Vitiligo and Leukoderma in Children MARIA ISABEL HERANE, MD

eukoderma and can be a man- present, these disorders have been classified.1,3 , ifestation of 2 main mechanisms by which mela- , (WS), tuberous Lnin might disappear from the skin. One is a dys- sclerosis complex (TSC), depigmentosus (ND), function of the ; the other is loss of the and hypomelanosis of Ito (HI) are reviewed in this melanocytes themselves. Hypopigmentation disorders article. can be localized or generalized. They can be either congenital/hereditary or acquired. The pattern of in- Vitiligo volvement can be circumscribed, diffuse, linear, or re- Vitiligo is an acquired, progressive disease character- ticulated. Hypopigmented skin may be the only feature, ized by of the epidermis (leukoderma) the main feature, or part of a syndrome with other or infrequently, by partial loss of (hypopig- clinical manifestations. Recent scientific advances have mentation). This depigmentation is a result of the de- provided valuable insights into the molecular basis of struction of pigment cells in postnatal life by mecha- these diseases and a better understanding of their nisms not yet well identified.4 pathogenesis. Vitiligo is relatively frequent. It affects 0.5–2% of the general population, being more prominent in darker- Pigment Cell Biology complected people and after solar exposure.5,6 It usu- Melanocytes are the pigment-producing cells of the ally begins in childhood or young adulthood. Approx- skin. They reside mainly in the basal layer of the epi- imately 30% acquire the disease before the age of 20 dermis and the matrix of the hair follicle. Melanocytes years and 14% before the age of 10 years; the incidence are highly dendritic cells; their origin is the neural crest, decreases in later life, and fewer than 10% develop 7 from where they migrate during embryogenesis. vitiligo by the age of 42 years. The existence of “con- Within the cytoplasm of the melanocytes, the melanin genital vitiligo” is still unclear. Infants 4–6 months of pigment is deposited in specific organelles named mela- age, however, may develop typical vitiligo mainly in nosomes. As the melanosomes mature and acquire mel- the genital or perianal area (Fig 1). Some studies show anin, they move to a perinuclear position into the den- a female preponderance, but this observation is not drites. Each interconnects with 36 statistically significant. All races are equally affected. keratinocytes. These surrounding keratinocytes phago- In about 30% of patients with vitiligo, there is a 8–11 cytize the tips of the melanosome-containing dendrites familial clustering of cases. Vitiligo is not inherited, and transfer the pigment. This transference is essential but the predisposition to have it is inherited. Some for normal skin pigmentation.1,2 The differences be- observations support an autosomal dominant inheri- tween color in skin resides not in the number or density tance with variable expression. Case reports of concor- of melanocytes but in the activity of the individual dance in identical twins support a genetic basis. Control melanocytes. In darker skin, a greater number of ma- studies on human leukocyte antigens (HLA) show a ture melanosomes with an increased level of melanin positive association with HLA-DR4 (in blacks), HLA- 12 production is found.2 B13 (Moroccan Jews), and HLA-B35 (Yemenite Jews). Hypopigmentation cutaneous disorders can be a Other HLA antigens have been reported (HLA-DRB4, 13 consequence of different disturbances in the pigmen- DQB1, Dw7, DR7, DR1, etc). A mutation in the tary system that include defects in the number or func- guanosine triphosphate (GTP) cyclohydrolase I gene tion of melanocytes, decrease melanization of melano- has been described as the cause of vitiligo. GTP cyclo- 14 somes, or decrease of the transfer process from hydrolase I is essential for the synthesis of melanin. melanocytes to keratinocytes. According to the defect Vitiligo is characterized by the destruction and ab- sence of melanocytes in postnatal life. Pigment cells of the skin, follicles, and other extracutaneous sites are From the Department of , University of Chile, Santiago, Chile commonly involved in the destructive process. Histo- Address correspondence to Maria Isabel Herane MD, Assistant Professor logic studies and histochemical and immunohistochem- of Dermatology, Dermatology Department, University of Chile, Hospital ical stains have confirmed the absence of melanocytes San Juan de Dios, Guardia Vieja 255 Oficina 901, Providencia, Santiago, Chile. in the depigmented skin and marked abnormalities in E-mail address: [email protected] the pigment cells and keratinocytes of the spreading edge and at distant sites from a vitiliginous lesion. or hypopigmentation (eg, neurofi- Attempts to culture melanocytes from depigmented bromatosis, tuberous sclerosis). skin have failed. The fact that glabrous skin does not In patients with vitiligo, depigmented areas tends to respond to treatment as hairy areas do is an indirect sweat less, and to have different temperature regula- probe of the absence of melanocytes. Follicular orifices tion, electrical resistance, and other related neural dys- act as a reservoir of melanocytes. Vitiligo also affects the functions in the skin. An increased release of cat- destruction of pigment cells in other sites like the mu- echolamines from the autonomic nerve endings of 22 cous membranes and eyes. Ocular pigmentary distur- melanocytes has been suggested. The potential role of bances associated to vitiligo are common (15). a biochemical defect in the tetrahyobiopterin pathway and/or the thioredoxin reductase system may also be 4 Etiology involved. There are 3 theories concerning the etiology of vitiligo. They are autoimmune, autocytotoxic, and neural hy- Clinical Features and Classification potheses. The autoimmune theory initially developed Vitiligo is mainly a disease of young people. Depig- from the association between vitiligo and autoimmune mented patches may occur anywhere on the body, but diseases (thyroid disease, adrenal insufficiency, alope- they are most often seen on the face, backs of the hands cia areata, diabetes mellitus, pernicious anemia, lym- and wrists, axillae, umbilicus, nipples, genitalia, body phocytic malignancies, multiple myeloma, and thy- folds, elbows, knees, and tibial surfaces. Vitiligo is es- moma). Subsequent research has been able to pecially prominent around body orifices (eyes, nostrils, demonstrate antibodies against melanocyte surface an- mouth, genitalia). Small patches from a few millimeters tigens,16 common tissue,17 pigment cells,18 melanin, to many centimeters tend to appear first, enlarging and tyrosinase.19 peripherally, with new lesions appearing occasionally. The immune mechanisms responsible for melano- Progression of the depigmentation is variable. Early or cyte destruction probably involve complement-depen- advancing lesions may be partially depigmented and dant and antibody-dependant cellular toxicity, as vitil- may have a freckled-type appearance or multishaded igo antibodies can kill melanocytes in vitro by both hue. Later lesions become completely white. Lesions mechanisms.20 after sun exposure and after trauma, such as the Koeb- The autocytotoxic hypothesis is based on the obser- ner phenomenon, are common. Other precipitating fac- vation that chemicals (catechols and phenols) formed tors include physical injury, emotional trauma, illness, 23 during the synthesis of melanin are cytotoxic to the cell. pregnancy, and drug-induced erythroderma. These chemicals are toxic to melanocytes in vitro. In dark-complected people, a trichromic coloration is Others investigators have suggested that melanin relatively common, with a central depigmentation, pe- synthesis is disrupted by anomalies of the melatonin ripheral hypopigmentation, and a surrounding border of normal-pigmented skin. In 5% of patients, a pruritic, receptor. Melatonin is a natural inhibitor and modula- inflammatory border is associated with edema, and tor of melanin synthesis. A defective receptor may re- erythema is visible. sult in the uncontrolled production of melanin, with the The skin of the scalp is commonly involved. The release of free radicals and toxic products of melano- scalp hairs may become gray prematurely, and a few genesis. Abnormal activation of the melatonin receptor patients develop totally white hair of the scalp, eye- can occur because of an increased release of cat- brows, and eyelashes. Poliosis might be present mainly echolamines and other neurotransmitters, because of a in segmental vitiligo (48.6%).24 The area least recog- hereditary tendency toward expression of an increased nized but more often involved is the oral cavity. A good number of melatonin receptors, or because of a dys- examination is essential because depigmentation in this function of melatonin receptors (due to intrinsic activa- area probably occurs in all individuals. tion or via stimulating autoantibodies against the recep- According to the extent of involvement and the dis- tors). The melatonin hypothesis could explain the tribution of the depigmentation, vitiligo has been cate- association of vitiligo and Graves disease, stress, neu- gorized.6,8,25–27 Attempts to classify types of vitiligo rologic/psychiatric disorders, melanoma, hereditary have often given confusing results. A simple classifica- 21 factors, and Koebner’s phenomenon. tion is presented in Table 1 27 The localized type can be The neural hypothesis is based mainly on circum- focal, with 1 or more macules in 1 area, but not clearly stantial evidence. The clinical support is the distribution in a segmental or zosteriform distribution (Fig 2). The of segmental, dermatomal vitiligo. Others have pointed segmental type appears with 1 or more macules involv- out the common origin of melanocytes as derivatives of ing a unilateral segment of the body, ie, part of the face, the neural crest and the fact that certain disorders of the part of the trunk and extremity, or 1 extremity. The central nervous system are expressed in the skin with lesions stop abruptly at the midline of the affected VITILIGO AND LEUKODERMA IN CHILDREN

Figure 1. Vitiligo in the perianal area Figure 3. Extensive .

segment. Segmental vitiligo represents a particular type stages: limited (Ͻ10%) involvement, moderate of vitiligo for many investigators, and it is common in (10–25%) involvement, moderately severe (26–50%) in- younger people, with the trunk, neck, extremities, and volvement, and severe disease (Ͼ50%) depigmentation. scalp being the most common sites of involvement. It This classification is very useful to evaluate different usually persists unchanged for life and is rarely associ- therapeutics regimens.28 ated with autoimmune disorders.25 The mucosal type involves vitiligo of the mouth and mucous membranes Childhood Vitiligo and the genitalia. Generalized vitiligo is subdivided into 1) acrofacial, with involvement of distal parts of the Very few studies have been done on the clinical spec- extremities and face; 2) vulgaris, with scattered mac- trum of vitiligo in the pediatric population. In general, ules; and 3) mixed, when acrofacial and vulgaris, or there is a female predominance; an increased frequency segmental and acrofacial and/or vulgaris vitiligo of a positive family history of vitiligo; a strong family present together. The universal type implies complete history of autoimmune disorders; an increased fre- or nearly complete depigmentation. quency of HLA-DR5, DQW3, BfS, C4A3 and C4B1; the The incidence of each type of vitiligo in this classifi- presence of Koebner’s phenomenon; halo nevi; and pre- cation varies from different studies. Generalized types mature graying. Children with vitiligo have a much account for 50–90%; localized types represent ϳ50% of higher incidence of autoantibodies than do other chil- cases, with the focal type being the most common dren, but despite this, rarely have clinical disease. In (33.7%). Segmental vitiligo always remains in this type; relation to the clinical types of vitiligo in children, the it does not represent a transitional stage. Very few generalized pattern is the most common. The frequency patients have segmental and generalized types of vitil- of segmental vitiligo is also higher in children com- igo simultaneously.26,27 pared with adults. The most common locations for the Based on the severity, vitiligo can be divided into 4 appearance of vitiligo in children include the face and

Figure 2. Focal vitiligo. Figure 4. Piebaldism: white forelock. HERANE

Table 1. Clinical classification of vitiligo production of cytotoxic antibodies. With vitiligo’s being Localized a rather common disorder, it is not surprising that it has Focal also been associated with a long list of many other Segmental organ systems abnormalities. Halo nevi, increased Mucosal number of skin cancers, and metastatic melanoma have Generalized been reported associated with vitiligo. To date there is Acrofacial Vulgaris still great controversy, and epidemiologic data have not 40–45 Mixed found such associations. Universal In children and adolescents, the frequency of associ-

SK Hann and JJ Nordlund.7 ated diseases is significantly less than in adults, with thyroid disease and polyglandular autoimmune syn- dromes being the most common associations.40 neck (50%), lower extremities (28%), trunk (18%), upper extremities (17%), and perineum (6%).8,29–32 Evolution and Psychological Impact Associated Findings The onset of vitiligo is usually gradual. A rapid increase in the number of patches can occur during several A number of reports show the association of vitiligo months. The progression may stop, and the lesions and eye and ear disturbances. Both organs contain pig- remain for years or for life. A partial spontaneous repig- mented cells susceptible to be affected. About 40% of mentation might occur and is common in isolated mac- individuals with vitiligo will have pigmentary distur- ules or patches but is rarely sufficient to be cosmetically bances in the uveal tract.15,33 The most significant ocu- acceptable; however, it is a good indication that therapy lar abnormality is ocular inflammation or uveitis. The can be helpful. inflammation can be an anterior uveitis (iridocyclitis) or The cosmetic disfigurement that accompanies vitil- a posterior inflammation (chorioretinitis). The most se- igo may have a profound effect on patient self-esteem vere form of uveitis associated with vitiligo is the Vogt- and social relationships. Feelings of inferiority, discrim- Koyanagi-Harada (VKH) syndrome. ination, and embarrassment in social and sexual rela- The VKH syndrome is a multisystem disorder char- tions are common feelings in adults.46–48 acterized by idiopathic uveitis, central nervous system Children start having problems with vitiligo at 5–6 abnormalities, and cutaneous signs, including vitiligo. years old when they enter school. The child may expe- It is more common in those of Asian, Hispanic, African, rience ridicule, physical embarrassment, and social iso- or American Indian descent34,35 and has been occasion- lation, but usually at this age, cosmetic appearance is of ally reported in children. Women are slightly more more concern to the parents than to the child. At 11–12 affected than men, and most affected patients are in the years, the disfigurement can be intolerable, and it is the second to fifth decade at the time of diagnosis.34–37 time when they seek medical treatment. Vitiligo in chil- Less severe ocular inflammation (5%), sympathetic dren requires good support from the family, doctors, ophthalmia, and depigmented lesions of the ocular fun- medical staff, and the community to accept the disease dus are also observed in patients with non-VKH vitil- and to reinforce in the patient positive values to help igo. Other immune disorders, like thyroid disease, dia- him or her live with the disease.4,46 betes mellitus, multiple myeloma, and mycosis fungoides, which are seen more frequently in vitiligo Differential Diagnosis patients, can also cause visual symptoms.38 Uveitis ap- pears to be most common with vitiligo associated with The classic presentation of vitiligo as acquired, well- cutaneous melanoma.39 The ear can also be affected demarcated, depigmented, milky white patches with an because pigmented cells are present in the inner ear, absolutely normal epidermis has a very limited differ- and sensorineural hearing loss may be seen in VKH ential diagnosis. When the distribution of the lesions is syndrome and in non-VKH vitiligo. acral, facial, or generalized, and symmetrical, segmen- Disorders of other organ systems have been associ- tal, or quasi-dermatomal, the diagnosis is relatively ated with vitiligo. Thyroid disorders, either hyper- or easy. There are, however, atypical clinical presentations hypothyroidism or thyroiditis, polyglandular dysfunc- in which the diagnosis is quite difficult, and histochem- tion syndrome (hypoparathyroidism, chronic mucocu- ical and electron microscopy studies are needed. For taneous candidiasis, and Addison’s disease), adrenal some patients, however, no definite diagnosis can be dysfunction, diabetes mellitus, glucose intolerance, sar- made, and the evolution of the lesions is the clue for a coidosis, leprosy, pernicious anemia, various forms of definitive diagnosis. lymphomas, and leukaemias have been associated with The list of differential diagnosis can be divided in 2 vitiligo. Many of these diseases are related to a dysfunc- groups. The first group is for generalized or bilateral, tion in the immune system, which may explain the symmetrical leukoderma, and the second group is for VITILIGO AND LEUKODERMA IN CHILDREN

Table 2. Vitiligo differential diagnosis nosis. Histology frequently reveals sarcoidal granulo- 50 Generalized or bilateral vitiligo mas. Genetic disorders Lichen sclerosis et atrophicus (LSA) presents in all Piebaldism age groups and is very common in prepubertal chil- Hypomelanosis of Ito dren, postmenopausal women, and middle-aged men. Tuberous sclerosis The lesion appears after a long period of pruritus, burn- Inflammatory/neoplastic disorders Lupus erythematosus ing, and dysesthesia in the affected area. The plaques Scleroderma are often symmetrical, ill-defined, hypo pigmented or Sarcoidosis depigmented, and atrophic, with telangiectasias and Lichen sclerosis et atrophicus purpura. In women, they are localized to the inner parts Halo nevi of the vulva, sometimes extending to the perineum and Pityriasis alba Mycosis fungoides perianal area. Extragenital lesions located on the neck, Infectious disorders shoulders, trunk, and extremities may be present. Early Tinea versicolor genital or extragenital LSA in young girls may be dif- Treponemal infections ficult to distinguish from vitiligo. The histology is use- Leprosy ful. Simultaneous occurrence of genital LSA and vitiligo Idiopathic disorders 51,52 Idiopathic guttate hypomelanosis has been reported. Postinflammatory hypopigmentation Halo nevi characteristically begin as well-defined, Segmental vitiligo depigmented macules around a junctional or com- Nevus anemicus pound melanocytic nevus that advances, leaving a dis- crete, depigmented patch of 0.5–5 cm that is usually Steroid-injection-related hypomelanosis located on the trunk. Many lesions can occur simulta- PB Sheth.49 neously, and differentiation may be difficult. Histologic examination revealing melanocytic nevus cells or dense, lymphocytic mononuclear infiltrate differentiate segmental or unilateral, asymmetric leukoderma (Table halo nevi from vitiligo. It should also be borne in mind 2). 49Genetic disorders and ND are discussed in detail that both entities might present simultaneously. Halo later in this article. nevi are mainly associated with segmental vitiligo; they Lupus erythematosus can cause depigmentation in are common in adolescents, especially those using birth various forms. Systemic lupus might present with de- control pills.24 Some investigators consider halo nevi a pigmentation plus fatigue, arthralgias, prominent nail form of vitiligo; however, the majority consider both as fold capillary loops, and other symptoms. Leukoderma separate entities. is more often seen in cutaneous discoid lupus erythem- Pityriasis alba is a very common disorder usually atosus. This presents as localized, well-demarcated, er- seen in children and young adults (80–90% under the ythematous, infiltrated plaques associated with epider- age of 15), often with a history of atopic diathesis. The mal atrophy, telangiectasia, and scaling. The lesions are hypopigmented macules, 0.5–5 cm, with progression of the lesions results in hypopigmentation ill-defined borders, slight scaliness, and variable mild or depigmentation with atrophy and scarring, and pa- erythema, generally located on the face, neck, shoul- tients usually disclose a history of sun-induced lesions, ders, and extensor surfaces of the arms. In general, the mainly located on the face, scalp, or arms. If doubt differentiation from vitiligo is not difficult, but in an exists, a skin biopsy and antinuclear antibody tests are unusual extensive form with numerous, long-lived le- helpful. sions, the differential diagnosis must be considered. Scleroderma may present clinically as hypopigmen- Histology might be helpful in doubtful cases. In pityri- tation in areas of sclerosis and as patches of vitiligolike asis alba, an epidermal and follicular spongiosis, focal depigmentation, with follicular repigmentation on a parakeratosis, acanthosis, and superficial perivascular background of complete pigment loss, giving the area a lymphocytic infiltrate are common findings. Ultrastruc- “salt-and-pepper” appearance to the skin. This type of tural studies may also reveal a reduced number of scleroderma is localized mainly to the back and upper active melanocytes and a decreased number and size of chest, and the lesions are histologically indistinguish- melanosomes. Localized lesions are treated with topical able from those of vitiligo. Other manifestations of steroids; extensive involvement sometimes requires scleroderma help in the diagnosis. UVA therapy with psoralen (PUVA)3,53 (Fig 3). Sarcoidosis is rare in children. The lesions are ill- Mycosis fungoides is a differential diagnosis that defined, hypopigmented macules scattered on the should be ruled out in adults. The typical age range of trunk and extremities; more noticeable in dark-skinned affected patients is 30–40 years. The lesions are hy- patients; and frequently associated with other cutane- pomelanotic macules with some scale or erythema, of ous lesions or systemic findings that suggest the diag- variable size (1 cm to many centimeters), located mainly HERANE

on the trunk and extremities. Differentiation from viti- extent of the disease. All forms of therapy require time ligo on a clinical basis should be straightforward; how- (a minimum 3 months) and a reservoir of melanocytes ever, a biopsy to confirm the diagnosis is needed. (usually from the outer root sheath of hair follicles). Infectious disorders to be differentiated from vitiligo Vitiligo is an asymptomatic disease, and many chil- include tinea versicolor, syphilis (secondary), and lep- dren with minimally affected skin do not want any rosy, the last 2 being very rare in children. treatment. There is no evidence that early treatment of Tinea versicolor is a chronic infection due to minimal disease will alter the natural history. All pa- Malassezia furfur, which may present as hyperpig- tients should be counseled to avoid sun exposure and to mented or, more commonly, hypopigmented macules use sunscreen. and scaly patches. It affects mainly young people be- tween 15 and 35 years of age, with lesions localized to Topical Steroids the chest, neck, upper arms, and back. In neonates and Ͻ small children, there are cases affecting the face through In children 2 years of age, treatment with medium- transmission from infected parents. The diagnosis is potency steroids, applied 1 or 2 times a day for 1 or 2 easy using a Wood’s lamp (yellow fluorescence), and months and then tapered to a lower-potency steroid, is KOH staining reveals hyphae and spores. Nonactive indicated. In older children, treatment can be initiated lesions might need a histochemical and electron micros- with a superpotent topical steroid. Patients must be copy examination to confirm the diagnosis, showing the monitored for side effects. Also, short courses of sys- presence of melanocytes in lesional skin.54 temic steroids are indicated in patients with rapidly In endemic areas, leprosy caused by Mycobacterium progressive disease. leprae can present clinically with hypopigmented le- sions with a morphology dependent on the type of Topical PUVA leprosy. Associated erythematous, well- or ill-defined Topically applied PUVA can be used safely in children. patches, and indurated plaques are present. Most le- It has the advantage of avoiding the systemic side ef- sions have a partial or complete loss of sensation of fects of psoralens, but it requires a very motivated and temperature, touch, and pain. The clinical picture and compliant patient and family. This modality is indi- histology, with compact granulomas around the nerves Ͻ or diffuse granulomatous inflammation with foamy cated for patients with 20–25% involvement. Concen- macrophages, help in the diagnosis.55 trations of 0.01% or 0.1% Oxsoralen ointment plus UVA Idiopathic guttata hypomelanosis is a disorder of in increasing doses in a very careful technique can be adulthood. Lesions are well-circumscribed, sharply de- used. A mean repigmentation rate of 58% has been 57 fined, oval or round, polygonal, hypopigmented or de- reported with this treatment. Ͻ pigmented areas of very small size (2–5mmupto1cm). In patients with 10% involvement, another option They are localized mainly on the extremities and are is PUVASOL (topical psoralens ϩ sunlight). The con- related to sun exposure. The age of onset, clinical pre- centration of Oxsoralen ointment should not be greater sentation, slow progressive nature, lack of confluence, than 0.001% combined with 15–30 minutes of sunlight and absence of depigmented hairs differentiate these exposure (between 10 am and 4 pm). This treatment is entities from vitiligo. If necessary, histology and bio- easier, less expensive, and a good option to be em- chemical studies can be done. ployed in sunny weather. Reports of mean repigmen- Although unlikely, hypopigmentation secondary to tation obtained are 71%.57 Side effects are minimal. exposure to products containing catechols and phenols, such as germicides or after using toothpaste containing l-Phenylalanine cinnamic aldehyde, may occur as a chemically induced Variable results have been reported with oral and top- vitiligo. Hypopigmentation secondary to cutaneous dis- ical l-phenylalanine with UV light in children and orders resolve, like psoriasis, varicella, and atopic der- adults.58 matitis. Intralesional corticosteroid therapy can induce The exact mechanism of action is unknown. hypopigmentation in a focal distribution. Usually, the l-Phenylalanine is an essential amino acid, the precur- history, pattern, and ill-defined borders of the lesion sor of tyrosine, that apparently alters the Langerhans help in the diagnosis.49,55 cells and inhibits antibody production. Recommended dosages are 50 mg/kg or a maximum of 2 g per day. The usual initial dose is 500 mg plus sun exposure at Treatment noon for 5–10 minutes. In case of lack of response, the Treatment is empirical and often difficult. Children dose is increased after 2 months. l-Phenylalanine is demonstrate an enhanced therapeutic response to dif- contraindicated in patients with phenylketonuria, liver ferent modalities compared with adults.29 The options or renal dysfunction, , arsenic exposure, be- for therapy are dependent on the age, location, and fore radiation therapy, pregnancy, and lactation.59 VITILIGO AND LEUKODERMA IN CHILDREN

Systemic PUVA cytes are seen, they are morphologically abnormal, with 70 - Oral psoralens are not used before 9 years of age and spherical, granular melanosomes. In the hyperpig mented macules, a normal number of melanocytes and are reserved for patients with moderate to severe dis- an abundance of melanosomes in melanocytes and ker- ease involving Ͼ20–25% of the cutaneous surface. The atinocytes are found. The most classic clinical finding in standard dose of 8-Methoxypsoralen is usually 0.2 to 0.4 piebaldism is the frontal white forelock, a tuft of white mg/kg. Treatment must be continued for 4 to 6 months hairs over the mid-frontal scalp found in 80–90% of to see if any repigmentation develops. Ocular toxicity, patients (Fig 4). This is often V-shaped and associated long-term risk of skin cancer, and other minor side 60 with the loss of pigment in the underlying scalp. Poli- effects are complications of the treatment. Psoralen plus sunlight has also been used but requires careful osis of the eyebrows and eyelashes and premature gray- supervision to limit the risk of . The combina- ing of scalp hair may be present. The other hypomela- tion of PUVA and topical calcipotriol has been success- notic areas are characteristically distributed over the ful in refractory cases.61 forehead, neck, anterior trunk, flanks, and mid-portion of the extremities (Fig 5). Typically spared are the cen- UVB Phototherapy tral back, shoulders, hips, hands, and feet, which helps to differentiate it from vitiligo. The affected areas are Recent reports of narrow-band UVB (311-nm) therapy milky white on Wood’s lamp examination. Often, hy- have shown its efficacy and safety compared to 62,63 perpigmented or normally pigmented macules and PUVA. patches are present within the areas of leukoderma and Other treatment modalities include vitamin supple- 28 in uninvolved skin. They represent cafe au lait macules, mentation (B complex, E, and C), camouflage and and their presence does not mean that the patient also dyes helpful in children with small lesions, tattooing, has neurofibromatosis.67,68,71 pseudocatalase calcium cream and UVB,64 oral and top- 65 66 Individual cases of piebaldism have been associated ical khellin, topical melagenina, microphotoener- with mental retardation, cerebellar ataxia, short stature, getic UVB rays and immunomodulators (levamisole, HirschprungЈs disease, chondrodysplasia, pulmonic isoprinosine, cyclosporine, cyclophosphamide, nitrogen stenosis, and heterochromia irides.72 mustard, and others). Depigmentation with monoben- The differential diagnosis of piebaldism includes zylether of hydroquinone is a viable therapy for pa- vitiligo, which differs from piebaldism because it is an Ͼ tients with 50% cutaneous depigmentation but is acquired and progressive disorder rather than a con- rarely used in children and young adults. genital and stable one, and the areas of involvement are Surgical Therapies different. The major entities for a differential diagnosis are the piebaldism syndromes associated with deafness Transplantation of the epidermis, autologous suction-blis- (Woolf syndrome) or with facial dysmorphism (WS). ter grafts, autologous punch grafts, and autologous mela- Because of the presence of deafness in these 2 syn- nocyte transplant are some of the possible surgical proce- dromes, patients with piebaldism should routinely dures that should be practiced only on teenagers or adults. have auditory testing. Piebaldism should also be differ- entiated from Ziprkowski-Margolis syndrome or albi- Piebaldism nism-deafness syndrome. This is characterized by a Piebaldism is a congenital disorder of hypopigmenta- diffuse, pigmentary dilution of hair-skin, with th excep- tion characterized by a white forelock in association tion of the buttocks and genital region, plus hyperpig- with hypopigmented macules and patches. In general, mentation with a leopardlike appearance, deaf-mutism, lesions are stable in size and increase in proportion to and heterochromia irides. The clinical appearance dif- the child’s growth. The lesions are mainly located on fers considerably from piebaldism, and the mode of the anterior trunk, mid-portions of the extremities, mid- inheritance is recessive (gene mapped to Xq forehead, and frontal scalp. Hyperpigmented macules 26.3–27.1).72 Scalp poliosis should be differentiated, are present in normal skin and within the areas of with a large group of diseases associated with this leukoderma. The distribution and pattern of pigmenta- particular finding. tion are very characteristic.67,68 No treatment is available for piebaldism. Sunscreens Piebaldism is an inherited disorder, autosomal dom- should be applied to the hypopigmented areas. Mini- inant, with a high degree of penetrance. A mutation in grafts transplantation of uninvolved skin into areas of 1 of the 2 copies of the proto-oncogene KIT located on leukoderma have been successful.73 chromosome 4 has been described.69 Histopathologic and electron microscopic examina- Waardenburg Syndrome tions of hypopigmented skin or hair follicles of the white forelock show the complete absence of melanin WS is an autosomal dominant disorder described in and melanocytes or a reduced density. When melano- 1951 and characterized by a white forelock (present in HERANE

Figure 5. Piebaldism: typical skin lesions. Figure 7. Nevus depigmentosus, systematized form.

35–37 for WS types I and III and mutations of the 17% of patients) and skin lesions of piebaldism (12%), microphthalmic transcription factor gene on chromo- increased distance between the inner canthi with nor- some 3p13 for WS II have been reported.72 mal interpupillary distance (dystopia canthorum), a Poliosis of the eyebrows and eyelashes, premature broad nasal root, hypertrichosis and fusion of the me- graying of the scalp hair, and palmoplantar kerato- dial eyebrows, heterochromia irides, and congenital derma might be present. The white forelock and the sensorineural hearing loss (Fig 6). Three types of WS leukodermic patches can be less noticeable with age. have been described. WS I and II are mainly differen- Other associated findings include Hirschprung’s dis- tiated by the presence or not of dystopia canthorum. ease, facial clefts, congenital heart defects, and myelo- Other ocular findings can be present (dystrophy of the meningocele.75 lacrimal puncta, blepharophimosis, hypopigmentation WS should be differentiated from other syndromes of the fundus). Type III (Klein-Waardenburg syndrome) related to hearing loss. Woolf syndrome, originally de- is associated with congenital musculoskeletal anoma- scribed in 2 American Indian brothers, is a piebaldism lies, mainly of the upper limbs (hypoplasia of muscles, plus congenital sensorineural hearing loss without any flexion contractures, fusion of carpal bones, syndacty- 68,72,73,74 other features of WS. Patients with VKH syndrome ly). associated with vitiligo might have decreased hearing. Mutations in the PAX-3 gene on chromosome 2q Dystopia canthorum is also seen in the oral digital-type I syndrome. The prognosis of WS is dependent on the severity of the associated deafness and the presence of anomalies. Tuberous Sclerosis Complex Tuberous sclerosis complex (TSC), also named Bourneville’s disease, Pringle’s disease, or epiloia, is an

Figure 6. Waardenburg syndrome type II. Figure 8. Hypomelanosis of Ito. VITILIGO AND LEUKODERMA IN CHILDREN

autosomal dominant inherited condition with a high patic, renal hamartoma, and lung involvement is com- mutation rate of ϳ65%. The prevalence ranges from 1 in mon.77,78 6000 to 1 in 170,000 inhabitants in various populations. The diagnosis is made on a clinical basis. Diagnostic Two gene loci have been identified for TSC, on chro- criteria for the disease, based on a combination of pri- mosome 9q3.4 (TSC1) and on chromosome 16p13 mary, secondary, and tertiary features, have been de- (TSC2). These 2 linkages occur in ϳ90% of patients with fined.79,80 Radiologic confirmation of the intracranial TSC. The genetic heterogeneity may explain the vari- lesions is useful in evaluation of patients. CT scans ability in clinical manifestations in TSC.76 demonstrate intracranial nodules. The MRI scan is the Involvement of all organs, except muscle and the best method to detect cortical tubers and localize more peripheral nervous system, has been reported in TSC. accurately the brain lesions. The differential diagnosis The skin lesions often provide the clue to the diagnosis: of hypopigmented macules includes nevus anemicus, cutaneous hamartomas are pathognomonic of TSC and vitiligo, ND, and idiopathic guttate hypomelanosis. include forehead plaques, hypomelanotic macules, Management of these patients is related to the dif- shagreen patches, facial angiofibromas, and periungual ferent clinical manifestations. Hamartomas (most com- fibromas. monly renal) can be excised. Infantile spasms are Forehead plaques may be present at birth or appear treated with corticotropin injections. Recurrent seizures shortly afterward, and the common first sign is as a soft, are usually associated with subnormal intelligence. Ap- red plaque on the face, neck, or scalp. Shagreen patches proximately 20% of patients die before 30 years of age. are yellow to orange, raised, firm, and fleshy, usually First-degree relatives of patients of TSC can be diag- located on the trunk. Periungual fibromas appear at nosed through radiologic screening in 7–15% of cases. puberty or thereafter as a smooth, firm, clove-shaped tumors around the nail plate. Facial angiofibromas are Nevus Depigmentosus rarely obvious before the age of 2 years and are flesh- colored to brown, small papules located on the midpor- ND is defined as a congenital, nonprogressive, well- tion of the face; these occur in 47–90% of patients. circumscribed macule or patch of hypopigmentation, Hypomelanotic macules, present at birth but occasion- stable in size and shape throughout life. Although ally developed later, are usually several lesions located present at birth, the hypopigmented area may go un- on the trunk and limbs. These can be localized macules noticed for the first months of life and be clinically or patches of any shape from oval, lance-ovate, polyg- apparent later in life in children with light skin. There onal, to an ash leaf configuration, with a size range are not hyperpigmented borders around the achromic between 1 and 3 cm. Once they appear, they remain area (clinical diagnostic criteria Coupe 1976).81 Both stable in size and shape. Rarely, confettilike lesions 2–4 sexes are equally affected. The pathophysiology is prob- mm in size are seen, mainly in young adults on the ably associated with a clone of cells that have reduced arms and legs, or a segmental distribution may be melanogenic potential and that arises primarily via a present. All of these hypomelanotic macules reflect postzygotic somatic mutation. Inheritance for ND has light because of the absence of melanin, so the use of a not been determined. UV lamp is helpful in their detection. The number of The histologic findings by light microscopy show a hypopigmented macules can vary from 1 to Ͼ100. Fifty normal or decreased number of melanocytes. Electron percent of patients have 5 or fewer, and 11% have only microscopy can detect a large reduction in the number 1 lesion. These are considered part of the secondary of melanosomes and aggregated melanosomes of vari- diagnostic criteria. Histologically, these lesions have able morphology. A decrease in the synthesis and trans- normal numbers of melanocytes but an absence of fer of melanosomes has been observed; however, the melanosomes.76 Poliosis of the scalp, eyebrows, eye- size and degree of melanization of the melanosomes are lashes, and pubic and body hair is also seen, as well as normal.82 circumscribed hypopigmentation of the iris or fundus. ND is present in approximately 1 in 130 newborns.83 Central nervous system involvement is common in Clinically, an ND in the majority of cases is an isolated, TSC and includes infantile spasms, seizures, learning uniformly hypopigmented, but not completely depig- and behavioral problems, focal neurological deficits, mented, area that becomes more noticeable with multiple cortical tubers, subependymal glial nodules, Wood’s lamp examination. The majority of lesions are and cerebral calcifications. Retinal astrocytomas are Ͻ6cm2 in size They are rectangular, oval, or polygonal, present in 25% of affected individuals, are usually with irregular, serrated borders except at the midline. asymptomatic, and are also of diagnostic importance. Solitary lesions are most commonly seen on the trunk Cardiac rhabdomyomas can be seen as early as the (44.8%) or proximal extremities, but the head and neck second trimester of pregnancy and are present in 60% of may be also sites of involvement. There are 3 different affected individuals. Dental enamel pits are a highly forms of ND: isolated, segmental, and systematized specific sign of TSC, especially in adult patients. He- (unilateral whorls and streaks) (Fig 7). The isolated HERANE

form is by far the most common (59.7%), and as a rule, alence of the disease is ϳ1 in 800 children in a general the lesions do not cross the midline.83 Hair within an pediatric hospital.89 ND may also be hypopigmented. Poliosis can be Skin pigmentation is the hallmark of HI. The hypo- present (6%). Lentigines might develop within the ND. pigmented macules in a whorled and streaked marble- Systemic manifestations associated with ND are rare; 3 cake configuration, usually bilateral, are present mainly patients with unilateral hypertrophy of the extremities on the trunk and extremities. These narrow bands fol- on the involved side and 1 patient with seizures and low the lines of Blaschko and occasionally can have a mental retardation have been reported.84,85 blocklike configuration (cutaneous pattern of mosa- The differential diagnosis of ND include a list of icism). They may be present at birth or gradually ap- entities. Nevus anemicus is a localized area of vasocon- pear during infancy or childhood (Fig 8). striction whose borders are obscured by diascopy, dis- Histopathologic examination of the hypopigmented tinguished from focal, segmental vitiligo, which is an skin reveals either a normal or a decreased number of acquired, localized area of complete pigment loss. Le- melanocytes and melanosomes. A decrease in the mel- sions of segmental vitiligo are relatively stable but show anin content is also present. There are no inflammatory no melanocytes on histopathologic examination. The cells in the dermis, and no pigment incontinence is ash leaf spots of TSC can be easily confused with the found. Other ectodermal defects are scalp abnormalities isolated or the segmental form of ND, but can be dis- (alopecia, unilateral coarse and curly hair), high-arched tinguished only by the presence in TSC of other cuta- palate, and teeth alterations (conical teeth, partial an- neous signs and by the systemic involvement. Some- odontia, dental dysplasia and hypoplasia, enamel alter- times electron microscopy examination can help, ations). showing small and poorly melanized melanosomes. About two thirds of patients with HI have neuro- When linear streaks or a blocklike configuration of logic, musculoskeletal, and ocular abnormalities. The hypomelanosis is present, the major differential diag- most common neurologic symptoms are mental retar- nosis is HI, a neurocutaneous disorder characterized by dation, seizures, and motor deficits, whereas musculo- unilateral or bilateral, hypopigmented streaks and skeletal findings include craniofacial dysmorphism, swirls that follow Blaschko’s lines and that are asso- scoliosis, and thoracic and finger deformities. The most ciated with ocular, musculoskeletal, and central ner- common ocular anomalies are strabismus, nystagmus, vous system abnormalities; however, if systemic abnor- scleral , myopia, congenital cataract, amauro- malities are absent, then the differential diagnosis can sis, and dacryostenosis. Cardiac, renal, and urethral be quite difficult. The fourth stage of incontinentia pig- alterations have been described.89–92 menti, which appears late in life, may be considered in The differential diagnosis of HI includes all linear the differential diagnosis in adults. Children with atax- lesions that follow the lines of Blaschko, the most com- ia-telangectasia may have hypomelanotic macules in mon being the fourth stage of , addition to telangiectasias, premature graying and cafe´ Goltz syndrome, and the systematized form of au lait macules. In female carriers of Menke’s kinky hair ND.78,87,93 syndrome, an X-linked recessive disorder related to Incontinentia pigmenti in its fourth stage might leave dysfunction of a copper-transporting protein, streaks hypopigmented lesions, usually in the extremities, in and swirls of hypopigmentation are present in the skin, adults. The eruption is usually preceded by the vesi- plus patches of pili torti in the scalp. Rarely, the differ- cobullous, verrucous, and hyperpigmented stages. ential diagnosis of ND needs to be made with other There are also ectodermal, neurologic, and musculo- conditions associated with hypopigmentation follow- skeletal abnormalities The histopathologic examination ing Blaschko lines (ie, lichen striatus, epidermal nevus, 81,86,87 shows the absence of eccrine glands and hair follicles. linear keratosis follicularis). In the Goltz syndrome, also called focal dermal hypo- There is no effective treatment for this disorder. Cos- plasia, bands of hypopigmentation associated with the metic cover-up may be a good recommendation. Partial linear areas of telangiectasias, dermal atrophy with fat repigmentation with autologous melanocyte grafting 88 herniation, hyperpigmentation, periorificial papillo- has been used. mas, nail dystrophy, and focal alopecia help in the clinical differential diagnosis. Additional musculoskel- Hypomelanosis of ITO etal, eye, and tooth alterations are present. The system- First described in 1952 under the name of incontinentia atized form of ND is the most important differential pigmenti achromians, it is nowadays considered under diagnosis. Mosaicism may be the presumed underlying the group of genetic mosaicism.87 HI is clinically etiology for both clinical pictures. ND, however, is a present as a neurocutaneous syndrome, with 62–94% congenital, stable leukoderma, not associated with sys- associated with abnormal systemic features. The prev- temic manifestations. VITILIGO AND LEUKODERMA IN CHILDREN

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