Hypopigmented lesions

Case #1 Piebaldism is a rare autosomal-dominant disorder characterized by the congenital absence of melanocytes in the skin and hair due to a mutation of the c-kit gene, which affects the differentiation and migration of melanoblasts from the neural crest....

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Case #1

Piebaldism is a rare autosomal-dominant disorder characterized by the congenital absence of melanocytes in the skin and hair due to a mutation of the c-kit gene, which affects the differentiation and migration of melanoblasts from the neural crest. Affected individuals typically present at birth with a white forelock and stable, persistent depigmentation of the skin that primarily affects the frontal scalp, forehead, ventral trunk, and extremities. It is a permanent, albeit benign, skin condition, and treatment can be challenging.

Piebaldism is estimated to affect approximately 1 in 20,000 to 40,000 men and women of all races, although the true prevalence is unknown.^1,2 Individuals typically present at birth with a stable and persistent depigmentation of the hair and skin. The hallmark of piebaldism is a triangular white forelock, which is present in 80% to 90% of cases.^1,3 In some cases, it may be the only manifestation, but its absence does not exclude the diagnosis. Underlying the forelock may be an amelanotic triangular or diamond-shaped patch that may extend to include the root of the nose and medial third of the eyebrows and eyelashes in severe cases.^1,4


The leukoderma of piebaldism is distinctive. Depigmented macules may be rectangular, rhomboid, or irregular in shape and are well-circumscribed and milk-white in color.^4,5 The macules are characteristically symmetrically distributed over the central anterior trunk, extending to the flanks, mid-extremities, central forehead, and mid-frontal portion of scalp (with the forelock).¹ Lesions typically spare the posterior midline, hands, feet, and periorificial areas. Normally pigmented or hyperpigmented macules or patches may be found within or at the border of the depigmented macules. 


Piebaldism is inherited in an autosomal-dominant fashion. Most cases are linked to mutations in the KIT proto-oncogene, c-kit, on chromosome 4q12, which encodes a transmembrane cell-surface receptor of the tyrosine kinase family on the surface of melanocytes.^6-11 This cell-surface receptor binds steel factor, an embryonic growth factor. To date, 14 point-mutations, 9 deletions, 2 nucleotide splice mutations, and 3 insertions of the c-kit gene, which present with a range of phenotypes, have been reported in the literature.⁶ 


Histopathologic evaluation of the hypopigmented macules reveals considerably reduced or absent melanocytes, whereas the hyperpigmented macules have a normal number of melanocytes but an increased number of melanosomes. The significant or complete loss of melanocytes in the amelanotic lesions is caused by improper migration of melanocytes from the neural crest in the embryo.^1,4 


The diagnosis of piebaldism is well-established based on the presence of stable, depigmented macules since birth in the typical distribution, a white forelock in the frontal region, and the presence of depigmented macules in other family members. However, the differential diagnosis includes other conditions that present with depigmentation of the hair and skin (e.g., vitiligo) and other congenital conditions of hypopigmentation (e.g., albinism, nevus depigmentosus, and the hypomelanosis of tuberous sclerosis).^12-18 Piebaldism is distinguished from vitiligo by the presence of lesions since birth, hyperpigmented macules within and at the border of the depigmented areas, and the static course of the condition. Vitiligo may be present at birth, but usually is acquired later in life. It follows an unstable course, and typically involves the acral and periorifical areas. Piebaldism spares the acral and periorificial areas. 


Some syndromes may present with piebald-like hypopigmentation of the skin and hair, but also with additional anomalies and no association with c-kit mutations. Waardenburg syndrome is an autosomal-dominant disorder characterized by a congenital white forelock, lateral displacement of the medial canthi, a hypertrophic nasal root, partial or total heterochromia of the iris, and sensorineural deafness.¹⁹ Ziprkowski-Margolis syndrome, now called the albinism-deafness syndrome (ADFN), is a rare X-linked recessive disorder that presents with hypomelanosis, hyperpigmented macules, deafness, mutism, and heterochromic iridis.²⁰ Woolf syndrome is an autosomal-recessive disorder that presents with piebaldism and congenital deafness.²¹ Tietz syndrome is an autosomal-dominant condition with congenital generalized depigmentation and sensorineural deafness associated with a mutation in the microphthalmia-associated transcription factor (MITF) gene.²²


Treatment of piebaldism is challenging. Sunscreen is recommended to avoid burns and reduce carcinogenesis. Tanning agents such as dihydroxyacetone (DHA) may be used as a temporary pigmenting agent along with makeup to camouflage affected areas.²³ The depigmented skin is considered to be generally unresponsive to medical treatment or phototherapy. Numerous surgical techniques have had varying results, including split-thickness grafting, minigrafting, transplant of in vitro cultured epidermis and suction-blister epidermal grafting, and a combination of dermabrasion and grafting of pigmented skin into the depigmented areas.^24,25 Culture and transfer of autologous melanocytes or of melanocytes and keratinocytes has been described as safe and effective.^26,27 This typically requires multiple procedures, and phototherapy may be effective if used afterward.¹ 


In this case, the patient and family were educated about the disease. Because the skin findings were cosmetically acceptable to the family, no intervention was required. 


Case #2 


Vitiligo is a common skin disease characterized by acquired, circumscribed depigmentation of the skin and hair. Loss of epidermal melanocytes is believed to result from autoimmune destruction. The etiology of vitiligo is multifactorial and likely polygenic. The course of the disease is unpredictable, but often progressive. 


Vitiligo is the most common disorder that results in depigmentation, affecting 0.5% to 2% of the world’s population.²⁸ There is no predilection for sex, age, race, or skin type.^29,30 Onset may be at any time from shortly after birth to adulthood, although it is rarely seen in infancy or old age. Peak onset is between ages 10 and 30 years, with approximately half of patients presenting by age 20 years.^29,31 


Many patients attribute the disease onset to a physical or emotional injury, sunburn, illness, or pregnancy. However, there is little evidence to support this, with the exception of the Koebner phenomenon.²⁸ 


Histopathologic evaluation of the completely depigmented epidermis of affected skin in patients with vitiligo shows an absence of functional melanocytes and melanin, which is generally agreed to be a result of their destruction.²⁸ Hypopigmented areas on the peripheries of expanding lesions demonstrate few melanocytes with some melanosomes. Furthermore, the outer hyperpigmented borders contain prominent melanocytes with many melanosomes. The observation of vacuolated keratinocytes and extracellular granular material in the skin that appears normal in patients with rapidly progressive disease suggests that vitiligo affects not only melanocytes but the entire epidermal melanin unit.³² 


The etiology of vitiligo is multifactorial, including both genetic and nongenetic factors. Although there is no Mendelian inheritance pattern, there is often a positive family history, and it has been reported in monozygotic twins.^33-35 Some studies suggest a polygenic mechanism,³⁶ which include genes that are also associated with autoimmune disease. This strengthens the hypothesis for the autoimmune destruction of melanocytes. Other theories to explain the destruction of melanocytes include the neurogenic hypothesis and the self-destruct hypothesis, whereby melanocytes are destroyed through interaction with nerve cells or by toxic metabolites, respectively.²⁹ 


Patients typically present with 1 or more depigmented macules or patches with a normal or hyperpigmented convex border. The lesions are well-demarcated and may be round, oval, irregular, or linear in shape. Lesions vary in size and tend to enlarge centrifugally at an unpredictable rate over time. Distribution is often symmetric and lesions can appear on any body site, including mucous membranes. Lesions are most commonly found on the face, the upper part of the chest, axillae, dorsal aspects of the hand, and the inguinal and anogenital region. There is a predilection for the skin around orifices, including the eyes, nose, mouth, ears, nipples, umbilicus, penis, vulva, and anus. Lesions also appear at areas of physical trauma (the Koebner phenomenon), and so, they may be present on the elbows and knees. Involvement of the palms, soles, lips, and oral mucosa may be subtle in light-skinned individuals and may not be evident without a Wood lamp skin examination.^28,29,31


Lesions are often asymptomatic but may be pruritic. White hairs may be present in the affected regions. Vitiligo of the scalp may present as one or several localized patches of white hair, scattered white hairs, or total depigmentation. In general, up to 30% of patients may experience some spontaneous repigmentation of the skin.²⁹


Depigmentation of the retinal pigment epithelium and choroids may occur in patients with vitiligo. Uveitis is the most important ocular abnormality associated with vitiligo. Involvement of the melanocytes in the membranous labyrinth of the inner ear may manifest as hearing impairment. Destruction of the leptomeningeal melanocytes may result in aseptic meningitis. Vogt-Koyanogi-Harada (VKH) syndrome is characterized by vitiligo with uveitis, hearing loss, tinnitus, meningismus, and poliosis.^37-39


Occasionally, patients with vitiligo may present with unusual variants. Vitiligo ponctué or confetti-type vitiligo is characterized by several tiny, discrete hypomelanotic macules, which may be superimposed on hyperpigmented macules. Vitiligo macules that have an erythematous border are referred to as inflammatory vitiligo. Vitiligo that develops in an area already affected by post-inflammatory hyperpigmentation is referred to as blue vitiligo. Also described are trichrome, quadrichrome, and pentachrome vitiligo, which refer to additional colorations. Trichrome vitiligo has an additional uniform tan hypopigmented zone between normal and depigmented skin. The hypopigmented macules progress to full depigmentation. Quadrichrome vitiligo features a fourth, dark-brown pigment, which surrounds hair follicles. Pentachrome vitiligo has a fifth shade and presents with the addition of blue-gray hyperpigmented macules.^28,40


Vitiligo is generally classified into either the segmental form, which is rare, or the nonsegmental form, which is common. Segmental vitiligo is characterized by lesions that are restricted to a given body segment and do not cross the midline; it is generally stable after rapid onset and occurs more frequently in children than adults. The nonsegmental form of vitiligo is characterized by widely distributed patches; it is progressive and may be associated with the Koebner phenomenon and autoimmune disease. It is possible for the segmental and nonsegmental forms to coexist, but these cases are rare and the two forms are generally regarded as distinct, with separate pathogeneses.^31,40 Vitiligo may also be classified as localized, generalized, or universal, based on the pattern and extent of involvement.²⁸ The generalized type is most common. 


Most patients have no associated conditions. However, there have been reports of vitiligo associated with autoimmune diseases.^{28,29,31,41-44} These conditions include thyroid disease (Hashimoto thyroiditis and Graves disease), pernicious anemia, systemic lupus erythematosus, rheumatoid arthritis, insulin-dependent diabetes, alopecia areata, Addison disease, myasthenia gravis, and autoimmune polyglandular syndrome. 


The diagnosis can be established on the basis of acquired, well-demarcated, depigmented lesions on the skin, which tend to enlarge centrifugally over time. The lesions are accentuated on skin examination with a Wood lamp. Differential diagnosis includes other causes of acquired hypopigmentation, such as post-inflammatory hypopigmentation, tinea versicolor, pityriasis alba, leprosy, sarcoidosis, and leukoderma that is induced by chemicals or drugs or that is associated with melanoma or scleroderma.^28,29,41 Vitiligo can be easily distinguished from piebaldism because piebaldism typically presents at birth with a single white forelock and amelanocytic lesions distributed on the head and anterior trunk, without periorificial involvement. Piebaldism may also feature hyperpigmented macules within amelanotic areas and is typically stable over time, in contrast to the progressive nature of vitiligo. 


Treatment options for vitiligo include medical, photo-, and surgical therapy. Repigmentation is the cornerstone of treatment; it is based on the stimulation of melanocytic reserves in the hair follicles. Adults with localized disease and children can be treated for 6 to 12 months with topical corticosteroids, ultraviolet B (UVB) phototherapy, or phototherapy that combines psoralen with long-wave ultraviolet radiation (PUVA) phototherapy. Narrow-band (311-nm) UVB is most effective and safe for generalized vitiligo and can be used for up to 24 months. Immunomodulators, such as tacrolimus and pimecrolimus, may be used as alternatives to steroids.³¹


Segmental vitiligo and vitiligo of the lips and digits are often treated with autologous transplantation.


Patients with extensive disease or those who do not respond to repigmentation may opt for depigmentation therapy with bleaching creams, such as monobenzyl ether of hydroquinone or the Q-switched ruby laser, to achieve complete depigmentation. All patients should be advised to wear sunscreen, because vitiligo lesions are ultrasensitive to UV light and decreased tanning of the uninvolved skin will reduce the contrast with hypopigmented areas. In addition, makeup and tanning lotions that contain dihydroxyacetone (DHA) may help to camouflage affected areas temporarily.³¹


In this case, the patient was treated with tacrolimus ointment. UVB phototherapy was initially recommended but the patient was unable to come in for the thrice-weekly treatments. She was educated regarding the use of camouflaging makeup and with that, she feels less self-conscious. After 3 months of tacrolimus ointment, the patient only had partial repigmentation. She continues to use camouflaging makeup and occasionally gets a “spray tan,” which also provides an acceptable — albeit temporary — cosmetic result.

Andrew S. Fischer, BS, and Christopher B. Rizk, BS, are medical students at Baylor College of Medicine in Houston.

Adam Rees, MD, is a dermatologist in Los Angeles. 


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This The Clinical Advisor CME activity consists of 3 articles. To obtain credit, read Purple plaque on foot after swim in river
 and Papules on girl with Down syndrome. Then take the post-test here.

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