 as ocular albinism type 2 (OA2) [30].

●OCA8 – Variants of the dopachrome tautomerase gene (TYRP2), which encodes an enzyme involved in melanogenesis, have been described in a French female child and a North African female with oculocutaneous albinism type 8 (OCA8) [31].

PATHOLOGY — 

The number of epidermal and hair follicle melanocytes is normal in OCA. Melanosome development has been studied in fetal tissues and found to be altered in oculocutaneous albinism type 1 (OCA1). Postmortem eye examination of a 20-week fetus with presumed oculocutaneous albinism type 1A (OCA1A) showed only stage 1 or 2 melanosomes and absence of melanin in the retinal pigment epithelium, while mature melanosomes are normally present by week 7 of gestational age [45].

Absence of the fovea and a rod-free zone were found with postmortem pathology of a young boy with presumed OCA1A [46]. Stage 3 melanosomes in the retinal pigment epithelium were normal but reduced in number.

Postmortem eye histopathology in an older female with presumed OCA1A showed absent foveal development and absent melanosomes in the retinal pigment epithelium [47]. Electron microscopy examination of skin samples of a 20-week-old fetus with OCA1 showed melanosomes only up to stage 2, consistent with absent melanin synthesis [48]. (See 'Defective melanin biosynthesis' above.)

CLINICAL MANIFESTATIONS — 

Individuals with OCA, preferentially referred to as "persons with albinism" instead of "albinos," display wide phenotypic heterogeneity, ranging from complete absence of skin, hair, and eye melanin pigmentation in those with oculocutaneous albinism type 1A (OCA1A) to a variable amount of brown pigmentation in oculocutaneous albinism type 1B (OCA1B), oculocutaneous albinism type 2 (OCA2), and oculocutaneous albinism type 4 (OCA4) or a reddish-brown pigmentation in oculocutaneous albinism type 3 (OCA3). The ocular manifestations, including congenital nystagmus, photophobia, iris transillumination, reduced pigmentation of the retinal pigment epithelium, foveal hypoplasia, and reduced visual acuity, are common to all types of OCA. All of these findings might not be present in rare individuals with very mild types of albinism [49].

Ocular findings — Patients with all types of OCA present ocular changes, including:

●Reduced iris pigmentation – The iris color varies from pink to light blue, green, gray, or light brown and is typically lighter in color than other family members.

●Iris transillumination – The light shone into the pupil with a biomicroscope (slit lamp) reflects back from the posterior lining of the eye through a hypopigmented iris. However, this is not unique to albinism.

●Ocular sensitivity to light (photophobia) – Ocular sensitivity to sunlight results in squinting or eyelid closure. Infants may appear to be sensitive to bright light, closing their eyes or putting their chin down with exposure to bright light. This is likely due to light scattering within the eye, as light enters the eye not only through the pupil but also through the hypopigmented iris and through sclera in those with significantly reduced retinal pigment. They may show poor eye contact, representing a delay in visual development [10,50].

●Nystagmus – Patients with OCA present involuntary to-and-fro movement of the eyes (nystagmus), often more noticeable with fatigue, illness, anxiety, or excitement and often increasing when one eye is covered. Nystagmus typically appears between six and eight weeks corrected gestation age. Parents/caregivers may misinterpret nystagmus as a preference to look to the side in "side gaze," as this position may dampen the nystagmus. The amplitude of nystagmus is greater in infants than older children or adults.

●Fundus hypopigmentation – Due to reduced melanin content, the retinal pigment epithelium often appears yellowish or orange rather than red.

●Foveal hypoplasia – The fovea at the center of the retinal macula is the structure responsible for our sharpest central vision. Normally, the fovea has a dip, which reduces light scatter to improve the amount of light reaching the highly sensitive photoreceptors at this location. Foveal hypoplasia is the maldevelopment of this vital part of the retina. There is a wide range of abnormalities, with persistence of the inner retinal layers being common across the types of foveal hypoplasia. In addition, there is often elongation of retinal outer segments, and the normally thickened outer nuclear layer may be decreased or absent. There are classification systems that provide general predictions of average vision expected based on the type of foveal hypoplasia. However, there is great variation in visual acuity across each severity of foveal hypoplasia [40].

●Reduced visual acuity – Patients with OCA have delayed visual maturation or reduced visual acuity for age due to various ocular phenotypic and anatomical features, including degree of foveal hypoplasia, intensity of nystagmus, and iris and fundus pigmentation [51-56]. The average visual acuity is approximately 20/80 but varies widely, ranging from rare 20/20 to 20/400 [51]. Of note, visual acuity may differ in siblings with albinism despite similar ocular findings [57].

Children tend to hold toys or books closely and may not identify their parents/caregivers across a room without auditory clues. School-age children may move close to the board to see it. Adults with OCA report difficulty reading road signs or newspapers without magnification. Visual acuity often improves progressively after the first decade of life independently from changes in refractive error, eye muscle surgery, or ongoing nystagmus [58].

Skin and hair — Individuals with OCA typically have markedly hypopigmented skin and hair compared with other family members. The hypopigmentation is best appreciated in patients whose family members have more intensely pigmented skin [51].

●Children with oculocutaneous albinism type 1 (OCA1) are likely to have white hair and lashes at birth (table 1), which may provide a clue to diagnosis. White hair remains white in children with OCA1A (picture 1A) or may darken over time in those with OCA1B (picture 1B). Although individuals with OCA1A may appear to develop slight darkening of the hair due to staining from shampoos and water minerals, their eyebrows and eyelashes may remain white. Evaluation of hair near the roots typically shows the continued absence of color.

●A gray or silver sheen of hair is characteristic of Chediak-Higashi syndrome (picture 2). (See 'Disorders associated with hair and skin hypopigmentation' below and "Chediak-Higashi syndrome".)

●Children with OCA2 are typically born with blond or reddish-blond hair (picture 1C).

●OCA3 presents with either the rufous (red) or the brown OCA phenotype in African individuals. They have copper-red (reddish-brown) skin, ginger (yellowish-red) hair color, and diluted iris color or have light brown hair and skin and blue-green to brown eyes [59]. White patients with OCA3 are clinically similar to patients with OCA2.

With age, sun-exposed skin may become rough and thickened with increased actinic keratoses and solar damage. Solar lentigines (freckles) develop in patients able to synthesize some melanin.

Risk of skin cancer — Individuals with OCA have an increased risk of early-onset skin cancer, possibly by their teenage years. Squamous cell carcinoma and basal cell carcinoma are the most common types of cancer in patients with OCA [60-63].

Melanoma is thought to be rare [64-66]. In most cases, it presents as a pink or red (amelanotic) lesion that is difficult to recognize, delaying diagnosis [67].

Psychosocial issues — Studies from around the world report that people with albinism and their families may face psychosocial challenges, including discrimination. They may develop behaviors to avoid being noticed [68]. Social discrimination and isolation may lead to emotional instability, struggle to form a relationship and marry, and decreased quality of life. The risk of dropping out of school is increased. Since people with albinism have noticeably fairer pigmentation than family members, paternity may often be questioned. Involuntary shaking of the eyes (nystagmus), in addition to visual impairment, may also cause a sense of "other" [68,69]. Education of society is necessary to help prevent these issues, with appropriate support and counseling for affected individuals and families as needed [70].

DIAGNOSIS — 

A heightened awareness of OCA is necessary for early diagnosis and management, providing the best opportunity for vision to develop to its fullest potential.

Clinical diagnosis — The clinical diagnosis of OCA is based on the presence of the following findings on physical examination and comprehensive ophthalmologic examination [71]:

●Hypopigmentation of skin and hair, including brows and lashes (picture 1A-C), compared with family members and members of the same ethnic group.

●Reduced iris pigmentation, with eye color ranging from pink to blue, green, gray, or light brown.

●Characteristic ocular changes and vision abnormalities detected on ophthalmologic examination. These include photophobia, nystagmus, iris transillumination, foveal hypoplasia, and reduced visual acuity and are common to all types of OCA. (See 'Ophthalmologic examination' below.)

Patients with all OCA types, except those with oculocutaneous albinism type 1A (OCA1A; who have a complete absence of melanin pigment in the skin, hair, and eyes), show significant overlap in clinical phenotypes. This makes clinical diagnosis difficult. For these patients, genetics referral for testing, if available, may provide a precise diagnosis and allow genetic counseling and assessment of reproductive risk. (See 'Molecular diagnosis' below.)

It is critically important to assess the presence of associated systemic symptoms (eg, bleeding diathesis, pulmonary symptoms, recurrent infections) that suggest the diagnosis of syndromic OCA subtypes, such as Hermansky-Pudlak syndrome and Chediak-Higashi syndrome, as individuals with these conditions require anticipatory, multispecialty care to prevent complications. (See "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome".)

Ophthalmologic examination — In patients with suspected OCA, it is recommended to have the first visit around four to six months of age. A comprehensive eye examination should include:

●Visual acuity measurement – Infants and preverbal, developmentally delayed patients should have vision assessed with the use of the induced tropia test, teller acuity cards, Cardiff cards, or similar preferential viewing tools (see "Vision screening and assessment in infants and children"). Both monocular and binocular visual acuity should be assessed in all patients [52].

●Sensorimotor examination with special attention to the presence of nystagmus.

●Positive angle kappa.

●Any abnormal head posture.

●Iris examination for transillumination defects.

●Dilated fundus examination looking for foveal hypoplasia and hypopigmentation.

●Careful cycloplegic refraction.

The examination typically reveals a constellation of findings that support the diagnosis. Changes detected in all types of OCA include:

●There is commonly reduced best corrected vision that is not due to amblyopia.

●Nystagmus (horizontal pendular/jerk and/or rotary/torsional or periodic alternating nystagmus) is typically present, with or without a compensatory head posture. Certain head postures dampen the nystagmus (called the null zone), improving vision. At times, the null zone is in the primary gaze, and no preferred head posture is identified. Nystagmus is also dampened with convergence (eg, with viewing at near ranges) [10].

●High refractive errors (hyperopia, myopia, astigmatism) are common [72].

●Strabismus (misalignment of eyes), including exotropia (divergent alignment), esotropia (crossing of eyes), and/or vertical misalignment of the eyes, is commonly detected with alternate cover testing. Because the visual axis is typically located nasally to the pupillary center in albinism (seen with monocular fixation on a penlight held directly in front of the examiner [also known as a "positive angle kappa"]), esotropia appears less than measured with prism and alternate cover tests, and exotropia appears greater than measured with prisms [73]. While not pathognomonic, when paired with associated features of albinism, a positive angle kappa is helpful in making a clinical diagnosis of albinism.

●Absent or reduced stereoacuity (fine depth perception), often in the presence of strabismus, is frequently seen in patients with OCA and can be measured with standard stereo tests in clinic. However, even when the eyes are straight, stereoacuity is reduced or absent due to excessive crossing of the retinostriate nerve fibers at the chiasm in albinism. Stereopsis is typically absent, but some patients with better visual acuity will show reduced stereopsis [74].

●On slit lamp examination, using small, bright light with magnification sufficient to view the entire undilated iris, some degree of iris transillumination is usually noted (picture 3A-B) [75]. Iris color is not a sensitive indicator of whether albinism is present. "Pink" irides refer to the almost full iris transillumination that can be detected without the slit lamp in certain lighting conditions. Iris transillumination is not unique to albinism. A lighter retina (ie, yellowish or orange compared with red) is also noted.

●On dilated eye examination, at least some degree of foveal hypoplasia is noted (picture 4 and picture 5 and picture 6) [49,76]. An annular reflex can be seen in the macula in some individuals with better vision, but an umbo is not usually identified [49,74]. Choroidal vessels may or may not be visualized in the macula, and the normal foveal avascular zone is typically absent (vessels may appear to even course through the macula) [77]. While melanin pigment in the retinal pigment epithelium is generally absent, granular melanin pigment may be occasionally found in the macula and is associated with relatively better visual potential (picture 7) [74,78]. Optic nerves typically have a modest, peripapillary halo and minimal to absent cupping due to mild optic nerve hypoplasia [79-81].

●Optical coherence tomography (OCT) provides quick volumetric imaging of the macula to support and delineate the extent of foveal hypoplasia [38-40,82-85]. Grading of foveal hypoplasia using spectral domain OCT technology is noninvasive and provides an estimation of visual prognosis [38,39,54,85]. However, some individuals with nearly normal foveal morphology will still have poor visual acuity, suggesting that other factors contribute to vision impairment in albinism [51,79].

●If performed, visual evoked potential (VEP) using a flash or pattern onset checkerboard recording from the occiput shows the misrouting of the retinostriate fibers due to excess retinostriate decussation [86-89]. VEP is used less frequently to establish the diagnosis of albinism since molecular testing has become more available. The excessive decussation has also been shown with functional magnetic resonance imaging (MRI) and positron emission tomography (PET) [86-88].

Molecular diagnosis — Due to the considerable phenotypic overlap of different types of OCA, molecular testing using a multigene panel or comprehensive genome sequencing is generally preferred for a precise diagnosis and is available for most types of OCA (table 1) [90]. However, based on current technology, molecular testing is more sensitive in certain types of OCA than others [91].

Molecular testing may impact patient management, surveillance, prognosis, and genetic counseling (eg, reproductive planning). (See "Genetic testing".)

As in all autosomal recessive disorders, two pathogenic variants of the involved gene, each on an opposite allele, must be identified. Therefore, genetic testing results may be suggestive but inconclusive in affected individuals who are compound heterozygotes, as only one pathogenic variant may be detectable based on current technology [92].

Undetectable pathogenic variants are likely to be in a region not covered by deoxyribonucleic acid (DNA) sequencing of relevant OCA genes, and evaluation for duplications and deletions of these genes (eg, introns, regulatory domains, large genomic deletions, single exon deletions) is not routinely performed. In these cases, the diagnosis is based on clinical features alone. Some patients with clinical features of OCA but negative genetic testing may have other unidentified types of OCA. In rare cases, OCA may be of digenic etiology [93,94]. As technology is rapidly advancing, periodic follow-up for updated genetic testing is recommended (eg, in two to three years) in the case of an unconfirmed molecular diagnosis.

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of OCA includes disorders associated with early-onset nystagmus and cutaneous hypopigmentation.

Disorders associated with early-onset nystagmus — Primary causes of early-onset nystagmus include the following:

●Ocular albinism type 1 – Ocular albinism type 1 (OA1) is an X-linked disorder characterized by hypopigmentation limited to the eye. Affected individuals share the ocular features of OCA but lack the hair and skin hypopigmentation. OA1 primarily affects males, with only a few female carriers manifesting nystagmus and low vision [95]. Approximately 90 percent of obligate maternal carriers have pigmentary mosaicism in their fundi, representing lyonization or X-inactivation, and this is considered to be diagnostic (picture 8). It can be difficult to diagnose OA1 in a male with lightly pigmented skin and hair as he may appear to have OCA. Fundus examination of the mother or molecular testing of the patient are helpful. (See "The genodermatoses: An overview", section on 'Ocular albinism'.)

●Optic nerve atrophy and hypoplasia – Optic nerve atrophy and hypoplasia is detected with a dilated examination of the fundi. Other central nervous system disorders (structural or progressive) may also present with nystagmus and low vision. If an eye examination discloses no ocular cause for nystagmus and low vision, imaging may be considered. (See "Congenital and acquired abnormalities of the optic nerve".)

●Inherited retinal dystrophy – Inherited retinal dystrophies may present with early-onset nystagmus and vision loss. Examination may initially be normal or show retinal arteriolar attenuation and blunting of the foveal light reflex associated with macular pigment mottling. A full-field electroretinogram (ffERG), which evaluates both rod and cone photoreceptor functions, will often establish the diagnosis (ffERG is normal or supranormal in albinism). This includes static disorders, such as achromatopsia (absent/reduced cone photoreceptors in the retina) and congenital stationary night blindness (absent/reduced rod photoreceptor function), and progressive retinal degenerations that may or may not be associated with other systemic abnormalities (eg, rod-cone retinal dystrophies, retinal degenerations associated with lysosomal diseases).

●Infantile nystagmus syndrome and idiopathic infantile nystagmus – Infantile nystagmus syndrome and idiopathic infantile nystagmus develop in the first few months of life in children with associated retinal or optic nerve anomalies or in isolation [96,97]. Some patients show an FRMD7 pathogenic variant, causing the X-linked disorder (also called FRMD7-related infantile nystagmus), while others have an undetermined etiology [98,99]. Infantile nystagmus syndrome and idiopathic infantile nystagmus can also be inherited as autosomal recessive and dominant disorders.

Foveal hypoplasia and nystagmus may occur in individuals with autosomal recessive variants in AHR [100]. Autosomal recessive variants in SLC38A8 are associated with nystagmus and FHONDA (foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis; MIM #609218) [101].

●Aniridia – Aniridia is a rare congenital abnormality caused by pathogenic variants in the paired box gene 6 (PAX6) [102]. Patients with aniridia have low vision, light sensitivity, nystagmus, and foveal hypoplasia similar to albinism, but their rudimentary iris remnant establishes the diagnosis and directs genetic testing.

Disorders associated with hair and skin hypopigmentation — Disorders associated with hypopigmentation include:

●Angelman syndrome and Prader-Willi syndrome – Angelman syndrome (MIM #105830) and Prader-Willi syndrome (MIM #176270) are neurodevelopmental disorders caused by microdeletions in chromosome 15q11-13 of maternal and paternal origin, respectively. Approximately 1 in 100 have OCA due to a contiguous gene deletion on chromosome 15 that includes the adjacent OCA2 gene. The deletion unmasks a second OCA2 gene mutation on the opposite chromosome. Angelman syndrome and Prader-Willi syndrome require systemic evaluation and genetic testing to establish the diagnosis. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion (Angelman syndrome)' and "Prader-Willi syndrome: Management".)

●Vici syndrome – Vici syndrome (MIM #242840) is an autosomal recessive, multisystem disorder characterized by skin hypopigmentation, findings similar to OA1, microcephaly, failure to thrive, immunodeficiency, cardiac abnormalities, cleft lip and palate, and neurologic abnormalities (eg, agenesis of the corpus callosum) [103]. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Disorders of the corpus callosum'.)

●Waardenburg syndrome type 2 – Waardenburg syndrome type 2 is a genetically heterogeneous, autosomal dominant disorder associated with variants in AX3, MITF, SOX10, KITLG, EDNRB, and EDN3 [104]. Patients have congenital sensorineural hearing loss and pigment hypopigmentation without lateral displacement of the inner canthi (telecanthus or dystopia canthorum). (See "Piebaldism", section on 'Waardenburg syndrome'.)

●Tietz albinism-deafness syndrome – Tietz albinism-deafness syndrome (MIM #103500) is an autosomal dominant disorder caused by variants in MITF and characterized by profound congenital sensorineural deafness, white brows and lashes at birth, and hypopigmentation of fundi but without vision problems [105].

●Hermansky-Pudlak syndrome – Hermansky-Pudlak syndrome is a group of rare autosomal recessive disorders characterized by OCA, a bleeding diathesis due to absence of platelet dense bodies, and other organ involvement (eg, lung fibrosis, granulomatous colitis, neutropenia) (picture 9) [106]. The presence of a bleeding diathesis, epistaxis, gingival bleeding, and/or easy bruising differentiates Hermansky-Pudlak syndrome from OCA. However, individuals with oculocutaneous albinism type 1 (OCA1) may also report easy bruising in the absence of a bleeding diathesis, as bruises are more visible on lightly pigmented skin. (See "Hermansky-Pudlak syndrome".)

●Chediak-Higashi syndrome – Chediak-Higashi syndrome (MIM #214500) is a rare autosomal recessive disorder caused by variants in CHS1/LYST and characterized by OCA (picture 2), recurrent pyogenic infections, progressive neurologic abnormalities, mild coagulation defects, and hemophagocytic histiocytosis. The demonstration of giant cytoplasmic granules in leukocytes and platelets establishes the diagnosis. (See "Chediak-Higashi syndrome".)

●Griscelli syndrome – Griscelli syndrome is a genetically heterogenous disorder of skin hypopigmentation, silver-gray hair, and melanin pigment aggregation in the hair shaft with or without immunodeficiency, neurologic problems, and/or low vision with roving eye movements [107]. (See "Syndromic immunodeficiencies", section on 'Griscelli syndrome'.)

●CLCN7 gene variant – A single nucleotide variant in CLCN7 (chlorine channel 7) was found in two unrelated children (a female and a male) without osteopetrosis but with skin and hair hypopigmentation; delay in development and myelination; and organomegaly due to lysosomal hyperacidity, abnormal storage, and enlarged intracellular vacuoles [108]. The report indicated that the male child had albinism but no iris hypopigmentation; further details of eye examination were not provided. One of them had electroretinogram evidence of an early retinal dystrophy.

MANAGEMENT — 

The management of patients with OCA involves strict sun protection beginning from infancy and treatment of significant refractive errors with glasses or contact lenses [109]. Support groups and information sources, such as the Global Albinism Alliance and the National Organization for Albinism and Hypopigmentation, are available worldwide.

Sun protection — Individuals with OCA need lifelong photoprotection. Patients and parents/caregivers should be educated to adopt strict sun protection measures, including:

●Seeking shade and avoiding ultraviolet (UV) exposure during the peak hours of sunlight

●Use of protective clothing, such as wide-brimmed hats, ultraviolet protective factor (UPF)-labeled clothing, shirts with a collar, long sleeves, long pants, and socks (see "Selection of sunscreen and sun-protective measures", section on 'Photoprotective clothing')

●Liberal and frequent (every two hours) application of sunscreen of at least sun protection factor (SPF) 30 when in the sun (see "Selection of sunscreen and sun-protective measures")

●Avoiding tanning bed use

●Avoiding medications that increase photosensitivity whenever possible

Skin cancer surveillance

Clinician total body skin examination — Because of their increased risk of skin cancer, patients with OCA should have a skin examination at 6- to 12-month intervals starting in adolescence. Any new concerning or changing lesions should prompt a dermatology examination sooner than the recommended periodic interval. Clinicians should pay special attention to pink and red lesions because melanoma is typically amelanotic in individuals with OCA [110].

Role of dermoscopy — A study of benign nevi in 37 children with OCA revealed "structureless homogenous" or "globular" as the most common dermatoscopic patterns, which differs from the reticular pattern most common in nevi in individuals without OCA [111]. A comparative or so-called "ugly duckling" approach has been recommended for oculocutaneous albinism type 1A (OCA1A). That is, all red nevi should be evaluated with dermoscopy to verify similar vascular patterns and color; any differing lesion should be biopsied [112].

Dermoscopy findings in OCA-associated amelanotic melanoma include lineal, irregular vessels and polymorphous-appearing vessels over a central disposition of dotted vessels [113]. One additional study describes orange, structureless areas surrounded by large, yellow to orange clods among polymorphous vessels [114]. Further, clinical use of reflectance confocal microscopy is reported as a useful adjunct to dermoscopy to differentiate melanoma in difficult cases [67].

Patient education — Patients should also be educated about the following:

●Sun protection measures, including frequent and liberal application of sunscreen with an SPF of at least 30 every two hours while in sun (set alarm if necessary), seeking shade, using sun-protective clothing, and avoiding the peak hours of sunlight from 10 AM to 3 PM.

●Importance of skin self-examination. (See "Screening for melanoma in adults and adolescents", section on 'Patient self-examination'.)

●Awareness of concerning skin lesions, such as new lesions in sun-exposed areas; nonhealing lesions or lesions undergoing changes; and lesions associated with symptoms like pain, itching, or bleeding.

●The ABCDE rule of melanoma (asymmetry, border irregularity, color variegation, diameter >6 mm, evolution). Of note, most melanomas in patients with OCA are not pigmented. Patients should be educated about the importance of changes over time of pink or red skin lesions. (See "Melanoma: Clinical features and diagnosis", section on 'ABCDE criteria'.)

Management of eye abnormalities — Treatment of eye abnormalities focuses on improving quality of life [115]. In many cases, the primary goal is to maximize visual function, as reduced vision is identified as the major factor interfering with quality of life [2].

Frequency of eye examination — Children with suspected albinism should receive a comprehensive eye examination by approximately four to six months of age. Because refractive error changes frequently in young children, examinations every three to four months are ideal within the first two years of life. The frequency can be reduced to every six months for the next two years, and yearly examinations are appropriate by age 5. Less frequent examinations are reasonable in early childhood if the refractive error is insignificant or stable. By age 18 to 20 years, examinations can be performed every two to three years unless concerns arise.

Correction of refractive errors — Amblyogenic levels of refractive errors are common in albinism and require treatment with glasses or contact lenses [72]. Early correction of significant refractive errors is associated with improved visual and alignment outcomes; glasses to fully correct refractive errors are optimally prescribed by four to six months of age [116]. Prescription glasses changes are frequently needed within the first few years of life.

A lower threshold of refractive error for starting glasses may be beneficial. Cycloplegic refraction should be used to determine refractive error and glasses considered at the following levels [116]:

●Children six months to two years of age

•Myopia >3.5 D

•Hyperopia >3.0 D

•Astigmatism >3.0 D

●Children older than two years

•Myopia >2.5 D

•Hyperopia >2.0 D

•Astigmatism >2.0 D

Many children prefer filtering lenses, including photochromic lenses that darken with exposure to sunlight. However, such lenses do not darken in the car, and sunglasses may be needed when riding in a vehicle. Lenses with UV protection are vital. Caps or wide-brimmed hats can also help to alleviate ocular photosensitivity and provide UV protection.

Eye muscle surgery — Eye muscle surgery may be required to restore the alignment of the eyes in patients with strabismus [117]. Several eye muscle procedures are also used to improve the head posture that is compensatory for nystagmus by shifting the null zone closer to primary position, broadening the null zone, decreasing the amplitude of the nystagmus, and improving visual function (including visual acuity) [92,118-120]. At times, surgery may need to be repeated depending on the eye alignment and the head posture.

Oral and topical medicines (eg, memantine, brinzolamide) have been tried for nystagmus in albinism with limited benefit [121,122].

Low-vision aids — Bifocals and low-vision aids, such as a lighted magnifying glass, can be helpful for older children. High-contrast, enlarged print can be useful. Electronic low-vision applications that can assist children and adults in their school and work performance are also available.

Evaluation by a low-vision specialist can help to identify these resources, and a teacher for the visually impaired can ensure that educational needs are being met. It is rare that an individual with albinism will need to learn braille. Those with a greater reduction in vision may benefit from orientation and mobility training and low-vision aids [123].

Requirements for driving a motor vehicle vary by location, and not all locations allow bioptics. Some persons with albinism will be able to obtain a restricted driver's license. Driver's training for those with low vision may also be considered.

A simulation study showed that the preferred minimum safety boundary to a leading vehicle was significantly shortened in 12 patients with albinism compared with 12 controls without albinism, matched by sex, age, duration of driving experience, and time of day for participation in driving simulation [124], suggesting that individuals with albinism should take care to increase distance in following a lead vehicle.

Pharmacologic therapies

●Levodopa – Levodopa, an intermediary in melanin biosynthesis, has been postulated to improve visual acuity in individuals with albinism. However, in a randomized trial of 45 patients with OCA aged 3.5 to 58 years, treatment with levodopa for 20 weeks did not improve the best-corrected visual acuity compared with placebo [125].

In mouse models of human albinism, levodopa at either high-dose or human-equivalent dose given during the critical postnatal retinal neuroplasticity period "rescued" visual function as well as retinal morphology [126,127].

A study of retinal development in infants with and without albinism assessed by optical coherence tomography (OCT) showed changes in the rate of photoreceptor elongation in the fovea and changes in regression of the inner retinal layers in albinism in the first few years of life, suggesting a period of plasticity [128].

Studies are needed to evaluate the effects of early levodopa treatment in children with OCA.

●Nitisinone – A pilot trial of oral nitisinone, a drug used to treat tyrosinemia, given daily to five adults with oculocutaneous albinism type 1B (OCA1B) for one year resulted in an increase in skin and hair pigmentation, a decrease in iris pigment, and no change in retinal pigmentation [129]. The group had a statistically significant, but not clinically significant, improvement in visual acuity.

Experimental therapies — Early studies of gene therapy in animal models of OCA showed promising results. Subretinal injection of adeno-associated viral vector-mediated human TYR gene in a murine model of oculocutaneous albinism type 1 (OCA1) resulted in increased retinal pigmentation [130]. A CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 system was used to microinject rabbit embryos with TYR mutations, resulting in repair that increased melanin in the irises [131].

Learning and social concerns — Children should receive typical well-visit assessments recommended by the American Academy of Pediatrics: normal milestones, head circumference, weight, body mass index, language acquisition and expression, motor assessment, intellectual development, problem solving, school performance, and social adaptation. Significant delays should be evaluated and addressed [132].

Providers should discuss creating an effective learning environment starting with preschool. Low-vision resources should be provided from early childhood. For older children with reduced visual acuity that impacts reading fluency and processing of visual information, adaptations (eg, use of larger print size) in educational and vocational settings may be helpful [133]. Providers should encourage individualized education plans guided by low-vision specialists who should evaluate children in the learning environment to meet ever-changing visual demands. (See "Specific learning disorders in children: Evaluation", section on 'Clinician concerns'.)

As students progress to college age, they take on the role of advocating for their own accommodations. In higher education, accommodations relate to the Americans with Disabilities Act. Providing health information to the school disability office, at the patient's request, may be helpful.

Support groups — More educational information, advice, resources, and support groups for albinism, such as the Global Albinism Alliance and the National Organization for Albinism and Hypopigmentation, are available worldwide.

GENETIC COUNSELING — 

For patients with OCA and their families, genetic consultation is recommended for questions regarding inheritance patterns, recurrence risk, and reproductive options, such as preimplantation genetic diagnosis (PGD). Resources on institutions offering genetic counseling and testing information are available from the American College of Medical Genetics and Genomics.

Persons affected with autosomal recessive OCA are at minimal risk, in general, for a future affected child with an unrelated partner due to a low carrier frequency in the general population. If a person who has albinism chooses a partner who is also a carrier of the same type of OCA, the couple will have a 1:2 chance of having a child with albinism. If a person with OCA chooses a partner with another type of albinism (due to a variant in a different gene), the offspring are not expected to have albinism, but they will carry a heterozygous mutation for both types of albinism (with one allele inherited from each parent).

Parents of a child with albinism are considered obligate carriers and have a 1:4 chance of having another child with albinism in each future pregnancy. Prenatal diagnosis is possible in a family with albinism when the parental carrier mutations are known.

Pseudodominance is a phenomenon that occurs in consanguineous populations or in those with a high carrier frequency. In pseudodominance, an autosomal recessive disorder appears to be autosomal dominant in a pedigree with multiple family members (males and females) in multiple generations affected. This is common for oculocutaneous albinism type 2 (OCA2) in Africa due to the high frequency of OCA2 mutant alleles.

PROGNOSIS — 

Life expectancy for patients with OCA is similar to that of the general population. However, mortality from skin cancer can be increased in populations with limited access to sunscreen and sun protection measures. Although in some types of OCA, especially oculocutaneous albinism type 1B (OCA1B), skin and hair may darken with age, the risk of skin cancer (including melanoma) requires vigilance.

Children with OCA have normal intelligence and normal development with the exception of some delay in visual maturation [134]. An increased rate of attention deficit hyperactivity disorder (unrelated to visual deficit) has been reported in children and adults with albinism [135].

The best-corrected visual acuity improves through the second decade of life for most individuals with albinism [136,137]. Nystagmus typically diminishes in amplitude, and a compensatory head posture may develop to damp nystagmus and place the eyes in position where nystagmus amplitude is reduced or absent (null zone of nystagmus), improving vision. Retinal structure appears to have some plasticity early in life, offering an opportunity for intervention, but once development of the retinal structure is arrested, it does not further improve over time [76,115,138]. Despite this, vision does not usually deteriorate and typically improves [137].

Cataract surgery can be performed without concern beyond the usual for normally pigmented individuals. Because the retinal pigment epithelium typically lacks melanin pigment, treatment of retinal detachment with cryoablation and laser can be challenging, making retinal reattachment difficult in patients with albinism [139,140].

FOLLOW-UP — 

Individuals with OCA need lifelong, periodic skin examinations at 6- to 12-month intervals for early diagnosis and treatment of skin cancer, with special attention for the presence of amelanotic melanoma. Ophthalmic follow-up within the first two years of life may be required at three- to six-month intervals to maintain appropriate optical correction. The frequency diminishes until school age, when annual eye examination is recommended. Adults may require routine examinations every two to three years.

Affected individuals should be offered to update genetics consultation prior to childbearing years.

SUMMARY AND RECOMMENDATIONS

●Definition – Oculocutaneous albinism (OCA) is group of autosomal recessive disorders of melanin biosynthesis presenting with a spectrum of visual disturbances and hypopigmentation of the skin and hair. (See 'Introduction' above and 'Pathogenesis' above.)

●Classification – There are eight known types of nonsyndromic OCA (oculocutaneous albinism type 1 [OCA1] to oculocutaneous albinism type 8 [OCA8]), seven of which are associated with distinct single gene variants (table 1) (see 'Classification and terminology' above). Syndromic OCA includes Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. Hermansky-Pudlak syndrome includes a group of rare autosomal recessive disorders characterized by OCA, a bleeding diathesis due to absence of platelet dense bodies, and other organ involvement. Chediak-Higashi syndrome is a rare, autosomal recessive disorder characterized by recurrent pyogenic infections, partial OCA, progressive neurologic abnormalities, mild coagulation defects, and hemophagocytic histiocytosis. (See "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome".)

●Clinical manifestations – Individuals with OCA are preferentially referred to as "persons with albinism" instead of "albinos." They may face psychosocial challenges, including social discrimination and isolation that may lead to emotional instability, risk of dropping out of school, struggle to form a relationship, and decreased quality of life. (See 'Psychosocial issues' above.)

Individuals with OCA display wide phenotypic heterogeneity, ranging from complete absence of skin, hair, and eye pigmentation in those with oculocutaneous albinism type 1A (OCA1A) (picture 1A); to a variable amount of brown pigmentation in oculocutaneous albinism type 1B (OCA1B) (picture 1B), oculocutaneous albinism type 2 (OCA2) (picture 1C), and oculocutaneous albinism type 4 (OCA4); or a reddish-brown pigmentation in oculocutaneous albinism type 3 (OCA3). Ocular findings common to all types of OCA include dilution of iris pigmentation, photosensitivity, reduced visual acuity, nystagmus, and foveal hypoplasia. (See 'Clinical manifestations' above.)

●Diagnosis

•Clinical – The clinical diagnosis of OCA is based on the presence of skin, hair, and iris hypopigmentation compared with family members and members of the same ethnic group and characteristic ocular changes and vision abnormalities detected on ophthalmologic examination, including photophobia, nystagmus, iris transillumination, foveal hypoplasia, and reduced visual acuity. (See 'Clinical diagnosis' above and 'Ophthalmologic examination' above.)

•Genetic testing – Given the ample phenotypic overlap of different OCA types, genetic testing is generally preferred for a precise diagnosis and is available for most types of OCA (table 1). (See 'Molecular diagnosis' above.)

●Management – The management of patients with OCA involves:

•Sun protection – Strict sun protection beginning from infancy. (See 'Sun protection' above.)

•Early comprehensive eye examination – For all children with OCA, we suggest eye examinations every three to four months within the first two years of life. The first visit should ideally take place at the age of four to six months. The frequency can be reduced to every six months for the next two years, and yearly examinations are appropriate by age 5. (See 'Frequency of eye examination' above.)

•Correction of refractive errors – Amblyogenic levels of refractive errors are common and require treatment with glasses or contact lenses. Early correction of significant refractive errors is associated with improved visual and alignment outcomes. Glasses to fully correct refractive errors are optimally prescribed by four to six months of age. (See 'Correction of refractive errors' above.)

•Providing low-vision resources – Providing an effective learning environment using low-vision resources starting with preschool. Older children will benefit from adaptations (eg, use of larger print size) in educational and vocational settings. (See 'Learning and social concerns' above.)

●Follow-up – Individuals with OCA need lifelong regular skin examination at 6- to 12-month intervals for early diagnosis and treatment of skin cancer. Ophthalmic follow-up within the first two years of life may be required at three- to six-month intervals to maintain appropriate optical correction. The frequency diminishes until school age, when annual eye examination is recommended. (See 'Follow-up' above.)

●Prognosis – Children with OCA have a normal range of intelligence and normal development with the exception of some delay in visual maturation. The best-corrected visual acuity improves through the second decade of life for most affected individuals. Life expectancy is not reduced in nonsyndromic OCA, although mortality from skin cancer can be increased in populations with limited access to sun protection measures. (See 'Prognosis' above.)

●Support groups – Support groups and information sources for persons with albinism, such as the Global Albinism Alliance and the National Organization for Albinism and Hypopigmentation, are available worldwide. (See 'Support groups' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges C Gail Summers, MD, who contributed to earlier versions of this topic review.