eMedicine Specialties > Dermatology > Diseases of Pigmentation

Albinism

Author: Raymond E Boissy, PhD, Director of Basic Science Research, Professor, Departments of Dermatology and Cell Biology, University of Cincinnati College of Medicine
Coauthor(s): James J Nordlund, MD, Professor Emeritus, Department of Dermatology, University of Cincinnati College of Medicine
Contributor Information and Disclosures

Updated: Oct 30, 2009

Introduction

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, 2, 3, and 4; ocular albinism; Chediak-Higashi syndrome; Hermansky-Pudlak syndrome; and Griscelli syndrome.^1,2,3,4

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.

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.

Frequency

International

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 - Rare, except in Japan, where 24% of individuals with oculocutaneous albinism have this form
• 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

Mortality/Morbidity

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

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.

Clinical

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.
• 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.

Physical

• 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. 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 type 4 manifests with a phenotype resembling oculocutaneous albinism type 2.
• 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.

Causes

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.^5,6,7
• 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.^6,8
• 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.⁹ 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.⁶
• 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.^6,7,8
• 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.¹⁰
• 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.¹¹
• 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.¹²
• 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.¹³

• Search for CME/CE on This Topic »

• Ocular Manifestations of Albinism (Ophthalmology)
• Albinism (Ophthalmology)
• Hermansky-Pudlak Syndrome (Ophthalmology)
• Griscelli Syndrome (Dermatology)

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