Version May 2024
INTRODUCTION — Epidermal nevi are benign, hamartomatous growths of the skin that are present at birth or develop in early childhood. They may be composed of a variety of epidermal cells and structures, including keratinocytes, sebaceous glands, hair follicles, apocrine and eccrine glands, and smooth muscle cells, and are thought to represent a form of cutaneous mosaicism [1,2]. Lesions with prominent adnexal components (eg, sebaceous, follicular, and/or apocrine) are sometimes referred to as "organoid," while lesions with primarily epidermal differentiation are known as "non-organoid" or "keratinocytic" nevi.
Keratinocytic epidermal nevi, also called linear epidermal nevi or linear verrucous epidermal nevi, are the most common form. They present as linear or whorled, skin-colored to brown plaques that tend to follow linear patterns on the skin known as "lines of Blaschko" (figure 1 and picture 1A-C).
This topic will review the pathogenesis, clinical presentation, and management of linear epidermal nevus. Nevus sebaceous is discussed separately. (See "Nevus sebaceus and nevus sebaceus syndromes".)
EPIDEMIOLOGY — Epidermal nevi occur in approximately 1 to 3 per 1000 live births; males and females tend to be equally affected [2]. Most epidermal nevi occur sporadically as an isolated finding, but they also may occur in association with a variety of developmental abnormalities. Familial cases have been reported [3,4].
PATHOGENESIS — Epidermal nevi originate from pluripotential germinative cells in the basal layer of the embryonic epidermis. They are thought to represent forms of mosaicism, resulting from postzygotic mutations (or other genetic alteration) in embryonic cells destined to populate a particular area of the epidermis. Theoretically, mutations occurring very early in embryonic development give rise to more extensive epidermal nevi and may potentially affect additional organ systems [5].
Activating mutations in the fibroblast growth factor receptor 3 gene (FGFR3) and in the PIK3CA and HRAS oncogenes have been identified in keratinocytic nevi [6-8]. The epidermolytic variant of epidermal nevus harbors the same mutation in KRT1 or KRT10 genes responsible for epidermolytic hyperkeratosis (EHK), a rare, autosomal dominant genodermatosis [9,10]. Patients with this type of epidermal nevus may have gonadal mosaicism and may transmit the mutation to their offspring [11-13]. (See "Keratinopathic ichthyoses", section on 'Epidermolytic ichthyosis'.)
HISTOPATHOLOGY — Histologically, epidermal nevi are characterized by hyperkeratosis, acanthosis, and papillomatosis (picture 2) [14]. Some lesions may show the distinctive, church-spire pattern of acanthosis and hyperkeratosis that mimics acrokeratosis verruciformis, horn pseudocysts resembling seborrheic keratoses, or features of common warts [15].
Marked hyperkeratosis with lysis of epidermal cells above the basal layer is found in a histologic variant of epidermal nevus called "epidermolytic verrucous epidermal nevus." This variant carries the genetic mutation for epidermolytic hyperkeratosis (EHK), a rare, autosomal dominant genodermatosis caused by a mutation in KRT1 or KRT10 genes, encoding keratin 1 and 10, respectively [2].
The inflammatory linear verrucous epidermal nevus (ILVEN) is a clinically and histologically distinct variant of the epidermal nevus that displays a chronic dermal inflammatory infiltrate, psoriasiform epidermal hyperplasia, and alternating bands of ortho- and parakeratosis [16].
Appendageal anomalies may be seen in early childhood and include immature hair follicles, sebaceous, eccrine, or apocrine glands.
CLINICAL PRESENTATION
Linear verrucous epidermal nevus — Most epidermal nevi are present at birth or occur during the first year of life [2]. Occasionally, they may appear later in childhood or during adulthood (picture 1A-B). Initially, they appear as subtle, linear patches and/or thin plaques consisting of closely set or coalescing, skin-colored or brown, verrucous papules. Over time, particularly around puberty, they tend to darken and thicken (picture 1C).
The distribution and extent of epidermal nevi vary widely; they can be solitary, multiple, large, or small and usually are located on the trunk or extremities [2]. Rare cases involving the oral mucosa have been described [17]. Lesions tend to follow patterns of precursor cell migration and proliferation in the skin known as "lines of Blaschko" (figure 1) and often show a sharp midline demarcation.
A verrucous epidermal nevus with extensive bilateral distribution is called "systematized epidermal nevus" (picture 3A-B). A variant involving one-half of the body is termed "nevus unius lateris" (picture 4). Typically, systematized epidermal nevi take on a transverse configuration on the trunk and a linear configuration on the limbs.
Linear epidermal nevi are usually asymptomatic. Pruritus and scaling are common in the inflammatory variant described below.
Inflammatory linear verrucous epidermal nevus — Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare variant of epidermal nevus. It typically presents in early childhood and is characterized by pruritic, erythematous, and hyperkeratotic papules that often coalesce into plaques (picture 5) [1]. It is usually unilateral and most often located on the lower half of the body, with a linear distribution that follows the lines of Blaschko.
Clinical course and complications — The majority of epidermal nevi remain quiescent after adolescence. Flexural lesions may become macerated, superinfected, and foul smelling, causing discomfort and psychological problems. Rare cases of basal cell carcinoma and squamous cell carcinoma arising within epidermal nevi have been reported in older individuals [18-23].
EPIDERMAL NEVUS SYNDROME — The term "epidermal nevus syndrome" has been used to describe the association of an epidermal nevus with other developmental anomalies, which most commonly involve the brain, eye, and musculoskeletal system [1,2,24]. Syndromes associated with linear epidermal nevi include [25]:
●Proteus syndrome, a rare complex disorder presenting with malformations and overgrowth of multiple tissues (picture 6). (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Proteus-like syndrome'.)
●Type 2 (segmental) Cowden syndrome, a multisystem inherited disorder characterized by the presence of a specific keratinocytic nevus called linear Cowden nevus [25]. (See "PTEN hamartoma tumor syndromes, including Cowden syndrome", section on 'Cowden syndrome'.)
●Congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, an X-linked dominant, male-lethal phenotype caused by mutations in the NSDHL gene, encoding a 3-beta-hydroxysteroid dehydrogenase involved in cholesterol metabolism [26].
●Fibroblast growth factor receptor 3 epidermal nevus (FGFR3) syndrome, characterized by the presence of a systematized epidermal nevus and brain defects, including cortical atrophy, subdural hygroma, and hypoplasia of the corpus callosum [27]. This syndrome is considered a mosaic manifestation of thanatophoric dysplasia, a lethal skeletal dysplasia. (See "Approach to prenatal diagnosis of the lethal (life-limiting) skeletal dysplasias", section on 'Thanatophoric dysplasia'.)
●Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a rare disorder defined by the association of epidermal or melanocytic nevi, hypophosphatemic rickets, and elevated levels of circulating fibroblast growth factor-23 (FGF-23) [28,29]. It is caused by multilineage activating RAS mutations in skin and bone, resulting in elevated levels of circulating FGF-23 [28]. FGF-23 is a 30-kd phosphatonin normally secreted from osteocytes, which regulates both phosphate and vitamin-D homeostasis by modulating the expression of renal phosphate transporters and calcitriol-metabolizing enzymes [28].
DIAGNOSIS — In most cases, the diagnosis of linear epidermal nevus is made clinically, based upon the finding of verrucous papules and plaques in a linear distribution along the lines of Blaschko (picture 1C). If the diagnosis is in question, a skin biopsy may be necessary for histopathologic confirmation. (See 'Histopathology' above.)
Additional evaluation — Children with small, isolated epidermal nevi and a normal physical exam usually do not require further work-up. However, the presence of large or extensive epidermal nevi should prompt evaluation for potential involvement of other organ systems. (See 'Epidermal nevus syndrome' above.)
A thorough prenatal, perinatal, neonatal, and developmental history should be obtained, and a careful physical examination should be performed. A neurologic exam is critical, as is examination of the eyes, especially the conjunctiva, sclerae, and extraocular eye movements [1]. Skeletal exam should include evaluation for kyphoscoliosis and gait assessment. Limb length and size should be measured to ascertain any asymmetry.
The choice of imaging studies should be individualized depending upon the nature of the suspected abnormalities and might include skull and chest radiographs, skeletal imaging, magnetic resonance imaging (MRI) of the head, and electroencephalogram (EEG).
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of epidermal nevus includes the following:
●Lichen striatus – Lichen striatus is a rare, idiopathic papular eruption of childhood characterized by the sudden onset of flat-topped, skin-colored or hyperpigmented papules arranged in a linear configuration along the lines of Blaschko (picture 7A-B) [30,31]. The eruption typically resolves spontaneously in a few months to four years. Histology reveals a lichenoid lymphocytic infiltrate with overlying acanthosis and dyskeratosis. (See "Lichen striatus".)
●Linear psoriasis – Linear psoriasis is an exceedingly rare variant of psoriasis that may be difficult to differentiate from inflammatory linear verrucous epidermal nevus (ILVEN) both clinically and histologically [32-35]. Clinical features that distinguish linear psoriasis from ILVEN include family history of psoriasis, onset later in life, absence of verrucous lesions, involvement of other sites (eg, nails, scalp, palms, and soles), milder pruritus, and response to antipsoriatic treatments [32]. On histology, linear psoriasis shows hyperkeratosis, parakeratosis, absence of granular cell layer, elongation of rete ridges, suprapapillary thinning, and Munro microabscesses. ILVEN typically shows alternating orthokeratosis and parakeratosis and alternating presence and absence of granular cell layer. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)
●Linear porokeratosis – Linear porokeratosis is a rare form of porokeratosis that typically presents during infancy or early childhood with single or multiple plaques with hyperkeratotic rims on the limbs or trunk (picture 8A-B). Histology reveals the characteristic cornoid lamella, a thin column of tightly packed parakeratotic cells within a keratin-filled epidermal invagination (picture 9A-C). (See "Porokeratosis", section on 'Linear porokeratosis'.)
●Linear Darier disease – Darier disease is a rare, autosomal dominant genodermatosis that usually appears during the teenage years as skin-colored or yellow-brown keratotic papules that involve the face, chest, and back and, less frequently, the flexural areas (picture 10A-E). Linear forms of Darier disease can be differentiated from linear epidermal nevi by the typical histopathologic finding of acantholytic dyskeratosis. (See "Darier disease".)
●Incontinentia pigmenti – Incontinentia pigmenti is a rare, X-linked, male-lethal genodermatosis that presents in the neonatal period with linear papules and vesicles (picture 11). Within weeks or months, the initial lesions progress to verrucous streaks (picture 12) that may mimic a verrucous epidermal nevus. However, the verrucous lesions of incontinentia pigmenti gradually resolve, leaving hyperpigmented whorls and swirls along the Blaschko lines (picture 13). (See "Incontinentia pigmenti".)
MANAGEMENT — The management of epidermal nevi is difficult. Full-thickness excision provides definitive treatment for small lesions, but may not be an option for large or extensive lesions, due to the risk of disfiguring scarring [36]. Multiple alternative surgical or destructive approaches have been reported, including shave excision, cryotherapy, deep chemical peels, and laser ablation [37-42]. However, their efficacy is uncertain due to the lack of randomized trials or large observational studies with long-term follow-up.
Superficial excision techniques, such as shave excision, curettage, or dermabrasion, tend to produce only temporary benefit and are associated with a high risk of recurrence. Cryotherapy may be an option for small lesions. In one study, 11 patients with epidermal nevi were treated with two to five sessions of cryotherapy with good cosmetic results [41]. No recurrence was observed in 10 of 11 patients after a follow-up of 26 to 42 months.
Laser therapy is used increasingly for the treatment of epidermal nevi; improvements in technology and better selection of modality are gradually overcoming problems such as hypertrophic scarring, pigmentary changes, and partial recurrence. Continuous wave and pulsed carbon dioxide (CO2) laser vaporization has been used with good results in patients with soft, flat epidermal nevi [39]. Erbium:yttrium aluminum garnet (Er:YAG) laser ablation may provide better cosmetic results than CO2 laser with minimal or no scarring. In a series of 20 patients with verrucous epidermal nevi treated with Er:YAG laser, healing occurred within 10 days without scarring [37]. However, recurrence was reported in 5 of 20 patients in 3 to 12 months.
Topical therapies have a limited place in the treatment of epidermal nevi. There are isolated reports of successful treatment with topical retinoids, topical fluorouracil, topical corticosteroids, topical calcipotriol, and topical sirolimus [43-45].
Systemic retinoids, such as isotretinoin and acitretin, also have been used in patients with systematized epidermal nevi [46].
GENETIC COUNSELING — Patients with the epidermolytic histologic variant of epidermal nevus may have gonadal mosaicism for the mutation responsible for epidermolytic hyperkeratosis (EHK) and are at risk of having a child with EHK. For these patients, referral for genetic testing and counseling may be warranted. (See "Keratinopathic ichthyoses", section on 'Epidermolytic ichthyosis'.)
SUMMARY AND RECOMMENDATIONS
●Definition – Epidermal nevi are benign, hamartomatous growths of the skin; they may be composed of a variety of cells and structures and are thought to represent a form of cutaneous mosaicism. Keratinocytic epidermal nevi, also called linear epidermal nevi, are the most common form. (See 'Introduction' above.)
●Clinical presentation – Most epidermal nevi are present at birth or occur during the first year of life. They appear as linear patches or plaques of closely set, skin-colored or brown, verrucous papules that typically follow the lines of Blaschko (picture 1A-C and figure 1). Inflammatory linear verrucous epidermal nevus (ILVEN) is a rare erythematous and pruritic variant (picture 5). (See 'Clinical presentation' above.)
●Epidermal nevus syndrome – The term "epidermal nevus syndrome" has been used to describe the association of an epidermal nevus with other developmental anomalies, which most commonly involve the brain and the musculoskeletal system. (See 'Epidermal nevus syndrome' above.)
●Diagnosis – The diagnosis of linear epidermal nevus is clinical, based upon the typical finding of verrucous papules and plaques in a linear distribution. A skin biopsy may be necessary for histopathologic confirmation. (See 'Diagnosis' above.)
●Management – The management of epidermal nevi is difficult. Full-thickness excision provides definitive treatment for small lesions. Alternative therapies include shave excision, cryotherapy, and laser ablation. (See 'Management' above.)
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