BOCA, INCLUDED
ALBINISM II ALBINISM, BROWN OCULOCUTANEOUS, INCLUDED
OCULOCUTANEOUS ALBINISM, TYROSINASE-POSITIVE
BROWN OCULOCUTANEOUS ALBINISM, INCLUDED
OCULOCUTANEOUS ALBINISM, TYPE II
OCA2
Tyrosinase-positive oculocutaneous albinism (OCA, type II) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. Although affected infants may appear at birth to have OCA type I, or ... Tyrosinase-positive oculocutaneous albinism (OCA, type II) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in skin, hair, and eyes. Although affected infants may appear at birth to have OCA type I, or complete absence of melanin pigment, most patients with OCA type II acquire small amounts of pigment with age. Individuals with OCA type II have the characteristic visual anomalies associated with albinism, including decreased acuity and nystagmus, which are usually less severe than in OCA type I (Lee et al., 1994; King et al., 2001). OCA type II has a highly variable phenotype. The hair of affected individuals may turn darker with age, and pigmented nevi or freckles may be seen. African and African American individuals may have yellow hair and blue-gray or hazel irides. One phenotypic variant, 'brown OCA,' has been described in African and African American populations and is characterized by light brown hair and skin color and gray to tan irides. The hair and irides may turn darker with time and the skin may tan with sun exposure; the ocular features of albinism are present in all variants (King et al., 2001). In addition, previous reports of so-called 'autosomal recessive ocular albinism,' (see, e.g., Witkop et al., 1978 and O'Donnell et al., 1978) with little or no obvious skin involvement, are now considered most likely to be part of the phenotypic spectrum of OCA1 or OCA2 (Lee et al., 1994; King et al., 2001).
Trevor-Roper (1952, 1963) reported 2 albino parents who had 4 normally pigmented children. Inheritance was most likely autosomal recessive. X-linked albinism could be excluded because the obligate heterozygous daughters of the father did not have mosaic pigmentary patterns ... Trevor-Roper (1952, 1963) reported 2 albino parents who had 4 normally pigmented children. Inheritance was most likely autosomal recessive. X-linked albinism could be excluded because the obligate heterozygous daughters of the father did not have mosaic pigmentary patterns in the ocular fundus. Applying the chemical method of Kugelman and Van Scott (1961), Witkop (1962) found suggestive evidence of different forms of albinism. Witkop (1966) examined Trevor-Roper's family and found that, whereas the mother did not show pigmentation in the Kugelman-Van Scott test, the father did show pigment. Witkop (1966) asserted that it is difficult to distinguish tyrosinase-positive from tyrosinase-negative albinism clinically, especially in Caucasians. Pigmented nevi in tyrosine-positive cases may be the only clue. In blacks with this form of albinism, the hair is yellow and many pigmented spots develop in the skin. In such cases, Witkop (1966) hypothesized a block in the formation of eumelanin with a continuing formation of pheomelanin. Witkop et al. (1978) referred to 4 families in which males and females were equally severely affected with a form of ocular albinism without apparent skin involvement. Affected females had ocular changes similar to those of hemizygous males with X-linked ocular albinism (OA1; 300500). Some of the parents had diaphanous irides. None of the mothers had affected male relatives, and 2 of the families were Amish with consanguineous parents, suggesting autosomal recessive inheritance. The authors noted that ocular albinism had been reported in a female by Scialfa (1972). O'Donnell et al. (1978) observed 7 females and 2 males from unrelated Caucasian kindreds with ocular albinism. Affected individuals showed impaired vision, translucent irides, congenital nystagmus, photophobia, albinotic fundi with hyperplasia of the fovea, and strabismus. Unlike the X-linked form of ocular albinism, females were as severely affected as males, obligatory heterozygotes lacked the mosaic pattern, and skin and hairbulbs did not show giant pigment granules. Autosomal recessive inheritance was suggested. Castle et al. (1988) could demonstrate no asymmetry on monocular testing of visual evoked potentials to suggest an abnormality of decussation in heterozygotes. Witkop et al. (1989) stated that tyrosinase-positive albinism was the form present in the Hopi and Zuni Indians studied by Woolf (1965) and Woolf and Dukepoo (1969). This form was also found in the Brandywine triracial isolate (Witkop et al., 1972). In southern Africa, negroids with tyrosinase-positive ocular cutaneous albinism present with 2 distinctly different phenotypes, with or without darkly pigmented patches (ephelides, or dendritic freckles) on exposed areas of the skin. These phenotypes were concordant within families. Among 111 albinos from southern Africa, Kromberg et al. (1989) found a correlation between the presence of ephelides and a lower risk of developing skin cancer, possibly as the result of the presence of some melanin pigment offering photoprotection. Brown oculocutaneous albinism (BOCA) in humans is linked to the P locus, where mutations causing OCA2 are located. The occurrence of both OCA2 and BOCA within the same family suggested that these disorders are allelic (Manga, 1997). Using MRI, Schmitz et al. (2003) found that the size and configuration of the optic chiasm in humans with albinism are distinctly different from the chiasms of normal control subjects. These chiasmal changes reflect the atypical crossing of the optic fibers, irrespective of the causative gene mutation. Eight patients had tyrosinase gene-related OCA1, 4 patients had P gene-related OCA2, and 1 had ocular albinism (OA1); the albinism-causing mutation had not been identified in 4 other patients. - Clinical Variability Chiang et al. (2008) noted that heterozygous carriers of the common 2.7-kb deletion in the OCA2 gene (611409.0001) from sub-Saharan Africa are not hypopigmented. However, Caucasian individuals with Prader-Willi syndrome (PWS; 176270) or Angelman syndrome (AS; 105830), who are haploinsufficient for the OCA2 gene, often show hypopigmentation. The authors concluded that the phenotype of haploinsufficiency for the OCA2 gene depends upon the genetic pigmentary background of the individual. Chiang et al. (2008) presented a Hispanic family in which the proband with OCA2 was compound heterozygous for the 2.7-kb deletion and another pathogenic mutation in the OCA2 gene. Family members carrying the heterozygous 2.7-kb deletion had mild skin hypopigmentation without ocular defects. The findings suggested that haploinsufficiency of the OCA2 gene can contribute to skin hypopigmentation that may be more obvious in Caucasian or Hispanic populations compared to Africans, who have color above the threshold of distinction. The report of Chiang et al. (2008) was in agreement with the findings of Sulem et al. (2007), who found a role for variations in the OCA2 gene in skin/hair/eye pigmentation (SHEP1; 227220).
In affected members of a consanguineous kindred with OCA2, Durham-Pierre et al. (1994) identified a homozygous 2.7-kb deletion encompassing an exon of the P gene (611409.0001). The kindred was of African, Caucasian, and American Indian descent. The same ... In affected members of a consanguineous kindred with OCA2, Durham-Pierre et al. (1994) identified a homozygous 2.7-kb deletion encompassing an exon of the P gene (611409.0001). The kindred was of African, Caucasian, and American Indian descent. The same deletion allele was identified in unrelated African Americans, Haitian, and Africans with OCA2, suggesting a founder effect. In 4 unrelated patients with OCA2, Lee et al. (1994) identified mutations in the OCA2 gene (see, e.g., 611409.0002-611409.0006). Lee et al. (1994) studied 7 unrelated African American patients with OCA2 and identified different abnormalities of the P gene in all 7. In addition to the single exon deletion found by Durham-Pierre et al. (1994), they observed 2 large deletions, 2 small in-frame deletions, and 6 different point mutations. Stevens et al. (1995) also found that the 2.7-kb intragenic deletion first identified by Durham-Pierre et al. (1994) is a frequent cause of OCA2 in South African negroids, being found in 114 of 146 (78%) of OCA2 chromosomes. A common haplotype was found in 43 of 55 (78%) OCA2 chromosomes studied, confirming the African origin of this allele. On the basis of haplotype data, it appeared that at least 7 additional, less-frequent OCA2 mutations had occurred in this population. Spritz et al. (1995) found that the same 2.7-kb deletion allele accounted for most of the mutant P alleles in Tanzania. The 2.7-kb deletion includes exon 7 and results in a frameshift and premature termination of the predicted polypeptide product. In a screening of filter blood spots from 470 newborn African Americans in Michigan, Durham-Pierre et al. (1996) found that 2 were heterozygous for the 2.7-kb deletion. Kerr et al. (2000) screened the coding region of the P gene for mutations in the non-2.7-kb deletion alleles of OCA2 patients who did not carry the deletion allele in either 1 or both of their P genes. In a group of 39 unrelated black OCA2 patients with a total of 52 non-2.7-kb deletion OCA2 genes, they identified 4 mutations, including A334V (611409.0007). Manga (1997) found that a large proportion (9/10) of BOCA subjects are compound heterozygotes for the common 2.7-kb deletion and another pathogenic mutation in the OCA2 gene. Mutation analysis of the P gene in 10 unrelated individuals with BOCA in southern Africa revealed that 9 had 1 copy of the 2.7-kb deletion. Manga et al. (2001) suggested that the second mutation in the subjects with BOCA may be a milder mutation, possibly in the promoter region (downregulating expression) or in other regions of the P gene they did not screen. Rooryck et al. (2011) stated that rearrangements of the OCA2 gene may be present in about 20% of OCA2 patients, indicating that high-resolution array CGH analysis is important for adequate molecular diagnosis in candidate patients. - Modifier Genes Chiang et al. (2008) reported a Hispanic girl with OCA2 caused by compound heterozygous mutations in the OCA2 gene. She had pale skin, blue irides, and visual defects, including horizontal nystagmus, irides that transilluminated light, absence of foveal reflexes, albinotic fundi, and decreased visual acuity. However, she also had curly reddish-blonde hair, which was unusual for OCA2. The unaffected mother was of Puerto Rican and Cuban descent, and the unaffected father was of Dominican and Ecuadorian descent. Each parent was heterozygous for an OCA2 mutation. Further genetic analysis identified a heterozygous mutation in the TYRP1 gene (S166X; 115501.0002) in the girl and her father. The father, who had haploinsufficiency at the OCA2 and TYRP1 loci together, did not have a noticeable phenotype. Variations in the MC1R gene (155555) associated with red hair (SHEP2; 266300) were not identified. Chiang et al. (2008) concluded that haploinsufficiency of TYRP1 can modify the OCA2 phenotype, resulting in red hair in the absence of MC1R red alleles.
Lee et al. (1994) gave the overall frequency of OCA2 in the United States as approximately 1:36,000; however, the incidence is about 1:10,000 among African Americans and is said to have a prevalence of 1:1,100 in the Ibo ... Lee et al. (1994) gave the overall frequency of OCA2 in the United States as approximately 1:36,000; however, the incidence is about 1:10,000 among African Americans and is said to have a prevalence of 1:1,100 in the Ibo of Nigeria (Okoro, 1975) and a rate of about 1:3,900 in negroids of South Africa (Kromberg and Jenkins, 1982, 1984) where it is the most common recessive genetic disorder of this group. Throughout sub-Saharan Africa, OCA2 is responsible for a great deal of morbidity, with skin cancer and gross visual impairment being important sequelae. Kagore and Lund (1995) found that the prevalence of OCA2 in school children in Harare, the capital city of Zimbabwe, was 1:2,833. On the basis of this prevalence, the gene frequency for OCA2 was estimated to be 0.0188, with a carrier frequency of 1:27. Most of the school children with albinism belonged to the majority Shoney ethnic group. As consanguineous marriages were discouraged in the Shoney culture, this high rate was probably the result of genetic drift in a relatively small population showing limited mobility. Stevens et al. (1997) found the common 2.7-kb P gene deletion (611409.0001) in 10 (1.3%) of 780 OCA2 chromosomes in a normally pigmented southern African population, and at a lower frequency in normally pigmented individuals from central Africa, 2 (0.2%) of 834 OCA2 chromosomes. Among OCA2-affected individuals, the deletion was found in 131 (77%) of 170 OCA2 chromosomes in southern Africa, 11 (79%) of 14 OCA2 chromosomes in Zambia, and 4 (33%) of 12 OCA2 chromosomes in the Central African Republic. The study confirmed the African origin of the deletion allele. Haplotype analysis suggested that the deletion mutation occurred only once and that it arose before the divergence of these African populations, which was estimated to be about 2,000 to 3,000 years ago. The unusually high frequency of OCA2 mutations, in particular the 2.7-kb deletion, suggested selection or genetic drift. A high frequency of albinism has been found among several Native American populations, varying in frequency from 1:140 in the Jemez to 1:3,750 in the Navajo (Woolf, 1965; Woolf and Dukepoo, 1969). Yi et al. (2003) studied albinism among the Navajos, who live predominantly in northeastern Arizona. The phenotype of albinism in the Navajos overlaps those for OCA2 and for OCA4 (606574), which are caused by mutations in the P and MATP (SLC45A2; 606202) genes, respectively. Consequently, Yi et al. (2003) did a mutation screen of these 2 genes. Although no mutations were found in the MATP gene, all Navajos with albinism were found to have a homozygous deletion of 122.5 kb of genomic DNA, including exons 10 through 20 of the P gene (611409.0008). The deletion allele was not found in 34 other individuals with albinism who had other Native American origins, and had not been reported in any other ethnic group. The molecular characterization of the deletion allele allowed Yi et al. (2003) to design a 3-primer PCR system to estimate the carrier frequency in the Navajo population, an estimated 4.5%. The estimated prevalence of OCA2 in Navajos is between 1:1,500 and 1:2,000. They estimated that this mutation originated from a single founder 400 to 1,000 years ago. Suzuki et al. (2003) performed mutation analysis on 40 OCA1-negative Japanese albino patients and identified 6 different novel mutations in 6 unrelated patients. They estimated the frequency of OCA2 in the Japanese albino population to be 8%, indicating that OCA2 was not as common as OCA1. Thirty-four patients remained as unclassified OCA, supporting the idea that a third locus might be a major contributor to OCA. Rooryck et al. (2011) identified a 184-kb deletion in the OCA2 gene (611409.0015) as a founder mutation in 3 unrelated patients of Polish ancestry with OCA2. Sequence analysis indicated that the 2 breakpoints were located in repeat-rich regions containing numerous Alu and L1 repeats, suggesting nonhomologous end joining (NHEJ) as the molecular mechanism.
The diagnosis of oculocutaneous albinism type 2 (OCA2) [King et al 2001a] is established by presence of the following: ...
DiagnosisClinical DiagnosisThe diagnosis of oculocutaneous albinism type 2 (OCA2) [King et al 2001a] is established by presence of the following: Hypopigmentation of the skin and hairCharacteristic ocular changes found in all types of albinism, including the following findings detected on complete ophthalmologic examination: Infantile nystagmus (usually noticed between ages three and 12 weeks of lifeReduced iris pigment with iris transilluminationReduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examinationFoveal hypoplasia associated with reduction in visual acuityMisrouting of the optic nerve fiber projections at the chiasm associated with strabismus (that may not develop until later in infancy), reduced stereoscopic vision, and altered visual evoked potentials (VEP). Note: (1) The VEP is performed with a technique specifically designed to demonstrate the selective misrouting; a standard (conventional) simultaneous binocular VEP will not demonstrate this anomaly. (2) Normal routing of the optic nerves, demonstrated with a selective VEP, excludes the diagnosis of albinism/OCA. (3) A VEP is not necessary for the diagnosis of albinism because misrouting is implied by the finding of strabismus and reduced stereoscopic vision. In some individuals, particularly those who have near normal amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be a useful adjunct to demonstrate misrouting of the retinal to occipital projections.The clinical diagnosis of OCA is usually made in an individual who has poor visual fixation and/or reduced visual acuity early in life, and nystagmus, associated with hypopigmentation of the skin, hair, and eye. The diagnosis is often suspected by the pediatrician at the two- or four-month well-baby check-up, and the diagnosis is usually established after a thorough medical eye examination by an ophthalmologist. Molecular Genetic TestingGene. OCA2 (previously called P) is the only gene in which mutations are known to cause oculocutaneous albinism type 2 [Gardner et al 1992, Rinchik et al 1993, Brilliant et al 1994, Kedda et al 1994, Lee et al 1995]. Clinical testing Targeted mutation analysisSequence analysis. Most non-Africans with OCA2 are compound heterozygotes. Approximately one third of the reported non-African individuals have only one mutation detectable by sequence analysis of the coding region, the intron-exon boundaries, and several hundred bases of the 5' promoter region and 3' untranslated region of OCA2 [Oetting & King 1999, King et al 2001a, King et al 2001b, Gargiulo et al 2011]. To date, no mutation has been reported beyond 20 bp into the intron region of an exon/intron boundary. Approximately 20% of all individuals who have complete sequencing of the entire coding sequences and the flanking intron sequences have shown only one pathogenic mutation. Cryptic splice sites or mutations in regulatory regions could affect transcriptional regulation [King et al 2001a]. Table 1. Summary of Molecular Genetic Testing Used in Oculocutaneous Albinism Type 2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityOCA2Targeted mutation analysis 2.7-kb deletion Most individuals of sub-Saharan African heritage; less common in other populations 2Clinical Sequence analysis 3 OCA2 sequence variations other than 2.7-kb and other large deletions 4UnknownDeletion / duplication analysis 52.7-kb deletion and other exonic or whole-gene deletions 6Unknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Most individuals of sub-Saharan African heritage with OCA2 are homozygous for a common 2.7-kb deletion. The 2.7-kb deletion is less common in the US African American population and has been found in the Puerto Rican population [Kedda et al 1994, Spritz et al 1995, Stevens et al 1995, Durham-Pierre et al 1996, Puri et al 1997, Stevens et al 1997, Kerr et al 2000, Santiago Borrero et al 2006].3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.4. The majority of mutations in the non-African heritage population are missense mutations, but deletions of one or a small number of bases and base changes in introns are common. The missense mutation p.Ala481Thr has been described in the Japanese population; normally pigmented individuals who are homozygous and individuals who are compound heterozygous for this mutation have been identified [Saitoh et al 2000, Suzuki et al 2003b, Ito et al 2006]. This mutation was associated with substantial residual function of the P protein (hypomorphic mutation) and may not in itself be sufficient to cause OCA2 [Sviderskaya et al 1997, Suzuki et al 2003a]. The p.Val443Ile missense mutation is the most common mutation in the northern European populations. A common 122.5-kb deletion mutation found in the Navajo population is associated with a high prevalence of OCA2 in this population [Yi et al 2003]. 5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.6. See Table A, LSDB and HGMDInterpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband. To confirm a firm clinical diagnosis (with concordance between the dermatologic and ophthalmologic features), perform complete sequence analysis of OCA2.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: (1) Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. (2) Although some adult carriers may manifest clinically insignificant punctate iris transillumination defects at diligent biomicroscopic examination, a fraction of the normal population also does (depending on ethnic or national origin), thus making this observation useless for clinical counseling.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of both disease-causing mutations in an affected member of the family.Genetically Related (Allelic) DisordersNo other type of albinism or genetic form of congenital hypopigmentation has been associated with mutations of OCA2. Prader-Willi syndrome (PWS) and Angelman syndrome(AS).OCA2 is located in the region of chromosome 15q involved in causation of Prader-Willi syndrome (PWS) and Angelman syndrome (AS). Individuals with PWS or AS are often hypopigmented, with lighter hair and skin pigmentation than that of unaffected family members, but the ocular features of albinism, including nystagmus and the lack of foveal development, are usually absent or not completely manifest [Wiesner et al 1987, King et al 1993, Smith et al 1996, Thompson et al 1999, Mah et al 2000, Saitoh et al 2000]. The hypopigmentation correlates with the occurrence of a deletion of 15q11.2-q12 (on one allele) that includes the OCA2 locus [Nicholls et al 1996]. Individuals with PWS and AS with the ocular features of albinism have been reported; molecular studies indicate that an independent OCA2 mutation is present on the non-deleted chromosome 15 in the reported individuals [Horsthemke et al 1997, Fridman et al 2003], thus resulting in manifestation of the more complete phenotype. A paradox exists in the association of OCA2 and pigmentation, with no explanation at present: individuals with PWS or AS with a deletion are hypopigmented, suggesting that haploinsufficiency of the P protein may be involved (OCA2 is not imprinted in this region). Individuals who are heterozygous for an OCA2 mutation in a typical family with OCA2 have haploinsufficiency for functional P protein; however, they are normally pigmented, including those who are heterozygous for the 2.7-kb deletion mutation in the sub-Saharan African population. Single-nucleotide polymorphisms of OCA2 are also associated with normal variation in eye and skin color [Rebbeck et al 2002, Frudakis et al 2003, Duffy et al 2004, Sturm & Frudakis 2004, Zhu et al 2004, Duffy et al 2007, Lao et al 2007, Norton et al 2007, Yuasa et al 2007a, Yuasa et al 2007b]. Skin and eye color appear to be under multigenic control [Barsh 2003, Frudakis et al 2003, Shriver et al 2003, Sturm & Frudakis 2004, Duffy et al 2007], with variation in OCA2 having the predominant effect both evolutionarily and physically [Frudakis et al 2003, Duffy et al 2004, Sturm & Frudakis 2004, Zhu et al 2004, Duffy et al 2007].
The amount of cutaneous (including hair, lash, brow, and iris) pigmentation in OCA2 forms a continuum from minimal to near normal [King et al 2001a, King et al 2001b]. No established categories or subtypes, as in oculocutaneous albinism type 1 (OCA1), exist for OCA2. Newborns nearly always have some yellow or tan color in the hair, eyebrows, and lashes. The ocular features of all types of OCA2 are identical except for the density of iris and retinal pigment present. The phenotypic range of pigmentation is also dependent on the ethnic background of the family, and individuals with OCA2 from families with darker constitutional pigmentation generally tend to be more pigmented than those from families with lighter constitutional pigmentation; however, the spectrum of the variations precludes the predictive clinical utility of this generalization....
Natural HistoryThe amount of cutaneous (including hair, lash, brow, and iris) pigmentation in OCA2 forms a continuum from minimal to near normal [King et al 2001a, King et al 2001b]. No established categories or subtypes, as in oculocutaneous albinism type 1 (OCA1), exist for OCA2. Newborns nearly always have some yellow or tan color in the hair, eyebrows, and lashes. The ocular features of all types of OCA2 are identical except for the density of iris and retinal pigment present. The phenotypic range of pigmentation is also dependent on the ethnic background of the family, and individuals with OCA2 from families with darker constitutional pigmentation generally tend to be more pigmented than those from families with lighter constitutional pigmentation; however, the spectrum of the variations precludes the predictive clinical utility of this generalization.Individuals with OCA2 are usually recognized within the first few months of life because of the ocular features of nystagmus and strabismus. In many families, particularly in those with darker constitutional pigmentation, the cutaneous hypopigmentation is also obvious at birth and suggests the diagnosis. Eye. A few children with albinism have nystagmus at birth that is noticed by the parents and by the examining physician in the delivery room. However, most children with albinism do not have nystagmus at birth and the parents note slow wandering eye movements and a lack of visual attention. The parents may become concerned because the child does not seem to focus well, but the lack of nystagmus may delay the diagnosis. Most children with albinism develop nystagmus before age three to four months, and the diagnosis is often raised at the two- to four-month well-baby checkup. The nystagmus, which can be rapid early in life, generally slows during the first decade; however, nearly all individuals with albinism have nystagmus throughout their lives. Nystagmus is more noticeable when the individual is tired, angry, or anxious, and less marked when they are well rested and feeling well. For some, the nystagmus has a ‘null-point’ or direction of gaze in which the movement is minimized, leading to a compensatory face-turn that may be socially disconcerting and may lead to eye-muscle surgical intervention as the child matures.The strabismus found in most individuals with albinism is usually not associated with the development of amblyopia unless the often substantial refractive errors are ignored in infancy and childhood. Iris color ranges from blue to brown; the extreme iris transillumination associated with diaphanous light ‘grey-blue’, ‘pink’, or ‘ruby’ eyes seen with the OCA1A subtype of OCA1 is typically not present in OCA2. However, transillumination of the globe and/or the iris in a darkened room will be seen by the careful and skilled observer.Visual acuity in OCA2 is generally better than that in OCA1 (and always better than in OCA1A), but overlap is observed [Summers 1996, King et al 2001a, King et al 2001b]. Final (adult) visual acuity for individuals with OCA2 ranges from 20/25 to 20/200 and is usually in the range of 20/60 to 20/100. Best corrected visual acuity is stable after early childhood and never deteriorates (although refractive errors may change). Any loss of vision later in life should be explainable by changes in refraction, development of cataract, or causes unrelated to albinism. Skin/hair. The range of skin pigment in OCA2 is broad [Okoro 1975, Lund et al 1997, King et al 2001a, King et al 2001b, Manga et al 2001]. Individuals with OCA2 are almost always born with lightly pigmented hair; hair color at birth or the first few months of life can range from light yellow to blond to brown. The scalp hair may be light yellow, particularly in individuals of northern European ancestry. The scalp hair is never completely white; some parents may refer to the hair color as "white" or "nearly white" if it is very lightly pigmented. Scalp, brow, lash, and pubic hair color will usually darken with time but often with no substantive change in color after adolescence. Some individuals of northern European ancestry who have OCA2 have red rather than blond hair and typical ophthalmologic findings [King et al 2003b]. "Brown OCA," initially characterized in the African (of Nigerian and Ghanan ancestry) and African American population, is now recognized as part of the spectrum of OCA2; individuals with the “brown” phenotype in these populations are born with light brown hair and skin, but individuals from other populations (northern European, Asian) with the ocular features of albinism can have moderate to near-normal cutaneous pigmentation and only appear hypopigmented when compared to sibs and other family members [Manga et al 2001, King et al 1985]. When hair color is ‘blond’ or yellow, the skin usually has little generalized pigmentation and the skin color is creamy white. It should be noted that skin color in OCA2 is not as ‘white’ as that found in the OCA1A subtype of oculocutaneous albinism type 1, reflecting the fact that the melanocytes in the skin of individuals with OCA2 still can synthesize some melanin (as seen with the pigmented hairs), but that most melanin is yellow pheomelanin rather than black-brown eumelanin. With the OCA2 brown phenotype, generalized skin pigmentation is present and may darken over time and with sun exposure. Skin color is usually lighter than that of sibs and unaffected relatives. Skin cancer risk. 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 may occur. Melanoma is rare in individuals with OCA2, even though skin melanocytes are present. Skin cancer is unusual in individuals with all forms of OCA in the US because of the availability of sunscreens and the social acceptability of wearing clothes that cover the exposed skin, and because individuals with albinism often avoid prolonged time outside in the sun. In contrast, skin cancers in individuals with albinism are common in parts of the world such as sub-Saharan Africa because of the increased amount of sun exposure through the year, the cultural differences in protective dress, and the lack of skin-protective agents [Okoro 1975].
The lack of a functional assay for the activity of the protein product of OCA2 and the limited availability of data from OCA2 molecular genetic testing make genotype-phenotype correlations difficult [Sviderskaya et al 1997]. ...
Genotype-Phenotype CorrelationsThe lack of a functional assay for the activity of the protein product of OCA2 and the limited availability of data from OCA2 molecular genetic testing make genotype-phenotype correlations difficult [Sviderskaya et al 1997]. Genotype-phenotype correlations are not useful clinically and the amount of cutaneous pigmentation, ocular pigmentation, and visual development resulting from particular mutations of this gene cannot be predicted with any certainty. The 2.7-kb deletion Homozygosity for the 2.7-kb deletion mutation in the African and African American populations is associated with yellow/blond hair, creamy tan skin, and blue-to-tan irides, but this phenotype varies even in those who are homozygous for this mutation. African individuals with the "brown" phenotype are usually compound heterozygotes for this deletion mutation; the mutation on the homologous OCA2 allele has not been identified. In contrast, African American individuals with the "brown" phenotype can be compound heterozygous for two missense OCA2 mutations. The p.Val443Ile mutation is associated with residual function of the P protein (encoded by OCA2) and progressive development of cutaneous pigment with time in the affected individual [Saitoh et al 2000]. Individuals with OCA2 and red hair have common variants of MC1R, the gene encoding melanocortin-1 receptor [Sturm et al 2001, King et al 2003b].
Differential DiagnosisTable 2. Oculocutaneous Albinism: OMIM Phenotypic SeriesView in own windowPhenotypePhenotype MIM NumberGene/LocusGene/Locus MIM NumberAlbinism, brown oculocutaneous 203200 OCA2, P, PED, D15S12, BOCA, EYCL3, HCL3, SHEP1 611409 Albinism, oculocutaneous, type 1A 203100 TYR, SHEP3, CMM8 606933 Albinism, oculocutaneous, type 1B 606952 TYR, SHEP3, CMM8 606933 Albinism, oculocutaneous, type 2 203200 OCA2, P, PED, D15S12, BOCA, EYCL3, HCL3, SHEP1 611409 Albinism, oculocutaneous, type 3 203290 TYRP1, CAS2, GP75 115501 Oculocutaneous albinism, type 4 606574 SLC45A2, MATP, AIM1, SHEP5 606202 Oculocutaneous albinism, type 2, modifier of203200 MC1R, SHEP2, CMM5 155555 Data from Online Mendelian Inheritance in ManAlbinism. OCA can also be caused by mutations of TYR (OCA1), TYRP1 (OCA3), MATP (OCA4), at least seven genes associated with Hermansky-Pudlak syndrome (HPS 1-7), LYST (Chediak-Higashi syndrome), MYO5A (Griscelli syndrome type 1), and RAB27A (Griscelli syndrome type 2).Clinically, albinism is associated with the development of some cutaneous pigmentation (except in OCA1A), and the differential diagnosis for individuals with albinism who have pigment in their skin and hair includes the OCA1B subtype of oculocutaneous albinism type 1, OCA2, OCA3, OCA4, Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome, Griscelli syndrome, and X-linked ocular albinism (OA1). The diagnosis of albinism is made with an ophthalmologic examination. Different types can be distinguished in the following manner: A careful history of pigment development usually identifies individuals with OCA1. Molecular studies can distinguish OCA2 and OCA4A detailed medical history focused on bleeding or bruising and an analysis of platelet dense bodies are necessary to establish the diagnosis of HPS. A detailed medical history of recurrent infections and an examination of peripheral leukocytes may reveal findings that suggest the diagnosis of Chediak-Higashi syndrome. The presence of pancytopenia, immunodeficiency, hemophagocytic syndrome, and/or demyelination of the white matter of the brain suggest the diagnosis of Griscelli syndrome.Many of the ocular features of oculocutaneous albinism (OCA) and X-linked ocular albinism (OA1) (also known as Nettleship-Falls ocular albinism) are similar; however, the two conditions are separable molecularly, if not clinically. Males with X-linked ocular albinism (OA1) typically have less pigment in their skin, scalp, brow, and lash hair than their unaffected sibs and immediate relatives. However, this may be a difficult clinical judgment in some families: the distinction is obvious in families with darker constitutional pigmentation, but in families with light constitutional pigmentation, a young boy may have light hair (even be "tow-headed") and appear to have oculocutaneous albinism rather than ocular albinism. The correct diagnosis becomes clear when the ophthalmologist dilates the pupils of the eyes of the mother of a male child and finds the classic mosaic retinal pigmentation of the X-linked carrier state. A skin biopsy to demonstrate giant melanosomes by electron microscopy (EM) in the skin was used in the past to make the diagnosis of OA1 in this situation; OA1 molecular genetic testing is now possible, offering a more objective (and less invasive) diagnosis.The existence of another autosomal gene that is related to ocular or oculocutaneous albinism has not been substantiated, although families with OCA that do not map to the loci for TYR (OCA1), OCA2 (OCA2), or MATP (OCA4) have been reported in several studies. Mutations of TYRP1, the gene encoding tyrosinase-related protein-1, are associated with rufous or red OCA3 [Durham-Pierre et al 1994]; this phenotype has been described only in the African population. Although individuals with red skin and light hair have been described in Papua, New Guinea, the association of this phenotype with red/rufous OCA found in Africa is unknown. Affected individuals in Papua, New Guinea have nystagmus and reduced visual acuity, but the retina is normally pigmented and foveal hypoplasia is not present [Hornabrook et al 1980]. Molecular studies of individuals with this phenotype are not available.Naturally blond hair is rare in humans and found almost exclusively in Europe and Oceania. Recently an arginine-to-cysteine change at a highly conserved residue in tyrosinase-related protein 1 (TYRP1) was found as a major determinant of blond hair in Solomon Islanders. This missense mutation is predicted to affect catalytic activity of TYRP1 and causes blond hair through a recessive mode of inheritance. The mutation, occurring at a frequency of 26% in the Solomon Islands, is absent outside of Oceania [Kenny et al 2012].Congenital motor nystagmus presents as infantile nystagmus associated with reduced visual acuity FRMD-related infantile nystagmus. Some individuals with congenital motor nystagmus have been reported to have retinal hypopigmentation and foveal abnormalities; however, the studies were done before the molecular analysis of the different types of OCA was available, suggesting that they may have included individuals with OCA who were diagnosed incorrectly with congenital nystagmus. The visual evoked potential analysis to evaluate misrouting of the optic nerves is normal in congenital motor nystagmus. A single X-linked gene, FRMD7, for ‘congenital infantile nystagmus’ has been reported [Tarpey et al 2006, Self et al 2007].Additional confusion may occur in infants with blue cone monochromacy (males) [red green color vision defects] or rod monochromacy [achromatopsia] (both genders), in which nystagmus begins early in life, the foveas are underdeveloped, and myopia is common, leading to an exaggerated impression of underpigmentation of the retina. The severe loss of color perception clinically and the electroretinographic responses of abnormal cone and rod signals should separate these two entities from the albinisms.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease and needs of an individual diagnosed with oculocutaneous albinism (OCA), the following evaluations are recommended:...
ManagementEvaluation Following Initial DiagnosisTo establish the extent of disease and needs of an individual diagnosed with oculocutaneous albinism (OCA), the following evaluations are recommended:Evaluation of the pigmentation status of the skin and adnexa (eyebrows, eyelashes, and where appropriate, pubic hair) Medical genetics consultationTreatment of ManifestationsCorrection of refractive errors 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. Of note, visual acuity is never correctable to normal. Strabismus surgery is usually not mandatory (because the strabismus in most individuals with albinism is not associated with the development of amblyopia); however, if the strabismus is marked or fixed, surgery can be considered to improve peripheral binocular fusion or appearance. When an anomalous null point creates a substantial face turn, strabismus surgery may reposition the null point into a more central, straight-ahead location to allow more socially acceptable head position.Photodysphoria (discomfort in bright light; as distinct from ‘photophobia, painful aversion of light associated with intraocular inflammation) is common among 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 vision from the dark lenses. Note: Going without dark glasses does not harm vision. Darkly tinted contact lenses do not improve visual function because the reduction of transmission of the thin contact lens is no match for the density of a tinted spectacle lens. A hat with a brim (such as a baseball hat with a visor) is helpful to reduce overhead glare and to reduce some photodysphoria and to provide some sun protection to the face. Skin care in OCA2 is determined by the amount of pigment in the skin and the cutaneous response to sunlight. Individuals with white skin that does not tan need to be protected from any prolonged sun exposure for prevention of burning, skin damage, and skin cancer. This can be for exposures as short as five to ten minutes in highly sensitive individuals and 30 minutes or more in less sensitive individuals. Prolonged periods in the sun require skin protection with clothing (hats with brims, and long sleeves, pants, and socks) and appropriate sunscreens after the guidance and education from a dermatologist.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 numerical values and contents of sun-protective lotions and formulas. Skin cancer is treated as for the general population. Prevention of Primary ManifestationsNo dietary or ophthalmologic procedures or exercises will prevent or alter the clinical features of albinism. SurveillanceThe following are appropriate:Annual ophthalmologic examination and reassessment and accurate correction of refractive errors, and related strabismus or face turnAnnual to biennial search for evidence of sun-related skin damage and pre-cancerous or cancerous lesions, especially in areas of high intensity or prolonged sunlight exposureAgents/Circumstances to AvoidProlonged unprotected sun exposure should be avoided.Evaluation of Relatives at RiskRelatives at risk for OCA2 can be identified by clinical findings (hypopigmentation and eye features); additional testing is not indicated. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementNo form of classic OCA impairs fertility or compromises pregnancy or gestation. An obligate carrier (heterozygous) fetus of a mother with OCA2 faces no additional risks over an unaffected fetus of an unaffected mother.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Oculocutaneous Albinism Type 2: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDOCA215q12-q13P proteinAlbinism Database Mutations of the P gene Retina International Mutation Database Mutations of the P-GeneOCA2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Oculocutaneous Albinism Type 2 (View All in OMIM) View in own window 203200ALBINISM, OCULOCUTANEOUS, TYPE II; OCA2 611409OCA2 GENENormal allelic variants. Mutations and variants are listed in the Albinism database. OCA2 reference sequence NM_000275.2 has 24 exons. More than 42 normal allelic variants have been described in many exons and introns throughout the gene. Pathologic allelic variants. See Albinism database and HGMD and other LSDB (Table A). More than 147 OCA2 mutations have been reported [Lee et al 1994a, Lee et al 1994b, Spritz et al 1997, Oetting et al 1998, Oetting & King 1999, Passmore et al 1999, Kerr et al 2000, Kato et al 2003, King et al 2003a, Suzuki et al 2003a, Suzuki et al 2003b; Yi et al 2003, Ito et al 2006, Hongyi et al 2007, HGMD (www.hgmd.cf.ac.uk, accessed 15 June 2012]. Most are missense mutations, but deletions of one or a small number of bases and base changes in introns are common. The most common OCA2 mutation is the 2.7-kb deletion mutation in the African and African American populations. The p.Val443Ile amino acid substitution is the most common in the northern European populations. Most individuals with OCA2 are compound heterozygotes for OCA2 mutations, with different maternal and paternal mutations, and approximately half of the non-African reported individuals have only one identifiable mutation; the second mutation was not detected by the methods used. (For more information, see Table A.)Normal gene product. The protein product of OCA2, known as the P protein, is a transmembrane protein found in the melanosomal membrane [Brilliant et al 1994, Rosemblat et al 1994, Lee et al 1995]. The precise function of the P protein is unknown. Studies supporting a role in maintenance of proper intramelanosomal pH or in the melanosomal structural matrix have been reported [Brilliant 2001]. The P protein (NP_000266.2) has 838 amino acid residues.Abnormal gene product. Few studies are available on mutant P protein. The full-length normal human OCA2 cDNA or OCA2 cDNA-containing mutations associated with OCA2 (p.Ala481Thr, p.Val443Ile) have been expressed in mouse melanocytes derived from an animal with a mutation in the murine homologue (pink-eyed dilution or p) of OCA2 [Sviderskaya et al 1997]. The murine cells with the normal cDNA synthesized significantly more melanin than did those with the p.Ala481Thr mutation construct, and those with the p.Val443Ile construct synthesized a minimal amount of melanin. The mechanisms by which the mutant protein alters the ability of the cell to synthesize melanin are unknown.