Etiology And Pathogenesis

Disorders of skin pigmentation reflect disturbances in the complex homeostasis of melanin production. Neural crest cell-derived melanocytes lie at the basal layer of the epidermis and produce melanin in lysosomal-like structures termed melanosomes. Melanosomes are transported from melanocytes to surrounding keratinocytes via dendritic extensions, and most melanin is found within the keratinocyte. Differences in skin pigmentation reflect not a difference in the number of melanocytes, which remains relatively constant, but a difference in the size, distribution, and number of melanosomes within keratinocytes.

Hyperpigmented skin lesions can be described as being either circumscribed or diffuse in nature. Focal areas of hyperpigmentation reflect local influences ranging from the degree of ultraviolet radiation to biochemical signaling from neighboring keratinocytes to inflammatory mediators such as prostaglandins and leukotrienes. Disorders with diffuse hyperpigmentation may in part be caused by increased production of melanocyte-stimulating hormone (MSH) as exemplified in conditions such as Addison’s disease. MSH is a byproduct of adrenocorticotropic hormone (ACTH), secretion from the pituitary and stimulates the melanocytes’ melanin production. Disruption of the production, maturation, or transportation of melanosomes results in many of the conditions discussed within this chapter. A discussion of nevi and disorders of melanocyte overgrowth is provided in Chapter 126.

Circumscribed Hyperpigmented Skin Lesions

Lentigines

Lentigines are round, brown to black macules, 4 to 10 mm in diameter that increase in number during adolescence and, at times, can be almost indistinguishable from ephelides. Clinically, lentigines occur anywhere on the body, not just in sun-exposed areas, and do not fade in the winter. Lentigines are quite common and benign when few in number. However, when multiple, lentigines constitute the primary clinical feature of a number of syndromes. The most important syndromes with lentigines as a defining feature are LEOPARD (lentigines, electrocardiogram abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness) syndrome, also known as multiple lentiginous syndrome, Peutz-Jeghers syndrome, and Carney’s complex (Figure 124-1 and Table 124-1). The clinician evaluating a patient with innumerable lentigines on examination should keep the above diagnoses in mind, especially if lentigines are noted on mucosal surfaces or cross the vermillion border because these are not features of benign lentiginosis.

Figure 124-1 Lentigines.

Table 124-1 Major Lentiginous Syndromes

	Lentigines Distribution	Defining Features
LEOPARD syndrome	Neck and upper trunk (less often face, arms, palms, soles, and genitalia)	• Lentigines • Electrocardiograph abnormalities • Ocular hypertelorism • Pulmonary stenosis • Abnormal genitalia • Retardation of growth • Deafness (sensorineural)

Peutz-Jeghers syndrome Mucocutaneous (lips and buccal mucosa; rarely, gums, palate, and tongue); elbows; palms; soles; and the nasal, periorbital, periumbilical, perianal, and labial regions

• Mucocutaneous lentigines

• Gastrointestinal hamartomous polyps

• Increased risk of early-onset adenocarcinomas affecting the GI tract, pancreas, breast, thyroid, and reproductive organs

CALS, café-au-lait spots; GI, gastrointestinal.

Café-au-Lait Spots

Café-au-lait spots (CALS) are one of the most common hyperpigmented lesions, with one or two CALS present in approximately 25% of school-age children. Although CALS may be noted at birth, many CALS develop in early infancy and may increase in size and number throughout childhood. They are sharply defined, round to oval in shape, and light brown and homogenous in color and can range from 2 mm to more than 20 cm in diameter. CALS occur anywhere on the body but are generally located on the trunk and lower extremities, sparing the face and upper extremities. Similar to lentigines, CALS are benign in nature but may signal an underlying systemic disease.

The two most common disorders in which CALS are the principal cutaneous feature and may be the primary clinical finding at the time of diagnosis are neurofibromatosis type I (NF1) and McCune-Albright syndrome. The CALS seen in NF1 are multiple and have a smooth circumference often compared to the “coast of California” (Figure 124-2). The number or distribution of CALS is not associated with the severity of disease in NF1. Other principal cutaneous findings in NF1 are described in Table 124-2. Although one or two CALS are quite common, fewer than 1% of children younger than 5 years of age have more than five CALS without having NF1 or the newly described Legius’ syndrome. Recent literature suggests that many patients previously labeled as having mild NF-1 in fact have an “NF-like syndrome” termed Legius’ syndrome, resulting from the autosomal dominant inheritance of a mutation in the SPRED-1 gene. Legius’ syndrome is characterized by multiple CALS, skin fold freckling, and an increased risk of macrocephaly and learning disabilities but without the other distinguishing features of NF-1 (see Chapter 76 for diagnostic criteria for NF-1). The CAL of McCune-Albright syndrome tends to be unilateral and large, stops abruptly at the midline, creating a segmental appearance, and has a jagged border likened to the “coast of Maine” (see Figure 124-2). Other associated features of McCune-Albright syndrome include precocious puberty and polyostotic fibrous dysplasia, although many children with large segmental café-au-lait macules have no associated syndrome. The clinician should consider the number and size of CALS along with other salient features by examination and history to guide their workup.

Figure 124-2 Café-au-lait spots.

Table 124-2 Cutaneous Findings in Neurofibromatosis Type I

CALS, café-au-lait spots.

Mastocytosis

Cutaneous mastocytosis is defined by the collection of mast cells within the skin. Lesions of mastocytosis typically develop before the age of 2 years, but new lesions may be normal up to age 5 years. If mastocytosis develops after this age or if there are prominent symptoms of too much systemic histamine (watery diarrhea, consistent dermal flushing), a workup for systemic mastocytosis or mast cell leukemia should be considered. The time course for typical childhood-onset disease is self-limited, with 50% of cases resolving by puberty and the other 50% showing a significant reduction in symptoms. Cutaneous mastocytosis can be grouped into three forms: mastocytoma, urticaria pigmentosa, and diffuse cutaneous mastocytosis.

The term mastocytoma is used if only a few isolated lesions are present, but urticaria pigmentosa is defined by the presence of multiple smaller lesions. Mastocytomas typically develop in infancy manifesting as isolated flesh-colored to yellow-orange papules or plaques with a classic “peau d’orange” (orange peel) surface (Figure 124-3). Urticaria pigmentosa presents as multiple, tens to hundreds, of papules and plaques found throughout the skin, typically sparing the palms and soles. Urticaria pigmentosa is the most common form of mastocytosis and clinically can be mistaken for other hyperpigmented lesions ranging from CALS to purpura. Last, diffuse cutaneous mastocytosis is not as common as the two previous forms and reflects diffuse infiltration of the skin with mast cells, giving the skin a thickened and doughy texture with a yellow discoloration.

Figure 124-3 Mastocytosis.

Symptoms from cutaneous mastocytosis result from mast cell release of proinflammatory mediators such as histamine and prostaglandins. Local release produces edema, surrounding erythema, and even the formation of vesicles or bullae that may mimic cutaneous herpes or a bullous disorder of childhood. Systemic release can manifest as a range of symptoms, including flushing, colicky abdominal pain, nausea, diarrhea, hypotension, and rarely wheezing and respiratory distress. Beyond recognizing its typical appearance, the diagnosis of mastocytosis can be made by eliciting a positive Darier’s sign. The Darier’s sign involves stroking a solitary lesion to trigger mast cell degranulation, leading to the appearance of edema, erythema, and occasionally vesiculation at the site (see Figure 124-3). The mainstay of management of children with mastocytosis involves avoidance of the triggers of mast cell degranulation, including physical triggers (friction, pressure, or extremes in temperature), certain medications (aspirin, nonsteroidal antiinflammatory drugs [NSAID], opiates, amphotericin, topical polymyxin B), systemic anesthetics (pancuronium, decamethonium), alcohol, and iodine contrast media. Symptoms can be controlled with nonsedating histamine type 1 antagonists such as loratadine or cetirizine, and only rarely is an epinephrine pen needed for a history of severe reactions.

Acanthosis Nigricans

Acanthosis nigricans presents as dark brown, velvety thickening of skin folds classically involving the axilla and the posterior and lateral neck folds. Verrucous hyperpigmented thickening may also involve the knuckles, flexor regions of the elbows and knees, and the perineum. Acanthosis nigricans is strongly associated with obesity and insulin resistance and should raise the suspicion for type II diabetes and polycystic ovarian syndrome. Excess circulating insulin is believed to bind to insulin and insulinlike growth factor receptors on keratinocytes and dermal fibroblasts, leading to the hyperkeratosis seen histologically in acanthosis. In large sample studies, approximately 90% of patients with type II diabetes have acanthosis nigricans on examination. Furthermore, the presence of acanthosis nigricans in obese individuals with fairer complexion is essentially predictive of insulin resistance. All obese individuals with acanthosis nigricans should be evaluated for underlying insulin resistance.

Dermal Melanosis

Dermal melanosis, more commonly known as a mongolian spot, is one of the most common hyperpigmented lesions seen in the newborn period. They are poorly circumscribed patches that are slate-gray to blue-green in color. The prevalence of mongolian spots varies greatly by ethnicity, with up to 90% of black infants, 80% of Asian infants, and 10% of white infants affected. These lesions are typically found on the buttocks or lumbar sacral area or less commonly on the back, flanks, shoulder, or lower extremities and generally fade by 2 years of age. Mongolian spots are benign in nature; however, the presence of extensive atypical mongolian spots has very rarely been associated with Hunter’s syndrome or GM1 gangliosidosis.

Postinflammatory Hyperpigmentation

Postinflammatory hyperpigmentation is commonly seen throughout childhood. Local inflammatory mediators stimulate melanin production by melanocytes, leaving areas of hyperpigmentation in a distribution pattern consistent with the prior inflammatory insult (Figure 124-4). Common causes in childhood include eczematous eruptions, acne, mechanical trauma, and skin infections. Individuals with darker complexions are most often affected. Management involves treating any ongoing inflammation, particularly important in cases of atopic dermatitis and acne vulgaris, and appropriate sunscreen to avoid further hyperpigmentation, and the pigmentation will fade over months to years.

Figure 124-4 Postinflammatory hyperpigmentation.

Linear Circumscribed Hyperpigmented Lesions

In the evaluation of a child with linear hyperpigmentation, the clinician should note whether the pattern of hypermelanosis follows the lines of Blaschko. The lines of Blaschko represent embryologic lines of ectodermal development that have a V or “fountain” shape on the back, an S or “whorl” pattern on the flanks, and a linear pattern on the extremities.

Incontinentia Pigmenti

The most important diagnosis to consider in cases of hyperpigmentation following the lines of Blaschko is incontinentia pigmenti (IP; Bloch-Sulzberger syndrome). IP is an X-linked dominant disorder affecting largely girls because boys typically die in utero, and has been attributed to a mutation in nuclear factor-κB essential modulator (NEMO). The cutaneous component of the syndrome has four distinct phases: vesicular, verrucous, hyperpigmented, and hypopigmented. The vesicular phase is noted in the first 2 weeks of life with vesicles on an inflammatory base following a linear pattern on the trunk and extremities (Figure 124-5). With any blistering in the neonatal period, herpetic or bacterial infections should always be considered. In the vesicular stage, leukocytosis and peripheral eosinophilia are typically present. The vesicular phase typically fades by 4 months and is followed by the eruption of verrucous papules and plaques in a linear distribution on the extremities that fade by 6 months of age. The third stage, noted between 12 and 26 weeks and lasting up until young adulthood, is characterized by whorls of hyperpigmentation on the torso and extremities following the lines of Blaschko, which do not occur in the same areas affected in stages 1 and 2 (see Figure 124-5). Stage IV develops in adulthood and involves streaks of hypopigmentation and alopecia most commonly affecting the extremities. The importance of making of a diagnosis of IP is that this syndrome is associated with multiple noncutaneous findings involving the following: teeth (absence of teeth, conical or peg-shaped teeth), nails (nail dystrophy, subungual tumors), hair (alopecia), eyes (strabismus, optic atrophy, retinal neovascularization, placing infants at risk for retinal detachment), and the central nervous system (infantile spasms and seizures, spastic paralysis, and mental retardation). Children with IP should be followed by a pediatric ophthalmologist or retinal specialist, especially during the first year of life, and be monitored for seizures.

Figure 124-5 Incontentia pigmenti.

Diffuse Hyperpigmentation

Generalized hyperpigmentation may indicate an underlying endocrinopathy or be a side effect of certain medications. Common disorders leading to hyperpigmentation are Addison’s disease, hyperthyroidism, Cushing’s disease, acromegaly, hemochromatosis, and chronic renal and hepatic disease. In the case of Addison’s disease, Cushing’s disease, and acromegaly, an increased production of ACTH and its byproduct melanotropin-stimulating syndrome stimulates melanocytes to produce melanin. Hyperpigmentation is seen most notably in sun-exposed areas, skin creases on the palms and soles, and mucous membranes. Medications known to cause variable degrees of hyperpigmentation include NSAIDs, minocycline, antimalarials, amiodarone, psychotropic drugs (phenothiazine, imipramine), clofazimine, azidothymidine, chemotherapeutics (5-fluorouracil, bleomycin, cyclophosphamide, daunorubicin, doxorubicin), and heavy metals (gold, silver, bismuth, mercury). The hyperpigmentation associated with medications will fade with discontinuation but is often a process that takes months to years.