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Vitiligo research


By 10 November 2022March 27th, 2023No Comments

James J Nordlund


Vitiligo is a disorder that causes the destruction of melanocytes. It has three important factors underlying this destruction. The depigmented skin has many aberrant functions such as a muted response to contact allergens, a phenomenon also seen in mice that depigment. The white skin of those with vitiligo does not form non-melanoma skin cancers although the white skin of albinos, which has a similar color as vitiligo, is highly susceptible to skin cancer.


Vitiligo is a common and easily recognized disorder for all dermatologists, many physicians and some observant members of the general public. It is a disorder that is characterized by white spots typically first noted on the fingers, knuckles, around the eyes and mouth, and on the feet and genitalia. There are two basic mechanisms whereby the skin can become white. Melanin is synthesized by melanocytes within melanosomes that are transferred into the surrounding keratinocytes. The keratinocytes transport the melanin and melanosomes from the basal layer of the epidermis to the stratum corneum where they are desquamated into the environment. Some disorders inhibit or retard the production of melanin formation and the skin develops hypopigmentation. Such disorders include, among many others, oculocutaneous albinism, pityriasis alba, tinea versicolor and nevus depigmentosus. In these disorders, melanocytes are present in normal numbers in the epidermis but produce less than normal amounts of melanin. Typically, the skin exhibits mild to marked hypopigmentation.

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Depigmentation around the eyes (partially blocked), the nares and mouth, all classical and early manifestations of bilateral vitiligo

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Depigmentation of the feet, typical early manifestation of vitiligo

In contrast, other types of leukoderma are characterized by the absence of melanocytes and therefore, complete absence of melanin. Such disorders include piebaldism, the leukoderma of lupus erythematosus and other scarring disorders, and vitiligo. These types of leukoderma typically are totally depigmented. Vitiligo and lupus cause a destruction of melanocytes during postnatal life. Piebaldism affects the migration of melanocytes during embryogenesis and the infant is born with depigmentation of the hair and skin.

There seem to be three major factors involved in the destruction of melanocytes in patients with vitiligo.The first is that vitiligo patients inherit a set of three “vitiligo” genes which predisposes them to destruction of melanocytes. There probably are many different sets of three genes that can cause vitiligo so that not every individual would necessarily inherit the same three. The second abnormality relates to the melanocytes themselves. Melanocytes from patients with vitiligo differ from those obtained from a person without vitiligo. For example, vitiligo melanocytes require different and more fastidious culture conditions than those from normal individuals.Also, vitiligo melanocytes are much more sensitive to phenolic chemicals than normal melanocytes and readily undergo apoptosis when exposed to such agents.The third factor is an environmental agent(s) that activates (or inhibits) the genes involved, thereby setting in motion the process of destruction of the susceptible melanocytes. The vitiligo genes activated (inhibited) by the environmental agents seem to cause an excessive immune reaction that induces melanocytes to undergo apoptosis, and depigmentation of the skin results.

Vitiligo principally affects melanocytes. However, keratinocytes also manifest some damage, mostly a granular degeneration. It is not widely recognized that Merkel cells also are absent from depigmented skin. The significance of this absence and the impact it has on the function of the epidermis are not known. The cells of the epidermis, i.e., keratinocytes, Langerhans cells, melanocytes and Merkel cells, work closely together. It should be expected that loss of one or the other cells from the epidermis would alter its function. It is thought the Merkel cell functions as a neurosensory cell. It has been shown that sweating and bleeding times are altered in the depigmented skin of a patient with vitiligo.Alterations in cholinergic activity and morphology of sweat glands which are innervated by cholinergic sympathetic nerves have been observed by some investigators although not by all observers. The functional changes observed in depigmented skin might be related to the collateral damage to keratinocytes and/or Merkel cells. There are other functional abnormalities in vitiliginous skin which will be discussed later.

There are two main types of vitiligo, unilateral (often called segmental) and bilateral (usually termed generalized). Segmental vitiligo will be discussed later. However, the word “segmental” is often confused with the term “dermatomal”, the latter meaning the pattern of sensory innervation of the skin. Segmental is rarely, if ever, dermatomal, so unilateral is a better term to avoid confusion.

Bilateral or generalized vitiligo can begin at any age and tends to progress intermittently over the life of the patient. It produces depigmentation that is remarkably symmetrical in distributionA patch on the right side of the body is matched by a patch in a similar location on the left side. The entire body can depigment although it rarely does so. The classical presentation of the depigmentation is a remarkably symmetrical distribution of depigmentation beginning on the fingers, feet, wrists, elbows, axillae and around the mouth and eyes. There is no explanation for this symmetry. Yet, it is so typical and common that symmetrical depigmentation is one criterion for the diagnosis of vitiligo. (Depigmented patches can be randomly scattered. This has been labeled atypical vitiligo.) Dr. RB Goudie, a Scottish pathologist, was intrigued by the symmetry that characterized vitiligo. He noted that the distribution of some autoimmune endocrine disorders such as thyrotoxicosis resembled in some ways the distribution of vitiligo. He also noted that malignant lymphomas often appeared as tumors symmetrically involving both sides of the body. He hypothesized that benign lymphocytes honed to specific sites in the skin where they might be responsible for the symmetry of vitiligo.Although his ideas are no longer popular, they are based on the known propensity of cutaneous lymphocytes to migrate to specific sites in the skin and the role of lymphocytes in causing depigmentation. His ideas are worthy of reconsideration.

Extensive depigmentation of a woman which illustrates the symmetrical distribution of classical bilateral vitiligo

Unilateral (segmental) vitiligo differs from generalized vitiligo in many important aspects. It more commonly begins in children and young adults and progresses for a limited period, usually 1–2 years, and then remains static for the life of the individual.It affects just one side of the body. In contrast to bilateral vitiligo, the distribution is asymmetrical on the skin. However, the patterns also are not random. The various sites affected by the depigmentation are repetitious. The patterns on the face have been classified.There are patterns affecting the neck and trunk which resemble each other in location and shape.It is important to note that a nevus depigmentosus and a cafι-au-lait spot can have a similar shape, pattern and location as segmental vitiligo. These similarities of patterns and distribution for unilateral vitiligo and nevus depigmentosus suggest that unilateral vitiligo corresponds to embryological developmental patterns for melanocytes in their migration from the neural crest to the epidermis.

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Unilateral (segmental) vitiligo affecting one side of the face of a young boy. Note that the depigmentation does not correspond to a dermatome

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Unilateral depigmentation (segmental vitiligo) affecting the neck of a woman. Note the very similar distribution of depigmentation in the two men pictured below

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Unilateral depigmentation (segmental vitiligo) on the neck of a man with a distribution similar to the pictures below

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Nevus depigmentosus on the neck of a boy. The pigmentary abnormality was present at birth in the patient

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Nevus depigmentosus on the neck of a man. The pigmentary abnormality was present at birth in the patient

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Unilateral depigmentation (segmental vitiligo) of the neck of a man which is similar to the depigmentation seen  in previous photos

Typically, bilateral vitiligo progresses over the life of the individual so that the person has partially normal and partially depigmented skin. This probably is the worst outcome. Of course, it is best to be one’s own color but it is the worst condition for most people to have two colors at least on visible skin such as the hands, face, neck and arms. To avoid this, for some patients, the treatment of choice is depigmentation of the normal skin by applications of monobenzone by which they achieve a single color. This is what Michael Jackson did to achieve a single white color. Occasionally, nature achieves the same end. A very small number of patients will develop over a period of a few months a very rapid depigmentation of the entire integument and also the hair. Dr. Aaron Lerner called it “veloce vitiligo” or rapid vitiligo. These individuals go from having dark skin to having totally depigmented skin and hair in a period of months. It can occur spontaneously but in my personal experience has followed in a few individuals generalized erythematous drug eruptions. How or why this happens is not known.

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An Indian woman with veloce vitiligo. She lost almost all of her pigmentation on the skin and hair over a period of some months

The three cells of the epidermis, keratinocytes, Langerhans cells and melanocytes, form a troika so to speak and work together. As noted above, it should not be surprising that depigmented skin has some altered functions if one part of the troika is missing. Several Japanese workers noted that depigmented skin of vitiligo patients did not react to sensitization with dinitrofluoro benzene (DNFB) to produce contact dermatitis. In their experiments, DNFB was applied to normal skin to induce contact allergy. A challenge was applied to both normal and white skin. The white skin did not respond. In other experiments, the sensitizing dose of DNFB was applied to white skin and the challenge to both white and pigmented skin. The pigmented but not the white skin responded.These findings suggest that the afferent limb of the immune response is intact in the white skin, but the efferent limb is not so. In the same studies, Candida antigen was injected into the dermis of both white and pigmented skin and the dermal response was normal in both.The discrepancy between epidermal and dermal immune responses might be attributed to loss of the melanocytes which could have immune/inflammatory functions.

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The epidermis is composed of three main cell types that work together like a troika

Others have noted that depigmented skin does not respond to contact allergens. Monobenzone as noted above is used to depigment skin for those with depigmentation too widespread to repigment. Some individuals applying monobenzone develop a contact allergy to the medication. However, the allergic dermatitis is manifested only in the pigmented skin.In separate studies, investigators observed that the inflammatory response to irritants was abnormal in white skin compared to pigmented skin. It seems especially fascinating that graft versus host skin disease in one individual with piebaldism affected preferentially the white skin, emphasizing again that the three cells of the epidermis work together and that melanocytes likely play a role in inflammation.

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A woman treated with monobenzone, who developed a contact allergy. The dermatitis is exclusively confined to the pigmented skin

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A man treated with monobenzone, who developed a contact allergy. The dermatitis is exclusively confined to the pigmented skin

A muted response to contact allergens is not unique to humans. There is a species of mice that has an acquired form of depigmentation resembling vitiligo, called the mi/mivit/vit mouse. The skin and follicles of the mouse have normal numbers of Langerhans cells in both the pigmented and depigmented stages.However, the response of the mouse to potent contact allergens is highly muted after the skin and pelage have lost their melanocytes. This aberrant response might be due to inability of depigmented skin to express intercellular adhesion molecule 1 (ICAM-1). Humans with vitiligo show altered expression of ICAM-1 in the epidermis. ICAM-1 is critical to a normal immune response.

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Mice with mivit/mivit gene. The mouse on the left has a piebald band on the leg but a normal pigmented pelage in early life. The mouse on the right is undergoing depigmentation with loss of melanocytes from the epidermis and hair follicles

One of the most mysterious features of vitiligo is the resistance of skin depigmented by vitiligo to producing skin cancers. It is a common worry for physicians and patients with vitiligo that they might get a melanoma. It is possible for a patient with vitiligo to get a melanoma but only in their normally pigmented skin. The white skin is devoid of melanocytes and thus unable to generate a melanoma. It is baffling that the white skin is also highly resistant to formation of keratinocyte malignancies, i.e., basal and squamous cell carcinomas.

Vitiligo skin is totally depigmented. The color is similar to that of albinism. Albinos are known to have a high incidence of skin cancer, especially in Africa where most albinos have oculocutaneous albinism type 2, a disorder caused by mutations in the p-gene. Most of these are squamous cell carcinomas. Interestingly, few individuals with other forms of oculocutaneous albinism, types I, III and IV, have been reported to have skin cancer. There are many possible explanations for this, the most obvious being that those living in Africa have little access to sufficient sun protection. In contrast, it has been suggested the mutations in the p-gene are related to melanomas  as well as causing oculocutaneous albinism II. Similar studies on the p-gene and skin cancer have not been done for non-melanoma cancers but it is a project which may be worth doing. It must be stated that melanomas are very infrequent in albinos of any type.[

Patients with vitiligo can get skin cancer of any type in their normal skin but there is a paucity of reports of non-melanoma skin cancer in the white skin. This observation is particularly puzzling because the treatments for vitiligo include both ultraviolet B and psoralen-ultraviolet A (PUVA), both carcinogenic forms of light. Of interest is a recent report in which the incidence of skin cancer was studied in a cohort of 477 vitiligo patients. Half of these were Caucasians and the other half were dark skinned (Fitzpatrick skin types IV, V, VI). There with six patients with skin cancers, all with light colored skin (Fitzpatrick types I, II, III). Four of the six occurred in normal skin and only two affected the depigmented skin. Several points are worth noting. No individuals with type IV skin or darker had a skin cancer. Depigmented skin is of the same color in individuals of all ethnic backgrounds, i.e., totally white. One would expect that the cancers affected individuals of all skin color equally. The other point is that the cancers were most common (four of the six) in the normally pigmented skin. One would expect a majority to be in the depigmented skin. This is consistent with the idea that vitiligo skin is resistant to formation of skin cancers.

It is of note that actinic damage also is less visible in white skin than in the pigmented skin of those with vitiligo. Several studies on patients with vitiligo treated with PUVA showed no increase in skin cancer incidence. In contrast, albinos exhibit sun damage from early childhood. Some white skin caused by the absence of melanocytes from other causes seems susceptible to carcinogenesis. Thermal scars or depigmented skin of patients with discoid lupus are susceptible to formation of cancers. Of particular interest are patients with piebaldism caused by defects in the c-kit oncogene. As noted above, piebald skin reacts differently from normally pigmented skin to a graft versus host immune reaction. In my own series of three families with piebaldism, actinic damage is common and seems to have a predilection for the white skin rather than the pigmented normal skin . This seems to be the reverse of our observations for vitiligo skin. That the melanocytes have some role in inflammation, carcinogenesis and other processes seems probable.

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The neck of an African woman who had vitiligo for over 20 years. She was a farmer and worked in the sun daily. Note the elastosis of the neck, but the normal overlying white epidermis

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The hands of the African woman shown  above  who had vitiligo for over 20 years. She was a farmer and worked in the sun daily

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The arms of a woman with piebaldism (c-kit). She has marked sun damage and many actinic keratoses, mostly in the depigmented patches on her arms

There is no doubt that skin color and susceptibility to skin cancer are related. Lighter skin has a high propensity for all forms of skin cancer compared to darker skin. It has been enigmatic to me that my students from Asia, China, Korea and Japan have a skin color not that much darker than mine with a European ancestry (Swedish and Hungarian). Asians are not so pigmented as Africans, Indians or Middle Easterners. Yet, their risk for skin cancers is low. My conclusion is that skin color is just one factor related to skin cancer risk. Other factors related to repair of damage, resistance to mutation and/or other factors play as big or bigger role in defense against skin cancer as skin color. This point is made clear, especially from the data on vitiligo and albino patients and skin cancer and the types of skin cancer identified in albinos, mostly squamous cell carcinomas. Why don′t albinos get more basal cell carcinomas and/or melanomas?

Finally, it is well known among those who are interested in vitiligo that treatment is difficult and frustrating. Some of the areas of depigmentation are especially difficult to repigment, such as the hands and feet. It seems mysterious to many. However, it has been shown that the hair follicle is the reservoir for repigmentation. Nature, for reasons not clear, evolved skin on the fingers, ventral surface of the wrist, the feet and genitalia that is hairless, i.e., glabrous. Such skin or skin with white hairs cannot respond to medical treatment  but only to surgical treatments which are a means to make a reservoir where there was none.

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The leg shows repigmentation from the hair follicles

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The leg has all white hairs and no repigmentation is visible except in one spot (arrows and circle)

Clearly, these are the musings of an old person thinking over the decades about vitiligo. Most of the interest by investigators is focused on an immune basis for melanocyte destruction. These studies are important to understand the cause of vitiligo. Little has been done to study the defects in the melanocytes which make them susceptible to destruction. There is so little interest in the melanocyte as a member of the inflammatory response because the prevalent bias about the melanocyte is that it is exclusively a protection against sun damage, a role it plays as part of a much larger function in the skin. There must be an important message in the fact that skin cancer is unusual in vitiligo skin but common in albino skin, the obvious difference being the presence of dysfunctional melanocytes in the latter patients. It is my hope that a younger student will not only study these phenomena and find the causes of vitiligo but also find the answer to other important questions about the epidermis and pigmentation.


Photo Credit: Envato Elements

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