Clinical Diagnosis

The diagnosis of oculocutaneous albinism type 1 (OCA1) [Creel et al 1990] is established by the presence of the following:

• Hypopigmentation of the skin and hair (including brows and lashes) on physical examination
• Infantile nystagmus (usually noticed between ages 3 and 12 weeks)
• Markedly reduced iris pigment with iris transillumination
• Reduced retinal (pigment epithelial) pigmentation with visualization of the choroidal blood vessels on ophthalmoscopic examination
• Foveal hypoplasia associated with substantial reduction in visual acuity
• Misrouting of the optic nerve fiber projections at the optic chiasm frequently associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visually evoked potentials (VEP)
  
  Note: The VEP is performed with a technique specifically designed to demonstrate selective misrouting; thus, a conventional simultaneous binocular VEP will not demonstrate this anomaly. Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. The VEP is not necessary for the diagnosis of albinism because misrouting is implied by the observation of strabismus and reduced stereoscopic vision. In some persons with mild hypopigmentation (a few with OCA1B) and foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections [Creel et al 1990, Pott et al 2003]. MRI studies may demonstrate misrouting but this approach is not validated sufficiently to replace VEP [Schmitz et al 2003].

Molecular Genetic Testing

Gene. TYR is the only gene in which mutations are known to cause oculocutaneous albinism type 1 [Jeffery et al 1997, Simeonov et al 2013].

Most individuals with OCA1 are compound heterozygotes with different paternal and maternal TYR mutations. No mutations in the proximal promoter of the gene have been identified.

Evidence that additional undetected mutations are responsible for OCA1 comes from individuals with the OCA1A phenotype with only a single identifiable mutation, but who are likely to be compound heterozygotes with a second, as-yet unidentified, mutation.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of OCA1 is usually based on clinical findings, especially for OCA1A. Molecular genetic testing is rarely necessary for diagnosis except in those individuals who develop some cutaneous, hair, and ocular pigment after the first year of life, particularly if the light pigmentation is confused with the clinical appearance of infants and children with OCA2.

Genetically Related Disorders

No phenotypes other than those discussed in this GeneReview are known to be associated with mutation of TYR.

Natural History

Individuals with all variations of OCA1 have white or nearly white scalp hair, brows, and lashes; white skin; and blue irides with extensive transillumination at birth. The presence of white scalp hair at birth should not be the exclusive clinical criterion for OCA1 because some persons with OCA2 may seem exceedingly fair in the first six to twelve months of life as well.

The claim of "white" scalp hair is not universally understood in some infants because of sparse, short hair, and because of the discoloration that occurs with some yellow-tinted shampoos. Parents may describe hair that is light yellow/blond as "white“. In families with darker constitutional pigmentation, the white hair and skin are an immediate indication of hypopigmentation, and the diagnosis of OCA1 may be suspected at birth. In families with lighter constitutional pigmentation, the presence of a "tow-headed" child may not seem unusual and the diagnosis of oculocutaneous albinism may be suspected only after the ocular findings of nystagmus, photodysphoria, and reduced visual function are noted. Indeed, the initial diagnosis of oculocutaneous albinism may be delayed into adolescence until confirmed by an ophthalmologist aware of the spectrum of its clinical features.

Rarely, children with albinism have been reported to have nystagmus at birth; however, most children with albinism develop nystagmus between ages three weeks and three months. The nystagmus can be very rapid in early life but its speed and amplitude generally slow with time; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when an individual is tired, ill, or anxious, and less marked when s/he is well rested.

Many years of unprotected exposure to solar radiation of lightly pigmented skin may result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer, both basal cell carcinoma and squamous cell carcinoma. Melanoma is rare in individuals with OCA, but may occur because dermal melanocytes are present. Skin cancer is unusual in individuals with OCA1 in the US because of the availability of sun screens, the social acceptability of wearing clothes that cover most of the exposed skin, and the reality that individuals with albinism can be educated to minimize unprotected solar exposure. In regions of the planet where solar exposure is extensive and sunscreen difficult to obtain, the malignant cutaneous manifestations of oculocutaneous albinism are life-shortening.

OCA1 is divided into two categories: OCA1A, associated with no melanin synthesis in any tissue, and OCA1B, associated with minimal amounts of melanin synthesis in the hair, skin, and eyes. The ocular features of OCA1A and OCA1B are identical except for the amount of iris pigment.

• OCA1A. Affected individuals have white hair, brows, and lashes, and white skin at birth. The skin stays white throughout life in all ethnic groups and invariably burns but does not tan. Skin lesions such as nevi are pink and unpigmented. The irides are blue and fully translucent at birth and remain so throughout life. Nystagmus continues and the retinal pigment epithelium does not develop melanin pigment. Best correctable visual acuity ranges between 20/100 and 20/400, unless strabismic amblyopia adds to the deficit.
• OCA1B. Affected individuals typically have white or very light off-white (minimally yellow) hair at birth and develop observable light yellow hair color by age one to three years. The development of pigment in scalp hair is progressive and hair color usually goes through the stages of light yellow to light blond to golden blond to dark blond to light brown, but may stop at any color. The color of eyebrow hair is similar to that of the scalp hair, but the eyelash hair often turns mildly darker than the scalp hair.
  
  The skin color remains white and burns in prolonged solar exposure but may develop some generalized tan. Lightly pigmented nevi and freckles appear with time.
  
  Iris color may remain blue or change slowly in adolescence to a green/hazel or light tan color. Fine granular pigment may develop in the retina. The evolution of pigment in the iris and/or retina does not affect the nystagmus, which persists throughout life but does tend to dampen in speed and amplitude with age. Best corrected visual acuity is usually between 20/100 and 20/200, and tends to improve slowly until the late teens.

Some affected individuals report modest improvements in visual acuity over time; however, part of the response may be improved understanding of the ophthalmic acuity tests with maturation of the child. No longitudinal data have been published to firmly assess the frequency or extent of visual “improvement” over time. It is critically important that all parents of affected children realize that, although visually impaired, children with albinism never lose the visual acuity that they achieve, unless an intervening event such as amblyopia occurs.

Genotype-Phenotype Correlations

OCA1A is caused by null mutations of TYR that produce a completely inactive or an incomplete tyrosinase enzyme polypeptide [Gronskov et al 2007, Simeonov et al 2013]. The total lack of tyrosinase enzyme function blocks the first step of the melanin biosynthetic pathway and, thus, no melanin forms in any melanocyte.

OCA1B is caused by mutations of TYR that produce a partially active or hypomorphic tyrosinase enzyme [Gronskov et al 2007, Simeonov et al 2013]. Affected individuals may be homozygous for a single hypomorphic mutation, compound heterozygous for two different hypomorphic mutations, or compound heterozygous for a hypomorphic and a null or inactivating mutation.

Nomenclature

OCA1A is the classic "tyrosinase-negative" OCA phenotype, but the term "tyrosinase-negative OCA" should no longer be used.

In the past, numerous clinical descriptions have attempted to quantitate the amount of pigment in persons with OCA, such as minimal pigment OCA, platinum OCA, temperature-sensitive OCA, and yellow OCA. Still, no universal nomenclature has been established for the various levels of pigmentation resulting from combinations of hypomorphic alleles and, indeed, the overlap of clinical phenotypes with variants of OCA2.

Prevalence

OCA1 is estimated to occur at a frequency of approximately 1/40,000 in most populations throughout the world. Most individuals with OCA1 identified to date are those with OCA1A who are diagnosed by the obvious phenotype. The frequency of OCA1B is unknown.

The calculated carrier frequency for OCA1 is approximately 1/100 in most populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed oculocutaneous albinism type 1 (OCA1), the following evaluations are recommended:

• Complete ophthalmologic evaluation, including assessment for the presence of nystagmus, ocular alignment and strabismus, iris pigmentation and transillumination, dilated retinal examination assessing retinal pigment epithelial hypopigmentation and foveal hypoplasia, and best corrected visual acuity (with cycloplegic refraction);
• Evaluation of the pigmentation status of the skin, especially the solar-exposed skin, and the adnexa (brows, lashes, and when appropriate extremity hair and pubic hair), linked to a (pediatric) dermatologic consultation for sun-protective clothing, lotions, and future self-care;
• Medical genetics consultation to review natural history, pattern of inheritance and recurrence risks, and to clarify genotype.
• Parents should be assured repeatedly that the visual disability with OCA1 does not deteriorate over time, that changes in acuity are usually refractive in nature, that the nystagmus tends to dampen with age (but never disappears), that many children with OCA1B manifest slow improvement in acuity and some plateau by their teen years, and that intellectual disabilities are not a component of this group of disorders.

Treatment of Manifestations

Ophthalmologic care. Correction with spectacles or (when age-appropriate) contact lenses of the refractive errors of either hyperopia or myopia and astigmatism found in most individuals with albinism can optimize visual acuity. Notably, visual acuity is never correctable to normal, but parents should be advised that the achievable acuity never deteriorates.

Strabismus surgery is usually not mandatory but may be performed if the strabismus is marked. Surgery may improve peripheral binocularity or appearance. When an anomalous null point creates a substantial face turn or head tilt, strabismus surgery may reposition the null point to a more central, straight-ahead location to allow more socially acceptable head position. Nystagmus surgery remains highly controversial; no comparative clinical trial has compared the surgical reduction of amplitude of nystagmus to the outcomes of the natural history of dampened nystagmus with age among those forms of albinism in which increasing pigment occurs normally over time.

Photodysphoria (discomfort in bright light; as distinct from ‘photophobia’, which is painful aversion of light associated with intraocular inflammation) is common among all individuals with OCA; however, the severity of discomfort varies and is not completely concordant with the amount of pigment present in the iris or the skin.

• Dark glasses or transition lenses may be helpful, but many individuals with albinism prefer to go without the tint because of the reduction in acuity from the dark lenses. Note: Going without dark glasses does not harm vision.
• Darkly tinted contact lenses do not improve visual function substantively because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens.
• Most children with albinism should remain in mainstream classrooms, as long as the school attends to their special needs resulting from visual limitation. Preschoool evaluations allow teachers and parents to develop an Individual Education Plan (IEP). Neither Braille nor ‘white cane” mobility training is needed in the overwhelming majority of children with albinism.
• Additional classroom aids may include:
• High contrast reading materials (black on white);
• Large font texts or xerographically enlarged worksheets;
• Preferential seating near the front of the class and work boards;
• Selective optical devices, especially mobile ones such as stand magnifiers and monocular telescopes, and closed circuit chip-camera televisions; and
• Computers and tablets with zoom-magnification text software.

A hat with a brim (such as a baseball hat with a visor) is helpful to reduce overhead glare, to reduce some photodysphoria, and to provide some sun protection to the face.

Prevention of Primary Manifestations

Skin care in individuals with OCA1 is guided by the amount of pigment in the skin and the cutaneous response to sunlight.

For individuals with OCA1A, the white skin is completely devoid of melanin and needs to be protected whenever exposed to the sun. Sun exposure as short as five to ten minutes can be substantial in very sensitive individuals, and exposure of 30 minutes or more is usually substantial in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves, pants, and socks) and sun screens with a high SPF value (blocks with SPF 45-50+). Even early in life, a (pediatric) dermatologic consultation is warranted to teach parents about the use of sun-protective clothing and interpretation of the often confusing validity of numerical values and contents of sun-protective lotions and formulas.

For individuals with OCA1B, the amount of skin pigmentation varies and the use of sun screen should correlate with skin pigmentation and the ability to tan. Skin that burns with sun exposure needs protection. An early (pediatric) dermatologic consultation is warranted.

Surveillance

The following are appropriate:

• During the first few years of life, annual ophthalmologic examination, including assessment of refractive error and strabismus
• In adults, dermatologic surveillance of unusual skin thickening, hyperkeratosis, and erosive lesions that may be harbingers of skin cancer

Agents/Circumstances to Avoid

Other than the avoidance of prolonged solar exposure because of the enhanced damage to the skin and increasing cumulative risk of cutaneous neoplasms, no special precautions are needed.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In classic OCA1 of either type, an affected mother who is pregnant needs no exceptional consideration. Similarly, a pregnancy affected with OCA1 requires no exceptional prenatal care.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

OCA1 is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are obligate heterozygotes; therefore, each carries a single copy of a disease-causing mutation in TYR.
• Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

• At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers.
• Once an at-risk sib is known to be unaffected clinically, the risk of his/her being a carrier is 2/3.
• Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. Offspring of an individual with OCA1 are obligate heterozygotes (carriers) for one of the parental disease-causing mutations in TYR.

Other family members of a proband. Each unaffected sib of the proband's parents is at a 50% risk of being a carrier of that parent’s disease-associated mutation.

Carrier Detection

Carrier testing for at-risk family members is possible if both disease-causing mutations in the affected individual in the family have been identified.

Molecular genetic testing is not offered routinely to the reproductive partners of family members identified as carriers because of the difficulty of interpreting test results in an unaffected individual with a negative family history.

Related Genetic Counseling Issues

Rarely, families displaying two-generation “pseudodominant” inheritance have been identified; this results from an affected individual having children with a reproductive partner who is heterozygous (i.e., a carrier).

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like OCA1) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Literature Cited

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Suggested Reading

1. Dessinioti C, Stratigos AJ, Rigopoulos D, Katsambas AD. A review of genetic disorders of hypopigmentation: lessons learned from the biology of melanocytes. Exp Dermatol. 2009;18:741–9. [PubMed: 19555431]
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4. Ray K, Chaki M, Sengupta M. Tyrosinase and ocular diseases: some novel thoughts on the molecular basis of oculocutaneous albinism type 1. Prog Retin Eye Res. 2007;26:323–56. [PubMed: 17355913]
5. Scherer D, Kumar R. Genetics of pigmentation in skin cancer-a review. Mutat Res. 2010;705:141–53. [PubMed: 20601102]

Author History

Richard King, MD, PhD, FACMG; University of Minnesota (1999-2013)
Richard Alan Lewis, MD, MS (2013-present)

Revision History

• 16 May 2013 (me) Comprehensive update posted live
• 1 October 2004 (me) Comprehensive update posted to live Web site
• 3 December 2002 (rk) Revisions
• 16 September 2002 (me) Comprehensive update posted to live Web site
• 19 January 2000 (me) Review posted to live Web site
• 23 July 1999 (rk) Original submission