Oculocutaneous Albinism Type 1

[OCA1, Tyrosinase-Related OCA. Includes: Oculocutaneous Albinism Type 1A (OCA1A, Tyrosinase-Negative Oculocutaneous Albinism, Tyrosinase-Negative OCA); Oculocutaneous Albinism Type 1B (OCA1B, Yellow Oculocutaneous Albinism, Temperature-Sensitive OCA, Platinum Oculocutaneous Albinism, Minimal Pigment Oculocutaneous Albinism)]

Summary

Disease characteristics.  Oculocutaneous albinism type 1 (OCA1) is characterized by reduced synthesis of melanin in the skin, hair, and eyes, associated with ocular findings of nystagmus, reduced iris pigment with iris translucency, reduced retinal pigment, foveal hypoplasia with significantly reduced visual acuity usually in the range of 20/100 to 20/400, and misrouting of the optic nerves resulting in alternating strabismus and reduced stereoscopic vision. Individuals with OCA1A have white hair, white skin that does not tan, and fully translucent irises that do not darken with age. At birth, individuals with OCA1B have white or very light yellow hair that darkens with age, white skin that over time develops some generalized pigment and may tan with sun exposure, and blue irises that change to green/hazel or brown/tan with age. Visual acuity may be 20/60 or better in some individuals.

Diagnosis/testing.   The diagnosis of OCA1 is established by clinical findings of hypopigmentation of the skin and hair and characteristic eye findings. Molecular genetic testing of the tyrosinase gene, TYR, is clinically available; it is rarely used in diagnosis and is most commonly used in genetic counseling for carrier detection.

Genetic counseling.   OCA1 is inherited in an autosomal recessive manner. 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. Prenatal diagnosis of OCA1 by fetal skin biopsy or molecular genetic testing is possible in pregnancies at 25% risk.

Diagnosis

Molecular Genetic Testing

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Gene.   TYR is the only gene known to be associated with oculocutaneous albinism type 1 [Beermann et al 1990; Giebel, Strunk et al 1991; Jeffery et al 1997].

Most individuals with OCA1 are compound heterozygotes with different maternal and paternal TYR mutations. Large deletions of the TYR gene are rare, with only one being reported [Schnur et al 1996]. No mutations in the proximal promoter of the gene have been identified.

Molecular genetic testing: Clinical uses

• Confirmatory diagnostic testing. Molecular genetic testing is rarely necessary for diagnosis except in those individuals who develop cutaneous and ocular pigment after the first year of life, particularly if the cutaneous pigment is within the normal range for the ethnic background of the affected individual.

• Carrier testing

• Prenatal diagnosis

Molecular genetic testing: Clinical method

• Sequence analysis.   Approximately 85% of TYR disease-causing mutations are identified by sequence analysis of the coding region, the intron-exon boundaries, and several hundred bases of the 5' promoter region and 3' untranslated region [King et al 2003]. The remaining TYR gene mutations are thought to be located in regulatory regions of the gene or in the introns, resulting in alterations in gene transcription [Fryer et al 2003]. To date, techniques have not been developed to identify these mutations. 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.

Table 1 summarizes molecular genetic testing for this disorder.

Table 1. Molecular Genetic Testing Used in OCA1

Test Method	Mutations Detected	Mutation Detection Rate  1		Test Availability
Sequence analysis	TYR mutations	OCA1A	2 mutations: 83% 1 mutation: 17%	Clinical
		OCA1B	2 mutations: 37% 1 mutation: 63%

1.  Mutation detection rates are based on research studies in which sequence analysis was performed on the coding region, the intron-exon boundaries, and several hundred bases of the 5' promoter region and 3' untranslated region in individuals who meet the clinical criteria of OCA1. (The mutation detection rate may be lower if sequence analysis is not performed on all of these gene regions.) Some of the identified mutations affect splice sites and would be missed if adjacent introns were not sequenced [Matsunaga et al 1999, King et al 2003].

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Clinical Description

Individuals with all variations of OCA1 have white or nearly white scalp hair, white skin, and blue irises at birth; the presence of white scalp hair at birth is used as the clinical criterion for OCA1. The definition of "white" scalp hair is not easy in some young children because of sparse, short hair, and because of discoloration that occurs with some shampoos. Parents occasionally 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 is suspected at birth. In families with lighter constitutional pigmentation, the presence of a "tow-headed" child may not seem unusual and the diagnosis of albinism is suspected only after the ocular findings of nystagmus and reduced visual acuity are noted.

Some children with albinism have nystagmus at birth, a finding often noticed by the parents in the delivery room and by the examining physician. Many other children with albinism do not have nystagmus at birth; the parents note slow wandering eye movements and an inability to focus visually, but the absence of nystagmus may delay the diagnosis. Nystagmus develops in most children with albinism by the age of three to four months. The initial diagnosis of albinism is often suggested or made by the ophthalmologist. The nystagmus can be very fast early in life and generally slows with time; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when an individual is tired, angry, or anxious, and less marked when s/he is well rested and feeling good.

Long-term (i.e., over many years) exposure to the sun of lightly pigmented skin can result in coarse, rough, thickened skin (pachydermia), solar keratoses (premalignant lesions), and skin cancer. Both basal cell carcinoma and squamous cell carcinoma can develop. Melanoma is usually rare in individuals with OCA, though skin 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 fact that individuals with albinism often do not spend a great deal of time outside in the sun. Skin cancer in an individual with any type of OCA is very rare in northern areas of the US.

OCA1 is divided into two categories: OCA1A, associated with no melanin synthesis in any tissue, and OCA1B, associated with variable 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 and white skin at birth. The skin stays white throughout life in all ethnic groups and does not tan. Skin lesions such as nevi are pink and unpigmented. The irises are blue and fully translucent at birth and remain so throughout life. Nystagmus continues and the retina does not develop melanin pigment. Visual acuity is usually between 20/100 and 20/400.

• OCA1B.   Affected individuals have white or very light yellow hair at birth and start to develop obvious hair color by the age of one to three years. The development of scalp hair pigment 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 eyebrow hair color develops in a pattern similar to that of the scalp hair, but the eyelash hair often turns darker than the scalp hair.

  
  The skin color remains white but often appears to have developed some generalized pigmentation. Many individuals with OCA1B tan with sun exposure. Pigmented nevi and freckles develop with time.

  
  Iris color may remain blue or change to a green/hazel or brown/tan color. Globe transillumination shows peripupillary clumps or streaks of pigment in the iris that appear like spokes of a wagon wheel. Fine granular pigment may develop in the retina. The development of pigment in the iris or retina does not affect the nystagmus, which persists throughout life. Visual acuity is usually between 20/100 to 20/200, but may be 20/60 or better in some individuals.

Differential Diagnosis

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Albinism.   The ocular features of all types of oculocutaneous albinism (OCA) and X-linked ocular albinism are similar and the terms "OCA" and "albinism" can be used interchangeably when referring to these ocular features. Mutations of the TYR gene are the only known cause of oculocutaneous albinism with white hair, white skin, and blue eyes (OCA1A). As noted in the Clinical Description, the identification of white hair may be difficult because of the sparsity of hair in a young child and the different perceptions of family members as to what qualifies as "white" hair.

The differential diagnosis for individuals with albinism who have pigment in the skin and hair (OCA1B) includes OCA2, OCA3, OCA4, Hermansky-Pudlak syndrome 1-7, and X-linked ocular albinism (OA1). Previous studies suggested the existence of autosomal recessive ocular albinism, presenting with normal skin and hair pigment in males and females in a sibship, but this conclusion may have been incorrect. Individuals with this phenotype are now recognized as being part of the OCA1B or OCA2 spectrum. The existence of another autosomal gene that is related to ocular or oculocutaneous albinism has not been substantiated, although families with OCA that does not map to either the TYR or the P gene loci have been reported in several studies.

OCA2 is caused by mutations in the P gene. Individuals with OCA2 usually have pigmented hair at birth and usually do not tan later in life, but some have been identified who have white hair at birth [Passmore et al 1999, King et al 2003]. They may develop pigmented nevi and freckles, but the skin does not develop generalized pigment. The irises usually develop some pigment that can be seen by the hazel/green to tan/brown color or by globe transillumination.

OCA3 is caused by mutations in the TYRP1 gene (tyrosinase-related protein 1) [Shibahara 1992, Boissy et al 1996]. The phenotype for OCA3 has not been fully determined, except for individuals of African descent.

OCA4 is caused by mutation in the MATP gene (membrane-associated transporter protein), the human orthologue to the mouse Underwhite gene [Newton et al 2001]. OCA4 was initially identified in one male of Turkish origin. Studies now suggest that this is the second most common type of OCA in Japanese individuals [Inagaki et al 2004]. The phenotype is similar to that of OCA2 in Caucasian individuals.

Hermansky-Pudlak syndrome is caused by mutations in one of seven genes: HPS1 [Shotelersuk et al 2000], HPS2/ADTB3A (ß-3A-adaptin)] [Shotelersuk et al 1998], HPS3 [Huizing et al 2001], HPS4 [Suzuki et al 2002], HPS5 [Zhang et al 2003], HPS6 [Zhang et al 2003], and HPS7/dysbindin [Li et al 2003]. All human HPS genes are human homologues to the mouse loci: HPS1 - pale ear, HPS2 - pearl, HPS3 - cocoa, HPS4 - light ear, HPS5-ruby-eyed 2, HPS6- ruby-eyed, HPS7-sandy. In addition to abnormalities of pigmentation, individuals with HPS have a bleeding disorder from a platelet storage pool defect and are at risk of developing pulmonary fibrosis.

X-linked ocular albinism (OA1) is caused by mutations in the OA1 gene. Males with OA1 have normal skin and hair pigment. In families with darker constitutional pigmentation, the normal pigmentation of skin and hair is obvious; in families with lighter constitutional pigmentation, a young boy may be lightly pigmented (even "tow-headed") and appear to have oculocutaneous albinism rather than ocular albinism. Although the correct diagnosis will usually become clear with time, skin biopsy to demonstrate the giant melanosomes in the skin melanocytes can be used to make the diagnosis of OA1 in this situation.

Congenital motor nystagmus.  Congenital motor nystagmus is an autosomal dominant or X-linked dominant disorder in which ocular structure is normal but nystagmus results in reduced visual acuity. Individuals with congenital motor nystagmus often have compensatory head movement (a "head bob") or posture (a "head turn") to reduce the amount of nystagmus and hence to improve acuity. Head bobbing and head turning are less commonly observed in individuals with albinism. Visual evoked potential (VEP) analysis is normal in congenital motor nystagmus. Some individuals with congenital motor nystagmus have been reported to have retinal hypopigmentation and foveal abnormalities, but the studies were done before molecular analysis of the different types of OCA was available, suggesting that these reports may have included individuals with OCA who were incorrectly diagnosed as having congenital motor nystagmus.

Management

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Normal allelic variants: Six polymorphisms of the TYR gene are known. The Y/S192 and the R/Q402 polymorphisms result in amino acid substitutions, while the remaining four do not involve the coding region. The Y/S192 polymorphism has not been associated with any pigmentation phenotype. The R/Q402 polymorphism has been associated with an OCA1B phenotype when found in a compound heterozygote who has a pathologic mutation on the homologous allele, but this association has not been observed in all studies [Gershoni-Baruch et al 1994]. The four noncoding polymorphisms include a (GA)n repeat at -713bp, -301T/C, -199C/A, and a Taq 1 RFLP in intron I.

Pathologic allelic variants: Many mutations of the TYR gene have been reported [Tomita et al 1989; Giebel et al 1990; Kikuchi et al 1990; Takeda et al 1990; Giebel, Musarella et al 1991; Giebel, Strunk, et al 1991; Giebel, Tripathi, King et al 1991; Giebel, Tripathi, Strunk et al 1991; King et al 1991; Oetting, Handoko et al 1991; Oetting, Mentink et al 1991; Spritz et al 1991; Tripathi et al 1991; Giebel & Spritz 1992; King & Oetting 1992; Shibahara et al 1992; Tripathi et al 1992; Oetting, Fryer et al 1993; Oetting, Witkop et al 1993; Tomita 1993; Tripathi et al 1993; Oetting et al 1994; Oetting & King 1994a; Oetting & King 1994b; Spritz 1994; Oetting et al 1995; Spritz et al 1997; Oetting et al 1998; Oetting 2000]. Several have been found to be common to multiple families, while the vast majority have been identified in one or two families.

Normal gene product: Tyrosinase is the key enzyme, catalyzing the initial conversion of tyrosine to dopaquinone, in the melanin biosynthetic pathway. This is a copper-containing enzyme with activity limited to the melanosome within the melanocyte.

Abnormal gene product: Most mutations of the tyrosinase gene are missense mutations that produce enzyme with no catalytic activity (TYR null mutations) associated with the OCA1A phenotype or small amounts of residual catalytic activity (TYR hypomorphic mutations) associated with the OCA1B phenotype [Halaban et al 1997, Halaban et al 2000]. The mechanism for partial activity is unknown and currently under investigation [Berson et al 2000].

Resources

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.

References

Medical Genetics Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.