Dermatologic Manifestations of Albinism

Background

The classification of congenital hypopigmentary diseases that result from a defect in the production of pigment (melanin) due to dysfunction of pigment cells (melanocytes) in the skin, the eyes, and/or the ears consists of the following: oculocutaneous albinism types 1-7; ocular albinism; Chediak-Higashi syndrome (see the image below); Hermansky-Pudlak syndrome; and Griscelli syndrome.^{[1, 2, 3, 4]}

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Infant with Chediak-Higashi syndrome presenting with hypomelanotic skin and white hair with a metallic sheen. From Carden et al, Br J Ophthal, 1998, 8....

See 11 Common-to-Rare Infant Skin Conditions, a Critical Images slideshow, to help identify rashes, birthmarks, and other skin conditions encountered in infants.

Chediak-Higashi syndrome and Hermansky-Pudlak syndrome also manifest with extrapigmentary defects consisting of leukocyte, platelet, pneumocyte, and reticular cell dysfunction. Griscelli syndrome can also manifest with immunodeficiency and neurologic defects.^[5]

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Infant with oculocutaneous albinism type 1 presenting with hypomelanotic skin, white hair, and pink irides and pupils resulting from the dysfunction o....

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Neonate with oculocutaneous albinism type 3 presenting with minimally pigmented skin and light hair coloration resulting from the dysfunction of tyros....

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Pathophysiology

These diseases present with a generalized complete or partial loss in pigmentation of the skin and the hair. Mutations in genes that regulate the multistep process of melanin synthesis, distribution of pigment by the melanocyte, and/or melanosome biogenesis are the basis for these diseases. The proteins/gene products (and respective gene) affected in each form of oculocutaneous albinism are as follows^[6] :

• Oculocutaneous albinism type 1 - Tyrosinase enzyme [11q14-21]
• Oculocutaneous albinism type 2 - P protein [15q11-13]
• Oculocutaneous albinism type 3 - Tyrosinase related protein-1 enzyme (TYRP1) [9p23]
• Oculocutaneous albinism type 4 - A membrane-associated transport protein (MATP/SLC24A2) [5p13.3]^[7]
• Oculocutaneous albinism type 5 - Protein unknown [4q24]
• Oculocutaneous albinism type 6 - A membrane-associated transport protein (SLC24A5) [15q21.1]
• Oculocutaneous albinism type 7 - Protein unknown [10q22.2-3]

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Etiology of Albinism

The causes of these diseases are mutations in specific genes.

Oculocutaneous albinism type 1 results from mutations in the tyrosinase gene, which maps to band 11q14-3 and is inherited as an autosomal recessive trait. The tyrosinase gene encodes an enzyme that initiates the synthesis of melanin using the substrate tyrosine. Specifically, tyrosinase hydroxylates tyrosine to dihydroxyphenylalanine (DOPA) and subsequently dehydroxylates DOPA to DOPA-oxidase. More than 70 mutations have been identified in tyrosinase that result in the dysfunction or lack of synthesis of this enzyme. Most patients with oculocutaneous albinism type 1 have compound heterozygosity for mutations in the tyrosinase gene.^{[8, 9, 10]}

Oculocutaneous albinism type 2 results from mutation in the P gene, which maps to band 15q12 and is inherited as an autosomal recessive trait. The P gene encodes a 110-kd protein with 12 putative transmembrane domains localized to the limiting membrane of the pigment granule (ie, melanosome). The function of the P protein in melanin synthesis has yet to be determined.^{[9, 11]}

Oculocutaneous albinism type 3 results from mutation in the tyrosinase-related protein-1 (Tyrp1) gene, which maps to band 9p23 and is inherited as an autosomal recessive trait.^[12] The Tyrp1 gene encodes a protein that has been shown to have a dihydroxyindole carboxylic acid (DHICA) oxidase activity in the murine system. DHICA oxidase is a catalytic step downstream from tyrosinase in the biosynthesis of melanin from tyrosine. The function of Tyrp1 in human melanogenesis may be involved as (1) an ionic transporter, (2) a chaperone, and/or (3) a stabilizer of the melanosome complex.^[9]

Oculocutaneous albinism type 4 results from mutations in the SLC45A2 gene, formerly called the membrane-associated transporter protein (MATP) gene, which maps to band 5p13.3 and is inherited as an autosomal recessive trait. The SLC45A2 gene encodes a 58-kd protein with 12 predicted transmembrane domains. The function of MATP in melanogenesis is presently unknown.^{[9, 10, 11]}

Oculocutaneous albinism type 5 results from mutations in an unknown gene, which maps to band 4q24 and is inherited as an autosomal recessive trait. The protein and its function is unknown.^[13]

Oculocutaneous albinism type 6 results from mutations in the SLC24A5 gene, which maps to band 15q21.1 and is inherited as an autosomal recessive trait. The SLC45A5 gene encoded an uncharacterized membrane-associated transport protein and its function is unknown.^[13]

Oculocutaneous albinism type 7 results from mutations in an unknown gene, which maps to band 10q22.2-3 and is inherited as an autosomal recessive trait. The protein is being provisionally labeled as C10orf11 and its function is unknown.^[13]

Ocular albinism results from mutation in a gene on the X chromosome, which maps to band Xp22.3-22.2 and is inherited as an X-linked recessive trait. The function of the ocular albinism gene product is unknown.^[14]

Chediak-Higashi syndrome results from mutation in the LYST gene, which maps to band 1q42-43 and is inherited as an autosomal recessive trait. The LYST gene encodes a large 429-kd protein that putatively functions in the translocation of material from the Golgi apparatus to target sites in affected cells. As a result, the synthesis of melanosomes by the melanocyte, of delta granules by the platelet, and of lysosomes by some of the leukocytes (ie, neutrophils and natural killer lymphocytes) is impaired.^[15]

Hermansky-Pudlak syndrome is inherited as an autosomal recessive trait and exists with loci heterogeneity. The initial form of Hermansky-Pudlak syndrome identified, termed Hermansky-Pudlak syndrome type 1, results from a gene that maps to band 10q23.1-23.3. To date, 8 genetically distinct forms of Hermansky-Pudlak syndrome have been identified in the human population (see Hermansky-Pudlak syndrome). Most of the Hermansky-Pudlak syndrome gene products combine to form several complexes that facilitate the trafficking of molecules from the Golgi to target organelles.^[16]

Griscelli syndrome is inherited as an autosomal recessive trait. Two primary genetic variants are known. One results from mutations in the RAB27A gene located at band 15q21 that encodes the GTP-binding protein Rab27a. The other results from mutations in the MYO5A gene located at band 15q21 that encodes the unconventional myosin motor protein myosin5a. Both gene loci are distinct from each other. In the melanocyte, these 2 gene products, along with a third bridging protein (ie, melanophilin) form a complex that facilitates the translocation of melanosomes along microtubules in the dendrites of the melanocyte and their subsequent capture by actin filaments at the dendritic tips.^[17]

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Epidemiology

Frequency

The approximate incidences of these diseases are as follows:

• Oculocutaneous albinism type 1 - One case per 40,000 population
• Oculocutaneous albinism type 2 - One case per 36,000 population, except in Africans and African Americans, in whom the incidence is 1 case per 10,000 population
• Oculocutaneous albinism type 3 - Unknown
• Oculocutaneous albinism type 4 - One case per 100,000 population, except in Japan, where 24% of individuals with oculocutaneous albinism have this form
• Oculocutaneous albinism type 5 - Unknown (reported in one family)
• Oculocutaneous albinism type 6 - Unknown (reported in two individuals)
• Oculocutaneous albinism type 7 - Unknown (reported in several individuals)
• Ocular albinism - One case per 50,000 population
• Chediak-Higashi syndrome - Extremely rare
• Hermansky-Pudlak syndrome - Rare, except in Puerto Rico, where frequency is 1 case per 1800 population
• Griscelli syndrome - Extremely rare

Race

All races appear to be equally affected by the associated mutations. However, oculocutaneous albinism type 2 is reportedly more common among Africans and African Americans (1 case per 10,000 population) than in whites (1 case per 36,000 population).

Sex

The incidence of these albino diseases is equal for men and women.

Age

All of these diseases present in neonates. Chediak-Higashi syndrome consists of an accelerated phase that occurs years to decades after birth.

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Prognosis

Oculocutaneous albinism types 1, 2, 3, and 4 and ocular albinism are not associated with mortality and/or morbidity outside of cutaneous sensitivity to solar irradiation and the associated visual defects described below (see Physical).

Children with Chediak-Higashi syndrome manifest easy bruising, mucosal bleeding, epistaxis and petechiae, recurrent infections primarily involving the respiratory system, and neutropenia. Approximately 85% of individuals with Chediak-Higashi syndrome enter an accelerated phase, including fever; anemia; neutropenia; and, occasionally, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and jaundice. Neurologic problems are variable in Chediak-Higashi syndrome and include a peripheral and cranial neuropathy, autonomic dysfunction, weakness and sensory deficits, loss of deep tendon reflexes, clumsiness with a wide-based gait, seizures, and decreased motor nerve conduction velocities. Death usually occurs in the first decade from infection, bleeding, or development of the accelerated phase.

Individuals with Hermansky-Pudlak syndrome manifest a bleeding diathesis resulting from a platelet storage pool deficiency. They also develop a ceroid storage disease in which a ceroid-lipofuscin material accumulates in various organ systems, resulting in pulmonary fibrosis, granulomatous colitis, gingivitis, kidney failure, and cardiomyopathy. Pulmonary fibrosis usually proves fatal in the fourth or fifth decade of life. There are nine different genetic forms of Hermansky-Pudlak syndrome.

Most individuals with Griscelli syndrome develop chronic infections resulting from severe immunodeficiency that can be fatal within the first decade of life.

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Patient Education

Patients should use broad-spectrum sunscreens and should wear appropriate clothing to prevent ultraviolet-induced damage to the skin. Visual impairment can be improved by using corrective lenses.

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History

The characteristic hypopigmentation of albinism is apparent at birth. An increase in the pigmentation of the skin and/or the hair may occur with age, especially in individuals who are mildly affected specifically with the non–oculocutaneous albinism type 1 subtypes.

In Chediak-Higashi syndrome, respiratory infections can occur within a few days of birth. Recurrent infections and bleeding diathesis increase with the age of the patient with Chediak-Higashi syndrome. The accelerated phase of Chediak-Higashi syndrome generally manifests by the first decade of life.^{[18, 19]}

In Hermansky-Pudlak syndrome, the bleeding diathesis can occur within a few days of birth generally during circumcision. Throughout life, patients with Hermansky-Pudlak syndrome experience mild-to-moderate bleeding events, including bruising, epistaxis, gingival bleeding, prolonged bleeding during menstruation or after tooth extraction, postpartum hemorrhage, and bleeding colitis. The respiratory system is the primary organ system affected. Restrictive lung disease usually progresses slowly for the first few decades of life and then advances rapidly. The occurrence and the extent of other organ system dysfunctions are variable.

In Griscelli syndrome, the immunodeficiency or neurological defects can occur shortly after birth.

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Physical Examination

Oculocutaneous albinism type 1 primarily manifests with complete absence of pigment in the skin, the hair, and the eyes, and this category is termed oculocutaneous albinism type 1A.^[20] However, some patients can present with moderate pigmentation in these tissues (termed oculocutaneous albinism type 1B) or pigment in hair follicles of the cooler areas of the body, such as the arms and the legs (termed oculocutaneous albinism type 1TS, ie, temperature sensitive). All forms of oculocutaneous albinism type 1 also present with photophobia, moderate-to-severe reduced visual acuity, and nystagmus. The latter two ocular dysfunctions result from a misrouting of the optic fibers from the retina to the visual cortex of the brain.

Oculocutaneous albinism type 2 does not present with complete absence of pigment but rather manifests with a minimal-to-moderate amount of pigment remaining in the skin, the hair, and the eyes. Many patients with oculocutaneous albinism type 2 can develop pigmented freckles, lentigines, and/or nevi with age. The ocular presentations are similar to those in oculocutaneous albinism type 1.

Oculocutaneous albinism type 3 manifests with minimal pigment reduction in the skin, the hair, and the eyes. This form of albinism was previously referred to as Rufous albinism and possibly Brown albinism. Hair coloration of individuals with oculocutaneous albinism type 3 generally has a yellow or reddish hue. The reduction of cutaneous and ocular pigmentation may only be apparent in comparison with the complexion coloration of family members. The ocular presentations are similar to those in oculocutaneous albinism type 1, but they are not as severe.

Oculocutaneous albinism types 4, 5, 6, and 7 manifest with a phenotype resembling oculocutaneous albinism type 2.^{[21, 13]}

Ocular albinism manifests with ocular depigmentation and iris translucency. In addition, patients with ocular albinism present with congenital motor nystagmus that may be accompanied by reduced visual acuity, refractive errors, fundus hypopigmentation, lack of foveal reflex, and strabismus. Cutaneous depigmentation is not apparent.

Chediak-Higashi syndrome manifests with moderate-to-complete absence of pigment in the skin, the hair, and the eyes. The hypopigmentation of the hair in Chediak-Higashi syndrome generally has a distinct silvery, metallic sheen. Respiratory tract infections frequently occur shortly after birth.

Hermansky-Pudlak syndrome manifests with a variable amount of depigmentation in the skin, the hair, and the eyes. Ophthalmic findings vary.

Griscelli syndrome manifests with a mild form of albinism (ie, pale skin). Distinctive in Griscelli syndrome is the presentation of silvery gray hair at birth.

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Complications

Complications of oculocutaneous albinism type 1 include photophobia, severe-to-moderate reduced visual acuity, and nystagmus. The ocular complications in oculocutaneous albinism type 2, oculocutaneous albinism type 3, and oculocutaneous albinism type 4 are similar to those in oculocutaneous albinism type 1, but, in oculocutaneous albinism type 3, they are not as severe.

Complications of Chediak-Higashi syndrome include easy bruising, mucosal bleeding, epistaxis and petechiae, recurrent infections primarily involving the respiratory system, and neutropenia. In the accelerated phase, fever; anemia; neutropenia; and, occasionally, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and jaundice may occur. Neurologic problems in Chediak-Higashi syndrome may include a peripheral and cranial neuropathy, autonomic dysfunction, weakness and sensory deficits, loss of deep tendon reflexes, clumsiness with a wide-based gait, seizures, and decreased motor nerve conduction velocities.

Long-term complications of Hermansky-Pudlak syndrome include pulmonary fibrosis, granulomatous colitis, gingivitis, and kidney failure.

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Laboratory Studies

The hair bulb tyrosinase assay has been used to differentiate between oculocutaneous albinism type 1 and the other forms of albinism. In this assay, scalp hair bulbs are gently plucked from the patient and placed in a 0.1% solution of L-dihydroxyphenylalanine (L-DOPA) for up to 4 hours. If the sample is from a patient with oculocutaneous albinism type 1 with mutations affecting the synthesis or catalytic function of tyrosinase, the hair bulbs remain white. In contrast, samples from all other forms of albinism turn dark during the incubation period.

For Chediak-Higashi syndrome, a confirmatory workup consists of analysis of a blood smear and the subsequent identification of neutrophils containing giant cytoplasmic granules.

For Hermansky-Pudlak syndrome, a confirmatory workup consists of electron microscopy of platelets and the subsequent identification of the absence of dense bodies (delta granules) and bleeding time determination that demonstrates a prolonged duration.

For Griscelli syndrome, confirmatory workup consist of immunological function evaluation plus both CT and MRI for neurological abnormalities.

These workups for albinism are not routine clinical tests.

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Other Tests

In Chediak-Higashi syndrome, findings on electroencephalograms and electromyograms may be abnormal.

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Medical Care

No treatment is available for hypopigmentation in the skin, the hair, or the eyes. The use of broad-spectrum sunscreens and clothing is recommended to prevent ultraviolet-induced damage to the skin. Visual impairment can be improved by using corrective lenses.

Most therapy for Chediak-Higashi syndrome and Griscelli syndrome is symptomatic in nature. Appropriate antibiotics should be administered to treat infections. Bone marrow transplantation can correct and improve hematologic and immunologic defects in persons with Chediak-Higashi syndrome and Griscelli syndrome, respectively.

No therapy is effective for the nonpigmentary disorders of Hermansky-Pudlak syndrome. If the bleeding diathesis is extreme, platelet and blood transfusions may be considered. If the granulomatous colitis or the pulmonary fibrosis becomes extreme, high-dose steroids may be considered.

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Long-Term Monitoring

Patients with oculocutaneous albinism should be frequently screened for skin cancer.^{[22, 23]}

Patients with Chediak-Higashi syndrome, Hermansky-Pudlak syndrome, and Griscelli syndrome should be routinely monitored for advancement of the nonpigmentary disorders.

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