Ocular Albinism, X-Linked

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Summary

Clinical characteristics.

X-linked ocular albinism (XLOA) is a disorder of melanosome biogenesis leading to minor cutaneous and adnexal manifestations and congenital and persistent visual impairment in affected males. XLOA is characterized by infantile nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus, and foveal hypoplasia. Significant refractive errors, reduced or absent binocular functions, photoaversion, and strabismus are common. XLOA is a non-progressive disorder and the visual acuity remains stable throughout life, often slowly improving into the mid-teens.

Diagnosis/testing.

A diagnosis of ocular albinism (OA) is probable in the presence of infantile nystagmus, iris translucency, substantial hypopigmentation of the ocular fundus periphery in males with mildly hypopigmented skin (most notably when compared to unaffected sibs), foveal hypoplasia, reduced visual acuity, and aberrant optic pathway projection as demonstrated by crossed asymmetry of the cortical responses on visual evoked potential testing. X-linked inheritance is documented by either a family history consistent with X-linked inheritance or the presence of typical carrier signs (irregular retinal pigmentation and mild iris transillumination) in an obligate carrier female. Molecular genetic testing of GPR143 (previously OA1) detects pathogenic variants in more than 90% of affected males.

Management.

Treatment of manifestations: Early detection and correction of refractive errors, use of sunglasses or special filter glasses for photoaversion, and prismatic spectacle correction for abnormal head posture. Strabismus surgery is often unnecessary but may be performed to improve peripheral visual fusion fields. The need for vision aids and special consideration in educational settings should be addressed.

Surveillance: For affected children younger than age 16 years: annual ophthalmologic examination (including assessment of refractive error and the need for filter glasses) and psychosocial and educational support. For adults: ophthalmologic examinations as needed.

Genetic counseling.

XLOA is inherited in an X-linked manner. An affected male transmits the pathogenic variant to all of his daughters and none of his sons. The risk to the sibs of a male proband depends on the carrier status of the mother. If the mother is a carrier, the chance of transmitting the GPR143 pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is most informative if the pathogenic variant has been identified in the proband. Prenatal testing is possible for a pregnancy at increased risk if the familial pathogenic variant is known.

Diagnosis

Suggestive Findings

Males

X-linked ocular albinism (XLOA) should be suspected in males with the following findings:

Ophthalmologic (common to all forms of albinism)

  • Infantile nystagmus. Nystagmus usually develops during the first three months of life and may be preceded by a period of poor fixation and poor visual contact, giving rise to a suspicion of delayed visual maturation or cerebral visual impairment (CVI). The nystagmus is most frequently of the pendular or jerk type and is sometimes associated with head nodding (titubation). With age, the nystagmus tends to diminish, although it rarely disappears completely.
    Nystagmus amplitude and/or frequency often varies with horizontal gaze position. The gaze position in which the nystagmus is least severe is known as the null point. At the null point, the decrease in ocular oscillations reduces retinal image motion and thereby maximizes visual acuity. Therefore, affected individuals whose null point is eccentrically located will adopt a compensatory face turn. A similar dampening of nystagmus can be obtained with the convergence that occurs with focus at a close range; thus, visual acuity at close range tends to be better than visual acuity tested at distance.
  • Hypopigmentation of the iris. Iris transillumination caused by hypopigmentation of the iris pigment epithelium (IPE), the posterior layer of the iris, is a frequent finding that is best visualized in a dark room by trans-scleral illumination with a light source placed directly on the bulbar conjunctiva or by slit lamp examination in which a strong beam is directed through an undilated pupil. Normally, incident light reflected from within the eye exits only through the pupil because it is blocked by the IPE. In albinism, reflected light can penetrate the iris. Since punctate iris transillumination defects can be seen in some individuals with light complexion, detection of these defects alone in this group is not a reliable indicator of albinism.
  • Hypopigmentation of the ocular fundus resulting from decreased concentration of pigment in the retinal pigment epithelium (RPE), which allows visualization of the choroidal vessels. The hypopigmentation is generally more profound in the periphery of the ocular fundus.
  • Foveal hypoplasia, characterized by diminution or absence of the foveal pit (umbo) and the annular foveal reflex. The foveal area is inconspicuous and sometimes retinal vessels extend through the normally avascular fovea. Optical coherence tomography (OCT) can document the retinal thinning. Some affected males in pedigrees with congenital X-linked nystagmus and molecular confirmation of XLOA have foveal hypoplasia as an isolated finding [Preising et al 2001].
  • Reduced visual acuity. In most individuals with albinism, the best corrected visual acuity is between 20/40 (6/12) and 20/200 (6/60). XLOA is a non-progressive disorder and the visual acuity typically slowly improves until mid-to-late teens and then remains stable throughout life.
  • Aberrant optic pathway projections consisting of an excessive crossing of the retino-striate fibers in the optic chiasm; i.e., the visual input from the right eye is almost exclusively directed towards the left hemisphere and vice-versa [Schmitz et al 2003, Lauronen et al 2005]. This "misrouting" can be demonstrated in specialized laboratories by selective VEP technique adapted for use in clinical practice [Soong et al 2000, Hoffmann et al 2005]. Lateral placement of recording electrodes over the occipital area allows for the detection of interhemispheric asymmetries in amplitude following monocular stimulation with a pattern-onset grating. Rather than the typical near-equal response from each hemisphere, the response amplitude is disproportionately larger in the hemisphere contralateral to the stimulated eye. Some authors contend that this VEP technique, albeit cumbersome, is a highly sensitive indicator of albinism [Sjöström et al 2001]. In several forms of albinism, MR imaging found variations in the size and configuration of the optic chiasm compared to normal controls. However, this feature is neither distinctive nor unique and, thus, is not helpful in clinical diagnosis [Schmitz et al 2003].

Dermatologic

  • Hypopigmentation of hair and skin compared to others of the same racial or ethnic backgrounds, especially when compared to unaffected male sibs. Of course, the cutaneous color spectrum is broad and overlaps the entire spectrum of other forms of albinism.

Note: None of the above findings is either specific or obligate for X-linked ocular albinism, and the diagnosis may be difficult in blond northern European males with only minimally reduced central visual acuity.

Family history

  • Maternal male relatives with ocular albinism
  • The most consistent clinical diagnostic clue for XLOA: presence of characteristic retinal pigment abnormalities in female relatives who are obligate carriers

Heterozygous Females

Depending on overall ethnic and racial skin and adnexal pigmentation, heterozygous females may show iris transillumination and a coarse pattern of blotchy hypo-and hyperpigmentation of the retinal pigment epithelium that becomes more dramatic outside the vascular arcades. Some carriers have isolated patches of hypopigmented skin that does not tan to the same degree as uninvolved skin.

Rarely, heterozygous females are affected, showing infantile nystagmus, foveal hypoplasia, reduced visual acuity, and diffuse hypopigmentation of the ocular structures.

Establishing the Diagnosis

The diagnosis of XLOA is established in a proband with identification of a pathogenic variant in GPR143 (see Table 1). If molecular testing is not available, the finding of macromelanosomes on skin biopsy would also establish the diagnosis.

Molecular testing approaches can include single-gene testing and use of a multigene panel:

  • Single-gene testing. Sequence analysis of GPR143 is performed first followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes GPR143 and other genes of interest (see Differential Diagnosis) may also 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 at the most reasonable cost 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.

Table 1.

Molecular Genetic Testing Used in X-Linked Ocular Albinism

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
GPR143Sequence analysis 3, 443% 5 (~90% 6)
Gene-targeted deletion/duplication analysis 748% 6
1.

See Table A. Genes and Databases for chromosome locus and protein.

2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by deletion/duplication analysis.

5.

Schnur et al [1998], Hegde et al [2002], Faugère et al [2003]

6.

Due to the high prevalence of deletions in this X-linked gene, attempts at sequence analysis may detect amplification failure resulting in an apparent detection rate of ~90% in affected males [Personal communications, Baylor Miraca Genetics Laboratory, Houston, TX]. Standard clinical laboratory practice does not consider assay failure to be diagnostic; therefore, deletion/duplication analysis would be necessary to confirm a diagnosis.

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

X-linked ocular albinism (XLOA) is a disorder of melanosome biogenesis leading to congenital and persistent visual impairment and mild to moderate skin changes in affected males.

Affected Males

Ophthalmologic phenotype is shared by all types of albinism, which in typical cases includes infantile nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the retinal pigment epithelium, foveal hypoplasia, and abnormal optic pathway projections. None of these findings is, however, either specific or obligate.

  • Hypersensitivity to light, often called "photoaversion," "photophobia," or more appropriately "photodysphoria," is present in most affected individuals but varies in intensity and significance from one individual to another. In some affected individuals, photodysphoria is the most incapacitating symptom.
  • Substantial refractive errors are common, most often as hypermetropia with oblique astigmatism. High myopia or compound myopic astigmatism may occur in some affected individuals.
  • Most affected individuals have reduced or absent binocular functions as a consequence of misrouted optic pathway projections, and ocular misalignment (strabismus). A positive angle lambda is often found in individuals with albinism [Brodsky & Fray 2004].
  • Posterior embryotoxon, a developmental anomaly of the anterior chamber angle, has been reported in 30% of a small series of affected males [Charles et al 1993].

Dermatologic phenotype. XLOA is characterized by mild cutaneous and adnexal involvement (albinismus solum bulbi), and the universal defect in melanosome biogenesis that may escape clinical notice, if not compared to unaffected sibs. Nevertheless, in families with dark complexion, affected males tend to be more lightly pigmented than their unaffected sibs. In some affected males, irregular hypopigmented spots are present on the arms and legs.

Prognosis. Persons with XLOA have normal life span, development, intelligence, and fertility.

Heterozygous Females

Heterozygous females may be considered mosaic with respect to the GPR143 pathogenic variant because random X-chromosome inactivation leads to variable degrees of ocular and cutaneous hypopigmentation.

  • Most heterozygous females demonstrate iris transillumination, which is most prominent in the periphery of the iris. In addition, the ocular fundus shows an easily recognizable pattern of irregular coarse hypopigmentation of the retinal pigment epithelium in splotches and streaks, more dramatic in the peripheral retina. Carrier signs are present in at least 80% to 90% of heterozygotes. Therefore, absence of carrier signs does not exclude a diagnosis of XLOA.
  • On occasion, carrier females are affected as severely as males as a result of either skewed X-chromosome inactivation, homozygosity for a GPR143 pathogenic variant, or partial or total monosomy of the X chromosome.

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been identified [Schiaffino et al 1999].

Even in the same family, the cutaneous and adnexal coloration and the visual acuities may vary widely [Preising et al 2011, Trebušak Podkrajšek et al 2012].

Prevalence

A minimum birth prevalence of one male in 60,000 live born children has been reported in a Danish cohort [Rosenberg & Schwartz 1998] and of approximately one in 50,000 in a US cohort [King et al 1995].

Differential Diagnosis

"Congenital" nystagmus is usually the initial clinical sign leading to suspicion of an underlying visual sensory or central nervous system disorder and to an ophthalmologic examination. Congenital or infantile nystagmus (which typically begins two to eight weeks after birth) is not specific or unique to XLOA, as it can appear as an isolated finding (so-called primary motor nystagmus) or as part of a hereditary ocular disorder, some of which are X-linked. Although infantile nystagmus is often a secondary manifestation of bilateral congenital eye disorders associated with vision loss (e.g., corneal opacities, aniridia, cataracts, retinopathy of prematurity, and optic nerve hypoplasia), the differential diagnosis in males with XLOA is usually limited to visual disorders in which infantile nystagmus is the predominant finding and the eye is anatomically normal.

A family history of X-linked inheritance for similarly affected individuals along with typical clinical findings supports the diagnosis of XLOA and further testing may not be indicated. However, when the family history is negative, XLOA must be distinguished from other forms of albinism and from X-linked disorders associated with infantile nystagmus.

X-linked congenital nystagmus (OMIM 310700) is a diagnosis of exclusion, characterized by normal electroretinogram (ERG) and normal optic pathways. In the absence of any demonstrable sensory defect, the involuntary eye movements are denoted "motor nystagmus." More than 50% of carrier females manifest congenital nystagmus, simulating autosomal dominant inheritance [Kerrison et al 1999]. Families with X-linked congenital nystagmus have absence of male-to-male transmission. Three X-chromosome loci, Xp11.4, Xp22.2 (GPR143), and Xq26.2 (FRMD7), have been identified. FRMD7 may manifest slightly different clinical and oculomotor characteristics than XLOA [Kumar et al 2011]. See also FRMD7-Related Infantile Nystagmus.

The oculocutaneous albinisms, inherited in an autosomal recessive manner, include types with moderate pigmentation of skin and hair that may be occasionally misinterpreted as "ocular albinism."

  • Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in TYR that encodes the protein tyrosinase. Individuals with OCA1A (OMIM 203100) have white hair, white skin that does not tan, and fully translucent irides that do not darken with age. At birth, individuals with OCA1B (OMIM 606952) 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 irides that change to green/hazel or brown/tan with age. Ocular findings are very similar to those of XLOA. The diagnosis of OCA1 is established by clinical findings of hypopigmentation of the skin and hair and characteristic eye findings.
  • Oculocutaneous albinism type 2 (OCA2) (OMIM 203200) is caused by pathogenic variants in OCA2 (previously called P). The amount of cutaneous pigmentation in OCA2 ranges from minimal to near normal. Newborns with OCA2 almost always have pigmented hair, with color ranging from light yellow to blond to brown. Hair color may darken with time. Brown OCA, initially identified in Africans and African Americans with light brown hair and skin, is part of the spectrum of OCA2.
  • Oculocutaneous albinism type 3 (OCA3) (OMIM 203290) is caused by pathogenic variants in TYRP1 (encoding tyrosinase-related protein 1, also called glycoprotein 75 or GP 75). Originally described in southern African blacks, the disorder is characterized by bright copper-red hair, lighter tan skin, and diluted pigment in the iris and fundus. This has been called "rufous oculocutaneous albinism."
  • Oculocutaneous albinism type 4 (OCA4) is caused by pathogenic variants in SLC45A2 (previously called MATP or AIM1). 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. This form of albinism is rarer than OCA2, except in the Japanese population.

Complete congenital stationary night blindness is characterized by night blindness (nyctalopia), moderate to severe myopia, normal fundi, complete lack of dark adaptation, and characteristic ERG. A subset of affected individuals have congenital nystagmus and mildly reduced visual acuity. The rod (dark-adapted) ERG shows a normal a-wave, indicating normal photoreceptor function, but an undetectable b-wave, indicating post-receptor dysfunction. This response pattern is often referred to as a "negative ERG" because the negative potential of the initial a-wave is not followed by the positive potential of the b-wave. The cone (light-adapted) ERG is mildly reduced and can show a squared-off b-wave caused by loss of the ON-response. The condition is inherited in an X-linked manner and caused by pathogenic variants in NYX (nyctalopin), a member of the leucine-rich proteoglycan family involved in cell adhesion and axon guidance. The protein product is found in ON-bipolar cells connected to both rods and cones.

Incomplete congenital stationary night blindness is characterized by congenital nystagmus, reduced visual acuity, and moderate night-blindness. Iris translucency is not part of the disorder and ERG shows characteristic negative ERG and severely reduced double-peaked cone amplitudes. (The designation "negative ERG" describes an ERG with an a:b wave ratio above unity.) The condition is inherited in an X-linked manner and caused by pathogenic variants in CACNA1F [Bech-Hansen et al 1998]. Female carriers are asymptomatic.

Blue cone monochromacy (OMIM 303700), sometimes referred to as X-linked incomplete achromatopsia, is a rare disorder (<1 in 100,000) characterized by X-linked inheritance, photophobia, congenital nystagmus, reduced visual acuity (20/60-20/200), impaired red-green color perception, and characteristic ERG. Fundi are usually normal, but atrophic macular changes have been reported. Formal color vision testing reveals absent or severely reduced responses to red-green stimuli and normal responses to blue stimuli. Standard ERG testing shows absent cone responses with normal rod responses. The S-(blue) cone response is normally undetectable by ERG because S-(blue) cones constitute about 5% of the total cone population. By special techniques, the blue cone response can be amplified and measured in a clinical setting.

Two common molecular defects are associated with this phenotype [Nathans et al 1989]. One is a deletion of a regulatory sequence (locus control region) upstream of the visual pigment genes, which consists of one red pigment (opsin) gene and one or more green (opsin) genes. The second defect involves unequal homologous recombination between red and green opsin genes (coding to a single mutated red opsin) or a 5' red-green hybrid gene having a p.Cys203Arg (c.607T>C, NM_000513.2) substitution that encodes for a nonfunctional protein. A rare third molecular defect found in a single family involved a deletion of exon 4 in an isolated red gene [Ladekjaer-Mikkelsen et al 1996].

Other disorders with sensory retinal early-onset nystagmus include autosomal dominant motor nystagmus, complete and incomplete achromatopsia, blue cone monochromacy, and other autosomal recessive stationary cone dysfunctions including enhanced S-cone syndrome, cone dystrophy with supernormal rod response, and Leber congenital amaurosis. In most of these diagnostic groups, the ERG is essential to establish the diagnosis.

PAX6 pathogenic variants can result in infantile nystagmus and foveal hypoplasia in individuals with only mild iris hypoplasia (see Aniridia). Such individuals do not have iris transillumination.

Failure to detect a pathogenic variant in GPR143 should lead the clinician to re-assess the patient for other non-ocular and constitutional features that will be useful for additional molecular diagnostic studies.

Ocular albinism with sensorineural deafness (OMIM 103470) is characterized by ocular albinism indistinguishable from XLOA (including the presence of macromelanosomes in the skin); additional findings are congenital deafness and vestibular dysfunction. In some affected individuals, heterochromia iridis and a prominent white forelock are present. Inheritance is autosomal dominant. A relation between this disorder and Waardenburg syndrome type 2 has been suggested and may result from digenic interaction between a transcription factor, MITF, and a missense pathogenic variant in TYR (encoding tyrosinase) [Morell et al 1997].

Ocular albinism with late-onset sensorineural deafness (OMIM 300650), an X-linked condition with a disease locus at Xp22.3, was reported in a large Afrikaner kindred. The disorder is possibly caused by an allelic GPR143 variant or a contiguous gene defect [Bassi et al 1999].

Hermansky-Pudlak Syndrome (HPS) is a multisystem disorder characterized by: tyrosinase-positive oculocutaneous albinism; a bleeding diathesis resulting from a platelet storage pool deficiency; and, in some cases, pulmonary fibrosis, granulomatous colitis, or immunodeficiency. The albinism is characterized by: hypopigmentation of the skin and hair; and ocular findings of reduced iris pigment with iris transillumination, reduced retinal pigment, foveal hypoplasia with significant reduction in visual acuity (usually in the range of 20/50 to 20/400), nystagmus, and increased crossing of the optic nerve fibers. Hair color ranges from white to brown; skin color ranges from white to olive and is usually a shade lighter than that of other family members. Because of the wide phenotypic variability in the colors of skin and hair in HPS, an observer might initially consider ocular albinism in the differential diagnosis, especially in a person of the less common ethno-geographic backgrounds; however, the clinician should always query the manifestations of the common bleeding diathesis in HPS. HPS is inherited in an autosomal recessive manner and is caused by pathogenic variants in HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1 (HPS7), BLOC1S3 (HPS8), and BLOC1S6 (PLDN).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with X-linked ocular albinism (XLOA), the following evaluations are recommended:

  • Medical history and physical examination, including a careful evaluation of pigmentation status at birth and later to distinguish between oculocutaneous and ocular albinism
  • A complete ophthalmologic evaluation
  • Dilated retinal examination of any at-risk possible carrier (mother, daughter) for the classic retinal carrier state
  • Dermatologic consultation for sun-protective lotion and sun-protective clothing and avoidance of associated cumulative solar damage
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Refractive errors should be treated with appropriate spectacle correction as early as possible.

Photodysphoria can be relieved by sunglasses, transition lenses, or special filter glasses, although many prefer not to wear them because of the reduction in vision from the dark lenses when indoors.

Abnormal head posture with dampening of the nystagmus in a null point may be modified with prismatic spectacle correction.

Strabismus surgery is usually not required but may be performed for cosmetic purposes, particularly if the strabismus or the face turn is marked or fixed. The need for vision aids and the educational needs of the visually impaired should be addressed.

Dermatologic counseling for age-appropriate sun-protective lotions and clothing should be sought.

Prevention of Secondary Complications

Appropriate education for sun-protective lotions and clothing (preferably by an informed dermatologic consultant) is indicated to moderate the cumulative lifelong effects of solar radiation.

Surveillance

Children younger than age 16 years with ocular albinism should have an annual ophthalmologic examination (including assessment of refractive error and the need for filter glasses) and psychosocial and educational support.

In adults, ophthalmologic examinations should be undertaken when needed, typically every two to three years.

Agents/Circumstances to Avoid

Although no formal trials exist, standard care avoids use or application of sun-sensitizing drugs or agents.

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.

Other

Nystagmus dampening has been achieved by bilateral horizontal rectus recession surgery in some centers, but this is not a generally accepted treatment nor is there evidence from a comparative clinical trial that such intervention improves the final visual outcome.