Albinism Clinical Presentation

Updated: Mar 22, 2016
  • Author: Mounir Bashour, MD, PhD, CM, FRCSC, FACS; Chief Editor: Hampton Roy, Sr, MD  more...
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Presentation

History

Patients with more severe forms of albinism with cutaneous manifestations are easier for a physician to diagnose compared with those with more subtle forms or those with ocular albinism. With respect to ocular complaints, patients typically report decreased central vision and photophobia. Skin symptoms include skin photosensitivity.

Search for a history of easy bruising, frequent nosebleeds, or bleeding after surgery or dental work. A positive history may point in the direction of HPS. A history of frequent infections may be consistent with Chediak-Higashi syndrome (CHS).

Inquire about a family history of albinism. Children with albinism tend to prefer reading with a head tilt and usually hold reading material up close.

The following is a more detailed description of the different subtypes of albinism:

Oculocutaneous albinism

Oculocutaneous albinism 1

OCA 1 is a disorder that results from mutations to the tyrosinase gene found on chromosome 11 (band 11q14-21). Several different types of mutations to the tyrosinase gene (missense, nonsense, and frameshift) are responsible for producing the 2 types of OCA 1 (OCA 1A and OCA 1B). Mutations can result in either inactive/no tyrosine (null mutations) or in the production of tyrosine enzyme that has reduced activity from normal (leaky mutations). Null mutations produce OCA 1A, while leaky mutations result in OCA 1B.

An important distinguishing characteristic of OCA 1 is the presence of marked hypopigmentation at birth. Most individuals with OCA 1 (especially OCA 1A) have white hair, milky white skin, and blue irides at birth. The irides can be very light blue and translucent, such that the whole iris appears pink or red in ambient or bright light. However, with age, the irides usually become darker blue and may remain translucent or lightly pigmented, with reduced translucency.

Oculocutaneous albinism 1A

OCA 1A (classic tyrosinase-negative OCA) is the most severe form of OCA. It is caused by nonsense, frameshift, and missense mutations of the tyrosinase gene on chromosome 11 (band 11q24). These null mutations produce completely inactive tyrosinase, resulting in no melanin formation throughout the patient's life.

The typical phenotype is white hair and skin, with blue and translucent irides. No pigmented lesions develop in the skin, although amelanotic nevi may be present. Because of a lack of pigmentation, these patients have no tanning potential and are at risk for sunburn and skin cancer. This phenotype is the same in all ethnic groups and in all ages. Visual acuity usually is diminished to as low as 20/400. Photophobia and nystagmus tend to be the worst in this subtype. Hair bulb incubation in tyrosinase is usually negative.

Oculocutaneous albinism 1B

OCA 1B (yellow mutant OCA, Amish albinism, xanthous albinism) is produced by leaky mutations of the tyrosinase gene that result in reduced/residual enzyme activity. To date, 55 mutations to the tyrosinase gene have been found to cause OCA 1B. These different mutations result in differing amounts of residual tyrosinase activity and are the primary reason for the variation in pigmentation in individuals with OCA 1B.

The range in pigmentation can vary from very little cutaneous pigment to nearly normal skin pigmentation. Occasionally, a moderate amount of residual activity can lead to near normal skin pigmentation and the wrong diagnosis of ocular albinism. These patients completely lack pigment at birth, which can cause difficulty in distinguishing it from OCA 1A. However, because some tyrosinase activity is still present, individuals may show an increase in skin, hair, and eye pigment with age and may tan with sun exposure.

Patients rapidly develop yellow hair pigment in the first few years of life and then continue to slowly accumulate pigment, principally yellow-red pheomelanin, in the hair, eyes, and skin. Interestingly, patients with OCA 1B tend to develop dark eyelashes, often darker than the scalp hair. The irides can produce hazel or light brown pigment that sometimes is limited to the inner third of the iris. Visual acuity may be 20/90 to 20/400 and may improve with age. Pigmented nevi can develop, although most nevi are amelanotic. Hair bulb testing shows greatly reduced activity of tyrosinase, though still present.

Temperature-sensitive albinism

Temperature-sensitive albinism is a subtype of OCA 1B. This type of OCA 1B is caused by a mutation of the tyrosinase gene that produces a temperature-sensitive tyrosinase enzyme. [4] Heat-sensitive tyrosinase has approximately 25% the activity of normal tyrosinase at 37°C and improved activity at lower temperatures. The enzyme does not work at regular body temperatures (axillary and scalp region) but functions in cooler areas of the body (arms and legs). Therefore, because melanin synthesis occurs in cooler areas of the body, arm and leg hair pigment is usually dark, while axillary and scalp hair remains white (occasionally developing a yellow tint with time). Individuals are believed to have OCA 1A during the first few years of life, with white hair and skin and blue eyes.

This may be because the temperature of the fetus is high, so the tyrosinase has low activity, resulting in absent pigment. However, postnatally, the skin is cooler, and, with time, body hair in the cooler areas of the body develops pigment, while the eyes remain blue and the skin remains white and does not tan. The eyes are warmer than other areas of the skin; therefore, they do not develop additional pigmentation.

Oculocutaneous albinism 2

OCA 2 (tyrosine-positive OCA) is the most prevalent type of albinism in all races. This disorder is also autosomal recessive but coded on a different chromosome from OCA 1 (band 15q11-13). This mutated region also is deleted in Prader-Willi syndrome (PWS) and Angelman syndrome (AS), accounting for the close linkage of OCA 2 to these syndromes.

In OCA 1, the genetic mutation affects the gene coding for tyrosinase; however, the OCA 2 genetic mutation affects the gene coding for the P protein and tyrosinase is normal. The human P gene located on band 15q11.2-q12 is the homologue of the mouse p locus (mutation causes reduction of eumelanin, a black pigment in the mouse, causing the mouse pink-eyed dilution). It is postulated that this human P gene encodes for a melanosomal membrane protein involved in the transport of tyrosine. [5]

The phenotypic spectrum of OCA 2 varies, ranging from absent pigmentation to almost normal pigmentation. Even though the tyrosinase genes are normal, most type 2 albino persons have no black pigment (eumelanin) in the skin, hair, or eyes at birth. As a result, pigment is nearly absent at birth, sometimes making it indistinguishable from OCA 1. However, pigmentation tends to develop with age. The exact mechanism of this delay in albinism is not known. The intensity of pigment accumulation depends on the racial background of the patients. As the child matures, the increased pigmentation also results in improved vision (20/100 to 20/40).

In whites with OCA 2, the amount of pigment at birth can vary substantially. The hair can have a light yellow-blond color, or it may be darker with a darker blond-red color. The normal delayed maturation of the pigment system can make it difficult to distinguish OCA 2 from OCA 1. The skin is white and does not tan. Iris color is blue-gray, and the degree of iris translucency is proportional to the amount of pigment present. As the child ages, increased pigmentation occurs with pigmented nevi and freckles developing in areas of repeated sun exposure. The hair also may turn darker with age.

In African Americans and Africans, OCA 2 has a distinct phenotype. At birth, the hair is usually yellow and tends to remain as such through life, although some darkening may occur. The skin is white and has no tanning potential. The iris is blue-gray, and pigmented nevi may develop in some individuals.

Brown OCA is part of the OCA 2 spectrum that is exclusive to Africans and African Americans. It is speculated that this syndrome may arise from leaky mutations to the P protein gene, resulting in reduced P protein activity. The hair and skin are light brown, and the irides are gray. As time passes, the hair and irides may darken, while the skin color remains mainly unchanged. The ocular features are characteristic, with punctate and radial iris translucency and retinal hypopigmentation. Visual acuity ranges from 20/60 to 20/150.

Oculocutaneous albinism 3

OCA 3 (previously known as red/rufous OCA) is caused by a mutation to the human gene coding for TRP-1. This protein is the product of the brown locus in the mouse. A mutation at this position causes the fur to be brown rather than black. In humans, the formation of TRP-1 is not fully understood. However, it acts as a regulatory protein in the production of black melanin (eumelanin). With mutation, a subsequent dysregulation of tyrosinase occurs, and brown pigment is synthesized instead of black pigment.

OCA 3 is autosomal recessive. The clinical phenotype in African patients is light brown or reddish brown skin and hair, and blue-brown irides. The ocular features are not fully consistent with the diagnosis of OCA because some do not have iris translucency, nystagmus, strabismus, or foveal hypoplasia. No misrouting of the optic nerves has been demonstrated by a visual-evoked potential, suggesting either that this is not a true type of albinism or that the hypopigmentation is not sufficient to consistently alter optic nerve development. The phenotype for whites and Asians is not known at this time.

Ocular albinism

Ocular albinism 1

OA 1 (X-linked recessive OA/Nettleshop-Falls type) involves the eyes only. Patients with OA 1 have normal skin; however, it may be paler than first-degree relatives. Ocular findings in OA 1 are similar to those of OCA, with decreased visual acuity, refractive error, fundus hypopigmentation, absent foveal reflex, strabismus, iris translucency, and posterior embryotoxon in 30% of patients (implying anterior segment dysgenesis). The presence of nystagmus occasionally has led to the misdiagnosis of congenital motor nystagmus.

The OA 1 locus is Xp22.3. Because this disorder is X-linked recessive, only males manifest the disease and females are carriers. Hence, males show the complete phenotype, while female carriers can show a mud-splattered fundus with hypopigmented streaks in the periphery and marked iris translucency.

The protein product of the OA1 gene, termed OA 1 (and also identified as GPR143 in GenBank), is a pigment cell–specific membrane glycoprotein, displaying structural and functional features of G protein-coupled receptors (GPCRs). However, in contrast to all other previously characterized GPCRs, OA 1 is not localized to the plasma membrane but is targeted to intracellular organelles, namely late endosomes/lysosomes and melanosomes. These unique characteristics suggest that OA 1 represents the first example described so far of an exclusively intracellular GPCR and regulates melanosome biogenesis by transducing signals from the organelle lumen to the cytosol. [2, 3]

Skin biopsy in carriers and in individuals with OA 1 usually shows the presence of macromelanosomes, which aids in the diagnosis of OA 1. It has been postulated that the OA1 gene is a glycoprotein necessary for the maturation of melanosomes, because macromelanosomes are formed when premelanosomes fail to separate from the endoplasmic reticulum–Golgi system.

Autosomal recessive ocular albinism

AROA was first described in the 1970s in a series of families in which children of normally pigmented parents had ocular features of albinism but did not have any cutaneous hypopigmentation.

AROA was classified as autosomal recessive because both males and females were affected. However, it has been shown that AROA is not a distinct entity. In fact, genetic analysis revealed that some of those diagnosed with AROA had either abnormalities of the tyrosinase gene or the P gene. Of those previously diagnosed with AROA, 14% have a mutation of the tyrosinase gene on chromosome 11, making them OCA 1, while 36% have an abnormality of the P gene on chromosome 15, actually making them OCA 2. Fifty percent have neither an abnormality of the tyrosinase gene nor the P gene.

Conditions with close linkage to albinism

Close linkage to OCA 2

PWS and AS are both caused by deletion to band 15q11-13, the same region coding the P protein gene. In OCA 2, the P gene mutation is adjacent to the area commonly deleted in PWS or AS. One percent of patients with PWS or AS has OCA 2. Both PWS and AS are caused by the same chromosomal deletion, but there are 2 separate phenotypes because of genomic imprinting. If the deletion occurs on the paternal band 15q11-13, then PWS results. However, if the same mutation occurs on the maternally derived chromosome, AS occurs. The cause of this is unknown.

AS is a developmental disorder characterized by developmental delay, severe mental retardation, inappropriate laughter, hyperactivity, tongue protrusion, widely spaced teeth microcephaly, hypotonia, and ataxia. PWS is a systemic disorder characterized by obesity, hypotonia, hypogonadism, short stature, dysmorphic facial features, and intellectual impairment.

Close linkage to OA 1

X-linked ichthyosis, Kallmann syndrome, X-linked recessive chondrodysplasia punctata, late-onset sensorineural deafness, and microphthalmia and linear skin defects (MLS) have been linked to the OA1 gene. These contiguous gene syndromes involve the band Xp22.3 region. Albino phenotypes result when the deleted region includes the OA 1 gene.

Conditions associated with albinism and not because of close linkage

HPS includes oculocutaneous albinism, platelet granule deficiency, and a lysosomal ceroid storage disorder leading to accumulation of ceroid in tissues throughout the body. It is an autosomal recessive inherited condition first described in Czechoslovakia by Hermansky and Pudlak. This syndrome has a high frequency in Puerto Rico. The HPS gene is localized to band 10q23.1-23.3. Skin pigmentation varies from none to almost normal, with ocular features of nystagmus, strabismus, foveal hypoplasia, retinal hypopigmentation, and decreased visual acuity. Late complications of HPS include interstitial pulmonary fibrosis, inflammatory bowel disease, renal failure, and cardiomyopathy secondary to ceroid deposition.

CHS is an autosomal recessive condition that is characterized by albinism, increased susceptibility to infections, and deficiency in natural killer cell activity. This rare condition is caused by mutation to band 1q42.1-q42.2, but the CHS gene product is unknown. The skin, hair, and eye pigment is reduced in CHS, but the patient usually does not have obvious albinism. Hair color is light brown to blond. The skin is creamy white to slate gray. Iris pigment is present, and nystagmus and photophobia may or may not be present.

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Physical

Begin with an external examination, checking hair and skin color for depigmentation.

Follow with a complete ocular examination, including a slit-lamp evaluation and dilated fundus examination. The ocular features common to all types of albinism include the following:

  • Refractive error and astigmatism
  • Nystagmus (may compensate with a head tilt that may help improve vision)
  • Iris depigmentation (usually blue-gray or light brown color) and iris transillumination
  • Strabismus
  • Fovea hypoplasia
  • Reduced depth perception secondary to abnormal neural connections
  • A positive angle kappa in patients with congenital nystagmus is associated with albinism. The pathophysiology of the positive angle kappa may relate to the anomalous decussation of optic axons that characterizes the albinotic visual system. [6]

Once albinism is suspected, the following steps should be taken to ascertain the type of albinism involved:

  • Assess the phenotype. If the patient (newborn or adult) completely lacks pigment in the skin and hair, OCA 1A is the probable diagnosis. The only type of albinism that is associated with white hair at birth is OCA 1. If a minimal amount of melanin is present, the diagnosis is OCA 1B, OCA 2, or OCA 3.
  • CHS should be suspected if the patient has silvery hair and neutrophils with large inclusions on a blood smear. HPS may be the diagnosis if a minimal-to-moderate hypopigmentation is present along with decreased blood clotting.
  • If OCA 1A is suspected, a hair bulb assay may be performed to confirm this diagnosis. A negative result indicates OCA 1A. However, a positive result could indicate OCA 1B, OCA 2, OCA 3, or OA 1.
  • A patient with minimal pigment and a positive hair bulb assay could have OCA 1B, OCA 2, or OCA 3. A patient with only ocular features, presence of hair and skin pigmentation, and a positive hair bulb assay probably has OA 1.
  • To distinguish between OCA 1B, OCA 2, or OCA 3, a sequence analysis of the genes coding for tyrosinase, P protein, and TRP-1 can be completed. Unfortunately, these tests may not be routinely available. Another alternative test (if available) is a shave skin biopsy (5-8 mm). Cultures of melanocytes can be assessed for function of tyrosinase, P protein, and TRP-1.
  • If OA 1 is suspected, a skin biopsy can be taken to check for the presence of macromelanosomes. It may be necessary to assess the ocular status of female family members. Since the disorder is X-linked recessive, females would be carriers. They typically have a mud-splattered fundus.
  • Albinism does not cause a delay in development or mental retardation. Suspect other causes if this is present.
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Causes

Albinism is inherited genetically through specific mutations along the melanin pathway.

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