Clinical characteristics.

Oculocutaneous albinism type 4 (OCA4) is characterized by hypopigmentation of the hair and skin plus the characteristic ocular changes found in all other types of albinism, including: nystagmus; reduced iris pigment with iris translucency; reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination; foveal hypoplasia associated with reduction in visual acuity; and misrouting of the optic nerves at the chiasm associated with alternating strabismus, reduced stereoscopic vision, and an altered visual evoked potential (VEP). Individuals with OCA4 are usually recognized within the first year of life because of hypopigmentation of the hair and skin and the ocular features of nystagmus and strabismus. Vision is likely to be stable after early childhood. The amount of cutaneous pigmentation in OCA4 ranges from minimal to near normal. Newborns with OCA4 usually have some pigment in their hair, with color ranging from silvery white to light yellow. Hair color may darken with time, but does not vary significantly from childhood to adulthood.

Diagnosis/testing.

Because the phenotype of OCA4 overlaps that of the other genetic forms of albinism (oculocutaneous and ocular), the diagnosis of OCA4 is established by molecular genetic testing with the identification of biallelic pathogenic variants in SLC45A2. A multigene panel or comprehensive genomic testing is the preferred molecular genetic testing method for this disorder.

Management.

Treatment of manifestations: Correction of refractive errors with spectacles or contact lenses to improve visual acuity. Strabismus surgery may be considered for cosmetic reasons. Dark glasses may alleviate photophobia but may reduce vision; a hat with a brim or visor best achieves reduction in photophobia. Protection from the sun, through the wearing of protective clothing and the regular application of sunscreen, is essential.

Prevention of secondary complications: Individuals with OCA4 should stay out of the sun from an early age, because cumulative ultraviolet exposure is a major risk factor for skin cancers.

Surveillance: Annual ophthalmologic examination and reassessment for accurate correction of refractive error. Evaluation of the skin for cancer screening every six months is recommended.

Agents/circumstances to avoid: Prolonged exposure to sun.

Genetic counseling.

OCA4 is typically inherited in an autosomal recessive manner. The parents of a proband are obligate heterozygotes and thus carriers of one SLC45A2 pathogenic variant. Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder, but may be light in pigmentation for their ethnic group. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

Oculocutaneous albinism type 4 (OCA4) should be suspected in individuals with the following clinical features:

• Hypopigmentation of the skin and hair varying from complete depigmentation to partial depigmentation with brown hair. In some individuals pigmentation increases during the first decade of life [Suzuki & Tomita 2008].
• Characteristic ocular changes found in all types of albinism, including the following findings detected on routine ophthalmologic examination:
  • Nystagmus
  • Reduced iris pigment with iris translucency
  • Reduced retinal pigment with visualization of the choroidal blood vessels on ophthalmoscopic examination
  • Foveal hypoplasia associated with reduction in visual acuity
• Vision abnormalities (due to misrouting of the optic nerves at the chiasm) including:
  • Alternating strabismus
  • Reduced stereoscopic vision
  • Altered visual evoked potential (VEP)
    Note: (1) A VEP is not necessary for the routine diagnosis of albinism; misrouting is implied by the finding of strabismus and reduced stereoscopic vision. (2) In some individuals, particularly those who have moderate amounts of cutaneous and retinal pigment, or those who have foveal hypoplasia and no obvious nystagmus, a VEP may be necessary to demonstrate misrouting of the optic nerves. (3) The VEP is performed with a technique specifically developed for demonstration of the misrouting and a regular VEP will not demonstrate this. (4) Normal routing of the optic nerves, demonstrated with a VEP, indicates that the diagnosis is not albinism/OCA.

Establishing the Diagnosis

The diagnosis of OCA4 is established in a proband with characteristic clinical findings and/or by identification of biallelic pathogenic (or likely pathogenic) variants in SLC45A2 on molecular genetic testing (see Table 1).

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of biallelic SLC45A2 variants of uncertain significance (or identification of one known SLC45A2 pathogenic variant and one SLC45A2 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include the use of a multigene panel or comprehensive genomic testing.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of OCA4 overlaps that of the other genetic forms of albinism (oculocutaneous and ocular), a multigene panel or comprehensive genomic testing (when available) is the preferred molecular genetic testing method for this disorder. Single-gene testing (sequence analysis of SLC45A2, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A multigene panel that includes SLC45A2 and other genes of interest associated with albinism (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

For this disorder a multigene panel that also includes deletion/duplication analysis or exome array is recommended if no or only one pathogenic variant is identified.

Note: Oki et al [2017] reported a multigenerational family in which OCA4 appeared to be inherited as an autosomal dominant condition associated with a heterozygous pathogenic variant in SLC45A2. The authors of this GeneReview feel that this may represent a rare occurrence, but note that no functional assay for the specific variant was performed and that concomitant heterozygous pathogenic variant(s) in a regulatory region or in other (unknown) OCA-related genes cannot be ruled out.

Clinical Description

A wide range of clinical phenotypes has been recognized to date [Suzuki & Tomita 2008]. The amount of cutaneous pigmentation in OCA4 is a continuum from minimal to near normal [Newton et al 2001, Inagaki et al 2004, Rundshagen et al 2004, Ikinciogullari et al 2005, Inagaki et al 2005]. The amount of iris and retinal pigment varies and visual acuity covers a wide range; however, no subtypes of OCA4 are recognized.

Individuals with albinism (including OCA4) are usually recognized within the first year 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.

Genotype-Phenotype Correlations

The lack of a functional assay for the SLC45A2 protein and the limited data from SLC45A2 molecular genetic testing make genotype-phenotype correlations difficult [Newton et al 2001, Rundshagen et al 2004, Ikinciogullari et al 2005, Inagaki et al 2005, Konno et al 2009].

Two common pathogenic alleles, p.Asp157Asn and p.Gly188Val, have been reported in Japanese individuals. The p.Asp157Asn allele may have very low functional activity in melanogenesis; p.Gly188Val may have some residual functional activity [Inagaki et al 2004].

Recently, a family with autosomal dominant OCA4 has been reported [Oki et al 2017], with a novel heterozygous pathogenic variant: c.208T>C (p.Tyr70His). Family members with the variant demonstrate a relatively mild phenotype, with a slightly creamy complexion, brown to black hair, and mild iris hypopigmentation.

The degree of cutaneous pigmentation, ocular pigmentation, and visual development resulting from particular SLC45A2 pathogenic variants cannot be predicted at this time.

Nomenclature

The ocular features of all types of oculocutaneous albinism (OCA) and X-linked ocular albinism (OA1) are similar and the terms "oculocutaneous albinism" and "albinism" can be used interchangeably when referring to these clinical features.

Prevalence

Prevalence of OCA4 is thought to be on the order of 1:100,000 in most populations throughout the world. It is likely to be more common in Japan, where it accounts for 24% of individuals with OCA [Inagaki et al 2004, Inagaki et al 2005].

OCA4 has also been described in individuals of German, Turkish, Korean, Indian, Chinese, Danish, and Moroccan descent [Newton et al 2001, Rundshagen et al 2004, Ikinciogullari et al 2005, Suzuki et al 2005, Sengupta et al 2007, Grønskov et al 2009, Konno et al 2009].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with oculocutaneous albinism type 4 (OCA4), the following evaluations are recommended if they have not already been completed:

• Complete ophthalmologic evaluation including measurement of visual acuity and refractive error
• Assessment for strabismus
• Assessment by dermatologist to instruct parents regarding use of sun-protective clothing, lotions, and formulas
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Ophthalmologic care is the most important part of the ongoing care for most individuals with OCA4.

The majority of individuals with albinism have significant hyperopia or myopia and astigmatism. Correction of these refractive errors with spectacles or contact lenses can improve visual acuity. Except in the very unusual individual, correction of refractive errors cannot restore visual acuity to normal because of the foveal hypoplasia.

The alternating strabismus found in most individuals with albinism is generally not associated with the development of amblyopia. Strabismus surgery is usually not required, but can be considered for cosmetic reasons if the strabismus is marked or fixed.

Photophobia is common in individuals with OCA4, but the degree of discomfort varies and does not depend entirely on the amount of melanin pigment present in the iris or skin. In general, opaque contact lenses or darkly tinted lenses do not improve visual function. Dark glasses may be helpful for individuals with albinism, but many prefer to go without dark glasses because of the reduction in vision from the dark lenses. A hat with a brim (e.g., a baseball hat with a visor) is often the best way to achieve reduction in photophobia and sun protection.

Protection from the sun through the wearing of protective clothing and the regular application of sunscreen is essential to prevent sunburn and secondary skin changes, and to decrease the risk of skin cancer in later life. Regular skin check-ups for skin cancer are recommended for adult individuals with OCA4, especially in cases of severe hypopigmentation.

Prevention of Secondary Complications

Individuals with OCA4 should stay out of the sun from an early age, as cumulative ultraviolet exposure is a major risk factor for skin cancers (see Hair/Skin, Skin cancer risk).

Prolonged periods in the sun require skin protection with clothing (hats with brims, long sleeves and pants, socks) and sunscreen with a high SPF number (total blocks with SPF 45-50+). There is no scientific evidence to indicate how high an SPF value is enough; individuals with OCA4 should use sunscreen with higher SPF values (45-50+) to lessen as much as possible the cumulative effect of ultraviolet to their skin.

Surveillance

Annual ophthalmologic examination and reassessment for accurate correction of refractive error are appropriate.

There is no definitive guideline supported by scientific evidence as to how often an individual should be evaluated by a dermatologist, though an evaluation of the skin for cancer screening every six months is recommended.

Agents/Circumstances to Avoid

Avoid prolonged exposure of the skin to the sun.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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

OCA4 is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one SLC45A2 pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and not at risk of developing the disorder; they may be light in pigmentation for their ethnic group.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder, although they may be light in pigmentation for their ethnic group.

Offspring of a proband. Unless an affected individual's reproductive partner also has OCA4 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in SLC45A2.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a SLC45A2 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the SLC45A2 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA of probands in whom a molecular diagnosis has not been confirmed (i.e., the causative genetic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the SLC45A2 pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

A fetal skin biopsy will not provide an accurate diagnosis and is not appropriate for prenatal diagnosis of OCA4.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The phenotype resulting from heterozygosity of a single Slc45a2 pathogenic variant in mice results in hypopigmentation that may be analogous to some of the autosomal dominant forms of albinism reported in humans. Apparent autosomal dominant inheritance of OCA4 has been recently reported in a single Japanese family [Oki et al 2017].

Gene structure. SLC45A2 has seven exons and spans 40 kb at chromosome 5p13.3 (NM_016180.3).

Pathogenic variants. See International Albinism home page. Fifty-three pathogenic variants of SLC45A2 have been reported. Most are missense variants, but deletions of one or a small number of bases and base changes have been detected [Newton et al 2001, Inagaki et al 2004, Rundshagen et al 2004, Ikinciogullari et al 2005, Inagaki et al 2005, Suzuki et al 2005, Sengupta et al 2007, Grønskov et al 2009, Konno et al 2009]. The most common SLC45A2 pathogenic variant in Japanese individuals, accounting for 39% of pathogenic alleles, is the p.Asp157Asn missense variant [Inagaki et al 2004].

Most individuals with OCA4 are compound heterozygotes for SLC45A2 pathogenic variants. Approximately 17% of reported Japanese individuals and a cohort from India have only one identifiable pathogenic variant; the second variant could not be detected with the methods used [Inagaki et al 2004, Sengupta et al 2007]. (For more information, see Table A.).

Normal gene product. Membrane-associated transporter protein (MATP) consists of 530 amino acids, contains 12 transmembrane domains, and is only expressed in mealocytes (NP_057264.3) [Newton et al 2001]. The precise function of MATP is yet to be elucidated, although it appears to play a role in tyrosinase processing, intracellular trafficking of tyrosinase to melanosome, and regulating tyrosinase activity through controlling melanomal pH [Costin et al 2003, Bin et al 2015].

Abnormal gene product. The mechanisms by which the abnormal protein alters the ability of the cell to synthesize melanin are unknown. However, tyrosinase, the rate-limiting enzyme in the biosynthesis of melanin that is associated with OCA1, appears to be mislocalized in mouse melanocytes that are homozygous for pathogenic SLC45A2 alleles [Costin et al 2003]. This phenotype is shared with melanocytes that contain pathogenic variants in OCA2, the gene associated with OCA2 [Toyofuku et al 2002].

Author History

Murray H Brilliant, PhD; University of Wisconsin School of Medicine (2005-2011)
Masahiro Hayashi, MD, PhD (2011-present)
Tamio Suzuki, MD, PhD (2011-present)

Revision History

• 7 September 2017 (ha) Comprehensive update posted live
• 15 September 2011 (cd) Revision: deletion/duplication analysis of SCL45A2 available clinically
• 5 May 2011 (me) Comprehensive updated posted live
• 14 June 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically
• 17 November 2005 (me) Review posted live
• 21 April 2005 (mb) Original submission

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