Dermatologic Manifestations of Albinism

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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]}

See 13 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]

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] :

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]

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

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).

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

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

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.

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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Raymond E Boissy, PhD Director of Basic Science Research, Professor, Departments of Dermatology and Cell Biology, University of Cincinnati College of Medicine

Raymond E Boissy, PhD is a member of the following medical societies: Sigma Xi

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society

Disclosure: Nothing to disclose.

Van Perry, MD Assistant Professor, Department of Medicine, Division of Dermatology, University of Texas School of Medicine at San Antonio

Van Perry, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.

Jean Paul Ortonne, MD Chair, Department of Dermatology, Professor, Hospital L’Archet, Nice University, France

Jean Paul Ortonne, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

James J Nordlund, MD Professor Emeritus, Department of Dermatology, University of Cincinnati College of Medicine

James J Nordlund, MD is a member of the following medical societies: American Academy of Dermatology, Sigma Xi, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Dermatologic Manifestations of Albinism

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