AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

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 (OCA) types 1, 2, 3, and 4; ocular albinism (OA); Chediak-Higashi Syndrome (CHS); Hermansky-Pudlak Syndrome (HPS); and Griscelli Syndrome (GS).

CHS and HPS also manifest with extrapigmentary defects consisting of leukocyte, platelet, and reticular cell dysfunction. GS 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:

• OCA type 1 - One case per 40,000 population

• OCA type 2 - One case per 15,000 population

• OCA type 3 - Unknown

• OCA type 4 - Rare, except in Japan, where 24% of individuals with OCA have this form

• OA - One case per 50,000 population

• CHS - Extremely rare

• HPS - Rare, except in Puerto Rico, where frequency is 1 case per 1800 population

• GS - Extremely rare

Mortality/Morbidity

• OCA types 1, 2, 3, and 4 and OA 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 CHS manifest easy bruising, mucosal bleeding, epistaxis and petechiae, recurrent infections primarily involving the respiratory system, and neutropenia. Approximately 85% of individuals with CHS enter an accelerated phase, including fever; anemia; neutropenia; and, occasionally, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and jaundice. Neurologic problems are variable in CHS 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 HPS 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 GS 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, OCA 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). In addition, OCA type 3 has only been genetically confirmed in African and African American individuals.

Sex

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

Age

All of these diseases present in neonates. CHS consists of an accelerated phase that occurs years to decades after birth.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

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-OCA1 subtypes.

• In CHS, respiratory infections can occur within a few days of birth. Recurrent infections and bleeding diathesis increase with the age of the patient with CHS. The accelerated phase of CHS generally manifests by the first decade of life.
• In HPS, the bleeding diathesis can occur within a few days of birth generally during circumcision. Throughout life, patients with HPS 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 GS, the immunodeficiency or neurological defects can occur shortly after birth.

Physical

• OCA type 1 primarily manifests with complete absence of pigment in the skin, the hair, and the eyes, and this category is termed OCA type 1A. However, some patients can present with moderate pigmentation in these tissues (termed OCA type 1B) or pigment in hair follicles of the cooler areas of the body, such as the arms and the legs (termed OCA type 1TS, ie, temperature sensitive). All forms of OCA 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.
• OCA 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 OCA type 2 can develop pigmented freckles, lentigines, and/or nevi with age. The ocular presentations are similar to those in OCA type 1.
• OCA 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. To date, OCA type 3 has only been genetically confirmed in dark-skinned individuals (of African heritage). 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 OCA type 1, but they are not as severe.
• OCA type 4 manifests with a phenotype resembling OCA type 2.
• OA manifests with ocular depigmentation and iris translucency. In addition, patients with OA 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.
• CHS manifests with moderate-to-complete absence of pigment in the skin, the hair, and the eyes. The hypopigmentation of the hair in CHS generally has a distinct silvery, metallic sheen. Respiratory tract infections frequently occur shortly after birth.
• HPS manifests with a variable amount of depigmentation in the skin, the hair, and the eyes. Ophthalmic findings vary.
• GS manifests with a mild form of albinism (ie, pale skin). Distinctive in GS is the presentation of silvery gray hair at birth.

Causes

The causes of these diseases are mutations in specific genes.

• OCA type 1 results from mutations in the tyrosinase gene, which maps to band 11q14-2 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 OCA type 1 have compound heterozygosity for mutations in the tyrosinase gene.
• OCA type 2 results from mutation in the P gene, which maps to band 15q11-13 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.
• OCA 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. 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 has yet to be confirmed.
• OCA type 4 results from mutations in the membrane-associated transporter protein (MATP) gene, which maps to band 5p13.3 and is inherited as an autosomal recessive trait. The MATP gene encodes a 58-kd protein with 12 predicted transmembrane domains. The function of MATP in melanogenesis is presently unknown.
• OA 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 OA gene product is unknown.
• CHS 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.
• HPS is inherited as an autosomal recessive trait and exists with loci heterogeneity. The initial form of HPS identified, termed HPS type 1 (HPS1), results from a gene that maps to band 10q23.1-23.3. The HPS gene encodes a 79-kd protein of unknown function. HPS type 2 (HPS2) results from mutations in a gene that encodes the beta subunit of the adaptin 3 complex (AP3). AP3 is involved in trafficking specific glycoproteins from the Golgi apparatus to target sites in affected cells. Many patients with HPS have normal HPS1 and HPS2 genes/gene products, suggesting that additional genetic causes for other subsets of HPS exist. To date, 8 genetically distinct forms of HPS have been identified in the human population (see related e-medicine chapter).
• GS 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. 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.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

Other Problems to be Considered

Histidinemia
Menkes steely hair disease
Tietz syndrome
Prader-Willi syndrome
Angelman syndrome

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

Lab Studies

• The hair bulb tyrosinase assay has been used to differentiate between OCA 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 OCA 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 CHS, a confirmatory workup consists of analysis of a blood smear and the subsequent identification of neutrophils containing giant cytoplasmic granules.
• For HPS, 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 GS, confirmatory workup consist of immunological function evaluation plus both CT and MRI for neurological abnormalities.
• These workups for albinism are not routine clinical tests.

Other Tests

• In CHS, findings on electroencephalograms and electromyograms may be abnormal.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

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 CHS and GS 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 CHS and GS, respectively.
• No therapy is effective for the nonpigmentary disorders of HPS. 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.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

Further Outpatient Care

• Patients with OCA should be frequently screened for skin cancer.
• Patients with CHS, HPS, and GS should be routinely monitored for advancement of the nonpigmentary disorders.

Complications

• Complications of OCA type 1 include photophobia, severe-to-moderate reduced visual acuity, and nystagmus. The ocular complications in OCA type 2, OCA type 3, and OCA type 4 are similar to those in OCA type 1, but, in OCA type 3, they are not as severe.
• Complications of CHS 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 CHS 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 HPS include pulmonary fibrosis, granulomatous colitis, gingivitis, and kidney failure.

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.

MULTIMEDIA

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

Media file 1:  Infant with oculocutaneous albinism type 1 presenting with hypomelanotic skin, white hair, and pink irides and pupils resulting from the dysfunction of tyrosinase in the melanocytes of these tissues and the subsequent lack of melanin synthesis. From Carden et al, Br J Ophthal, 1998, 82:189-195, with permission from BMJ Publishing Group.
	View Full Size Image
Media type:  Photo

Media file 2:  Neonate with oculocutaneous albinism type 3 presenting with minimally pigmented skin and light hair coloration resulting from the dysfunction of tyrosinase-related protein-1 in the melanocytes of these tissues and the subsequent reduction in melanin synthesis. The infant's parents are African American. From Carden et al, Br J Ophthal, 1998, 82:189-195, with permission from BMJ Publishing Group.
	View Full Size Image
Media type:  Photo

Media file 3:  Infant with Chediak-Higashi syndrome presenting with hypomelanotic skin and white hair with a metallic sheen. From Carden et al, Br J Ophthal, 1998, 82:189-195, with permission from BMJ Publishing Group.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Multimedia
• References

• Bassi MT, Schiaffino MV, Renieri A, De Nigris F, Galli L, Bruttini M, et al. Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome. Nat Genet. May 1995;10(1):13-9. [Medline].
• Carden SM, Boissy RE, Schoettker PJ, Good WV. Albinism: modern molecular diagnosis. Br J Ophthalmol. Feb 1998;(2):189-95. [Medline].
• Helip-Wooley A, Westbroek W, Dorward HM, Koshoffer A, Huizing M, Boissy RE, et al. Improper trafficking of melanocyte-specific proteins in Hermansky-Pudlak syndrome type-5. J Invest Dermatol. Jun 2007;127(6):1471-8. [Medline].
• Huizing M, Boissy RE, Gahl WA. Hermansky-Pudlak syndrome: vesicle formation from yeast to man. Pigment Cell Res. Dec 2002;15(6):405-19. [Medline].
• Inagaki K, Suzuki T, Shimizu H, Ishii N, Umezawa Y, Tada J, et al. Oculocutaneous albinism type 4 is one of the most common types of albinism in Japan. Am J Hum Genet. Mar 2004;74(3):466-71. [Medline].
• Introne W, Boissy RE, Gahl WA. Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome. Mol Genet Metab. Oct 1999;68(2):283-303. [Medline].
• King RA, Hearing VJ, Creel DJ. Albinism. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, eds. The Metabolic and Molecular Bases of Inherited Disease. Vol 3. 7^th ed. New York, NY: McGraw-Hill; 1995:4353-92.
• Ménasché G, Fischer A, de Saint Basile G. Griscelli syndrome types 1 and 2. Am J Hum Genet. Nov 2002;71(5):1237-8; author reply 1238. [Medline].
• Newton JM, Cohen-Barak O, Hagiwara N, Gardner JM, Davisson MT, King RA, et al. Mutations in the human orthologue of the mouse underwhite gene (uw) underlie a new form of oculocutaneous albinism, OCA4. Am J Hum Genet. Nov 2001;69(5):981-8. [Medline].
• Oetting WS, Brilliant MH, King RA. The clinical spectrum of albinism in humans. Mol Med Today. Aug 1996;(8):330-5. [Medline].
• Oetting WS, King RA. Molecular basis of albinism: mutations and polymorphisms of pigmentation genes associated with albinism. Hum Mutat. 1999;(2):99-115. [Medline].
• Shotelersuk V, Gahl WA. Hermansky-Pudlak syndrome: models for intracellular vesicle formation. Mol Genet Metab. Oct 1998;(2):85-96. [Medline].
• Wei ML. Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res. Feb 2006;19(1):19-42. [Medline].
• Zühlke C, Criée C, Gemoll T, Schillinger T, Kaesmann-Kellner B. Polymorphisms in the genes for oculocutaneous albinism type 1 and type 4 in the German population. Pigment Cell Res. Jun 2007;20(3):225-7. [Medline].

Article Last Updated: Jun 29, 2007