Oculocutaneous albinism

INTRODUCTION — Oculocutaneous albinism (OCA) is a group of rare genetic disorders of melanin biosynthesis inherited in an autosomal recessive pattern [1]. Eight types of OCA caused by mutations 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. Some additional rare types of OCA caused by mutations in genes involved in lysosomal biogenesis are associated with systemic abnormalities such as a bleeding disorder (Hermansky-Pudlak syndrome) or a propensity to pyogenic infection (Chediak-Higashi syndrome).

The ocular manifestations, including reduced vision, photosensitivity, 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 [3-8].

This topic will review the pathogenesis, clinical manifestation, 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, likely related to cultural norms [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 Africans, OCA2 is almost always 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 but is extremely uncommon in Africa and 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 (HPS1) [25]. A Danish study of 62 OCA patients identified 26 percent with OCA1, 15 percent with OCA2, and 3 percent with OCA4 [26]. Oculocutaneous albinism type 5 (OCA5) has been reported in a Pakistani family, oculocutaneous albinism type 6 (OCA6) has been described in a Chinese cohort, and oculocutaneous albinism type 7 (OCA7) has been described in a family from the Faroe Islands and in a Lithuanian individual [27-29]. Oculocutaneous albinism type 8 (OCA8) has been described in a French girl and a North African woman [30]. The phenotypic spectrum and prevalence for OCA5, OCA6, OCA7, and OCA8 have not been completely described.

CLASSIFICATION AND TERMINOLOGY — 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) [31]. Syndromic OCA includes 11 types of Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. (See "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome".)

PATHOGENESIS

Defective melanin biosynthesis — OCA is caused by mutations 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 (table 1) [32].

The pigmentation of the hair, skin, and eye depends upon enzymatic biosynthesis of melanin, a complex pigment that absorbs ultraviolet radiation and protects against sun-related skin damage, nonmelanoma skin cancers, and melanoma. The TYR enzyme catalyzes the first step in melanin biosynthesis by oxidizing L-tyrosine to DOPA (dihydroxy-L-phenylalanine). Melanin comprises two main types: eumelanin, colored brown or black, and pheomelanin, colored yellow [33]. Individuals with albinism typically have reduced eumelanin but may have normal levels of pheomelanin in hair [34].

Melanin biosynthesis is compartmentalized within melanosomes, lysosome-like organelles within melanocytes. From the cutaneous basal layer, mature, pigment-filled melanosomes are transferred from melanocytes to keratinocytes by a poorly understood intercellular transfer process to give skin its color. Melanosomes mature through four stages, I through IV. Premelanosomes in stages I and II do not yet contain melanin, whereas stages III and IV are melanized [35]. Gene mutations disrupting enzymes such as TYR in the melanin-synthetic pathway reduce skin, hair, and eye pigmentation. Syndromic forms of albinism with extracutaneous and extraocular features often result from gene mutations 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 (table 1).

In humans, binocular vision requires some nerve fibers from each eye to cross to the opposite side of the brain at the optic chiasm. Several factors present during embryogenesis, including melanin, guide the development of retinal and vascular structures and the routing of ganglion cells in the retina to the lateral geniculate nucleus and on to the occipital cortex [36,37]. When ocular melanin is deficient during embryogenesis, misrouting of the nerve fibers and abnormal foveal development occur. Reduced visual acuity is likely due to a combination of factors (eg, foveal morphology and foveal cone specialization, nystagmus, optic nerve fiber misrouting) [38,39]. Melanocytes derived from the neuroectoderm, located in the posterior iris epithelium and the retinal pigment epithelium, are affected in albinism. 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 affected in albinism.

Genetics — Most types of OCA display autosomal recessive inheritance. There are eight types of OCA (oculocutaneous albinism type 1 [OCA1] to oculocutaneous albinism type 8 [OCA8]), seven of which are associated with distinct single gene mutations (table 1) [32]. The gene for OCA5 has not been identified.

OCA1 is caused by mutations in the TYR genes at the 11q14.3-encoding TYR enzyme. OCA1 is further subdivided into two subtypes: oculocutaneous albinism type 1A (OCA1A; MIM #203100) and oculocutaneous albinism type 1B (OCA1B; MIM #606952). Individuals with OCA1A carry two null (severe) mutations resulting in the complete absence of TYR activity, which causes complete, lifelong absence of melanin pigment in the skin, hair, and eyes (picture 1A). OCA1A is, therefore, considered to be the most severe type of OCA. 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).

Oculocutaneous albinism type 2 (OCA2; MIM #203200) is caused by mutations in the OCA2 (previously called P) gene, which encodes a pH-regulating protein to support melanogenesis. Oculocutaneous albinism type 3 (OCA3; MIM #203290) is caused by mutations in TYRP1 at 9p23. Oculocutaneous albinism type 4 (OCA4; MIM #606574) is caused by mutations in the membrane-associated transporter protein gene (MATP). 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]. Oculocutaneous albinism type 6 (OCA6; MIM #113750) is caused by mutations in SLC24A5, encoding a solute carrier protein [28]. Oculocutaneous albinism type 7 (OCA7; MIM #615179), described in individuals from the Faroe Islands, is associated with mutations in C10orf11, a gene involved in melanocyte differentiation [29]. Variants of the dopachrome tautomerase gene (TYRP2), which encodes an enzyme involved in melanogenesis, have been described in a French girl and a North African woman with OCA8 [30].

PATHOLOGY — The number of epidermal and follicular melanocytes is normal in OCA. Melanosome development is 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 I or II melanosomes and absence of melanin in the retinal pigment epithelium, while mature melanosomes are normally present by week 7 of gestational age [40]. Absence of the fovea and a rod-free zone was found with postmortem pathology of a young boy with presumed OCA1A; stage III melanosomes in the retinal pigment epithelium were normal but reduced in number [41]. Histopathology in an older woman with presumed OCA1A showed absent foveal development, and no melanosomes were identified in the retinal pigment epithelium [42]. Electron microscopic examination of skin samples of a 20-week-old fetus with OCA1 showed melanosomes only up to stage II, consistent with absent melanin synthesis [43]. (See 'Defective melanin biosynthesis' above.)

CLINICAL MANIFESTATIONS — Individuals with OCA 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 (abnormal light reflection through the iris by slit lamp examination), 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 [44].

Ocular findings — Patients with all types of OCA present similar 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.

●Ocular sensitivity to sunlight, resulting in squinting or eyelid closure.

●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.

●Iris transillumination. The light shone into the pupil with a biomicroscope reflects from the posterior lining of the eye through a hypopigmented iris, which is not unique to albinism.

●Reduced melanin pigmentation of the retinal pigment epithelium, which often appears yellowish or orange rather than red.

●Delayed visual maturation or reduced visual acuity for age [10,45,46]. Siblings with albinism often have similar ocular structure, but their visual acuity may differ [47].

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. They may show poor eye contact, representing a delay in visual development [10,45].

Nystagmus typically appears between six and eight weeks after full-term birth; parents may misinterpret nystagmus as a preference to look to the side in "side gaze," which may damp the nystagmus. The amplitude of nystagmus is greater in infants than older children or adults.

Older children tend to hold toys or books closely and may not identify their parents across a room unless they speak. School-age children move close to the board to see it. Adults with OCA report difficulty reading road signs or newspapers without magnification.

Skin and hair — Individuals with OCA have markedly hypopigmented skin and hair compared with other family members. Hypopigmentation is more easily identified in families with highly pigmented skin types.

Children with white hair and lashes at birth likely have oculocutaneous albinism type 1 (OCA1) (table 1). White hair noted at birth may remain 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 shampoos and water minerals, their eyebrows and eyelashes 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 "Chediak-Higashi syndrome".)

Individuals 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 light brown hair and skin and blue-green to brown eyes [48]. White patients with OCA3 are clinically similar to patients with OCA2.

With age, sun-exposed skin becomes rough and thickened with increased actinic keratoses. 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 is the most common type of cancer occurring in OCA patients, but basal cell carcinoma also occurs. Melanoma is thought to be rare and potentially life-threatening; diagnosis is difficult and requires a high index of suspicion [49,50]. Due to reduced pigmentation, melanomas often present as pink or red (amelanotic) lesions, making them difficult to recognize and more advanced at the time of diagnosis [51,52]. Most melanomas in OCA are reported to occur on the back or legs [53,54].

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 upon the presence of the following findings on physical examination and comprehensive ophthalmologic examination [55]:

●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 pigmenting albinism types (all types except oculocutaneous albinism type 1A [OCA1A]) show significant overlap in clinical phenotypes, which makes clinical diagnosis of the type of albinism difficult. In these patients, molecular diagnosis, if available, is important not only for a precise diagnosis but also for accurate genetic counseling and assessment of reproductive risk.

The presence of associated systemic symptoms (eg, bleeding diathesis, pulmonary symptoms, recurrent infections) suggests the diagnosis of syndromic OCA subtypes, such as Hermansky-Pudlak syndrome and Chediak-Higashi syndrome. (See "Hermansky-Pudlak syndrome" and "Chediak-Higashi syndrome".)

Ophthalmologic examination — In patients with suspected OCA, a comprehensive eye examination reveals a constellation of findings that establish the diagnosis (see "Vision screening and assessment in infants and children"). Changes detected in all types of OCA include:

●The perception of poor eye contact and reduced vision for age is common despite reducing illumination and providing best refractive correction [46].

●Nystagmus (horizontal pendular/jerk and/or rotary/torsional or periodic alternating nystagmus) is typically present, with or without a compensatory head posture. The head posture damps the nystagmus (called the null zone), improving vision. At times, the null zone is in primary gaze, and no preferred head posture is identified. Nystagmus is also damped with convergence (eg, with viewing at near ranges) [10]. While siblings with albinism typically have similar ocular structure, visual acuity can be discordant [47,56].

●High refractive errors (hyperopia, myopia, astigmatism) are common [57].

●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 nasal 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 [58].

●Absent or reduced stereoacuity (fine depth perception), often due to strabismus, is frequently seen in OCA patients and can be measured with standard 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 [59].

●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) [60]. 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 5A-B) [44,61]. An annular reflex can be seen in the macula in some individuals with better vision, but an umbo is not usually identified [44,59]. Optical coherence tomography (OCT) provides quick volumetric imaging of the macula to support this finding [38,39,62-64]. Grading of foveal hypoplasia using spectral domain OCT technology is noninvasive and provides an estimation of visual prognosis [38,39,65]. However, some with nearly normal foveal morphology will still have poor visual acuity, suggesting that other factors contribute to vision impairment in albinism [66,67]. 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) (picture 4) [68]. 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 6) [59,69]. Optic nerves typically have a modest, peripapillary halo and minimal to absent cupping due to mild optic nerve hypoplasia [66,70,71].

●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 [72-75]. 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 and positive emission tomography [72-74].

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). (See "Genetic testing".)

As in all autosomal recessive disorders, two mutated copies of the involved gene, each on an opposite allele, must be identified. However, genetic testing results may be suggestive, but inconclusive, in affected individuals who are compound heterozygotes, as only one mutation may be detectable based on current technology [76]. Undetectable mutations are likely to be in a region not covered by 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). In these cases, the diagnosis is based upon clinical features alone. Some patients with clinical features of OCA but negative genetic testing may have other unidentified types of OCA. There is no evidence for digenic inheritance of OCA.

Molecular testing may impact patient management, surveillance, prognosis, and genetic counseling (eg, reproductive planning for a condition that causes disability). As an example, the precise molecular diagnosis of Hermansky-Pudlak syndrome (table 2) may affect the outcome by altering medical management and follow-up recommendations, based on the clinical manifestations associated with specific types.  

Issues related to genetic testing, such as psychosocial issues and practical issues including costs and insurance reimbursement, are discussed separately. (See "Genetic testing".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of OCA includes a number of 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 – Ocular albinism (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 [77]. 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 7). It can be difficult to diagnose OA1 in a male with lightly colored skin and hair (eg, in a child of Scandinavian ancestry) as he may appear to have OCA. Fundus examination of the mother or molecular testing of the patient is helpful. Autosomal recessive oculocutaneous albinism type 3 (OCA3) is genetically heterogeneous and, in many cases, has been shown to be a pigmenting type of OCA with a milder phenotype [78].

●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 (CSNB; 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 [79,80]. Some patients show an FRMD7 mutation, causing the X-linked disorder (also called FRMD7-related infantile nystagmus), while others have an undetermined etiology [81,82]. 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 mutations in AHR [83]. Others with autosomal recessive mutations in SLC38A8 have nystagmus, foveal hypoplasia, abnormal decussation of optic nerve fibers, and, in some, anterior segment dysgenesis (FHONDA; MIM #609218) [84].

●Aniridia – Aniridia is a rare congenital abnormality caused by mutations in the paired box gene 6 (PAX6) [85]. 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 — The differential diagnosis of OCA also includes other disorders associated with hypopigmentation:

●Angelman syndrome and Prader-Willi syndrome – Angelman syndrome (AS; MIM #105830) and Prader-Willi syndrome (PWS; 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. AS and PWS require systemic evaluation and genetic testing to establish the diagnosis. (See "Microdeletion syndromes (chromosomes 12 to 22)", section on '15q11-13 maternal deletion syndrome (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, such as agenesis of the corpus callosum [86]. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Disorders of the corpus callosum'.)

●Waardenburg syndrome type II – Waardenburg syndrome type II is an autosomal dominant disorder with genetic heterogeneity due to mutations in the MITF gene [87]. Patients have congenital sensorineural hearing loss and pigment abnormalities, including iris stromal atrophy, iris heterochromia, and areas of skin hypopigmentation without the finding of telecanthus [88]. (See "The genodermatoses: An overview", section on 'Waardenburg syndrome'.)

●Tietz albinism-deafness syndrome – Tietz albinism-deafness syndrome (MIM #103500) is an autosomal dominant disorder caused by mutations in the MITF gene and characterized by profound congenital sensorineural deafness, white brows and lashes at birth, and hypopigmentation of fundi but with no vision problems [87].

●Hermansky-Pudlak syndrome – 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 light-colored skin [89]. Hermansky-Pudlak syndrome is a rare autosomal recessive disorder characterized by OCA, a bleeding diathesis due to absence of platelet dense bodies, and other organ involvement (eg, lung fibrosis, granulomatous colitis, neutropenia) specific to certain types of Hermansky-Pudlak syndrome. Electron microscopy of platelets shows absence of dense bodies, and molecular typing identifies the risks of associated abnormalities. (See "Hermansky-Pudlak syndrome".)

●Chediak-Higashi syndrome – Chediak-Higashi syndrome (MIM #214500) is a rare autosomal recessive disorder characterized by OCA (picture 2), recurrent pyogenic infections, progressive neurologic abnormalities, mild coagulation defects, and a lymphoma-like accelerated phase. 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 [90]. (See "Syndromic immunodeficiencies", section on 'Griscelli syndrome'.)

●Chlorine channel 7 (CLCN7) gene variant – A single nucleotide variant in CLCN7 was found in two unrelated children (a girl and a boy) 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 [91]. The report indicated that the boy 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 high refractive errors with glasses or contact lenses [92]. Support groups and information sources, such as the World Albinism Alliance and the National Organization for Albinism and Hypopigmentation (NOAH), are available worldwide (table 3). Individuals with albinism are preferentially referred to as "persons with albinism" instead of "albinos."

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

●Seeking shade and avoiding ultraviolet 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 — 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. Patients should also be educated about the following:

●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 (asymmetry, border irregularity, color variegation, diameter >6 mm, evolution) criteria of melanoma. (See "Melanoma: Clinical features and diagnosis", section on 'ABCDE criteria'.)

Any new concerning or changing lesions should prompt a dermatology examination, sooner than the recommended periodic interval. Clinicians should pay special attention to changing pink and red lesions, because in individuals with OCA, melanoma is typically amelanotic [51].

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 without OCA [93]. 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 must be biopsied [94].

Dermoscopy findings in OCA-associated amelanotic melanoma include lineal, irregular vessels and polymorphous-appearing vessels over a central disposition of dotted vessels [95]. One additional study describes orange, structureless areas surrounded by large, yellow to orange clods among polymorphous vessels [96]. Further, clinical use of reflectance confocal microscopy is reported as a useful adjunct to dermoscopy to differentiate melanoma in difficult cases [97].

Management of eye abnormalities — Treatment of the eye abnormalities focuses on improving the quality of life (QOL) [98]. In many cases, the primary goal is to maximize visual function, as reduced vision is identified as the major factor interfering with QOL [2]. Children with suspected albinism should receive a comprehensive eye examination by approximately four to six months of age. Because refractive error changes frequently when children are young, 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 by age 5, yearly exams are appropriate. 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 − High refractive errors are common in albinism and require treatment with glasses or contact lenses [57]. 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 [99]. Prescription glasses changes are frequently needed within the first few years of life.

Many children prefer filtering lenses, including photochromic lenses that darken with exposure to sunlight. Filtering lenses that change with exposure to light do not darken in the car, and sunglasses may be needed when riding in a vehicle. Glasses with ultraviolet protection are desirable. In addition, the side windows of a vehicle may be tinted darker than the windshield. Caps or wide-brimmed hats can also help to alleviate ocular photosensitivity.

●Eye muscle surgery − Eye muscle surgery may be required to restore the alignment of the eyes in those with strabismus [100]. 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 [76,101-106]. At times, surgery may need to be repeated, depending on the eye alignment and the head posture. Oral and topical medicines have also been tried for nystagmus in albinism but have not been particularly successful in improving visual function [107,108].

●Low-vision aids −Bifocals and low-vision aids, such as a lighted magnifying glass, can be helpful to older children. High-contrast, enlarged print can be useful. There are electronic low-vision applications that can assist children and adults in their school and work performance. Evaluation by a low-vision specialist can help to identify these resources, and a teacher for the visually impaired can assure that educational needs are being met. It is rare that an individual with albinism will need to learn braille. Those with greater reduction in vision may benefit from orientation and mobility training.

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. 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 for gender, age, duration of driving experience, and time of day for participation in driving simulation [109], suggesting that individuals with albinism should take care to increase distance in following a lead vehicle. Driver's training for those with low vision may also be considered.

Pharmacologic therapies — Levodopa, an intermediary in melanin biosynthesis, does not seem to improve visual acuity in individuals with albinism. 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 [110]. However, when levodopa was given to a mouse model of human albinism for the first 15 days of life, not only was visual function "rescued" but so was retinal morphology [111].

Another 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 [112]. Studies are needed to evaluate the effects of early levodopa treatment in children with OCA.

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; the group had a statistically significant, but not clinically significant, improvement in visual acuity [113].

Experimental therapies — Early studies of gene therapy in animal models of OCA showed promising results. Subretinal injection of adeno-associated viral (AAV) vector-mediated human TYR gene in a murine model of OCA1 resulted in increased retinal pigmentation [114]. 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 [115].

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 [116].

Providers should discuss creating an effective learning environment starting with preschool. 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 [117].

Students may benefit from an individualized education plan in school (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, at the patient's request, to the school disability office may be helpful.

More educational information, advice, and resources are available through the NOAH and other support groups available worldwide (table 3).

GENETIC COUNSELING — For patients with OCA and their families, genetic consultation can be helpful in answering questions and discussing inheritance patterns, recurrence risk, and reproductive options, such as preimplantation genetic testing. Information on institutions offering genetic counseling and testing information is available from the American College of Medical Genetics and Genomics.

Persons affected with autosomal recessive OCA will have a 1:2 chance of having a child with albinism if they choose a partner who is also a carrier for the same type of albinism. If a person with OCA mates with an individual with another type of albinism (mutations on a different gene), no offspring will have albinism (unless one parent carries a mutant allele for the other parent's type of albinism), but each will carry a heterozygous mutation for both types of albinism with one allele inherited from each parent.

Parents of a child with albinism have a one in four 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 of both sexes 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 [118]. An increased rate of attention deficit and hyperactivity disorder (unrelated to visual deficit) has been reported in children and adults with albinism [119].

The best-corrected visual acuity improves through the second decade of life for most individuals with albinism [120,121]. 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 [61,98,122]. Despite this, vision does not usually deteriorate and typically improves [121].

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 [123,124].

FOLLOW-UP — Individuals with OCA need lifelong, periodic 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. Adults may require routine exams every two to three years.

Patients should be offered to update genetics consultation prior to childbearing years.

SUMMARY AND RECOMMENDATIONS

●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. Eight types of OCA caused by mutations in different genes have been recognized (table 1). (See 'Introduction' above and 'Pathogenesis' 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.)

●The clinical diagnosis of OCA is based upon 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.)

●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.)

●The management of patients with OCA involves strict sun protection beginning from infancy, a comprehensive eye examination early in life, and treatment of refractive errors with glasses or contact lenses. Support groups and information sources are available (table 3). (See 'Management' above.)

●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.)

●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.)

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