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.
Physical examination
Linear nevus comedonicus
Nevus comedonicus is evident clinically as confluent clusters of dilated follicular orifices plugged with keratin, giving the appearance of aggregated open comedones. These clusters are often arranged in a linear or zosteriform pattern, occasionally paralleling the lines of Voigt or the lines of Blaschko.
Although usually unilateral, bilateral occurrences have been noted. As with other epidermal nevi, the most common sites are the face, the trunk, and proximal extremities.
Nevus comedonicus may be associated with a number of other cutaneous and internal defects, such as skeletal anomalies (eg, scoliosis, fused vertebrae or hemivertebrae, spina bifida occulta, absent fifth finger), central nervous system defects (eg, seizures, changes noted on EEG, transverse myelitis), and ocular alterations (eg, cataracts). Nevus comedonicus syndrome has ocular, skeletal, and central nervous system anomalies. [1]
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. Inflammatory linear verrucous epidermal nevus is characterized by tiny, discrete, erythematous, slightly warty papules, which tend to coalesce in a linear formation.
Altman and Mehregan [2] delineated 6 characteristic features: early age at onset, predominance in females (with a female-to-male ratio of 4:1), frequent involvement of the left leg, pruritus, marked refractoriness to therapy, and a distinctive psoriasiform and inflammatory histologic appearance.
The lesions may be observed at birth, but most appear during infancy and childhood. In the study by Altman and Mehregan, [2] one half of patients were noted to have lesions by age 6 months with three quarters of the 25 patients developing lesions by age 5 years. Several patients were noted to develop lesions at an older age (eg, 1 patient developed a lesion at 49 y). The left side of the body, particularly on the left lower extremity, was more often involved.
Inflammatory linear verrucous epidermal nevus may occur with musculoskeletal abnormalities in a few children, prompting the classification of inflammatory linear verrucous epidermal nevus as part of epidermal nevus syndrome. One infant had inflammatory linear verrucous epidermal nevus with congenital dislocation of the ipsilateral hip and Fallot tetralogy of the heart. Another infant had congenital inflammatory linear verrucous epidermal nevus with congenital bony anomalies of the ipsilateral extremities. Nevus depigmentosus and inflammatory linear verrucous epidermal nevus may occur together, as may inflammatory linear verrucous epidermal nevus and melanodontia.
Linear sebaceous nevus (Jadassohn nevus phacomatosis)
In 84% of patients with linear sebaceous nevus, skin lesions are on the face, and in approximately 50%, lesions are on the scalp, the neck, and the forehead. In most patients, the lesions appear on 1 side of the body (nevus unius lateralis), as shown in the images below. Lesions on the scalp are devoid of hair.
Characteristic epidermal nevus in the axillary fossa of a child with Jadassohn nevus phakomatosis.
An extensive plaque is observed over most of the left scapula, neck area, and lumbosacral location.
Plaque is evident in the region of the left groin, and it has a unilateral distribution.
Seizures are reported in 75% of patients with linear sebaceous nevus, mostly appearing in the first 6 months of life. The morphology of the seizures varies from infantile spasms or focal motor seizures to generalized tonic or tonic-clonic seizures. In some children, seizures are drug resistant and may result in progressive intellectual disability, which is noted in approximately 70% of patients with Jadassohn nevus phacomatosis. Such regression of mental capacity is not observed in older children or adolescents.
Approximately 50% of patients demonstrate different neurologic deficits, including cranial nerve paresis (cranial nerves VI and VII), hemiparesis, or cortical blindness.
Linear sebaceous nevus syndrome is composed of multiple, well-demarcated linear, hairless plaques with evidence of neurologic or skeletal alterations, such as epilepsy or intellectual disability. Skin lesions in linear sebaceous nevus syndrome are less obvious in infancy, and they are a smooth yellow-orange plaque. The nevus distribution pattern in this Schimmelpenning syndrome usually follows the lines of Blaschko. With age, these lesions become more visible, darker, verrucous, and hyperkeratotic. The last stage of development occurs in late adolescence or early adult life.
The verrucous nature of the lesions is further emphasized with cutaneous benign or malignant neoplasms noted in as many as 20-30% of patients. Trichoblastomas and syringocystadenoma papilliferum are the most likely benign neoplasms, whereas basal cell carcinoma, squamous cell carcinoma, and keratoacanthoma are the most common in the malignant category. [3] A trichilemmoma has been described as well. [4] Rarely, the squamous cell carcinoma may be of the spindle cell type. [5] Trichoblastic carcinoma developing with a nevus sebaceus has been described along with seven secondary benign neoplasms. [6]
Apocrine carcinoma was documented arising in a sebaceous nevus. [7]
Note the images below:
Extensive unilateral linear epidermal nevi in a 14-year-old girl with Jadassohn nevus phakomatosis. The plaques are elevated; some have verrucous characteristics.
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.
Epidermal nevus syndrome has been described in association with a complex ocular choristoma. [8] Further experience may show whether this linkage is significant.
Linear epidermal nevus may be bilateral or distributed on most of the body. The lesions appear as asymptomatic patches or plaques, with the head and the neck, as well as the trunk, being the most common sites.
The lesions may have a somewhat verrucous appearance. They lack erythema, and they are not pruritic.
An epidermal nevus may be associated with oral involvement and cleft palate. [9]
Epidermal nevus syndrome has been described with a combination of widespread eccrine proliferation, multiple facial and oral poxlike lesions, gingival synechiae, blepharophimosis, body asymmetry, and intellectual disability. This complex phenotype fits the genetic mosaicism theory. [10] An association of systematized epidermal nevus syndrome with papillary transitional cell bladder cancer has been noted too. [11]
Complications
A newborn girl was documented with a right-sided extended epidermal nevus, congenital rhabdomyosarcoma of the inguinal area, and hemihypertrophy. One should watch for a spectrum of organ system involvement in epidermal nevus syndrome at a very early age life. [12]
Facial paralysis due to an inflammatory pseudotumor of the facial nerve as a rare complication of epidermal nevus syndrome has been described. [13]
Diagnostics
Also see Histologic Findings.
MRIs can be used to evaluate intracranial involvement. MRIs may show cerebral atrophy, dilated ventricles, hemimegalencephaly, pachygyria, or enlarged white matter.
Multiple abnormalities are found on neuroimaging studies in patients with Jadassohn nevus phacomatosis. [14] Findings include hemimegalencephaly (usually ipsilateral to the major skin lesions and contralateral to neurologic deficits), cortical atrophy, pachygyria, cortical heterotopias, agenesis of the corpus callosum, and Dandy-Walker syndrome.
Ultrasound patterns are a good method for aiding in the diagnosis of many of these patients. [15]
EEG findings are abnormal in approximately 90% of patients. In almost all patients who had focal paroxysmal electroencephalographic abnormalities, the epileptiform focus was ipsilateral to the major skin lesions.
Management
No ideal medical therapy for the cutaneous lesions of epidermal nevus syndrome exists. The vitamin D analogue calcipotriol may be tried in each form of this disease, particularly inflammatory linear verrucous epidermal nevus.
Therapy is often challenging. Epidermal nevi are usually resistant to topical and intralesional steroids, dithranol, topical retinoids, and cryosurgery. Topical calcipotriol may be effective. In the United States, calcipotriol is not approved for children younger than 12 years. [16, 17]
For Schimmelpenning syndrome, antiepileptic medications (if needed) should be promptly considered.
Inpatient care is indicated only when potentially serious or life-threatening medical problems result from internal defects of the brain, eyes, or skeleton.
Ultrasound patterns are a good method for monitoring many of these patients. [15]
If the size and the site are suitable, the nevus may be excised if desired by the patient. [18] Inflammatory linear verrucous epidermal nevus of the digits may require surgical excision and skin grafting. [19]
A neonate with seizures, linear sebaceous nevus syndrome, and hemimegalencephaly benefited from a hemispherectomy at 36 weeks' gestational age. [20]
Carbon dioxide laser therapy for linear nevus sebaceous in the Schimmelpenning-Feuerstein-Mims syndrome may be beneficial. [21]
For nevus comedonicus syndrome, if an associated cataract is present, consult an ophthalmologist for therapy.
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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