Genetics of vitiligo

Both twin and family studies point to the importance of genetic factors in the development of vitiligo . For example, a survey in the US and UK found that 7% of the first-degree relatives of vitiligo probands had vitiligo. However, a 23% concordance rate in monozygotic twins supported the additional role of environmental factors . Genome-wide linkage analyses have been performed in multiple patient populations, resulting in the identification of a number of susceptibility loci and candidate genes. Many of these genes are involved in melanogenesis, immune regulation, or apoptosis and have been associated with other pigmentary, autoimmune, or autoinflammatory disorders ( Table 66.1 ).

Pathogenic hypotheses for vitiligo

Many pathogenic hypotheses have been proposed for vitiligo, in part reflecting the incomplete understanding of the mechanisms that underlie this complex condition ( Fig. 66.1 ). A primary challenge is the fact that what is referred to as vitiligo likely represents a heterogeneous group of diseases with different genetic backgrounds and environmental triggers.

Proposed model for the pathogenesis of vitiligo.

Inherited genetic risk (see Table 66.1 ) and environmental insults (e.g. monobenzyl ether of hydroquinone [MBEH], 4-tertiary butyl phenol [4-TBP]) induce melanocyte stress, exemplified by endoplasmic reticulum (ER) stress. Stressed melanocytes signal to local innate and resident skin cell types via exosomes containing antigen and damage-associated molecular patterns (DAMPs), soluble heat shock protein 70 (HSP70), and other factors. These signals activate several cell types, some of which migrate to the draining lymph nodes and stimulate T cells, which secrete interferon-γ (IFN-γ). IFN-γ signals through the IFN-γ receptor (IFN-γR) on keratinocytes and/or other cells; this involves phosphorylation of the transcription factor STAT1 by Janus kinases (JAK) 1 and 2. Phosphorylated STAT1 homodimerizes and then translocates into the nucleus, where IFN-γ-dependent genes such as CXCL10 (C-X-C chemokine ligand 10) are transcribed. Autoreactive CD8 ⁺ T cells that express C-X-C chemokine receptor 3 (CXCR3) follow secreted CXCL10 to the skin, where they kill melanocytes. Approaches targeting this IFN-γ–STAT1–CXCL10 axis that drives melanocyte destruction (e.g. with JAK inhibitors or antibodies against CXCR3) hold promise as potential treatments for vitiligo. ROS, reactive oxygen species; STAT1, signal transducer and activator of transcription 1; TYRP-1, tyrosinase-related protein 1.

Adapted from Strassner JP, Harris JE. Understanding mechanisms of autoimmunity through translational research in vitiligo. Curr Opin Immunol. 2016;443:81–8.

The immune system clearly plays a central role, in particular Th1 and Th17 cells, along with cytotoxic T cells, regulatory T cells, and dendritic cells; key mediators include interferon-γ (IFN-γ), C-X-C chemokine ligand 10 (CXCL10), and interleukin-22 (IL-22) . Animal models of vitiligo in which there are T cells reactive against melanocyte antigens have demonstrated the importance of an inflammatory dendritic cell (DC) phenotype and the INF-γ pathway .

Intrinsic defects of melanocytes and exogenous triggers may also play a role in vitiligo development. In addition, oxidative stress has been investigated as a pathogenic factor that could activate the immune response in vitiligo and underlie impaired WNT signaling that prevents melanoblast differentiation . Accumulating data highlight the complexity of vitiligo, with involvement of multiple cell types, including keratinocytes, fibroblasts, and stem cells as well as immune cells . These hypotheses are not mutually exclusive and the various pathways may converge to induce the disappearance of melanocytes from the skin and hair follicles. However, the exact cascade of events remains to be elucidated.

Clinical variants

Vitiligo ponctué , an unusual clinical presentation of vitiligo, is characterized by multiple, small, discrete amelanotic macules (confetti-like), sometimes superimposed upon a hyperpigmented macule. Erythema at the margin of a vitiligo macule is referred to as “vitiligo with raised inflammatory borders” or inflammatory vitiligo ( Fig. 66.6 ); a figurate papulosquamous variant has also been described. Occasionally, a hyperpigmented margin is seen. Blue vitiligo can result when vitiligo develops in areas of postinflammatory dermal pigmentation.

Inflammatory vitiligo.

An erythematous inflammatory border is evident. Such lesions are sometimes misdiagnosed as tinea corporis.

Trichrome vitiligo is characterized by a hypopigmented zone between the normal and depigmented skin. This intermediate zone has a fairly uniform hue rather than gradually progressing from white to normal. The number of melanocytes is also intermediate in this zone, suggesting a slower centrifugal progression compared with typical vitiligo. Quadrichrome and pentachrome vitiligo have also been described.

Hypochromic vitiligo (vitiligo minor) was recently described in patients with skin types V and VI . They presented with persistent hypopigmented macules in a seborrheic distribution, with lesions coalescing on the face and scattered on the neck, trunk, and scalp. A few individuals had additional achromic macules, and there was no history of prior inflammatory lesions. Decreased melanocyte density was noted histologically.

One of the manifestations of vitiligo is the isomorphic Koebner phenomenon (IKP), which is characterized by the development of vitiligo in sites of trauma, such as a surgical excision, burn, or abrasion. The IKP is more common in patients with progressive vitiligo, and it can occur in various forms of vitiligo. There appears to be a minimal threshold of injury required for the IKP to occur, bringing into question the hypothesis that minor trauma, such as friction from clothes (in the absence of true injury), can induce vitiligo lesions.

Clinical classification of vitiligo

Multiple attempts to classify the different types of vitiligo have resulted in confusing terminology. Two major forms are generally recognized: (1) segmental , which usually does not cross the midline; and (2) non-segmental , also simply called “vitiligo” without qualification . Mixed vitiligo refers to segmental and non-segmental forms occurring in the same patient .

The following classification scheme divides vitiligo into two major types, localized and generalized (see Fig. 66.4 ).

Localized:

• •
  

  Focal : one or more macules in one area, but not clearly in a segmental distribution

  
  
• •
  

  Unilateral/segmental : one or more macules involving one or rarely multiple segments of the body ( Fig. 66.7 ); lesions are typically unilateral and stop abruptly at the midline

  
  

  
  

  
  

  

  
  

  
  

  Segmental vitiligo.

  
  

  Unilateral band of depigmentation on the face, the most common location for segmental vitiligo. Note the pigmented and depigmented hairs within the affected area.

  
  

  Courtesy, Kalman Watsky, MD.

  
  
  
  
• •
  

  Mucosal : mucous membranes alone

• •
  

  Vulgaris : scattered patches that are widely distributed

  
  
• •
  

  Acrofacial : distal extremities and face

  
  
• •
  

  Mixed : combination of segmental and generalized (acrofacial and/or vulgaris) types

  
  
• •
  

  Universal : complete or nearly complete depigmentation

Course of the disease

The onset of vitiligo is usually insidious. Many patients become aware of the depigmented macules and patches, especially in sun-exposed areas, during the summer when tanning increases the contrast between involved and uninvolved skin. Clinical erythema or pruritus rarely precedes vitiligo.

The course of vitiligo is unpredictable. It becomes more extensive by the appearance of new depigmented macules, centrifugal enlargement of pre-existing lesions, or both processes. Peripheral hypopigmentation and poorly defined borders appear to be predictive of active vitiligo . A spotty pattern of depigmentation may also represent a marker of progressive disease. The natural course of generalized vitiligo is usually one of slow spread, but it may stabilize for a long period of time or evolve rapidly. Rarely, total body involvement develops within a few weeks or even days. In contrast, segmental vitiligo usually reaches its full extent within 1–2 years and remains restricted to the initial segmental area. The presence of halo nevi and leukotrichia increases the likelihood of evolution from segmental to mixed vitiligo . Some degree of sun-induced or spontaneous repigmentation of vitiligo is not uncommon, but complete and stable repigmentation is rare.

The v itiligo a rea s coring i ndex (VASI) and V itiligo E uropean T ask F orce (VETF) score represent validated quantitative assessment scales . However, universally accepted definitions for active and stable vitiligo are still lacking.

Vitiligo and ocular disease

The uveal tract (iris, ciliary body, and choroid) and retinal pigment epithelium contain pigment cells. Uveitis is the most significant ocular abnormality associated with vitiligo. Vogt–Koyanagi–Harada (VKH) syndrome is characterized by: (1) uveitis; (2) aseptic meningitis; (3) otic involvement (e.g. dysacusia); and (4) vitiligo, especially of the face or sacral region, and associated poliosis. Histologic examination of amelanotic skin, which classically appears after the extracutaneous symptoms, demonstrates an infiltrate consisting primarily of CD4 ⁺ lymphocytes, suggesting a prominent role for cell-mediated immunity.

Non-inflammatory depigmented lesions of the ocular fundus are evident in some patients with vitiligo, presumably representing focal areas of melanocyte loss. Although abnormal sensory hearing loss has been described in vitiligo patients, suggesting impairment of cochlear melanocytes, clearcut evidence of otic abnormalities remains to be demonstrated.

Alezzandrini syndrome is a rare disorder characterized by unilateral whitening of scalp hair, eyebrows, and eyelashes as well as ipsilateral depigmentation of facial skin and visual changes. In the affected eye, there is decreased visual acuity and an atrophic iris. The pathogenesis of Alezzandrini syndrome is unknown, but it is believed to be closely related to VKH syndrome.

Associated disorders

Although most vitiligo patients are otherwise healthy, generalized vitiligo is associated with a number of other autoimmune diseases, especially in patients with a family history of vitiligo and other forms of autoimmunity. Autoimmune thyroid disease occurs in ~15% of adults and ~5–10% of children with vitiligo , and other less frequently associated conditions include pernicious anemia, Addison disease, lupus erythematosus, rheumatoid arthritis, and adult-onset insulin-dependent diabetes mellitus . Of note, these conditions have been linked to the same autoimmunity predisposition genes as in vitiligo (e.g. PTPN22 , NLRP1 ; see Table 66.1 ). Halo melanocytic nevi, alopecia areata, and lichen sclerosus are additional autoimmune skin conditions that may be associated with vitiligo.

Patients with the autosomal recessive a utoimmune p oly e ndocrinopathy– c andidiasis– e ctodermal d ystrophy (APECED) syndrome often develop vitiligo. The gene responsible for APECED, AIRE ( a uto i mmune re gulator), encodes a transcription factor that promotes expression of tissue-specific self-antigens in the thymus, which facilitates development of peripheral tolerance. In APECED, failure to delete autoreactive T cells leads to autoimmune disease. In a mouse model, AIRE deficiency was found to result in tyrosinase-related protein-1 (TYRP1)-specific T cells that enhanced immune responses against melanoma .

Childhood vitiligo

Although vitiligo vulgaris is the most common clinical type observed in children, the frequency of segmental vitiligo (~15–30%) is significantly increased compared to that in adults (<5–10%) . The incidence of associated endocrinopathies is less than in the adult vitiligo population. A family history of vitiligo is associated with an earlier age of onset .

Corticosteroids

Topical corticosteroids are useful for localized areas of vitiligo. A meta-analysis showed that approximately half of patients with vitiligo affecting ≤20% of the body surface area (BSA) achieved >75% repigmentation with class 1 (superpotent) or 2–3 (high potency) topical corticosteroids; cutaneous atrophy was observed in 14% and 2% of these groups, respectively . To minimize side effects, class 1 corticosteroids can be used in 6–8-week cycles or on a twice-weekly basis, alternating with topical tacrolimus or a less potent topical corticosteroid . Treatment should be discontinued if there is no visible improvement after 2–3 months.

In general, intralesional corticosteroids should be avoided because of the pain associated with injection and the higher risk of cutaneous atrophy (≥30%). Systemic corticosteroid regimens utilizing high-dose pulses, mini-pulses, or low daily oral doses have been reported to arrest rapidly spreading vitiligo and induce repigmentation . However, given the potential for serious side effects, the role of systemic corticosteroids in the treatment of vitiligo remains controversial.

Topical calcineurin inhibitors (TCIs)

Multiple studies have shown that topical tacrolimus 0.1% ointment or pimecrolimus 1% cream applied twice daily can result in repigmentation of vitiligo, with response rates in pediatric patients similar to those achieved with topical corticosteroids. The best results are obtained when these agents are used on the face and other sun-exposed areas, suggesting a synergistic effect. TCIs can also enhance repigmentation when used in conjunction with narrowband UVB phototherapy or the excimer laser . Of note, avoidance of UV light is suggested by the package insert for TCIs, and the risk:benefit ratio should be discussed. Topical tacrolimus can also be used together with topical corticosteroids on a rotational basis (see above) or as maintenance therapy after repigmentation. In a recent randomized controlled study, bi-weekly application of tacrolimus 0.1% ointment to sites of previous vitiligo reduced the rate of recurrent depigmentation to 10%, compared to 40% with placebo .

Photo(chemo)therapy

Lasers and related light devices

Surgical therapies

For vitiligo patients who fail to respond to medical therapy, surgical treatment with autologous transplantation techniques may be an option . The general selection criteria for autologous transplantation include stable disease for ≥6 months, absence of the Koebner phenomenon, no tendency for scar or keloid formation, and age >12 years . A minigraft test showing retention/spread of pigment at the recipient site and no koebnerization at the donor site after 2–3 months can also assist in patient selection.

Several methods of surgical repigmentation have been successfully utilized. Minigrafting is the simplest technique. Small punch grafts (1–2 mm) from uninvolved skin are implanted within achromic areas, separated from each other by 5–8 mm. A cobblestone effect, a variegated appearance of the grafts, and sinking pits represent potential unfavorable outcomes. Because scarring and dyspigmentation may occur at the donor sites, cosmetically insensitive areas are chosen. The advantages of suction blister epidermal grafting are the absence of scarring at the donor site and the possibility of reusing this area. However, failure of the graft to take and koebnerization may occur. Grafting of cultured autologous melanocytes is an expensive technique that requires specialized laboratory expertise; grafts consist of pure melanocytes or melanocytes admixed with keratinocytes . To avoid the need for in vitro culture, which involves mitogens to enhance cell growth, grafting of non-cultured epidermal cell suspensions that include melanocytes has been advocated . Grafting of individual hairs to repigment vitiligo leukotrichia has also been successfully performed. Most of these techniques require clinical expertise.

Combination therapy

Combination therapy may produce higher rates of repigmentation compared to traditional monotherapies. Examples include phototherapy following surgical procedures as well as combining TCIs and/or topical corticosteroids with NB-UVB or excimer laser therapy . Although topical vitamin D derivatives are relatively ineffective as monotherapy, these agents may result in additional repigmentation when used in conjunction with phototherapy.

Micropigmentation

The technique of permanent dermal micropigmentation utilizes a non-allergenic iron oxide pigment to camouflage recalcitrant areas of vitiligo. This tattooing method is especially useful for the lips, nipples and distal fingers, which have a poor rate of repigmentation with currently available treatments. Although the color may not match perfectly with the normal surrounding skin and can fade over time, the result is immediate and can represent a dramatic aesthetic improvement.

Depigmentation

Depigmentation represents a treatment option for patients who have widespread vitiligo with only a few areas of normally pigmented skin in exposed sites. The patients must be carefully chosen, i.e. adults who recognize that their appearance will be altered significantly and who understand that depigmentation requires lifelong strict photoprotection (e.g. sunscreens, clothing, umbrellas). The most commonly used agent is 20% monobenzyl ether of hydroquinone (MBEH), applied once to twice daily to the affected areas for 9–12 months or longer . MBEH is a potent irritant and allergen, and an open application test can be performed before more widespread application. It typically takes 1–3 months to initiate a response, and a loss of pigment can occur at distant sites. Although depigmentation from MBEH is considered permanent, repigmentation (especially perifollicular in areas with pigmented hairs) can be seen following a sunburn or intense sun exposure. Monomethyl ether of hydroquinone (MMEH) in a 20% cream can be used as an alternative to MBEH . Side effects include contact dermatitis, exogenous ochronosis, and leukomelanoderma en confetti. Depigmentation via Q-switched ruby laser therapy was reported to achieve faster depigmentation than that achieved with a bleaching agent , and this laser has also been used in combination with topical 4-methoxyphenol to induce depigmentation . Lastly, depigmentation with the Q-switched alexandrite laser has been described .

Psychological support

The impact of vitiligo on quality of life is severe in many affected individuals, and it is critical for physicians to recognize this aspect of the condition and address their patients’ psychological needs. Although a “magic” treatment is not yet available, there is always something beneficial that can be done for vitiligo patients. They first need to know what their skin disorder is. Explaining the nature of the disease process and the potential and limits of available therapies is important and more productive than a fatalistic attitude that there is no cure and vitiligo is “only” a cosmetic disorder. Even helping patients to conceal the condition so that it is not visible can be part of the management plan. The use of support groups and, if indicated, psychological counseling are important supplementary therapies.

Additional controversial therapies

Potential emerging treatments

Epidemiology

OCA is the most common inherited disorder that leads to diffuse hypomelanosis. In most populations, the estimated frequency is 1 : 20 000; however, it is as high as 1 : 1500 in some African tribes.

Pathogenesis

All well-characterized types of OCA have an autosomal recessive inheritance pattern, although a few rare families with autosomal dominant OCA have been described . Based upon molecular studies, four types of OCA have been defined (see Table 65.1 ). OCA type 1 (OCA1) results from reduced (OCA1B) or absent (OCA1A) tyrosinase activity; at least 320 distinct mutations in the tyrosinase gene ( TYR ) have been identified in patients with OCA1 . OCA2 is due to mutations in the P gene (pink-eyed dilution; now referred to as OCA2 ) . Although the function of the P protein is still debated, studies have pointed to a possible role in regulating organelle pH and facilitating vacuolar accumulation of glutathione.

OCA3 results from mutations in the tyrosinase-related protein 1 ( TYRP1 ) gene . The TYRP1 protein is a melanocyte-specific gene product involved in eumelanin synthesis (see Fig. 65.11 ), probably via stabilization of tyrosinase. Both OCA1 and OCA3 appear to be endoplasmic reticulum (ER) retention diseases wherein the abnormal proteins (tyrosinase or TYRP1) never leave the ER to become incorporated into melanosomes (see Fig. 65.7 ). Of note, dysfunction of the P protein can also lead to abnormal processing and trafficking of tyrosinase. OCA4 is caused by mutations in SLC45A2 which encodes solute carrier family 45 member 2 (formerly membrane-associated transporter protein [MATP]), a transmembrane transporter with roles in tyrosinase processing and intracellular trafficking of proteins to the melanosome .

OCA5 has been linked to chromosome 4q24, but the responsible gene has not yet been identified. OCA6 was recently found to result from mutations in SLC24A5 , which encodes a putative cation exchanger localized to the melanosomal membrane . Of note, this gene was previously identified as one of the determinants of the physiologic variation in human pigmentation. Lastly, mutations in C10orf11 (chromosome 10 open reading frame 11) underlie OCA7; the C10orf11 protein is expressed in melanoblasts as well as melanocytes and is thought to have a role in melanocyte differentiation .

Autosomal recessive OA (AROA) is genetically heterogeneous, and some cases actually represent OCA1B or OCA2 but with subtle cutaneous findings. The most common form of OA is an X-linked recessive disorder caused by mutations in the G protein-coupled receptor 143 gene ( GPR143 ; formerly OA1 ), which encodes a pigment cell-specific intracellular G protein-coupled receptor that regulates melanosome formation and transport within melanocytes and cells of the retinal pigment epithelium . Mutations in GPR143 that lead to ocular albinism can result in retention of the aberrant protein within the ER.

Clinical features

OCA2

The OCA2 phenotype (in addition to OCA1B) corresponds to the classic “tyrosinase-positive” OCA. The clinical spectrum of OCA2 is broad, ranging from minimal to moderate pigmentary dilution of the hair, skin, and iris, with little to no ability to tan. The vast majority of individuals of African descent who have “tyrosinase-positive” OCA have OCA2. With time, pigmented melanocytic nevi and lentigines may develop in sun-exposed areas ( Fig. 66.10 ); the latter can become rather large and darkly colored ( Fig. 66.11 ). Another phenotype called “brown OCA” in African and African-American populations results primarily from mutations in the P gene. In these individuals, the hair and skin are light brown, the irides are gray to tan at birth, and sunburns are unusual.

Oculocutaneous albinism type 2 (OCA2).

African patient with obvious squamous cell carcinomas on the cheek as well as multiple pigmented lentigines.

Courtesy, James Nordlund, MD.

Oculocutaneous albinism type 2 (OCA2).

African patient with hypopigmented hair and large pigmented lentigines.

Courtesy, James Nordlund, MD.

The hypopigmentation seen in a subset of patients with Prader–Willi syndrome (PWS) and Angelman syndrome (AS) represents a form of OCA2. PWS features hyperphagia, obesity, hypogonadism, and intellectual disability, whereas AS is characterized by severe intellectual disability, microcephaly, ataxic movements, and inappropriate laughter. Due to genomic imprinting (see Ch. 54 ), deletions of the 15q region (which includes the P gene) in the paternal chromosome lead to PWS, while deletions in the maternal chromosome give rise to AS. Approximately 1% of patients with AS or PWS also have OCA2, which occurs when deletion of one copy of the P gene is accompanied by a mutation in the second copy.

Pathology

Although there is a reduction in melanin content, a normal number of melanocytes are present within the epidermis.

Differential diagnosis

This is outlined in Fig. 66.12 . Occasionally, patients with total body vitiligo may be thought to have OCA, but their epidermis lacks melanocytes.

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