Chapter 361. Melanocytic Lesions and Disorders of Pigmentation

Melanocytic lesions are extremely common in pediatric patients. At least 1 melanocytic nevus develops by early childhood in more than 95% of fair-skinned individuals.1 Dermal melanocytosis and other pigmented lesions such as freckles, lentigines, café au lait macules, and Becker nevi are also frequently observed in children and adolescents. In addition, a variety of disorders characterized by increased or decreased cutaneous pigmentation can present in childhood, ranging from postinflammatory hyperpigmentation and hypopigmentation to vitiligo to patterned pigmentation reflecting cutaneous mosaicism. Genetic diseases with pigmentary manifestations (eg, oculocutaneous albinism, piebaldism, Waardenburg syndrome, tuberous sclerosis, neurofibromatosis) are reviewed in Chapter 360. It is important for pediatricians to be aware of the clinical spectrum and natural history of benign melanocytic lesions and self-limited disorders of pigmentation in children as well as of findings that should raise concern.

Melanocytic nevi (moles) are benign proliferations of a type of melanocyte. The 2 major differences between ordinary melanocytes that reside in the basal layer of the epidermis and nevus cells are that (1) nevus cells cluster as nests within the lower epidermis and/or dermis, whereas epidermal melanocytes are evenly dispersed as single cells; and (2) nevus cells do not have dendritic processes (with the exception of those within blue nevi). Like ordinary melanocytes, nevus cells are capable of producing the pigment melanin. Melanocytic nevi can be acquired or congenital, banal or atypical (dysplastic). There are several variants, such as halo, blue, and Spitz nevi, that have specific clinical and histologic characteristics.2

Acquired Melanocytic Nevi

Acquired melanocytic nevi begin to appear after the first 6 months of life and increase in number during childhood and adolescence, typically reaching a peak count during the third decade and then slowly regressing with age.3-5 Both environmental and genetic factors play a role in the development of acquired melanocytic nevi. Sun exposure is the primary environmental influence (eTable 361.1); hereditary components include pigmentary phenotype as well as a particular predisposition to “moliness.”

Sun exposure during childhood, especially when intense and intermittent, has a major influence on the number and location of nevi as well as the risk of melanoma during adulthood.6 Sunscreen use can be protective against nevus development if combined with a sensible approach to sun exposure.1 In a randomized controlled study, school-aged children supplied with and instructed to use a broad-spectrum sunscreen developed significantly fewer new nevi (particularly on the trunk) over a 3-year period than did controls.7 An inverse relationship between wearing sun-protective clothing and nevus count has also been observed.8 Surprisingly, some retrospective studies have demonstrated a positive correlation between sunscreen use in children and an increased number of nevi; this presumably reflects the sunscreen’s incomplete barrier to ultraviolet radiation that allows sun exposures of longer duration.8

In general, individuals with lightly pigmented skin have more nevi than those with darker complexions.1,3,4,9,10 The mean number of nevi in white adolescents is approximately 15 to 25 (with higher numbers in those living in tropical climates), compared to 5 or fewer in adolescents of African, Asian, or Native American heritage (Fig. 361-1). However, individuals with the fairest skin, especially when accompanied by red hair (the “red hair phenotype”), also tend to have fewer nevi.1,3,9,10 In addition, several studies have demonstrated a significant positive correlation with nevus counts in first-degree relatives that was independent of patterns of sun exposure and pigmentary phenotype.8,9 Twin studies have shown that more than half of variation in nevus density in adolescents is attributable to genetic factors not accounted for by pigmentary phenotype.10

The names applied to acquired nevi reflect the location of the nests of melanocytes. Nests are at the dermal-epidermal junction in junctional nevi, in the dermis in intradermal nevi, and at both sites in compound nevi. Clinically, with progressive migration of melanocytes from the dermal-epidermal junction into the dermis, nevi become more elevated and less pigmented (Fig. 361-2A–D). Although banal (common) acquired nevi have a wide range of clinical appearances (ranging from a dark brown macule to a tan pedunculated papule), they tend to be less than 6 mm in diameter and symmetric, with a homogenous surface, even pigmentation, round or oval shape, regular outline, and sharply demarcated border. Close inspection sometimes reveals pigmentary stippling or perifollicular hypopigmentation.

Fifty years ago, Stegmaier described 2 pathways for the evolution of melanocytic nevi: (1) the formation of soft, skin-colored papules (intradermal nevi) and (2) a gradual fading away via atrophy and/or fibrosis. More recently, Siskind and colleagues5 followed the nevi on the faces and necks of 110 adolescents over a 4-year period and noted a dynamic process of nevus turnover, with a greater than 50% net increase in nevus number and complete regression of approximately 15% of nevi. Most new nevi were small and flat (ie, junctional), and there was a general tendency for existing flat nevi to either develop a raised profile or disappear (ie, to follow the first or second Stegmaier pathway). Dermoscopic evaluation (ie, using a handheld illuminated magnifier) of acquired nevi measuring more than 5 mm in diameter in children typically reveals a globular pattern, which is also observed in enlarging nevi and congenital melanocytic nevi.11

Atypical (Dysplastic) Melanocytic Nevi

Atypical nevi are acquired melanocytic nevi that share, usually to a lesser degree, some of the clinical features of melanoma but are benign. For example, the color of atypical nevi is often variegated (eg, containing pink, tan, brown, and dark brown hues), and the borders are characteristically ill defined (“smudged”) and may be irregular. Lesions frequently have macular and papular components: a flat periphery with a slightly elevated center (“fried-egg” appearance) or a pebbly surface. Considerable controversy has surrounded terms such as dysplastic nevus, and the 1992 Nation Institutes of Health Consensus Conference recommended the use of the more clinically descriptive term atypical nevus. They also recommended that the lesions be described histologically as “nevi with architectural disorder,” with specification of the degree of melanocytic atypia present (none, mild, moderate, or severe).12 Of note, clinical and histologic atypia in melanocytic nevi are not highly correlated, and size is not a reliable criterion for atypical nevi with moderate or severe cellular atypia histologically.

Atypical nevi usually begin to appear around puberty and continue to develop throughout life.13 Their density is greater on areas of the body that receive intermittent sun exposure than in non-sun-exposed sites such as the buttocks. The prevalence of clinically atypical nevi in white populations is approximately 2% to 10%, and their presence is best predicted by an increased total number of acquired nevi. The tendency to develop atypical nevi has a genetic basis (eg, mutations in the melanoma-predisposition gene CDKN2A), and the diagnosis of atypical mole syndrome has been applied. A spectrum of clinical presentations ranging from individuals with multiple atypical nevi and no personal or family history of melanoma to the familial atypical mole and melanoma (FAMM) syndrome, which is defined as (1) melanoma in 1 or more first- or second-degree relatives; (2) large numbers of melanocytic nevi (often 50–100 or more), some of which are atypical in appearance; and (3) melanocytic nevi demonstrating histologic atypia.12

Although themselves benign, multiple atypical nevi represent a marker of patients with an increased risk of melanoma and thus in need of periodic total body skin examinations. Compared to the general population, patients with atypical nevi tend to develop melanomas at an earlier age; the relative risk varies from 2-fold to 8-fold in those with no personal or family history of melanoma to more than 100 in those with 2 or more family members with melanoma.13 Recent studies based on genetic analysis (eg, families with mutations in CDKN2A) have shown that the familial atypical mole and melanoma syndrome has an overall lifetime melanoma penetrance of about 70%, which varies depending on factors such as sun exposure and coexistent melanocortin-1 receptor (MC1R) mutations. The latter produce the red hair phenotype when homozygous/compound heterozygous and increase risk of melanoma independent of pigmentary phenotype when heterozygous.14,15

Halo Nevi

The halo nevus is a melanocytic nevus surrounded by a round or oval halo of depigmentation, which is usually (but not always) symmetric (see Fig. 361-3C).16 This pigment loss often heralds spontaneous regression of the central nevus via a process involving an immune response to nevus antigens. Halo nevi occur in approximately 5% of white children 6 to 15 years of age, with a higher incidence in patients with an increased number of nevi and a personal or family history of vitiligo. The back is the most common location for halo nevi, and half of patients have multiple lesions. Four clinical stages are observed, with the duration of the process ranging from weeks to several years: (1) pigmented nevus surrounded by a halo of depigmentation, (2) pink nevus surrounded by a halo of depigmentation, (3) circular area of depigmentation with disappearance of the nevus, (4) normal-appearing skin after repigmentation of the halo. In some patients, the halo may be preceded by an inflammatory phase characterized by scaling and crusting17; in others, the central nevus may darken rather than lighten, developing grayish hyperpigmentation. The halo phenomenon typically involves common acquired melanocytic nevi but may also be seen with congenital, blue, and Spitz nevi. A biopsy of the central nevus can be performed if it has worrisome features, but biopsy is usually not required.

Blue Nevi

Blue nevi represent benign proliferations of dendritic dermal melanocytes that produce melanin. As with dermal melanocytoses (eg, Mongolian spots and nevus of Ota; see below), the blue color of these dermal melanocytomas is explained by the Tyndall effect (the preferential scattering of shorter wavelengths of light by dermal melanin). Sites of predilection of blue nevi (head, neck, dorsal aspects of the distal extremities, sacral area) represent locations where active dermal melanocytes are normally still present at birth.

Several variants of blue nevi have been described.18 The common blue nevus typically presents as a solitary, uniformly blue to blue-black papule that measures less than 1 cm in diameter. These nevi frequently arise in adolescence and are most often found on the face or dorsal surfaces of the hands and feet. The cellular blue nevus tends to be a larger nodule or plaque, measuring 1 cm or more in diameter, with a smooth or mammillated surface. Cellular blue nevi can be congenital or acquired and are most often located on the scalp or buttocks. If multiple blue nevi are present (particularly epithelioid blue nevi, a form of pigmented epithelioid melanocytoma), the Carney complex of myxomas (mucocutaneous and cardiac), spotty pigmentation (lentigines as well as blue nevi), and endocrine neoplasia should be considered.19

Stable blue nevi require no intervention, although small lesions that grow rapidly should be biopsied. Surgical excision can be considered for cellular blue nevi that are difficult to follow due to location or topography. Malignant blue nevi (a type of melanoma) have been reported, especially within cellular blue nevi located on the scalp; in addition, cellular blue nevi may infiltrate deeply into local tissues in the absence of malignancy.

Spitz Nevi (Spindle-Cell and Epithelioid-Cell Nevi)

Spitz nevi are benign, usually acquired proliferations of melanocytes with histopathologic features that sometimes overlap with those of melanoma. Most Spitz nevi appear during childhood, often with a rapid initial growth phase. The face and lower extremities represent the most common locations. Lesions classically appear as uniformly pink (Fig. 361-2E), tan, red or red-brown, solitary, dome-shaped papules. They are usually symmetric, well-circumscribed, and less than 1 cm in diameter. The surface may be smooth or verrucous; darkly pigmented lesions are occasionally observed. Disseminated Spitz nevi can also occur.20 They may occur as agminated lesions without a tan background, in speckled lentiginous nevi. The pigmented spindle cell nevus of Reed, a variant of the Spitz nevus, typically presents in an adolescent girl as a dark brown to black, flat-topped papule on the thigh; spontaneous resolution of such lesions has been observed.21

A presumed Spitz nevus with atypical clinical features (eg, diameter > 1 cm, asymmetry, or ulceration) should be biopsied with a goal of completely, yet conservatively, removing the lesion. Clinical monitoring represents an option for children with small, stable, clinically classic Spitz nevi.22 If the margins of a biopsy specimen are positive but a histologic diagnosis of classic Spitz nevus can be established with certainty, reexcision to ensure complete removal may not be necessary.23 However, lesions with unusual histologic features need to be excised in their entirety. Occasionally, unequivocal histologic distinction of atypical Spitz tumors from melanoma is not possible.24

Acral Nevi

Children with darkly pigmented skin have a relative predisposition to develop nevi on the palms and soles, which is not related to sun exposure.25 These nevi are usually flat or slightly elevated and brown to dark brown in color, exhibiting linear streaks of darker pigmentation along the prominent skin markings.

Nevi that involve the nail matrix can present as longitudinal melanonychia, a tan, brown or black streak caused by increased melanin deposition in the nail plate. In darkly pigmented individuals, longitudinal melanonychia is commonly seen on multiple nails due to increased melanin production by normal matrix melanocytes. Although streaks that develop in childhood are usually benign,26 single bands that are dark in color or wide (⩾ 6 mm), become darker or wider with time, are associated with nail dystrophy, or have extension of pigmentation beyond the nail fold warrant consideration of biopsy of the nail matrix to exclude melanoma.

Congenital Melanocytic Nevi

Congenital melanocytic nevi (CMN) are classically defined as melanocytic nevi present at birth or within the first few months of life. In clinicopathologic studies, histologically confirmed nevi have been found in approximately 1% of newborns, whereas 2% or more of infants have pigmented lesions clinically compatible with this diagnosis. Some nevi that are programmed from birth do not become clinically apparent until 3 months to 2 years of age; these are called tardive CMN or early-onset nevi.27 Compared to acquired nevi, the melanocytes in congenital nevi tend to extend deeper into the dermis and even the subcutaneous tissues, tracking along appendages such as hair follicles.

CMN enlarge in proportion to the child’s growth, with estimated factors for increase in size from infancy to adulthood as follows: head, 1.7-fold; trunk and upper extremities, 2.8-fold; lower extremities, 3.4-fold.28 The lesions are categorized on the basis of final size into 3 major groups: small (< 1.5 cm); medium (1.5–20 cm) (Fig. 361-3A); and large (> 20 cm; in a neonate, > 9 cm on the head and > 6 cm on the body) (Fig. 361-3B). Most CMN are small; a recent population-based study found that 0.7% of young Italian men (157 of 23,354) had a medium-sized or large CMN,29 and large CMN are estimated to occur in only approximately 1 of 20,000 births. Large CMN may have a “garment” distribution (eg, bathing trunk, cape) and are frequently accompanied by multiple smaller, widely disseminated “satellite” nevi.

The color of CMN ranges from tan to black, and the borders are often geographic and irregular (see Fig. 361-3A). Many CMN have an increased density of dark, coarse hairs (Fig. 361-3C). CMN may undergo age-related changes in appearance, frequently beginning as flat, evenly pigmented patches, then later becoming elevated and developing mottled pigmentation and a pebbly, verrucous, or cerebriform surface. Superimposed papules and nodules can arise and, depending on their clinical characteristics, may require histologic examination to exclude the possibility of a cutaneous melanoma.

Speckled Lentiginous Nevi (Nevus Spilus)

Several lines of evidence suggest that speckled lentiginous nevi (SLN), which have a prevalence of approximately 2% to 3%,30,31 represent a subtype of CMN.32 The “background” tan patch (café au lait macule–like) of an SLN (which in larger lesions may have a linear or blocklike configuration with sharp midline demarcation) is usually noted at birth or soon thereafter, with spots appearing over time. The superimposed pigmented macules and papules that develop on the background tan patch over time can range from lentigines to junctional, compound, and intradermal nevi to blue, Spitz, and classic congenital nevi (Fig. 361-3D). It was recently proposed that there are 2 distinct variants of SLN: those with exclusively macular speckles and those with papular (± macular) speckles.33 The risk of developing melanoma in SLN is thought to be similar to that of classic CMN of the same size range. SLN should therefore be followed clinically with periodic examinations and biopsy of suspicious areas.

Management and Complications

Management of the “Moley” Child

The appearance of new nevi and the growth of such lesions are expected findings in children and adolescents. Individuals tend to develop nevi with a particular clinical appearance (eg, uniformly pink in color or tan with a brown rim).34 This results in a predominant type of nevus, or “signature nevus.”35 A nevus that has different characteristics from other nevi in a given patient (the “ugly duckling”) should be regarded with particular suspicion.36 For example, the most worrisome lesion in an adolescent with 10 large fried-egg nevi on the back could be a small black nevus with irregular borders. A biopsy should be considered for nevi with characteristics such as unexpected rapid growth, ulceration, or development of asymmetry in shape or color. When a biopsy is performed, partial sampling should be avoided (with the exception of a large lesion in a cosmetically sensitive area).

A large number of acquired nevi and the presence of clinically atypical nevi each represents a marker of increased risk for development of melanoma, and patients with either trait should be followed with periodic total body skin examinations beginning around puberty.13,37 However, acquired nevi (banal or atypical) themselves have minimal malignant potential, with the lifetime risk of a particular nevus transforming into melanoma estimated to be about 1 in 10,000,38 and most cutaneous melanomas arise de novo (not in association with a nevus). As a result, there is no benefit to prophylactic removal of nevi.

The development of scalp nevi during childhood can represent an early indicator of a “moley” individual, sometimes heralding the eventual development of numerous (>50) nevi. In a recent study of 8- to 9-year-old Swedish children (N = 1069), 7% had at least 1 scalp nevus, the presence of which was associated with an approximately 2-fold higher total number of nevi than children without scalp nevi (median 14 versus 8, p < 0.001).10 Nevi arising on the scalp during childhood can represent an early clue to the diagnosis of atypical mole syndrome in those at risk due to their family history. However, scalp nevi themselves have a tendency to involute over time. Gradual lightening and regression has been observed for various types of scalp nevi, ranging from eclipse nevi (common acquired lesions with a tan center and stellate brown rim) (see Fig. 361-2D) to congenital melanocytic nevi.34,39

Potential Complications and Management of Large Cmn

Large CMN can be associated with systemic disease (eg, affecting the central nervous system [CNS]), whereas the consequences of small and medium-sized CMN are usually limited to the skin. There is ongoing debate regarding the magnitude of melanoma risk associated with CMN of various sizes and the best approach to their management.40-42 For patients with large CMN, the risk of developing melanoma (cutaneous or extracutaneous) is estimated to be 5% over a lifetime, with approximately half of this risk during the first 5 years of life (eTable 361.2).27,28 Cutaneous melanomas can arise subepidermally, making early recognition difficult. In some patients, the site of the primary melanoma is the central nervous system or retroperitoneum, while others have no identifiable primary site. Patients with a “giant” (> 40 cm) CMN in a posterior axial location that is associated with numerous satellite nevi have the greatest risk of developing melanoma.40,43 Melanomas less often arise within nevi restricted to the head or an extremity; to date, no well-documented primary cutaneous melanomas have been reported to develop within the satellite nevi themselves.43,44 Of note, deep soft tissue malignancies other than melanoma (eg, rhabdomyosarcoma, peripheral nerve sheath tumors) can also develop in association with large CMN.

Neurocutaneous melanocytosis (NCM) is due to a proliferation of melanocytes within the central nervous system in addition to the skin. NCM can occur in conjunction with (1) a large CMN, usually with a posterior axial location and (most importantly) accompanied by numerous satellite nevi (> 20 satellites); or (2) multiple (> 2) medium-sized CMN (accounting for about one third of NCM patients).45 In a recent study of patients with large CMN, 26 of 379 (7%) of whom had been diagnosed with NCM, those with more than 20 satellites had a 5-fold increased risk for NCM compared to those with 20 or fewer satellites.45 Of note, NCM can also develop in patients with nevus of Ota (oculodermal melanocytosis).

CNS melanosis is best detected by magnetic resonance imaging (MRI) with and without gadolinium, and it is divided into symptomatic and asymptomatic forms. Symptomatic NCM occurs in approximately 4% of patients with a high-risk CMN, with onset of clinical manifestations (eg, hydrocephalus and seizures) at a median age of 2 years and a poor prognosis even in the absence of malignancy.43,46,47Asymptomatic NCM, with a diagnosis based on MRI evidence of CNS melanosis, can be found in as many as 25% of infants with a high-risk CMN.48 In a 5-year follow-up study, only 1 of 10 patients with MRI evidence of CNS melanosis went on to develop neurologic symptoms.48 Of note, NCM is occasionally associated with structural abnormalities of the central nervous system (eg, Dandy-Walker malformation/posterior fossa cysts), defects of the vertebrae or skull, and intraspinal lipomas.

For large CMN, early and complete surgical removal is often recommended as prophylaxis against the development of melanoma; removal typically requires staged excision with use of tissue expanders and skin grafting.49,50 However, it is usually difficult to remove every nevus cell in the lesion because of location, extensive size, and involvement of deeper structures (eg, fat, fascia muscle). Even theoretically complete excision of a large CMN does not eliminate the risk of melanoma, as primaries in the central nervous system and other sites can also occur (see eTable 361.2). Although a trend toward lower incidence of melanoma in patients whose nevi were partially or completely excised has been noted in several studies,42 the largest nevi (which have a higher risk of developing melanoma) are also more likely to be inoperable. Performing an appropriately powered prospective trial to evaluate the efficacy of prophylactic excision of large CMN in preventing melanoma would be difficult for several reasons, including the rarity of large CMN, the relatively low incidence of melanoma even without intervention, and the multiple psychosocial as well as medical factors that play a role in the decision to pursue aggressive surgery.

In addition to the risk of melanoma, the stigma of having these highly visible lesions has significant psychosocial consequences.41,50 In patients in whom surgical excision is not feasible, cosmetic benefit may be obtained from procedures such as curettage, dermabrasion, and ablative laser therapy (eg, carbon dioxide or erbium:YAG, sometimes combined with pigment-directed lasers), especially when done during the newborn period when there is a lower risk of scarring and active melanocytes are concentrated in the upper dermis.51,52 For example, curettage can be performed during the first 2 weeks of life, taking advantage of a cleavage plain between the upper and mid dermis exclusive to neonatal skin.52 However, nevus cells remain in the dermis after such procedures, as evidenced by frequent repigmentation as well as several reports of the subsequent development of melanoma in treated areas.53

Whether or not resection of the CMN or other treatment methods are attempted, patients should be followed closely and any nodules or areas with suspicious changes examined histologically.]Proliferative nodules that develop within large CMN during early infancy can have histologic features of melanoma yet behave in a benign manner.50,54 Patients with a large CMN with satellite nevi or multiple medium-sized CMN should be screened with an MRI of the brain and (especially if the nevus overlies the posterior axis) spine during the first 6 months of life, then followed with serial neurologic examinations. A positive MRI in an asymptomatic patient does not necessarily preclude skin surgery (unless CNS involvement is especially extensive), and the frequency of repeat MRIs can be guided by the degree of involvement and clinical findings.27 Aggressive surgical procedures for removal of the CMN should be postponed in patients with symptomatic NCM.

Potential Complications and Management of Small and Medium-Sized Cmn

The risk for the development of cutaneous melanoma within small and medium-sized CMN is controversial and is thought to be 1% or less over a lifetime.49 Melanomas most often occur after puberty and tend to arise at the dermal-epidermal junction, in contrast to the earlier onset and deeper origin of many melanomas arising within large CMN.49,50 For example, over a period of more than 30 years, no child or adolescent followed at the Massachusetts General Hospital or New York University Pigmented Lesion Clinics developed melanoma in association with a CMN less than 5 cm in diameter.

Small and medium-sized CMN are managed on an individual basis depending on cosmetic concerns, factors that hinder monitoring (eg, very dark color, irregular topography, “hidden” location), and history of concerning changes. Removal for medical reasons is usually not necessary.

The overall incidence of cutaneous melanoma in the United States has increased dramatically in the past several decades, although it has leveled off in recent years. In adolescents, the rate of increase has been similar to that in adults (~ 3% annually), whereas in children (age < 10 years), it has been lower (< 1.5% annually).55 The lifetime risk of cutaneous melanoma in children born today is estimated to be 1 in 58, compared to 1 in 250 in 1980.56 However, cutaneous melanoma is rare in the pediatric population, accounting for approximately 2% of childhood malignancies. In the United States, 1% to 4% of all melanomas arise in individuals under 20 years of age, and only 0.3% to 0.4% (300–400 cases per year) occur before puberty.57

Melanomas in prepubertal children often fail to exhibit the ABC features (asymmetry, border irregularities, color variability) that characterize most melanomas in adults. Instead, childhood melanomas are often amelanotic and may clinically simulate a wart, vascular tumor, or keloid; histologically, they often have features reminiscent of Spitz nevi (spitzoid melanomas).58 Although a greater proportion are of the aggressive nodular subtype, with thicker lesions at diagnosis and a higher incidence of lymph node metastasis than melanomas in adults, there is actually a lower incidence of recurrences in children and overall survival parallels adult disease.59,60 In fact, a recent study showed significantly better survival in children under 10 years old compared to children 10 to 14 years old.59 The prognostic implications of a positive sentinel lymph node biopsy in pediatric patients (for either clear-cut melanomas or worrisome atypical Spitz tumors) remain unclear.60 Potential disease heterogeneity due to difficulties in differentiating spitzoid melanomas from atypical Spitz tumors complicates interpretation of studies.61

As discussed previously, the presence of numerous (eg, > 50) melanocytic nevi and/or atypical nevi are phenotypic markers of patients at increased risk for melanoma, particularly the superficial spreading type that occurs in adults and at times in adolescents. A family or personal history of melanoma, fair skin, red hair, and freckles represent additional risk factors that signal the need for especially diligent photoprotection and (particularly after puberty) periodic total body skin examinations. Rare conditions such as xeroderma pigmentosum (a group of inherited disorders of DNA repair) and large CMN can increase the risk of childhood melanoma.

Whereas in normal skin only melanocytes in the epidermis and hair follicles produce melanin, dermal melanocytosis is characterized by the presence of dermal melanocytes that actively synthesize melanin. The blue color of such skin (ceruloderma) is due to the preferential scattering of shorter wavelengths of light by the dermal melanin, a phenomenon known as the Tyndall effect. The spectrum of dermal melanocytosis in children includes Mongolian spots and nevi of Ota and nevi of Ito (nevus fuscoceruleus).

Mongolian Spots

Mongolian spots are ill-defined, homogeneous, gray-blue patches that are apparent at birth, typically on the sacral area and buttocks (Fig. 361-3E), in 85% to 100% of Asian neonates, more than 60% of black neonates, and less than 10% of white neonates.62 They are less often observed in extrasacral sites such as the upper back, shoulders, arms, and legs. The bluish discoloration results from the presence of active melanocytes in the middle to lower dermis. These melanocytes and the discoloration usually disappear by age 6 to 10 years; however, approximately 5% are still present in adulthood, especially those located on the distal extremities. Extensive dermal melanocytosis that affects the ventral as well as dorsal trunk, persists, and progresses in extent over time can represent a sign of a lysosomal storage disease (eg, Hurler syndrome or GM1 gangliosidosis).63

Nevi of Ota and Ito

Nevus of Ota (nevus fuscoceruleus ophthalmomaxillaris, oculodermal melanocytosis) presents as speckled grayish-brown to blue-black patches involving the skin, conjunctiva, sclera, tympanic membrane, and/or oral and nasal mucosa in areas innervated by the first and second divisions of the trigeminal nerve.64 Involvement is unilateral in approximately 90% of cases. In contrast to Mongolian spots, the discoloration is often mottled rather than uniform, and the density of melanocytes is greatest within the upper dermis. Nevus of Ota occurs most commonly in blacks and Asians (1–2/1000 in Japan), and there is an approximately 4:1 female-to-male ratio. The discoloration is evident at birth or within the first year of life in more than half of affected individuals, and in the remainder, it becomes apparent around puberty; in both instances, the lesions then persist throughout the patient’s life. Superimposed elevated areas with the histologic features of blue nevi occasionally develop, and iris mammillations may be observed.

Approximately 10% of patients with a nevus of Ota develop glaucoma, and ipsilateral sensorineural hearing loss has also been described. Symptomatic or asymptomatic neurocutaneous melanocytosis (see section “Potential Complications and Management of Large CMN”) can occur, typically with CNS involvement ipsilateral to the skin lesions. Melanoma of the uveal tract (and less often of the central nervous system, orbit, or skin) occasionally arises in association with nevus of Ota, most often in white adults (mean age, 50 years).65 Patients with nevus of Ota should be followed with yearly ophthalmologic examinations. The skin discoloration can be treated with pigment-specific lasers (eg, the Q-switched ruby, alexandrite, or Nd-YAG); this typically requires several sessions, but the outcomes are often excellent.66

Nevus of Ito (Nevus Fuscoceruleus Acromiodeltoideus)

Nevus of Ito is a type of congenital dermal melanocytosis involving areas of skin innervated by the posterior supraclavicular and lateral brachiocutaneous nerves. It is otherwise clinically and histopathologically similar to nevus of Ota.

Freckles and Lentigines

Freckles and lentigines are pigmented macules that result from increased activity of epidermal melanocytes.67 In contrast to freckles (ephelides), which are commonly observed in young children with fair skin and fade in the absence of sun exposure (eg, during the winter), lentigines are persistent. There are 2 major types of lentigines: solar lentigines and simple lentigines.

Like freckles, the distribution of solar lentigines is limited to sun-exposed areas, particularly sites of greatest cumulative exposure such as the face, dorsal aspect of the hands, extensor forearms, and upper trunk.67 Although the prevalence of solar lentigines increases with age, they can develop in fair-skinned children who have had significant sun exposure, especially on the shoulders following severe sunburns. Multiple tan to dark brown macules, often with irregular borders, are typically present; they range from a few millimeters to more than 1 cm in diameter. Children with xeroderma pigmentosum develop numerous solar lentigines at an unusually early age, and large, jagged solar lentigines are a characteristic finding in older children and adults with type 2 oculocutaneous albinism. Diligent sun protection is advisable for all children with freckles or solar lentigines.

Simple lentigines typically appear during childhood as sharply circumscribed, round to oval, uniformly brown or brownish-black macules that are less than 5 mm in diameter. They are usually few in number and (unlike solar lentigines) have no predilection for sun-exposed sites. However, multiple lentigines are observed in several genetic disorders including LEOPARD syndrome, Carney complex, Peutz-Jeghers syndrome, Cowden disease, Bannayan-Riley-Ruvalcaba syndrome, xeroderma pigmentosa, and neurofibromatosis type 1 (eTable 361.3). Lentigines may increase in number or darken in patients with Addison disease or other syndromes associated with elevated circulating levels of adrenocorticotropic hormone.

Labial melanotic macules, a variant of simple lentigo that most commonly develops on the vermilion portion of the lower lip, have a predilection for white adolescent girls. Mucosal melanotic macules may also occur on the oral mucosa and genitalia. Patients present with one or more brown to black macules, sometimes with irregular borders and mottled pigmentation. Genital lesions are occasionally more than 1 cm in diameter. Of note, multiple mucosal melanotic macules are a feature of disorders such as Peutz-Jeghers and Laugier-Hunziker syndromes (perioral and oral mucosal lesions) and Bannayan-Riley-Ruvalcaba syndrome (eTable 361.3).

Café Au Lait Macules

Café au lait macules (CALMs) are flat, pigmented lesions that may either be present at birth (see Fig. 361-3E) or appear during early childhood, often first becoming noticeable following sun exposure in lightly pigmented individuals. They represent localized oval areas of increased melanogenesis. Although a single CALM can be found in 25% to 35% of children, less than 1% of children have more than 3 CALMs.68 CALMs range from a few millimeters to more than 15 cm in size and enlarge in proportion to the child’s growth. Their color varies from tan to dark brown and is usually a few shades darker than that of the uninvolved skin. Interestingly, CALMs that occur within a Mongolian spot are often surrounded by a halo of normally pigmented skin.69

In patients with McCune-Albright syndrome or pigmentary mosaicism of other etiologies, CALMs may have a segmental distribution with sharp midline demarcation and an irregular, jagged outline (“coast of Maine”). McCune-Albright syndrome, which is due to mosaicism for activating mutations in the gene encoding the G protein Gsα subunit, also features polyostotic fibrous dysplasia, precocious puberty, and other endocrinopathies. The presence of 6 or more CALMs (measuring ⩾ 0.5 cm in prepubertal children and ⩾ 1.5 cm in adults) represents a criterion for the diagnosis of neurofibromatosis type 1(NF1) that is met by most affected individuals by adolescence (Chapter 360). In a longitudinal study of 41 children with 6 or more CALMs, 24 (60%) had NF1, 6 had segmental NF1, 3 were diagnosed with other syndromes, and only 8 (20%) had no manifestations of an associated condition.70 In contrast to NF1, multiple CALMs are found in a minority of patients with NF2 and tuberous sclerosis (see Chapter 360).

Becker Nevi (Becker Melanosis)

Becker nevi (Becker melanosis) represent fairly common cutaneous hamartomas characterized by variable epidermal thickening, enhanced melanocyte activity, increased size and number of hair follicles, and excess dermal smooth muscle. They exist on a spectrum with smooth muscle hamartomas (not melanocytic nevi). Becker nevi can be evident at birth, but most are first noticed around puberty. This timing, the male-to-female ratio of 5:1, increased terminal hairs within approximately half of lesions, and reports of acne vulgaris localized to lesions reflect hypersensitivity to androgens within Becker nevi.71 A Becker nevus classically manifests unilaterally on the shoulder and upper trunk as a large tan to brown patch that breaks up into smaller “islands” at its periphery. Lesions can also occur on the lower trunk and thigh. Associated developmental abnormalities, such as hypoplasia of the ipsilateral pectoralis major muscle or breast, are occasionally observed.

Postinflammatory Pigmentary Changes

Inflammatory dermatoses often lead to pigmentary changes, which are most pronounced and persistent in patients with darker skin. Although either hyperpigmentation or hypopigmentation can occur, particular skin diseases tend to resolve with pigmentary sequelae of a certain type. The nature and distribution of the pigmentary changes as well as the presence of active inflammatory lesions can provide clues to the primary dermatosis that is responsible. Most postinflammatory pigmentary alterations resolve spontaneously, albeit slowly, over months to years.

Postinflammatory Hypopigmentation

Postinflammatory hypopigmentation is commonly observed during and after flares of seborrheic dermatitis, atopic dermatitis (Fig. 361-4A), psoriasis, and pityriasis lichenoides chronica (Chapter 358). It is thought to result from a decrease in the transfer of pigment from melanocytes to keratinocytes, likely related to structural and phenotypic alterations in the latter cells.72

Pityriasis alba presents with ill-defined, round or oval, 0.5- to 3-cm hypopigmented macules and patches with slight scale on the cheeks or (less often) arms and legs of children and adolescents. The lesions become more apparent in the summer and are usually not preceded or accompanied by erythema or pruritus, although they have a predilection for atopic individuals. The differential diagnosis of pityriasis alba may include tinea (pityriasis) versicolor (Chapter 367), which is characterized by sharply demarcated hypopigmented macules (often coalescing centrally within areas of involvement) with fine scale that becomes more apparent upon stretching or scratching the skin; this condition, which favors the upper trunk and shoulders but also occurs on the face, can be diagnosed by a potassium hydroxide preparation of skin scrapings that reveals short hyphae and yeast (representing Malassezia).

Postinflammatory Hyperpigmentation

Postinflammatory hyperpigmentation can be predominantly epidermal (resulting from increased melanin production by melanocytes) or dermal (resulting from melanin that “falls” through a damaged basal epidermis into the dermis, where it is phagocytosed by melanophages). Dermal pigment often has a gray-brown rather than purely brown color. Acne, arthropod bites, and pityriasis rosea often lead to epidermal pigmentation, while lichen planus and fixed drug eruptions (conditions characterized by inflammation affecting the basal epidermis) eventuate in dermal pigmentation.

Contact with phototoxic furocoumarins in limes, other citrus fruits, and some weeds followed by exposure to sunlight may give rise to phytophotodermatitis, which often presents with delayed hyperpigmentation in the absence of recognized preceding erythema. Intense hyperpigmentation in bizarre streaks or patterns reminiscent of drips or thumbprints characterizes this condition (Fig. 361-4B).

Vitiligo

Vitiligo is a common acquired disorder (affecting ~ 1% of the population) characterized by complete loss of pigmentation (depigmentation) within well-demarcated areas of skin. Onset is before age 20 years in 50% of patients, and childhood vitiligo develops at a mean age of 5 years.73 Although it is a benign disorder, the disfigurement of childhood vitiligo (especially in darkly pigmented individuals) may lead to considerable psychologic distress, decreased self-esteem, and social isolation.

Classically, vitiligo is divided into segmental and generalized forms. The former has a unilateral distribution and favors the face, while the latter is fairly symmetric and typically involves the hands, feet, wrists, elbows, knees (Fig. 361-4C), axillae, and periorificial sites (eg, around the eyes, mouth, and genitalia). Segmental vitiligo tends to expand over 1 to 2 years and then stabilize, whereas generalized vitiligo has a natural history of gradual progression. Although generalized vitiligo (which includes acrofacial and universal variants) is the most common form overall, 30% to 50% of childhood vitiligo is segmental.

The absence of pigment in well-developed lesions of vitiligo is due to autoimmune destruction of melanocytes in the epidermis and (less often) hair follicles. Presumably, autoimmunity directed against melanocytes within the uveal tract, leptomeninges, and inner ear as well as the skin underlies the rare association of uveitis, aseptic meningitis, and dysacousia with vitiligo in Vogt-Koyanagi-Harada syndrome. Approximately 20% of patients with vitiligo have 1 or more affected first-degree relatives, and familial aggregation has a nonmendelian pattern suggestive of polygenic, multifactorial inheritance. Generalized vitiligo tends to run in families together with autoimmune diseases such as autoimmune thyroiditis, Addison disease, pernicious anemia, and systemic lupus erythematosus.74 Specific variants in genes such as NALP1, which encodes a regulator of the innate immune system, have been associated with vitiligo alone and extended autoimmune disease phenotypes.75

The goal of therapy for vitiligo is regeneration of the epidermal melanocyte population to achieve repigmentation of affected areas.73 Potential sources of melanocytes include lesional hair follicles, lesional epidermis (if any melanocytes remain), and adjacent uninvolved skin. Repigmentation usually occurs in a perifollicular pattern via activation of melanocytes in the outer root sheath of the hair follicle and their subsequent upward migration into the basal layer of the epidermis. Depigmented lesions that contain either no hairs (eg, the lips and distal digits) or only white hairs lack a follicular reservoir of melanocytes and are therefore more refractory to treatment.

The choice of therapy for vitiligo depends on the extent, location, and activity of disease as well as the patient’s age, skin type, and motivation.73 Some children with lightly pigmented skin and/or involvement limited to areas usually covered by clothing may not wish to pursue any treatment other than the use of broad-spectrum sunscreens. Others with even small lesions in exposed areas, particularly self-conscious adolescents and children who are ridiculed by their peers, may be eager to undergo therapy. Potent topical corticosteroids and topical calcineurin inhibitors are well suited for treatment of limited areas, and narrowband ultraviolet B phototherapy can be used for more extensive disease. Patience and perseverance are essential, since a trial period of at least 3 to 4 months is necessary to determine whether a particular treatment is effective.

Patterned Pigmentation Reflecting Cutaneous Mosaicism

Nevus Depigmentosus

A nevus depigmentosus is an area of circumscribed hypomelanosis that may be apparent at birth or, particularly in fair-skinned patients, first detected during infancy or early childhood. While a nevus depigmentosus is evident in approximately 1 in 150 infants, such lesions are found in 1 in 25 to 50 children and adolescents.76,77 A nevus depigmentosus is thought to result from a clone of cells with reduced melanogenic potential that arises during embryonic development and thus reflects cutaneous mosaicism (but on a smaller scale than in hypomelanosis of Ito; see next section).

Lesions are hypopigmented (not depigmented, as the name would suggest) patches with a polygonal or oval shape and an irregular border, often breaking apart at the periphery (see Fig. 361-4D). The term segmental nevus depigmentosus refers to larger, blocklike, unilateral areas of hypopigmentation with sharp midline demarcation. Nevus depigmentosus is rarely associated with extracutaneous abnormalities. However, one study reported that a significantly higher proportion of epileptic children (14%) than healthy children (2%) had a nevus depigmentosus (total N = 210 and 2754 respectively).77

Nevus depigmentosus is statistically a much more likely diagnosis than “ash-leaf spot” of tuberous sclerosis (incidence ~ 1/20,000; see Chapter 360). No further evaluation is indicated when an asymptomatic infant or child presents with 1 or 2 hypopigmented patches and no family history of tuberous sclerosis.76 More than 85% of patients with ash-leaf spots have 2 or more lesions, and approximately half of patients have 6 or more lesions. Although a lance-ovate shape is more specific for tuberous sclerosis, polygonal lesions outnumber lance-ovate lesions in patients with tuberous sclerosis; multiple guttate “confetti” lesions are particularly characteristic of tuberous sclerous.

Hypomelanosis of Ito

Hypomelanosis of Ito (pigmentary mosaicism with nevoid hypopigmentation) is a manifestation of cutaneous mosaicism characterized by linear streaks and swirls of hypopigmentation along the lines of Blaschko (see Fig. 361-4E).78 This occurs when a clone of cells with decreased pigment potential is established early in embryonic development, with the blaschkolinear pattern reflecting pathways of epidermal cell migration. Although congenitally programmed, the differential pigmentation may become progressively apparent during the first few years of life. Mosaicism for a variety of chromosomal abnormalities has been documented by cytogenetic analysis of fibroblasts or lymphocytes from affected individuals. Because the genetic defects that cause hypomelanosis of Ito are extremely heterogeneous, it is no longer considered as a discrete neurocutaneous syndrome, and the use of a more descriptive term such as pigmentary mosaicism with nevoid hypopigmentation has been advocated. A related blaschkolinear disorder, linear and whorled nevoid hypermelanosis, occurs via the same pathomechanism but represents pigmentary mosaicism with nevoid hyperpigmentation due to a clone of cells with increased pigment potential. A skin biopsy showing epidermal rather than dermal pigment can help to differentiate linear and whorled nevoid hypermelanosis from the third stage of incontinentia pigmenti (see Chapter 360).

Associated extracutaneous findings such as CNS (eg, seizures and developmental delay), ocular, craniofacial, and musculoskeletal abnormalities are present in approximately one third of children who present to a pediatric dermatologist at a tertiary care center with a diagnosis of hypomelanosis of Ito, and they usually become clinically evident during infancy.79 However, since the hypopigmented streaks of hypomelanosis of Ito in otherwise unaffected individuals (especially those with lightly pigmented skin) are likely to be overlooked, the actual frequency of systemic manifestations is probably lower. Evaluation should be guided by abnormal findings by history or observed upon careful clinical examination.

Other Pigmentary Disturbances

Diffuse pigmentary dilution of the skin and hair can develop in patients with kwashiorkor, selenium, copper deficiency, hypopituitarism, oculocutaneous albinism, Menkes syndrome, and other genetic diseases. Diffuse hyperpigmentation can occur with Addison disease, Cushing syndrome, congenital adrenal hyperplasia or with medications including chemotherapeutic agents, minocycline, zidovudine, amiodarone, and various psychotropic drugs. Heavy metal exposure can discolor the skin, and deficiencies of niacin (pellagra), vitamin B12, and folate can lead to diffuse hyperpigmentation. The brown color of skin lesions in urticaria pigmentosa (a form of cutaneous mastocytosis) is due to epidermal pigment.

Diffuse Pigmentary Dilution

In addition to forms of oculocutaneous albinism, Menkes syndrome, and other genetic diseases (see Chapter 360), diffuse pigmentary dilution of the skin and hair can develop in patients with kwashiorkor, selenium or copper deficiency, and hypopituitarism.

Diffuse Hyperpigmentation

Primary adrenal insufficiency (eg, Addison disease; see Chapter 534) serves as the prototype of metabolic disorders that can lead to diffuse hyperpigmentation. The generalized increase in epidermal pigment is accentuated in sun-exposed sites, areas of friction or pressure, flexural regions, palmoplantar creases, and the areolae. Darkening of the oral and genital mucosa may also be observed. The hyperpigmentation is caused by increased melanogenesis induced by elevated levels of proopiomelanocortin peptides such as adrenocorticotropic hormone and melanocyte stimulating hormone. Subtle hyperpigmentation of intertriginous areas, the genitalia, and palmoplantar creases can represent a clue to the diagnosis of congenital adrenal hyperplasia, especially in male neonates with salt-losing 21-hydroxylase deficiency (which leads to adrenocorticotropic hormone overproduction due to cortisol deficiency). Additional metabolic causes of diffuse hyperpigmentation include Cushing syndrome (due to pituitary or ectopic adrenocorticotropic hormone production), hyperthyroidism, hemochromatosis, chronic renal insufficiency, Gaucher disease(type 1), and Niemann-Pick disease(type A).

Medications that can lead to diffuse pigmentation include chemotherapeutic agents (eg, cyclophosphamide, dactinomycin, daunorubicin), heavy metals (slate-gray from silver, blue-gray from gold or bismuth, bronze with or without superimposed “raindrops” of hypopigmentation from arsenic), minocycline (blue-gray discoloration localized to the shins or sites of inflammation and occasionally generalized “muddy brown” hyperpigmentation favoring sun-exposed areas), hydroxychloroquine (blue-gray favoring the shins), zidovudine, amiodarone (slate-gray), and various psychotropic drugs (eg, chlorpromazine, imipramine; slate-gray).

Deficiencies in niacin (pellagra), vitamin B12, and folate can lead to diffuse hyperpigmentation. In pellagra, the hyperpigmentation favors sun-exposed areas including the dorsal aspects of the hands, extensor forearms, and upper chest (Casal necklace) and is accompanied by shellaclike transparent scale. Diffuse hyperpigmentation is commonly observed in patients with systemic sclerosis, often with accentuation in areas of pressure; of note, areas of depigmentation with sparing of perifollicular skin can also develop in patients with systemic sclerosis.

Primary Skin Conditions with Circumscribed Hyperpigmentation

The brown color of skin lesions in urticaria pigmentosa (a form of cutaneous mastocytosis; see Chapter 363) is due to epidermal pigment. In contrast, the gray-brown color of the oval macules of erythema dyschromicum perstans (“ashy dermatosis”), a condition with a predilection for the neck, trunk, and proximal extremities of children and adolescents of Latin American descent, is due to dermal pigment. Both epidermal and dermal pigment underlie melasma, a common acquired disorder characterized by irregular hyperpigmented patches in sun-exposed areas of the face that favors adolescent girls as well as young women with darker skin.