Are You Confident of the Diagnosis?
What you should be alert for in the history
Oculocutaneous albinism is a disorder that has two components: ocular and cutaneous. The ocular abnormalities are essential to the diagnosis of albinism. All albino individuals have poor vision and most are legally blind, with visual acuity usually less than 20/100.
Typically, albino individuals exhibit nystagmus, strabismus, marked myopia, photophobia, iris and global transillumination, and foveal hypoplasia. (Figure 1). In addition, their skin and hair are much less pigmented than expected from their parentage (Figure 2).
The various genetic defects responsible for albinism can partially or completely block the formation of melanin in the skin and eyes. Many people with albinism have virtually no pigment in their hair or skin, or very small quantities, i.e. there is a total or near total blockage of melanin synthesis. These individuals have the classical white appearance of albinism recognized by everyone; however, it is not necessary that there be no pigment at all, just less than expected from parental background.
Depending on the type of albinism and the severity of the mutated gene, some albinos have small to moderate amounts of pigmentation in their eyes, skin, and hair, and appear normal except for the typical visual abnormalities. Such individuals have blond hair, blue eyes, and pigmented nevi (Figure 3). These individuals are capable of synthesizing melanin but in insufficient quantities during embryogenesis to permit the normal formation of the neuroretina, the optic nerves and tracts, and occipital visual cortex. Therefore, the diagnosis of albinism starts wtih the abnormalities in the eyes.
There are four known types of oculocutaneous albinism defined by the defect in various genes that result in blockage of melanin formation. There are melanocytes in the skin, hair follicles, eyes, and ears. In each of these organs, the melanocyte plays an important role in their normal function.
Melanin is the major element determing skin, eye, and hair color in mammals. The synthesis of melanin involves over 100 genes. The embryological formation of the pigment system located in the skin, eyes, ears, and meninges is very complex and involves hundreds of other genes.
Early in embryogenesis, the neural crest develops from which melanoblasts migrate into the skin, ear, and uveal tract of the eye (the uveal tract is formed by the choroid, the ciliary body, and the iris) (Figure 4). About the same time, the primitive forebrain is forming. From it will come the brain and also the retinal pigment epithelium and neuroretina of the eyes.
The retinal pigment epithelium provides support for the neuroretina. It is the only tissue in the body not of neural crest origin that is capable of synthesizing the pigment melanin. The biochemistry of pigment formation in both neural crest and retinal pigment is identical and dependent on the same enzymes.
The melanin in the retinal pigment epithelium is a critical embryological organizer and inducer for the eye. It is synthesized in the pigment epithelium by the sixth week of gestation, and it induces and organizes the formation of the fovea essential for fine color vision, the optic nerves, the optic tracts and striations, and the visual cortex in the occipital lobe. If sufficient melanin is present, these structures form normally. If there is insufficient melanin, the neuroretina and fovea are malformed (Figure 5).
If the fovea is hypoplastic, the eye has poor vision, exhibits nystagmus, and has poor color perception. From the defective fovea to the visual cortex, the entire optic system is malformed. Obviously, this is a permanent deformity and so albinos have lifelong visual deficiencies. Thus, oculocutaneous albinsim, by definition, involves specific and identifiable defects in the eyes and in the vision. In the absence of these findings, the person might exhibit hypopigmentation of the skin but does not have albinism.
All four types of albinism, although caused by four distinct mutations, each retarding melnain formation, affect the development and formation of the optic system, an indicator that it is melanin itself that is the embryological inducer and organizer for the these stuctures.
Characteristic findings on physical examination
The skin of those with albinism classically is milky white and the hair on all parts of the body similarly white (Figure 1, Figure 3). Most albinos, with age, will form small quanities of melanin and have blond or fawn-colored hair and blue eyes (Figure 2). Their moles (nevocellular nevi) are a light tan color. Some have darker skin color that represents mutations in genes that only partially block melanin formation.
There are melanocytes in the inner ear in the stria vascularis and vestibular region. Data from studies on albino cats indicate there is dysfunction of the ears in albinos (Figure 6, Figure 7); however, it is very difficult to detect in humans and it has no clinical manifestations. Albinos clinically have normal hearing.
It can be difficult to diagnose albinism at birth because many neonates have very little pigment in their skin and hair; they acquire it with time. However, the baby will exhibit nystagmus and photophobia. Examination by a pediatric ophthalmologist can document foveal hypoplasia, iris transillumination (Figure 8, Figure 9) and other optic abnormalities that confirm the diagnosis. As the child grows older, the skin and hair remain hypopigmented when compared to the parents. Because all forms of albinism have a genetic basis, there usually is a family history of albinism.
White skin can be caused by two distinct mechanisms. In some disorders like piebaldism and vitilgio, the white skin is caused by absence of melanocytes in the skin and, at times, the hair bulb. Because melanocytes are the exclusive source of melanin, their absence results in white skin. In contrast, many other disorders are characterized by the presence of melanocytes in normal numbers but these are dysfunctional and fail to produce melanin in adequate quantities.
Oculocutaneous albinism is a genetic and congenital example of a disorder in which the person has normal numbers of melanocytes that are defective. Three examples include acquired disorders such as pityriasis alba, tinea versicolor, and nevus depigmentosus.
Expected results of diagnostic studies
Histological examination of the skin using routine staining techniques such as hematoxylin and eosin will show no defects for any or these disorders. Melanin stains will be negative in vitiligo and piebaldism and slightly to moderately positive in albinism and other disorders. Special stains for melanocytes such as dopa oxidase or HMB 45 will be negative in vitiligo and piebaldism but slightly to moderately positive in albinism and the other disorders. Generally, histologic studies are not required for diagnosis of albinism.
The diagnosis is not difficult for those thoroughly acquainted with albinism. It was noted above that light skin and hair with blue eyes is not sufficient for a diagnosis of albinism. The requisite ocular findings, e.g. foveal hypoplasia, global and iris transillumination, nystagmus, and strabismus, are some of the critical ocular defects that must be present. Consultation with an ophthalmologist can confirm the present or absence of these diagnostic findings.
The differential diagnosis includes other well-defined disorders that resemble oculocutaneous albinism. These include Hermansky-Pudlak syndrome, in which individuals with an albinoid appearance have a bleeding diathesis, pulmonary fibrosis, and colitis. Individuals with Chediak Higashi syndrome have an albinoid appearance but also have frequent bacterial infections caused by a lysosomal disorder, one type of lysosome being the melanosome.
The third abnormality is Griscelli syndrome, in which albinoid individuals have an immune deficiency and frequent infections caused by defects in myosin, myosin receptors, and binding. Inability of melanocytes to transfer melanosomes to their dendrites and thus into the surrounding keratinocytes causes the dilution of skin and hair color.
Who is at Risk for Developing this Disease?
Albinism is relatively uncommmon in western nations. The estimated prevalence is about 1:15,000 to 1:20,000 in the general population. It is much more common in African nations such as Tanzania, where the prevalence is 1:1500, i.e. a ten-fold higher prevalence.
The four types of albinism all have an autosomal recessive mode of inheritance. Usually there is a family history of albinism in a sibling (1:4 probability), parent, or more distant relative. It is possible for two carriers, unaware of any familial albinism, to have an albino child. It has been calculated that 1:70 individuals carry one mutated gene responsible for albinism.
The genetic defects causing each form are well described. Genetic testing is available to determine the precise defect in affected individuals or in carriers. Parents carrying genes for different types of albinism will have phenotypically normal children, although there is a 50:50 probability that each child will carry one or the other mutated gene.
Oculocutaneous albinism type 1 (OCA 1–MIM 203100) is called tyrosinase-related albinism. Tyrosinase is the first enzyme involved in converting tyrosine into melanin. It oxidizes tyrosine to dopa and then to dopaquinone. It is the rate-limiting enzyme. It is located on chromosome 11 and maps to 11q14-q21.
Those with OCA 1 have moderate to severe defects in their tyrosinase enzyme that limits the synthesis of melanin completely (OCA-1A) or partially (OCA-1B). Many different mutations have been described, some capable of completely eliminating the function of tyrosinase, others partially inhibiting enzyme function.
Babies with OCA-1A have white hair and skin at birth (Figure 10). As they age, the children retain white hair and skin. These individuals have less than 10% tyrosinase activity compared to individuals without OCA-1A .
Patients with OCA-1B have an appearance at birth that is similar to those with OCA-1A. Their hair and skin is very white. As they age, they these patients can synthesize small amounts of melanin, giving them blond or tan hair, lightly pigmented nevi, and the ability to tan slightly after exposure to sun (Figure 3). Most patients with OCA-1B will burn on exposure to sun and will subsequently tan. These individuals have less than 50% tyrosinase activity (heterozygous individuals have one normal gene, i.e. 50% activity) but more than those with OCA-1A.
OCA-2 is a disorder caused by mutations in the P gene (MIM203200), located at 15q11.2-q12. This gene product is located in the membrane of melanosomes and is involved in formation of eumelanin. Its precise function is unknown. OCA-2 albinos have the ability to synthesize small quanitities of pheomelanin. Eumelanin is synthesized exclusively from tyrosine and has a brown or black color. Pheomelanin is synthesized from a combination of tyrosine and cysteine and has a red-orange color.
OCA-2 is the most common form of albinism in the world, and is the predominant type of albinism found in Africa (Figure 1, Figure 2) and Central America. These individuals are born with slightly yellowish hair and creamy white skin. The hair can darken somewhat with age. The skin in many patients develops deeply pigmented lentigines (Figure 11) that probably represents a reversion of a point mutation to a normal functioning P gene. These reversion mutations are caused by sun exposure.
Albinism in Africa carries a severe social stigma, the myth being that an African woman would have a white baby only if she had had sexual relations with a white male. There are periodic pogroms in which albinos are indiscriminately murdered. Many of these individuals develop skin cancers, usually squamous cell carcinomas that can be fatal (Figure 12, Figure 13).
OCA-3 albinism has been labelled rufous or red albinism (ROCA). It is the least common form of albinism. It is caused by a mutation in the TYRP1 gene (MIM 203290), located at 9p23, that codes for the enzyme tyrosinae related protein 1.
This enzyme is involved at a distal site in the tyrosinase/melanin synthetic pathway. It was originally described in an African-American twin baby, his sibling being normal (Figure 14). It has been found in Caucasian individuals as well. These individuals have brown skin, reddish hair, and brown irides. They would be considered normal if they did not have the classical ocular findings. The ocular features are more subtle.
OCA-4 is the most recently identified type of albinism (MIM606574). The defective gene maps to 5p13.3. This gene MATP is a transporter gene responsible amongst other functions for the transport and maintenance of tyrosinase into the melanosome where melanin is formed. It has been identified in individuals in Europe and might be the second most common form of albinism in Japan. Phenotypically, these individuals appear to be similar to those with OCA-1B, with light brown hair, blue to brown irides, and lightly pigmented skin from tanning, as well as the classical ocular defects. .
What is the Cause of the Disease?
Oculocutaneous albinism type 1 (OCA 1–MIM 203100) is called tyrosinase-related albinism. Tyrosinase is the first enzyme involved in converting tyrosine into melanin. It oxidizes tyrosine to dopa and then to dopaquinone. It is the rate-limiting enzyme. It is located onchromosome 11 and maps to 11q14-q21.
OCA-2 is a disorder caused by mutations in the P gene (MIM203200) located at 15q11.2-q12. This gene product is located in the membrane of melanosomes and is involved in formation of eumelanin. Its precise function is unknown. OCA-2 albinos have the ability to synthesize small quanitities of pheomelanin. Eumelanin is synthesized exclusively from tyrosine and has a brown or black color. Pheomelanin is synthesized from a combination of tyrosine and cysteine and has a red-orange color.
OCA-3 is caused by a mutation in the TYRP1 gene (MIM 203290), located at9p23 that codes for the enzyme tyrosinae-related protein 1. This enzyme is involved at a distal site in the tyrosinase/melanin synthetic pathway.
OCA-4 is the most recently identified type of albinism (MIM606574). The defective gene maps to 5p13.3. This gene, MATP, is a transporter gene, responsible amongst other functions for the transport and maintenance of tyrosinase into the melanosome where melanin is formed.
Systemic Implications and Complications
Oculocutaneous albinism in any of the four varieties is a serious but not life-threatening disorder; however, it can have lethal consequences. In Africa, where albinism is common, albinos are ostracised. They are forced to work on menial jobs, usually in the sun where they have no protection from the carcinogenic ultraviolet rays. Many of the albinos exhibit severe sun damage such as actinic keratoses and solar lentigines (Figure 15, Figure 16).
The frequency of skin cancer in OCA 2 albinos is about 50%. Almost all of these are squamous cell carcinomas. They have few basal cell carcinomas. Albinos have melanocytes, but there have been few reported melanomas affecting albinos in medical history, with fewer than 30 reported cases worldwide.
Albinos in Africa are considered the offspring of voodoo events or sexual indiscretions between an African woman and a Caucasian male. There are periodic pogroms in which albinos are killed.
All albinos have poor eyesight. Most are severely myopic, with best visual acuity less than 20/100. Children need appropriate eye glasses in school. Because they have little melanin in the uvea, they have photophobia and need dark glasses when outdoors. Most albinos are not able to obtain a driver’s license.
All albinos require frequent applications of sunscreens, broad-brim hats, shirts with long sleeves, and long pants. Because of their propensity for skin cancer, they should receive frequent skin examinations. They require ophthalmological care for proper refractive eyewear.
In African countries, special programs to protect albinos and to provide proper clothing, activities, and occupations are required. There are successful albino programs in Tanzania and other West African nations.
Genetic testing is available for OCA1, OCA2, and under special circumstances, for the other forms of albinism. Individuals who are heterozygous or homozygous should receive genetic counseling and advice on prenatal testing.
Optimal Therapeutic Approach for this Disease
The key to treatment focuses on prevention of complications. All albinos require frequent applications of sunscreens, broad-brim hats, shirts with long sleeves and long pants. Because of their propensity for skin cancer, albinos should receive frequent skin examinations. Skin cancers, which are predominantly actinic keratoses and squamous cell carcinomas, should be treated by standard techniques. Careful follow-up examinations are absolutely essential.
Patients require ophthalmological care for proper refractive eyewear.
Patients are best managed in a multidisciplinary manner by dermatologists, opthalmologists, and geneticists. Patient and familial education about sun protection is essential.
Unusual Clinical Scenarios to Consider in Patient Management
If other systemic manifestations are present, one should consider diagnoses other than true oculocutaneous albinism. Hermansky-Pudlak should be considered in individuals with an albinoid appearance who have a bleeding diathesis, pulmonary fibrosis, and colitis.
Patients with Chediak Higashi syndrome have an albinoid appearance but frequent bacterial infections caused by a lysosomal disorder, one type of lysosome being the melanosome. Consider the Griscelli syndrome if albinoid individuals have an immune deficiency and frequent infections.
What is the Evidence?
Babadoran, P, Ortonne J: Albinoid disorders. In: Nordlund, JJ, Boissy, R, Hearing, V. “The pigmentary system: physiology and pathophysiology”. 2006. pp. 613-619. (This is a good review of albinoid conditions.)
King, RA, Oetting W: Oculocutaneous albinism.In: Nordlund, JJ, Boissy, R, Hearing, V. “The pigmentary system: physiology and pathophysiology”. 2006. pp. 599-613. (This is an excellent review of oculocutanous albinsim and references albinism to earlier chapters of the same volume that presents detailed information about the pigmentary system of the eyes and the basic science of melanocytes and melanogenesis.)
Nordlund, JJ, Boissy, RE, Hearing, VJ, King, RA, Oetting, W, Ortonne, JP. “The pigmentary system: physiology and pathophysiology”. 2006. (This is a comprehensive book on basic and clinical science of pigmentation, covering information on all pigmentary disorders and their biological basis.)
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