Practice Essentials
Epidermal nevi (EN) are congenital hamartomas of embryonal ectodermal origin classified on the basis of their main component; the component may be sebaceous, apocrine, eccrine, follicular, or keratinocytic. An estimated one third of individuals with epidermal nevi have involvement of other organ systems; hence, this condition is considered to be an epidermal nevus syndrome (ENS). Solomon defines epidermal nevus syndrome as a sporadic neurocutaneous linkage of congenital ectodermal defects in the skin, brain, eyes, and/or skeleton. Epidermal nevus syndrome is often termed the Solomon syndrome. Schimmelpenning first detailed epidermal nevi with neurologic anomalies; hence, the term Schimmelpenning syndrome. The term organoid nevus may be used to emphasize the admixture of epidermal cells often evident in individual lesions of epidermal nevi.
Signs and symptoms
Epidermal nevi are patches, plaques, or nodules that may be bilateral or distributed on most of the body. Usually, no symptoms of the nevi are present, with the exception of inflammatory linear verrucous epidermal nevus.
Inflammatory linear verrucous epidermal nevus is a linear, persistent, pruritic plaque, usually first noted on a limb in early childhood. The clinical history may reflect symptoms associated with underlying anomalies. Inflammatory linear verrucous epidermal nevus, unlike the other types of epidermal nevi, demonstrates erythema and sometimes pruritus.
Background
Gustav Schimmelpenning, born in 1928 in Oldenburg (Germany), served from 1971-1994 as the head of the Department of Psychiatry at the University of Kiel. [22] In 1957, he described a case of sebaceous nevus involving the head, with ipsilateral ocular lesions including coloboma of the upper lid, increased density of cranial bones, epileptic seizures, and intellectual disability. He called this combination of anomalies a new phacomatosis. Subsequently, others reported this phenotype as Schimmelpenning syndrome, Feuerstein-Mims syndrome, Schimmelpenning-Feuerstein-Mims syndrome, epidermal nevus syndrome, Solomon syndrome, linear sebaceous nevus (LSN) syndrome, organoid nevus phacomatosis, or Jadassohn nevus phacomatosis.
A clinical entity called epidermal nevus syndrome should be more precisely defined and distinguished by clinical, histopathologic, and genetic criteria. In this review, 4 distinct epidermal nevus syndromes, recognizable by the different types of associated epithelial nevi, are described. These include linear sebaceous nevus, linear nevus comedonicus (NC), linear epidermal nevus (LEN), and inflammatory linear verrucous epidermal nevus (ILVEN). Each type may be regarded as part of a syndrome with systemic associations.
Linear epidermal nevus syndrome is a congenital neurocutaneous disorder characterized by linear epidermal nevus with significant involvement of the nervous, ophthalmologic, and/or skeletal systems. [23] Clinical manifestations include intellectual disability, seizures, and movement disorders that are caused by a wide range of neuropathologic lesions. Intracranial and/or intraspinal lipomas may occur.
Linear sebaceous nevus, also known as organoid nevus syndrome, often has the term linear deleted because almost all syndromic sebaceous nevi are linear. It has also been called Schimmelpenning-Feuerstein-Mims syndrome and Jadassohn nevus phakomatosis. Schimmelpenning syndrome, as noted above, links a sebaceous nevus with cerebral anomalies, coloboma, and lipodermoid of the conjunctiva. This neurocutaneous disorder is characterized by a craniofacial nevus sebaceus that falls along embryonic cutaneous lines and tends to be associated with neurological, ocular, skeletal, and vascular abnormalities. [24] This rare disorder represents a mosaic RASopathy due to postzygotic HRAS or KRAS mutations. [25]
Linear nevus comedonicus is also known as comedone nevus, nevus follicularis keratosus, nevus acneiformis unilateralis, and nevus zoniform. Cataracts may be a prominent feature of nevus comedonicus syndrome.
Inflammatory linear verrucous epidermal nevus is a linear, persistent, pruritic plaque, usually first noted on a limb in early childhood. Originally described by Unna in 1896, a few patients were reported prior to 1971 when Altman and Mehregan [2] delineated inflammatory linear verrucous epidermal nevus as a distinct entity in 25 patients. They coined the name inflammatory linear verrucous epidermal nevus, labeling it a clinical and histopathologic type of linear verrucous nevus that is often inflammatory or psoriasiform. Inflammatory linear verrucous epidermal nevus accounts for approximately 5% of patients with epidermal nevi and has been described in a mother and daughter.
Six different syndromes with epidermal nevi as part of them have been delineated. These include (1) Proteus, (2) congenital hemidysplasia with ichthyosiform nevus and limb defect, (3) phakomatosis pigmentokeratotica, (4) sebaceous nevus, (5) Becker nevus, and (6) nevus comedonicus [26] syndromes.
Phacomatosis pigmentokeratotica is characterized by the presence of multiple organoid nevi with sebaceous differentiation, a speckled lentiginous nevus, and skeletal and neurologic abnormalities. [27] It may or may not be associated with extracutaneous involvement. One patient with it developed basal cell carcinoma, syringocystadenoma papilliferum, and trichilemmoma within the nevus sebaceous. [28] In a study of one affected family, phacomatosis pigmentokeratotica was found to be caused by a postzygotic HRAS mutation in a multipotent progenitor cell. [29]
The spectrum has been expanded with the description of linear Cowden nevus as a new distinct epidermal nevus. [30] This nonorganoid epidermal nevus is probably due to loss of heterozygosity, occurring at an early developmental stage in an embryo with a germline PTEN mutation, giving rise to Cowden disease. The combination of nevoid hypertrichosis, diffuse lipoatrophy, and epidermal nevus has been suggested as a possible new epidermal nevus syndrome. [31] Thus, the epidermal nevus syndrome may be best viewed as a heterogeneous congenital disorder that includes both the keratinocytic epidermal nevus syndrome and sebaceous nevus syndrome. [32] An individual patient may have the same postzygotic HRAS and KRAS gene mutations and be evident clinically with distinct features.
Pathophysiology
Epidermal nevi arise from pluripotential germinative cells of the basal layer of the embryonic epidermis.
Inflammatory linear verrucous epidermal nevus is distinct from psoriasis; however, they may share some common pathogenic pathways. These pathways are probably mediated by interleukin 1, interleukin 6, tumor necrosis factor-alpha, and intercellular adhesion molecule-1.
Epidermal nevus syndrome–associated skeletal disease focal bone defects may manifest as fibrous dysplasia, even without the typical radiographic or histopathologic findings of fibrous dysplasia. [33] A patient had elevated circulating fibroblast growth factor 23 (FGF-23) levels with no activating mutations. This focal skeletal disease may be a source of FGF-23 in persons with epidermal nevus syndrome and thus may be a clue to its pathogenesis.
A bilateral, systematized epidermal nevus syndrome patient was described with cerebral involvement caused by a mosaic FGFR3 mutation, possibly representing a distinct entity within the group of epidermal nevus syndromes. [34] Other mutations of FGFR3 have been described in keratinocytic epidermal nevus syndrome. [35] A mosaic KRAS mutation has also been documented. [36] A somatic KRAS mutation was documented in an infant with linear nevus sebaceous syndrome associated with lymphatic malformations. [37]
The Schimmelpenning-Feuerstein-Mims syndrome, which is composed of a craniofacial nevus sebaceus, seizures, developmental delay, and ocular and skeletal abnormalities, is a sporadic condition hypothesized to result from mosaicism involving a lethal autosomal dominant gene. [38] It has been described in severely affected discordant monozygotic twins, supporting the concept of a postzygotic mutation.
Etiology
The basis of the cause may be the activation of an autosomal dominant lethal mutation that survives by mosaicism. These cells might survive only by being adjacent to normal ones [39] Inflammatory linear verrucous epidermal nevus has been described in a mother and daughter.
Epidemiology
Frequency
The syndromes are uncommon. In a review by Rogers and associates [40] of 131 patients with epidermal nevi and epidermal nevus syndrome, one third of the patients had the nevus sebaceous type, 60% had the noninflammatory type, 6% had inflammatory linear verrucous epidermal nevus, and only 2 had nevus comedonicus.
Sex
Linear sebaceous nevus syndrome and nevus comedonicus syndrome have a female-to-male ratio of 1:1. This ratio may also be true of linear epidermal nevus.
Inflammatory linear verrucous epidermal nevus has a female predominance, with a female-to-male ratio of 4:1.
Age
The age at diagnosis ranges from birth to age 40 years.
Prognosis
The prognosis depends on the presence and the severity of any of a variety of associated internal defects. Mortality and morbidity are related to the associated systemic anomalies.
Patient Education
The patient and/or the family should be reassured that epidermal nevus syndrome is not a genetic disorder that can be passed to future children.
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Characteristic epidermal nevus in the axillary fossa of a child with Jadassohn nevus phakomatosis.
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An extensive plaque is observed over most of the left scapula, neck area, and lumbosacral location.
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Plaque is evident in the region of the left groin, and it has a unilateral distribution.
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Epidermal nevus syndrome, demonstrating extension of a plaque distally.
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Extensive unilateral linear epidermal nevi in a 14-year-old girl with Jadassohn nevus phakomatosis. The plaques are elevated; some have verrucous characteristics.
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An 8-year-old girl with Jadassohn nevus syndrome. Note typical plaques in the midline and on the arm and the neck. The plaques are darker and more verrucous on the arm and the neck than on the midline.
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