Acquired hypopigmentation disorders other than vitiligo

INTRODUCTION — The color of human skin is mainly determined by the two types of melanin, the black-brown eumelanin and the yellow-red pheomelanin. Other significant contributors include the capillary blood flow, chromophores such as carotene or lycopene, and the collagen content of the dermis. Altered skin pigmentation can result from increased or decreased melanin, abnormal melanin distribution, decreased hemoglobin, or deposition of exogenous substances [1].

"Hypopigmentation" is a general term that refers to any form of decreased or absent skin pigmentation caused by melanin, hemoglobin, or any other reasons. "Hypomelanosis" more specifically refers to a reduction of epidermal melanin. Hypopigmentation disorders may be congenital or acquired, diffuse (generalized) or localized, and may occur in isolation or be associated with a wide range of congenital or acquired disorders [2-4].

This topic will review the acquired hypopigmentation disorders other than vitiligo. Vitiligo is discussed separately. Congenital hypopigmentation disorders are also discussed separately.

●(See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)

●(See "Vitiligo: Management and prognosis".)

●(See "Oculocutaneous albinism".)

●(See "Pigmentary mosaicism (hypomelanosis of Ito)".)

DIAGNOSTIC APPROACH — The diagnosis of hypopigmentation disorders is in many cases made on clinical grounds, based upon a detailed medical history and physical examination [5]. The lesion morphology, color (hypopigmented or depigmented), distribution, and pattern are important clues to the diagnosis. However, examination with a Wood's light, a skin biopsy, and additional laboratory tests may be required if the clinical diagnosis is uncertain. The differential diagnosis of hypopigmentation disorders is illustrated in the algorithm (algorithm 1).

Patient evaluation — The initial patient evaluation involves a detailed family and personal history and a complete physical examination, which should include a careful search for additional cutaneous and extracutaneous signs and symptoms.

The following questions may be useful for the evaluation of patients presenting with hypopigmentation disorders (algorithm 1) [1]:

●Is the disorder congenital or acquired?

●Is the hypopigmentation localized or diffuse?

●Are lesions well circumscribed or ill defined?

●Does the hypopigmentation have a pattern (eg, linear, reticular)?

●Is the hypopigmentation associated with prior inflammation or cutaneous injury?

●Are the lesions stable, progressing, or regressing?

●Does the patient have concomitant systemic diseases?

●Does the patient have a history of exposure to medications or chemicals?

History — A detailed medical history should be obtained from the patient to determine if the hypopigmentation is related to an underlying disease. Patients should also be questioned about occupational and/or hobby-related exposure to chemicals that may cause hypopigmentation. The course of the disorder can help distinguish acquired hypopigmentations (which often show progression or regression) from inherited disorders (which are usually stable).

Skin examination — In all patients with hypopigmentation disorders, a complete skin examination should be performed under visible light and Wood's light (algorithm 1). Important clinical parameters include:

●Extent of the pigmentary abnormality (localized versus diffuse)

●Morphology of individual lesions

●Distribution (eg, sun-exposed areas, areas previously involved by inflammatory processes)

●Pattern (eg, linear, reticular, nonfigurate)

Wood's light examination — A Wood's lamp emits ultraviolet A light with a peak emission at 365 nm ("black light") that allows a better visualization of variations in skin pigmentation [6]. Patients should be examined in a darkened room with the light source held at 4 to 5 inches from the skin. (See "Office-based dermatologic diagnostic procedures", section on 'Wood's lamp examination (black light)'.)

Under Wood's light, depigmented lesions due to complete absence of melanin, such as vitiligo lesions, appear bright white and sharply delineated, as a result of the autofluorescence of dermal collagen. Hypopigmented lesions due to decreased melanin in the epidermis are also markedly enhanced. In contrast, hypopigmentations due to vascular causes (eg, nevus anemicus), in which the epidermal melanin content is normal, are not accentuated.

Examination under a Wood's lamp is especially helpful in fair-skinned individuals to identify hypopigmented or depigmented lesions that may not be visible to the naked eye (algorithm 1).

Skin biopsy — A skin biopsy for histopathologic evaluation is not routinely performed for the diagnosis of hypopigmentation disorders. However, a skin biopsy may be warranted if the clinical diagnosis is uncertain or there is a suspicion for hypopigmented mycosis fungoides. (See 'Hypopigmented mycosis fungoides' below.)

Standard stains (eg, hematoxylin and eosin, Fontana-Masson silver stain) and histochemical techniques (eg, Mart-1, Melan-A) can be used to evaluate the number and location of melanocytes and melanin granules in the epidermis and dermis.

LOCALIZED DEPIGMENTATION

Chemical leukoderma — Chemical leukoderma, also known as contact leukoderma, contact vitiligo, or chemical vitiligo, may result from occupational exposure to chemicals that have a specific melanocytotoxic effect [7,8]. The majority of these chemicals are derivatives of phenols and catechols such as para-tertiary butylphenol, para-tertiary butyl catechol, monobenzyl ether of hydroquinone (MBEH; monobenzone), and hydroquinone [9,10]. They may be found in rubber gloves and other rubber products, germicides, insecticides, adhesives, hair dyes, and clothing treated with azo dyes.

Many other substances have also been reported to cause chemical leukoderma, including sulfhydryls, mercurials (eg, thimerosal, used as a preservative in cosmetics or topical medications), and cinnamic aldehyde (a fragrance used in personal care products). Household exposure to these chemicals may be more common than occupational exposure in some countries [10] However, not all exposed individuals develop leukoderma, suggesting a variability in the individual susceptibility [11].

The depigmentation starts on the hands and forearms (which are the presumptive sites of contact) as small, confetti-like white macules that tend to spread and coalesce (picture 1). However, depigmentation can also occur in areas distant from the sites of exposure (chemical leukoderma syndrome). (See 'Diffuse depigmentation' below.)

Histopathologically, chemical leukoderma is indistinguishable from vitiligo. In patients presenting with multiple pea-like or confetti-like depigmented macules, a history of repeated exposure to melanocytotoxic chemicals is an important clue to the diagnosis.

Strict avoidance of the offending substance may lead to spontaneous repigmentation in some patients. Topical corticosteroids and narrowband ultraviolet B phototherapy have been reported as effective in some but not all patients. Depigmentation may be permanent.

Drug-induced leukoderma — Potent topical or intralesional corticosteroids may induce hypopigmentation at the site of application, particularly in darkly pigmented individuals [12,13]. Depigmentation mimicking vitiligo has been reported in patients treated with the epidermal growth factor receptor inhibitor gefitinib [14], the tyrosine kinase inhibitor imatinib mesylate [15,16], immune checkpoint inhibitors [17,18], pegylated interferon [19], topical imiquimod [20,21], and transdermal methylphenidate [22]. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors", section on 'Vitiligo-like depigmentation'.)

Halo nevus — Halo nevus, also called "leukoderma acquisitum centrifugum," refers to the development of a halo of depigmentation around a melanocytic nevus (picture 2A-B) [23]. This pigment loss often heralds the spontaneous regression of the central nevus, which is thought to be a T cell-mediated immune response to nevus antigens [24]. (See "Acquired melanocytic nevi (moles)" and "Acquired melanocytic nevi (moles)", section on 'Halo nevi'.)

Melanoma-associated leukoderma — Melanoma-associated leukoderma has been reported in approximately 3 percent of patients with melanoma [25]. It can occur spontaneously in the absence of treatment or follow treatment with various immunotherapies. Leukoderma has been reported in patients with advanced disease treated with high-dose interleukin (IL) 2 [26], interferon-alpha [27], anti-programmed cell death protein 1 (anti-PD-1; eg, nivolumab, pembrolizumab) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4; ipilimumab) immune checkpoint inhibitors, and IL-2 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) [17,18,25,28,29]. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation" and "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

However, in some patients, the hypopigmentation may precede the diagnosis of melanoma by years, while in others, it may appear concurrently with the diagnosis of metastatic disease.

Melanoma-associated leukoderma can occur around the primary tumor or cutaneous metastases or at distant sites, mimicking vitiligo. However, in contrast with vitiligo, lesions can be either hypopigmented or depigmented and tend to be extensive, patchy, and asymmetric (picture 3). Whether the occurrence of leukoderma in patients with melanoma is associated with a more favorable prognosis or response to therapy against melanoma remains uncertain [30]. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors", section on 'Vitiligo-like depigmentation'.)

The pathogenesis of melanoma-associated leukoderma is incompletely understood. Evidence suggests that it represents the host immune response against the tumor. Melanoma is a highly immunogenic tumor that commonly overexpresses several melanocytic lineage antigens such as tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2, gp100, and melanoma antigen recognized by T cells [31]. A cytotoxic T cell response against these "self" antigens can cause destruction of normal melanocytes expressing normal levels of these proteins.

DIFFUSE DEPIGMENTATION — Diffuse depigmented lesions are usually seen in patients with generalized vitiligo. However, in some patients with chemical leukoderma, the depigmentation can spread from the site of contact with the offending chemical or even develop at distant sites, sometimes when patients are no longer exposed to the offending chemical [7,32,33]. It is difficult or impossible to determine whether these patients have a true diffuse chemical leukoderma or generalized vitiligo that was triggered by the contact with a toxic chemical [7]. (See "Vitiligo: Pathogenesis, clinical features, and diagnosis".)

LOCALIZED HYPOPIGMENTATION

Postinflammatory hypopigmentation

General features — Postinflammatory hypopigmentation is an acquired partial or total loss of skin pigmentation that may occur following the resolution of a wide range of inflammatory or infectious dermatoses (algorithm 1) [34]. Contact with irritants and dermatologic or cosmetic procedures such as cryosurgery, laser therapy, or laser resurfacing may also induce postinflammatory hypopigmentation or depigmentation.

The pathogenesis of postinflammatory hypopigmentation is incompletely understood. Cutaneous inflammation can affect all steps of melanogenesis, particularly the transfer of melanosomes to keratinocytes [35]. Severe inflammation may lead to a loss of functional melanocytes or melanocyte death [34].

Postinflammatory hypopigmentation typically presents with hypomelanotic macules or patches that match the shape and distribution of previous inflammatory lesions (picture 4). In most cases, inflammatory lesions may be seen along with hypopigmented lesions. Complete pigment loss can be seen in scleroderma or lupus erythematosus lesions.

The diagnosis is in most cases clinical. Examination under Wood's light accentuates lesions. However, a skin biopsy of an inflammatory lesion, if present, may be helpful in identifying the underlying condition if the diagnosis is unclear or if there is a clinical suspicion of mycosis fungoides. Histologic findings can differ depending on the characteristics of the preceding, inflammatory condition. Epidermal melanin and/or number of epidermal melanocytes is decreased, although melanin primarily located in macrophages (melanophages) can be observed in the upper dermis and around the vessels in the upper dermis.

Postinflammatory hypopigmentation is usually reversible and resolves spontaneously over weeks to months after the resolution of the underlying condition. Depigmented lesions resulting from complete loss of melanocytes do not improve with time. In these cases, epidermal grafting may be a therapeutic option.

Pityriasis alba — Pityriasis alba is a common, benign dermatosis that occurs predominantly in children and adolescents and is more noticeable in those with darker skin types [36,37]. Although considered in many cases a minor manifestation of atopic dermatitis, pityriasis alba may also occur in nonatopic individuals [38].

Pityriasis alba typically presents with multiple asymptomatic hypopigmented macules and patches, round or oval in shape, involving predominantly the face, upper trunk, and upper limbs (picture 5A-B). Mild erythema and scaling may precede the development of hypopigmentation.

On histopathologic examination, changes are mild and nonspecific and consist of mild spongiosis, acanthosis, and hyperkeratosis. There is markedly reduced pigment in the epidermis without significant reduction in melanocyte count [36]. On electron microscopy, degenerative changes in melanocytes and a reduced number of melanosomes within keratinocytes have been seen [36].

The diagnosis is in most cases straightforward, based upon the clinical appearance and distribution of lesions in patients. On examination with a Wood's lamp, lesions are accentuated but nonfluorescent. The differential diagnosis includes postinflammatory hypopigmentation following psoriasis or atopic eczema, tinea versicolor, nevus depigmentosus, nevus anemicus, hypopigmented mycosis fungoides, and vitiligo.

Pityriasis alba is a self-limited disease, but the time to resolution varies from several months to a few years. Treatment with emollients and low-potency topical corticosteroids may be beneficial in some patients. Topical calcineurin inhibitors may be an alternative to topical corticosteroids for the treatment of facial lesions [39].

There is a single report on the use of targeted phototherapy for pityriasis alba [40]. In this small observational study, targeted phototherapy with a 308 nm excimer laser induced complete remission in 10 of 12 children with moderate to severe facial pityriasis alba.

Lichen striatus albus — Lichen striatus albus is a variant of lichen striatus presenting with hypopigmented macules and patches arranged in a linear pattern along the lines of Blaschko (picture 6). The clinical features, diagnosis, and treatment of lichen striatus are discussed separately. (See "Lichen striatus".)

Scleroderma — Skin hyperpigmentation or depigmentation ("salt and pepper") is seen in patients with scleroderma, usually in combination with other cutaneous manifestations of the disease (picture 7). (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

Extragenital lichen sclerosus — Extragenital lichen sclerosus is a chronic inflammatory disorder affecting predominantly women in the fifth or sixth decade of life. It is characterized by the presence of asymptomatic, porcelain-white, atrophic plaques most commonly located on the back (picture 8), chest (picture 9), shoulder, neck, wrists (picture 10 and picture 11), thigh, and inframammary areas. Early lesions appear as flat-topped and slightly scaly, hypopigmented, white, or mildly erythematous polygonal papules that may coalesce to form larger plaques (picture 12).

The diagnosis, differential diagnosis, and treatment of extragenital lichen sclerosus is discussed separately. (See "Extragenital lichen sclerosus: Clinical features and diagnosis".)

Discoid lupus erythematosus — The inflammatory lesions of discoid lupus erythematosus heal leaving depressed, atrophic scars, telangiectasias, and hyperpigmentation and/or hypopigmentation (picture 13). Histologically, the depigmented lesions show degeneration of basal layer with epidermal atrophy, a variable number of melanocytes, and pigmentary incontinence in the superficial dermis. (See "Overview of cutaneous lupus erythematosus".)

Sarcoidosis — Hypopigmented sarcoidosis is a rare subtype of cutaneous sarcoidosis seen predominantly in dark-skinned individuals. It presents with thin, nonscaly papules or plaques, 1 to 10 mm in diameter, most often located on the trunk and face (picture 14A-B) [41]. Erythematous or skin-colored papules are sometimes present in the center of the patch, giving the lesion a "fried egg" appearance. Histopathologic examination of a skin biopsy reveals characteristic noncaseating sarcoidal granulomas, consisting of aggregates of epithelioid histiocytes, giant cells, and mature macrophages (picture 15 and picture 16).

The clinical manifestations, diagnosis, and differential diagnosis of cutaneous sarcoidosis are presented in detail separately. (See "Cutaneous manifestations of sarcoidosis".)

Hypopigmented mycosis fungoides — Hypopigmented mycosis fungoides (HMF) is an uncommon variant of mycosis fungoides, mostly seen in children and in patients with darker skin types [42,43]. HMF presents with hypopigmented, scaly patches mainly distributed on the trunk, pelvic girdle, buttocks, and proximal portions of the extremities. In some patients, scaling may be minimal or absent, and lesions may mimic vitiligo [44,45]. HMF may also simulate pityriasis alba, pityriasis lichenoides, tinea versicolor, or leprosy.

The diagnosis of HMF is difficult and often delayed. Repeated skin biopsies for histopathologic, immunophenotypic, and molecular studies are often required for a correct diagnosis. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides".)

Pityriasis lichenoides chronica — Pityriasis lichenoides chronica is an inflammatory skin disease characterized by the development of multiple scaly, erythematous to brown papules on the trunk and extremities. Occasionally, patients present with widespread hypopigmented macules as the predominant clinical manifestation of the disease (picture 17) [46]. A skin biopsy can confirm the diagnosis. (See "Pityriasis lichenoides chronica".)

Infectious hypomelanoses

Tinea versicolor — Tinea versicolor (pityriasis versicolor) is a common, recurrent, superficial fungal disease most commonly occurring in adolescents and young adults that is caused by Malassezia yeasts, a component of normal skin flora [47,48]. Tinea versicolor can present with hypopigmented (picture 18), hyperpigmented (picture 19), or erythematous macules (picture 20) and patches involving predominantly the upper trunk. Inhibitory or damaging effects on melanocytes by azelaic acid (a dicarboxylic acid produced by Malassezia) may play a role in the development of hypopigmentation.

The diagnosis is in most cases clinical but may be confirmed with a potassium hydroxide preparation showing hyphae and yeast cells in a pattern described as "spaghetti and meatballs" (picture 21). Examination with a Wood's lamp will reveal a yellow to yellow-green fluorescence in approximately one-third of cases [49]. (See "Tinea versicolor (pityriasis versicolor)".)

Leprosy — Indeterminate (early) leprosy presents in most cases with ill-defined hypopigmented macules or patches with diminished sensation (picture 22A-C) [50,51]. Hair loss, mild atrophy, and reduced or absent sweating may also be present in the affected area.

The lack of sensory perception to a light touch or pinprick distinguishes leprosy lesions from vitiligo and other infectious and noninfectious hypomelanoses. (See "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Endemic treponematoses — Endemic treponematoses, which include yaws, bejel, and pinta, are chronic bacterial infections caused by organisms that are morphologically and serologically indistinguishable from Treponema pallidum, the causative agent of syphilis [52,53]. (See "Yaws, bejel, and pinta".)

Pinta is confined to the skin and is the mildest of the treponematoses, affecting both children and adults. Secondary lesions of pinta may remain active for several years and lead to extensive depigmentation resembling vitiligo (picture 23A-B). Yaws affects predominantly children. Secondary lesions of yaws consist of papules, plaques, or papillomatous lesions that may ulcerate and leave oval hypopigmented macules (picture 24).

Syphilis — Leukoderma syphiliticum may rarely occur following the resolution of classic papular lesions of secondary syphilis [54]. The diagnosis is suspected in patients with a history of primary syphilis or in patients with additional cutaneous lesions characteristic of secondary syphilis. On histopathologic examination, the presence of a band-like lymphoplasmacytic infiltrate in the upper dermis may represent a clue to the diagnosis. Serologic testing for syphilis will confirm the diagnosis.

Onchocerciasis — Onchocerciasis, also known as "river blindness," is caused by the filarial nematode Onchocerca volvulus. It affects rural communities and is a major cause of blindness and skin disease in endemic areas. Manifestations of onchocercal skin disease include generalized itching, acute or chronic papular onchodermatitis, lichenified onchodermatitis, skin atrophy, and depigmentation.

Depigmentation typically occurs on the anterior shins of older adults. Patches of complete pigment loss present perifollicular "spots" or islands of normally pigmented skin, resulting in the so-called "leopard skin" appearance (picture 25). (See "Onchocerciasis".)

Nevus depigmentosus — Nevus depigmentosus (picture 26A-C) is a circumscribed, segmental area of depigmentation or hypopigmentation usually present at birth or detected in the first years of life [55,56]. The lesion is usually solitary and shows little change over time, although it may enlarge as the patient grows. The well-defined, hypopigmented macule has an irregular, saw-toothed border, but hairs within the lesion generally remain pigmented.

Nevus depigmentosus is a form of cutaneous mosaicism, caused by an altered clone of melanocytes with a decreased ability to produce melanin, abnormal melanosomes, and inability to transfer pigment to keratinocytes. When examined under a Wood's lamp, nevus depigmentosus shows an off-white accentuation, in contrast with the bright-white fluorescence seen in vitiligo. Nevus depigmentosus may be confused with the ash-leaf spots of tuberous sclerosis complex (TSC) (picture 27). However, the ash-leaf spots are usually multiple and associated with other cutaneous and extracutaneous features of TSC. (See "Tuberous sclerosis complex: Clinical features".)

Localized hypopigmentations due to vascular causes

Nevus anemicus — Nevus anemicus is a congenital, localized, cutaneous vascular anomaly presenting as a pale, irregularly shaped patch on otherwise normal skin (picture 28). It is thought to be caused by a localized increased vascular sensitivity to endogenous catecholamines resulting in persistent vasoconstriction [57,58]. Nevus anemicus is in most cases an isolated finding but may occur in association with several genetic syndromes, including phakomatosis pigmentovascularis, neurofibromatosis, and TSC [59-61].

Nevus anemicus is not accentuated by Wood's light. On diascopy, which consists in applying pressure to the lesion and adjacent normal skin with a glass slide, nevus anemicus is indistinguishable from the blanched adjacent skin.

There are no treatments for nevus anemicus. Camouflage makeup may be an effective treatment for those patients who feel uncomfortable with its appearance.

Bier spots — Bier spots, also called physiologic anemic macules, represent an uncommon, benign vascular mottling of the skin [62]. They are thought to be an exaggerated physiologic vasoconstrictive response of the small cutaneous vessels to hypoxia induced by venous stasis or venous hypertension [63,64].

Bier spots present with multiple asymptomatic, small, and irregular white macules on a background of blanching erythema, predominantly located on the arms and legs of young adults (picture 29) [65]. Bier spots are usually an isolated finding in patients otherwise healthy. There are a few reports of association with deep vein thrombosis [66], lower extremity lymphedema [67], cyanosis and urticarial eruption [68], and cryoglobulinemia [69].

The diagnosis is clinical, based upon the disappearance of the white lesions on diascopy or with limb elevation. The observation that lesions are accentuated by placing a tourniquet around the affected limb and disappear after the tourniquet is removed is an additional clue to the diagnosis.

No treatment is required for Bier spots. Patients should be reassured about the benign and self-limited nature of the condition.

DIFFUSE HYPOPIGMENTATION

Vitiligo-like depigmentation associated with PD-1 inhibitors — Vitiligo-like lesions have been reported in patients receiving programmed cell death protein 1 (PD-1) inhibitors [70]. It is thought that these lesions share similar clinical features and mechanisms as vitiligo. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)

Idiopathic guttate hypomelanosis — Idiopathic guttate hypomelanosis (IGH) is a common hypopigmentation disorder characterized by small, round or oval, white macules that typically presents in middle-aged and older individuals (picture 30C). Its prevalence increases with age and is estimated to be around 70 to more than 80 percent in individuals older than 40 [71,72]. IGH affects predominantly individuals with light skin types, without sex predilection.

Patients present with multiple small, scattered, discrete, round- or oval-shaped macules 2 to 6 mm in size that are lighter than the surrounding skin (picture 30A-B). The surface of the lesions is usually smooth but may be occasionally scaly. IGH most commonly appears on sun-exposed areas, such as the anterior area of the lower extremities and outer surface of forearms. However, sun-protected areas and, rarely, the face can also be affected.

The exact cause of IGH is unknown. One hypothesis is that it results from chronic ultraviolet exposure in combination with the normal aging process [73,74]. However, trauma is still regarded as a triggering factor.

Histopathologically, IGH lesions demonstrate reduced number of melanocytes, decreased melanin pigment, and hyperkeratosis with flattened rete ridge [75-77]. An electron microscopy study suggests that IGH may be due to a functional defect in the transfer of melanosomes to keratinocytes, in the absence of structural melanocyte abnormalities [78].

IGH lesions usually do not increase in size, but their number increases with age. Spontaneous repigmentation has not been observed. Although treatment is not typically required, a variety of therapies have been tried for cosmetic reasons with inconsistent results, including topical calcineurin inhibitors [79-81], fractional carbon dioxide laser [81-84], phenol [85], fluorouracil tattooing [86], and cryotherapy [87].

Progressive macular hypomelanosis — Progressive macular hypomelanosis (PMH) is a relatively common skin disorder characterized by ill-defined, nonscaly hypopigmented macules typically located on the trunk around the midline (picture 31A-B) [88]. Rarely, PMH may involve the upper extremities and the head and neck area. PMH typically occurs in adolescents and young adults and is most frequent in females and in individuals with darker skin types.

The precise etiology and pathogenesis of PMH are unknown. Cutibacterium (formerly Propionibacterium) acnes or different subtypes of Cutibacterium species (anaerobic saprophytes of the human skin residing within the hair follicles) have been proposed as etiologic agents [88-91]. The electron microscopy finding of smaller and less melanized melanosomes in lesional skin, compared with normal skin, suggests a decreased melanin synthesis as the cause of hypopigmentation [92,93]. However, the role of C. acnes in the altered melanogenesis remains to be determined.

The diagnosis of PMH is usually clinical. Under Wood's light, the hypopigmented lesions often demonstrate a characteristic, punctiform, orange-red, follicular fluorescence. The examination of a potassium hydroxide preparation is typically negative. If performed, histologic examination of a skin biopsy shows decreased epidermal melanin content with a normal number of melanocytes [94].

Treatment for PMH is difficult. Therapies that have been used with inconsistent results include topical antibacterials (eg, 5% benzoyl peroxide gel, 1% clindamycin lotion) and phototherapy with ultraviolet A (UVA) or narrowband ultraviolet B [95], alone or in combination [95-98]. PMH may resolve spontaneously after the age of 40.

Leukoderma punctata — Some patients develop multiple punctiform, hypopigmented or achromic spots 0.5 to 1.5 mm in diameter after long-term topical or systemic psoralen plus UVA treatment [99-102]. Histologic examination shows a reduction in melanin content and melanocyte number. Leukoderma punctata is thought to be caused by phototoxic damage of keratinocytes and melanocytes.

Nutritional deficiencies — In children, severe protein malnutrition (kwashiorkor) may be associated with hypopigmentation of the skin and scalp hair [103]. Alternating bands of light and dark hair may result from alternating periods of malnutrition and adequate nutritional intake. (See "Malnutrition in children in resource-limited settings: Clinical assessment", section on 'Kwashiorkor (edematous malnutrition)'.)

Although the precise mechanism leading to decreased melanin production is not known, a reduced availability of tyrosine is thought to be a contributory factor. Vitamin B12, iron, and copper deficiency may also be associated with diffuse hypopigmentation with involvement of the scalp hair [104].

Endocrine disorders — The association of vitiligo with autoimmune endocrine disorders is well recognized. However, hypopigmentations other than vitiligo and pallor have been reported in patients with hypopituitarism, hypogonadism, and Cushing syndrome [104]. In patients with hypopituitarism, the light pigmentation is thought to result from a decreased production of melanocyte-stimulating hormone (MSH) and adrenocorticotrophic hormone (ACTH). In patients with ACTH-independent Cushing syndrome, depigmentation may result from suppressed pituitary production of MSH by high cortisol levels [105]. (See "Causes and pathophysiology of Cushing syndrome".)

Other — A diffusely pale skin is a normal finding in patients with fair skin complexions. However, a diffuse skin pallor, especially if associated with pallor of the nail beds or conjunctivae, may be a sign of anemia. (See "Evaluation of pallor in children" and "Diagnostic approach to anemia in adults".)

SUMMARY

●Definition – "Hypopigmentation" is a general term that refers to any form of decreased or absent skin pigmentation, while "hypomelanosis" more specifically refers to a reduction of epidermal melanin. Hypopigmentation disorders may be congenital or acquired, diffuse or localized, and may occur in isolation or be associated with a wide range of congenital or acquired disorders. (See 'Introduction' above.)

●Diagnosis – In many cases, the diagnosis of hypopigmentation disorders is made on clinical grounds, based upon a detailed history and physical examination. The lesion morphology, color (depigmented or hypopigmented), distribution, and pattern are important clues to the diagnosis (algorithm 1). However, examination under Wood's light, a skin biopsy, and additional laboratory tests may be required if the clinical diagnosis is uncertain. (See 'Diagnostic approach' above.)

●Localized depigmentation – Localized depigmentations other than vitiligo are uncommon and include chemical leukoderma (picture 1), drug-induced leukoderma, and melanoma-associated leukoderma. (See 'Localized depigmentation' above and 'Diffuse depigmentation' above.)

●Localized hypopigmentation – Localized hypopigmentation may occur following inflammatory dermatoses (picture 4) or dermatologic procedures (eg, cryotherapy, laser therapy). Skin infections, including tinea versicolor (picture 18), leprosy (picture 22B), and onchocerciasis (picture 25), are also frequent causes of localized hypopigmentation. (See 'Postinflammatory hypopigmentation' above and 'Infectious hypomelanoses' above.)

●Diffuse hypopigmentation – Relatively common causes of diffuse macular hypopigmentation include idiopathic guttate hypomelanosis (picture 30A-C) and progressive macular hypomelanosis (picture 31A). Vitiligo-like lesions have been reported in patients receiving immune checkpoint inhibitors. (See "Cutaneous immune-related adverse events associated with immune checkpoint inhibitors".)

Diffuse hypopigmentation often also involving the scalp hair may be seen in patients with severe protein malnutrition or iron, copper, or vitamin B12 deficiency and in patients with hypopituitarism, hypogonadism, or Cushing syndrome. (See 'Diffuse hypopigmentation' above.)