Section 12. Disorders of Pigmentation

Skin color is genetically determined and is caused by the total amount of melanin pigment in the skin. Normal constitutive melanin pigmentation determines skin type, which is currently classified by the Fitzpatrick phototypes as follows:

Disorders of hypopigmentation are caused by decreased melanin content in the skin owing to decreased or absent melanin production or melanocytes. Disorders of hyperpigmentation are caused by increased melanin content in the skin owing to an increase in melanin production or melanocytes.

Decreased or absent melanin in the skin can lead to hypomelanosis and can occur by two main mechanisms.

1. Melanocytopenic hypomelanosis: absent or decreased number of melanocytes (e.g., vitiligo).

2. Melanopenic hypomelanosis: absent or decreased melanin production, but normal number of melanocytes (e.g., oculocutaneous albinism).

Pityriasis Alba

Pityriasis alba is a common asymptomatic, sometimes scaly, hypopigmentation of the face, neck, and body.

Insight

Pityriasis alba entails both mild dermatitis and pigment alteration; generally, the former responds quickly while the latter continues to be an issue for many months or years.

Epidemiology

Age Young children, often between the ages of 3 and 16 years.

Gender M = F.

Race All races, more noticeable in darker skin types.

Prevalence Common.

Etiology Likely a form of atopic dermatitis.

Pathophysiology

Thought to be an eczematous dermatosis, with hypomelanosis resulting from postinflammatory changes and ultraviolet screening effects of the hyperkeratotic and parakeratotic epidermis.

History

Hypopigmented areas are usually stable then gradually disappear with age. Some lesions may persist into adulthood. The areas are typically asymptomatic, but can sometimes burn or itch.

Physical Examination

Skin Findings

Type Macules, may have slight scale.

Number One to twenty lesions may be present.

Color Pink, then off-white to tan-white.

Size and Shape 5 to 30 mm or larger.

Distribution Face (malar region), neck, trunk, extremities.

Sites of Predilection Face, especially the cheeks (Fig. 12-1), midforehead, and around the eyes and mouth.

General Findings

May be associated with atopy (eczema, allergies, hay fever, asthma).

Differential Diagnosis

Pityriasis alba can be confused with other hypopigmented skin disorders such as vitiligo, tinea versicolor, tinea corporis, pityriasis lichenoides, and postinflammatory hypopigmentation.

Laboratory Examinations

Dermatopathology Histology reveals hyperkeratosis, parakeratosis, moderately dilated vessels of the superficial dermis, slight perivascular infiltrate, and edema of the papillary dermis.

Electron Microscopy The number of melanocytes is reduced and those present contain fewer and smaller melanosomes.

Wood’s Lamp Accentuates hypopigmentation. Lesions are NOT depigmented.

Course and Prognosis

Pityriasis alba is a benign condition and often is self-limited, clearing at puberty. It is usually asymptomatic, but can be itchy or have a burning sensation.

Management

Treatment is unnecessary. The condition improves with age. For cosmetic reasons, emollient creams (hydrated petrolatum, Vaseline, mineral oil, moisturizers) may be useful to diminish the dry scales and ambient UV exposure can help repigment the area. In severe cases of pityriasis alba, a mild topical steroid can be used sparingly in appropriate strengths for short durations (bid for 2 weeks).

Postinflammatory Hypopigmentation

A common cause of benign hypopigmentation characterized by decreased melanin formation following cutaneous inflammation.

Synonym Postinflammatory hypomelanosis.

Epidemiology

Age Any age.

Gender M = F.

Etiology Usually follows involution of any inflammatory skin disorders (e.g., eczematous or psoriatic lesions, pityriasis rosea, burns, bullous disorders, infections, etc.).

Pathophysiology

Inflammatory conditions of the epidermis may result in transient alterations in melanosome biosynthesis, melanin production, and transport. Keratinocyte injury and may render them temporarily unable to accept melanin from melanocytic dendrites. Severe inflammation may even lead to a complete loss of melanocytes or melanocyte function.

History

Skin Symptoms None.

Physical Examination

Skin Findings

Type Macules, patches.

Color Off-white.

Shape Linear, oval, round, punctate depending on primary process (Fig. 12-2).

Distribution Localized or diffused depending on primary process.

Differential Diagnosis

A clinical history of an antecedent inflammatory dermatosis is helpful to differentiate postinflammatory hypopigmentation from tinea versicolor, tuberous sclerosis, vitiligo, albinism, or infectious disease (leprosy etc.).

Laboratory Examinations

Dermatopathology Skin biopsy may show decreased melanin in keratinocytes, inflammatory infiltrate may or may not be present depending on the etiologic primary process.

Wood’s Lamp Accentuates hypopigmentation. Lesions are NOT depigmented.

Course and Prognosis

Hypopigmentation gradually self-resolves over a period of months provided that the affected areas are kept disease-free. Common inflammatory conditions that lead to postinflammatory hypopigmentation include psoriasis, seborrheic dermatitis, atopic dermatitis, lichen sclerosus, lichen striatus, and lupus.

Management

Postinflammatory hypopigmentation is a benign reactive condition, thus no treatment is necessary. Prevention would focus on eliminating the primary inflammatory process, allowing the melanocytes to recover. Then the hypopigmentation will slowly self-resolve. Patients should be counseled that hypopigmentation may take weeks to months of inflammation-free periods to improve. Ambient UV exposure may be helpful in repigmenting affected areas.

Vitiligo

Vitiligo is an acquired pigmentary disorder characterized clinically by the development of completely depigmented macules, microscopically by the absence of melanocytes, and medically by the increased risk of autoimmune mediated disease (i.e., thyroid disorders).

Insight

Visible depigmentation carries deep cultural and religious stigma for many and, while not life-threatening, vitiligo should be approached with this understanding.

Epidemiology

Age Any age, 50% begin between ages 10 and 30 years.

Gender M = F.

Race All races. More noticeable in darker skin types.

Incidence Common. Affects up to 2% of the population.

Genetics Up to 30% of patients have a first-degree relative with vitiligo. Families with thyroid disease, diabetes, and other autoimmune processes are at increased risk of developing vitiligo. Several genetic loci have been implicated: AIS1 (FOXD3), PTPN22, VIT1 (FBXO11), CTLA4, MITF, MHC (HLA-DRB1, HLA-DRB4, HLA-DQB1), ESR1, AIS2, AIS3, MLB2, CAT, VDR, MYG1, GCH1, NALP1 (SLEV1), ACE, AIRE, COMT.

Etiology Likely autoimmune mediated.

Pathophysiology

In lesions of vitiligo, there is a decrease or absence of functional melanocytes in the skin. Numerous pathophysiologic mechanisms for vitiligo have been proposed: an autoimmune destruction of melanocytes, a defect in the structure and function of melanocytes, defective-free radical defenses, decreased melanocyte survival, autocytotoxic metabolites, faulty membrane lipid proteins in the melanocyte, defective melanocyte growth factors, neurochemical destruction of melanocytes, viral etiologies.

History

Both genetics and environment play a role in vitiligo. Many patients attribute the onset of their vitiligo to trauma, as with cuts, suture sites, etc. (Koebner or isomorphic phenomenon). Emotional stress (e.g., grief over lost partner) is also mentioned by patients as a cause. The depigmented areas gradually appear and 30% or more can undergo spontaneous repigmentation.

Physical Examination

Skin Findings

Type of Lesion Macule, patch.

Size 1- to 5-mm confetti macules, large several centimeter patches.

Color White depigmentation (Fig. 12-3A).

Shape Oval, geographic patterns; linear.

Distribution Face (periorificial), dorsa of hands, nipple, axillae, umbilicus, sacrum, inguinal, anogenital areas, extremities (elbows, knees, digits, wrists, ankles, shins), bony prominences.

Associated Cutaneous Findings

Hair White hair and premature gray hair, alopecia areata, and halo nevi.

Eye Iritis in 10%, but may not be symptomatic; retinal changes consistent with healed chorioretinitis in up to 30% of patients.

Perifollicular Repigmentation Repigmentation occurs around hair follicles (Fig. 12-3B) with macules that enlarge and eventually fuse to a confluent skin color.

General Examination

Hyper- or hypothyroidism is present in up to 30% of patients with vitiligo. Uncommon associations include diabetes mellitus, pernicious anemia, Addison’s disease, gonadal failure, polyendocrinopathy, halo nevi, alopecia areata, and lichen sclerosis.

Differential Diagnosis

The differential diagnosis of completely depigmented skin lesions include lupus erythematosus, pityriasis alba, tinea versicolor, piebaldism, chemical leukoderma, scleroderma, leprosy, nevus depigmentosus, tuberous sclerosis, leukoderma with metastatic melanoma, and post- inflammatory hypopigmentation.

Laboratory Examinations

Dermatopathology On skin biopsy, melanocytes are completely absent in fully developed vitiligo macules, but at the margin of the lesions, there may be melanocytes present and a mild lymphocytic response.

Laboratory Examination of Blood Blood tests for T4, TSH, glucose, CBC, and cortisol (in high-risk patients) may be indicated to rule out concurrent autoimmune diseases.

Wood’s Lamp Depigmented areas will light up brightly with the Wood’s lamp examination.

Course and Prognosis

The course of vitiligo is unpredictable; lesions may remain stable for years or progress rapidly. Approximately 30% of patients have some degree of sun-induced or spontaneous repigmentation. Children tend to have a better prognosis and have less associated endocrinopathies as compared to adults.

Management

Ambient sunlight with sunscreen can help repigmentation, especially is cosmetically noticeable areas such as the face or hands. In older children that are sunlight responsive and compliant, phototherapy (narrowband UVB > PUVA) is useful. Limited use of topical steroids to the affected areas has been successful, but should be discontinued if there is no clinical improvement after 2 months. Topical tacrolimus 0.1% ointment has reported success without the adverse effects of light or steroid therapy and can be tried alone or in conjunction with other treatment modalities. In older refractory adults, autologous small skin punch grafts from normal skin areas can be grafted to depigmented areas, but scarring and dyspigmentation may result.

Oculocutaneous Albinism

Oculocutaneous albinism (OCA) is a rare group of inherited disorders that present as a congenital absence of pigment in the skin, eyes, and hair. The pigment deficiency is caused by decreased or absent melanin, despite normal numbers of melanocytes in the skin.

OCA is primarily AR-inherited and can be categorized into four forms:

1. 1. OCA type 1: absent (OCA1A) or decreased (OCA1B) tyrosinase activity.

   2. OCA type 2: mutations in the P gene (? accumulation of glutathione).

   3. OCA type 3: mutations in tyrosinase-related protein 1 (TRYP1) gene.

   4. OCA type 4: mutations in membrane-associated transported protein (MATP) gene.

Ocular albinism (OA) patients primarily have XLR-inherited retinal depigmentation cause by a mutation in the ocular albinism type 1 (OA1) gene.

Epidemiology

Age Present at birth.

Incidence 1:20000 in whites. 1:1500 in some African tribes.

Genetics OCA: AR (rare cases of AD). OA: XLR (rare cases of AR).

Pathophysiology

OCA1 and OCA3 are endoplasmic reticulum (ER) retention diseases where the mutated proteins (tyrosinase or TYRP1, respectively) cannot leave the ER to become part of the melanosomes. OCA2 leads to a dysfunctional P protein which leads to abnormal processing or transport of tyrosinase. OCA4 leads to a defective transporter protein. OA has a mutated membrane glycoprotein that is thought to influence melanosomal growth and maturation.

Physical Examination

Skin Findings

Type Macular depigmentation of entire body (Fig. 12-4).

Color White or light tan (tyrosinase-negative).

Hair White or light brown (tyrosinase-positive), red.

Eyes Iris translucency, reduced visual acuity, photophobia, strabismus, nystagmus, lack of binocular vision.

Laboratory Examinations

Dermatopathology

Light Microscopy Melanocytes are present in normal numbers in the skin and hair bulb in all types of albinism. The dopa reaction is markedly reduced or absent in melanocytes of the skin and hair depending on the type of albinism.

Electron Microscopy Melanosomes are present in melanocytes in all types of albinism but, depending on the type of albinism, there is a reduction of the melanization of melanosomes, with many being completely unmelanized.

Tyrosine Hair Bulb Test Hair bulbs are incubated in tyrosine solutions for 12 to 24 hours and develop new pigment formation from normal and tyrosinase-positive OCA patients, but no new pigment formation is present in tyrosinase-negative OCA types.

Differential Diagnosis

The differential diagnosis would be whole-body vitiligo, but iris translucency and the presence of other eye findings in the fundus are reliable signs of albinism.

Course and Prognosis

Depending upon the OCA type and degree of tyrosinase activity, patients may vary in severity from complete loss of pigment to subtle pigmentary dilution (Table 12-1). Patients with OCA learn early in life to avoid the sun because of repeated sunburns, especially as toddlers. They have a normal life span but can have problems with vision, to the point of blindness, and skin cancers later in life: squamous cell carcinomas (with metastases), basal cell carcinomas, and melanomas (typically amelanotic).

Management

Recognition of OCA early in life is important to begin early patient education about rigorous protective skin care. Daily application of topical, potent, broad-spectrum sunblocks, including lip protection (SPF higher than 30) is necessary. Special UV protective clothing and wide brim hats help to reduce sun exposure.

Avoidance of direct sun exposure between the hours of 10 am and 2 pm, especially in high-intensity seasons or climates is recommended. OCA patients should have regular periodic skin examinations as they help to detect skin cancers as early as possible. Patients should also have UV protective eyewear and regular ophthalmologic care.

Nevus Depigmentosus

Nevus depigmentosus is a congenital hypomelanotic lesion characterized by a single depigmented spot, a segmental absence of pigment, or a Blaschkoid streak of hypopigmentation with a chronic persistent course.

Synonym Nevus achromicus, nevoid linear hypopigmentation.

Epidemiology

Age Present at birth.

Gender M = F.

Prevalence 1 in 75 people.

Pathophysiology

Proposed mechanism for nevus depigmentosus is chromosomal mosaicism.

History

Patients are born with the depigmented area of skin and the area is asymptomatic but persists for life.

Physical Examination

Skin Findings

Type Macules or patches.

Color Depigmented white or light tan (Fig. 12-5).

Size Few millimeters to several centimeters.

Shape Isolate, segmental, or linear following Blacshko’s lines.

Distribution Trunk, lower abdomen, proximal extremities > face, neck.

Differential Diagnosis

An isolated nevus depigmentosus must be differentiated from vitiligo, nevus anemicus, and lesions of tuberous sclerosis. Very extensive lesions, multilinear Blaschkoid hypomelanosis should raise the possible diagnosis of hypomelanosis of Ito in which the pigmentation is associated with abnormalities of the hair, CNS, eyes, or musculoskeletal system.

Laboratory Examinations

Dermatopathology Lesions may show normal or decreased melanocyte numbers.

Electron Microscopy Melanization is decreased or normal.

Wood’s Lamp Accentuation of depigmented areas.

Course and Prognosis

Lesions persist for life, but remain asymptomatic.

Management

A nevus depigmentosus is asymptomatic and for small lesions, treatment is not necessary. Extensive lesions, or those on the face, can be cosmetically upsetting to the patient. Since nevus depigmentosis lesions do not tan as well as the surrounding skin, they become more noticeable with UV exposure. Thus rigorous sun protection (SPF 30 of higher) would keep lesions less cosmetically detectable.

Nevus Anemicus

Nevus anemicus is a rare congenital area of pale skin that represents localized, decreased perfusion.

Synonym Pharmacologic nevus.

Epidemiology

Age Newborn.

Gender F > M.

Prevalence Rare.

Pathophysiology

It has been suggested that nevus anemicus arises from a focal increased blood vessel sensitivity to vascular catecholamines and thus are permanently vasoconstricted.

History

Lesions are present at birth and persist asymptomatically for life.

Physical Examination

Skin Findings

Type Macule or patch (Fig. 12-6).

Size Few millimeters to several centimeters, average 5 to 10 cm.

Color Hypopigmented, avascular.

Distribution Chest > face and extremities.

Differential Diagnosis

The differential diagnosis includes nevus depigmentosus, tuberous sclerosis, vitiligo, hypomelanosis of Ito, and incontinenti pigmenti. Three factors may be helpful for differentiating a nevus anemicus from a pigmentary problem: (1) a nevus anemicus does not accentuate by Wood’s lamp; (2) pressure on the lesion by a glass slide makes the lesion unapparent from surrounding normal skin; and (3) stroking or heat application fails to induce erythema in the lesion (Fig. 12-6).

Laboratory Examinations

Dermatopathology A skin biopsy reveals normal numbers of blood vessels and melanocytes. The biopsy would most likely be interpreted as normal skin.

Wood’s Lamp Does not enhance the lesion.

Course and Prognosis

Nevus anemicus persists for life and is usually asymptomatic. They are usually only noticeable when there is surrounding vasodilation because of heat or stress.

Management

No treatment is effective or necessary.

Increased melanin in the skin can lead to hypermelanosis and can occur by two main mechanisms:

1. Increased melanocytes in the epidermis producing melanocytic hypermelanosis.

2. Normal melanocyte numbers in the epidermis, but increased amounts of melanin-producing melanotic hypermelanosis (e.g., postinflammatory hyperpigmentation).

Postinflammatory Hyperpigmentation

Postinflammatory hyperpigmentation (PIH) is a common entity characterized by increased melanin formation and deposition following cutaneous inflammation.

Synonym Postinflammatory hypermelanosis.

Epidemiology

Age Any age.

Gender M = F.

Race More severe and longer lasting in darker skin types.

Etiology An acquired increase of melanin pigment can follow any inflammatory process (physical trauma, acne, friction, irritant dermatitis, eczematous dermatitis, lichen simplex chronicus, psoriasis, pityriasis rosea, fixed drug eruptions, lichen planus, pyoderma, photodermatitis, dermatitis herpetiformis, lupus erythematosus).

Pathophysiology

Inflammatory conditions of the skin may result in increased melanin within the epidermis or dermis. The epidermal forms of PIH are caused by an increase in melanin synthesis and/or transfer to the keratinocytes. The dermal forms of PIH are caused by dermal melanophages phagocytosing melanosomes after skin injury.

Physical Examination

Skin Findings

Type Macules, patches (Fig. 12-7).

Size Few millimeters to several centimeters.

Color Epidermal PIH: tan to dark brown. Dermal PIH: gray-blue to gray-brown.

Shape Linear, oval, round, punctate depending on primary process.

Distribution Localized or diffused depending on primary process.

Differential Diagnosis

A clinical history of a previous inflammatory process is helpful to distinguish PIH from melanocytic proliferations (ephelides, lentigines, nevi), endocrine abnormalities (Addison’s disease, estrogen therapy, ACTH and MSH producing tumors, hyperthyroidism), metabolic disorders (hemochromatosis, porphyria cutanea tarda, ochronosis), melasma, melanoma, scleroderma, pregnancy, drug-induced hyperpigmentation, ashy dermatosis, and macular amyloidosis.

Laboratory Examinations

Dermatopathology Epidermal PIH: increased melanin in the epidermal keratinocytes. Dermal PIH: increased melanin within the dermal melanophages.

Wood’s Lamp Accentuation of epidermal pigmentation.

Course and Prognosis

Epidermal hyperpigmentation gradually fades over a period of months provided the underlying dermatosis is kept under good control. Dermal hyperpigmentation is more difficult to clear, and may persist for life. Darker skin types have a more refractory course.

Management

Treatment is not necessary and with good control of the underlying dermatosis, the hyperpigmentation (epidermal PIH > dermal PIH) will fade over time. To hasten the resolution of PIH, several topical approaches have limited successful: sun protection (SPF 30 of higher), azelaic acid, hydroxyl acid, hydroquinone (2%–4%), or a steroid/hydroquinone/retinoid combination. Patients should be warned that with all therapies, worsening of the hyperpigmentation is possible. They should also be informed about sun protection when using these products as well as about their slow therapeutic action (3–4 months are required before a therapeutic effect is achieved).

Laser treatments are more successful for epidermal PIH than dermal PIH. But lasers have their limitations, especially in darker skin types where constitutive pigment can be lost.

Linear and Whorled Nevoid Hypermelanosis

Linear and whorled nevoid hypermelanosis is a benign, congenital, streaky hyperpigmentation along Blaschko’s lines resulting from mosaicism.

Synonyms Linear nevoid hyperpigmentation, zebralike hyperpigmentation in whorls and streaks, reticulate, and zosteriform hyperpigmentation

Epidemiology

Age At or soon after birth.

Gender M = F.

Race No racial predilection.

Prevalence Rare.

Etiology Chromosomal mosaicism may be present.

Pathophysiology

Nevoid hyperpigmentation along Blaschko’s lines is thought to be owing to somatic mosaicism during embryogenesis likely because of a heterogenous group of genetic abnormalities rather than just one specific entity. The whorled lines of pigment likely represents the clonal migration and proliferation of embryonic melanocyte precursors.

History

Whorled “marble cakelike” streaks of hyperpigmentation appear soon after birth with no antecedent rash, persists asymptomatically for life, and may become less prominent with time. There are rare reports of associated cardiac, neurologic, or musculoskeletal defects.

Physical Examination

Skin Findings

Type Macular whorled hyperpigmentation (Fig. 12-8).

Color Hyperpigmentation. Occasionally hypopigmentation.

Size Several centimeters to entire body.

Distribution Localized area, entire limb, quadrant, or the whole body. Mucous membranes, palms, soles spared.

Differential Diagnosis

History and physical examination with no antecedent rash and no associated anomalies differentiates linear and whorled nevoid hypermelanosis from incontinentia pigmenti (third stage), hypomelanosis of Ito, epidermal nevi, or other reticulated pigmentary syndrome.

Laboratory Examinations

Dermatopathology Skin biopsy shows basilar hyperpigmentation with a slight increase in basal melanocytes without incontinence of pigment.

Course and Prognosis

Skin findings are congenital, asymptomatic, and persist for life without complications. A few cases fade in pigmentation with time.

Management

Linear and whorled hyperpigmentation is benign and asymptomatic, but can be cosmetically distressing to the patient. Topical treatments are not effective. Camouflage cosmetics may be helpful. Laser treatments as a possible treatment modality are being investigated.