The term epidermal nevus syndrome (ENS) was originally used as an all-encompassing term used to describe epidermal nevi in association with other syndromic features. In more recent years, this term was expanded to include several more well-defined neurocutaneous syndromes and their association with an epidermal nevus. The genetic basis of many of these syndromes has been elucidated in recent years. However, much is still to be learned about the genotype-phenotype correlation.
Common epidermal nevi include non-epidermolytic keratinocyte nevus, nevus sebaceous, nevus comedonicus, Becker’s nevus, and CHILD nevus. These are hamartomas of the skin, which are grouped as either organoid or keratinocytic.
The syndromes included within this umbrella term are somewhat controversial. Therefore, the most frequently included syndromes will be discussed further. Schimmelpenning syndrome, phacomatosis pigmentokeratotica, nevus comedonicus syndrome, and Becker’s nevus syndrome are among the syndromes associated with organoid epidermal nevi. The syndromes associated with keratinocytic nevi include Proteus syndrome and congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome.
In the last 10 years, significant knowledge regarding the most common epidermal nevus syndromes has been acquired.
Schimmelpenning syndrome is the most well-known epidermal nevus syndrome and was first described in 1957. The nevus sebaceous is the signature epidermal nevus of this condition which commonly follows a blaschkoid distribution and is seen in combination with skeletal, neurologic, and ophthalmologic features. Craniofacial defects, limb deformities, cognitive impairment, seizures, structural brain abnormalities, and coloboma are among some of the described features of this syndrome.
Phakomatosis pigmentokeratotica is also characterized by a nevus sebaceous but is seen in combination with a papular nevus spilus. Of note, in infancy, the nevus spilus component of this syndrome may be characterized by a light brown patch that does not develop the papules until several years later. Similar to Schimmelpenning syndrome, neurologic deficits are usually observed. Interestingly, a propensity to develop hypophosphatemic rickets is observed with greater frequency in this condition in comparison to Schimmelpenning syndrome.
Nevus comedonicus syndrome is characterized by a nevus comedonicus in combination with neurologic and ocular manifestations such as cataracts, microcephaly, anatomic cerebral malformations, and seizures among others. Most frequently these findings are ipsilateral to the nevus comedonicus.
Becker’s nevus syndrome is defined as an epidermal nevus in combination with ipsilateral muscular and or skeletal defects. The most commonly described findings include breast hypoplasia, scoliosis, vertebral defects, and hypoplasia of the muscles in the upper trunk. One notable finding is a lack of typical blaschkoid distribution in the epidermal nevus.
Proteus syndrome is an overgrowth syndrome affecting the bones and connective tissue that results in asymmetric growth of the limbs. The characteristic connective tissue nevi of this condition are frequently found on the plantar surface. The other cutaneous findings are vast but include lymphangiomas, patchy dermal hypoplasia, and lipomas among others. Neurologic deficits associated with disproportionate and asymmetric overgrowth of the underlying bony structures are a hallmark feature of this syndrome.
Congenital hemidysplasia, ichthyosiform erythroderma, and limb defects (CHILD) syndrome is inherited in an X-linked dominant pattern and therefore a predominance of those affected are females. This condition has very characteristic ipsilateral findings. Most striking include the ipsilateral hypoplasia of limbs, facial hemiplasia, and hypoplasia of various organ systems. The classic epidermal nevus is well defined, abruptly stops at midline, and tends to improve with age. Stippled calcification of the epiphysis, a unique bone finding, can be found early in infancy and can help clue clinicians into the diagnosis.
The diseases included within the epidermal nevus syndromes are quite rare. Most of the data are based on case reports and case series. The incidence and prevalence are not well reported at this time, however there does appear to be a clear female gender predilection in CHILD syndrome as a result of X-linked dominant inheritance.
The genetic basis for the development of the ENS has been a topic of significant research over the last 10 years.
What was once thought to be spontaneous, is now known to be a picture of somatic mosaicism.
Post zygotic mutations in the specified genes appear to result in epidermal nevus syndromes, however when germline mutations in the same genes occur there is significant variability in their phenotypic presentation, sometimes with very little to no overlap with the findings in the ENS.
Keratinocytic EN harbor many known mutations including RAS, fibroblast growth factor receptor 3 (FGFR3), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and keratins.
Most of the epidermal nevi have some characteristic histologic findings.
Keratinocytic epidermal nevi are characterized by linear or whirled pink to hyperpigmented plaques that can become verrucous with time. Unilateral or bilateral involvement can be seen, but they tend to abruptly stop at the midline and are most frequently found on the trunk and extremities.
Sebaceous nevus is more frequently found on the head and neck. They have a striking salmon or yellow color with a waxy surface and are associated with an alopecic patch. They are typically noted around the time of birth, but around puberty become more pronounced due to hormonal influences.
Nevus comedonicus is characterized by a grouping of dilated follicles plugged with keratin. Similar to acne lesions, they can be complicated by superimposed bacterial infections and inflammation.
Becker’s nevi are typically located on the upper trunk or shoulder girdle and consist of a light brown hyperpigmented patch that can develop hypertrichosis usually around puberty.
CHILD nevus is characterized by unilateral and sometimes blaschkoid involvement of waxy yellow plaques, which can become verrucous with time.
An integrated team of experts is required to manage and work up a proven or suspected case of an ENS due to the vast systemic and cutaneous manifestations of these syndromes.
Generally, treatment is only required for the extracutaneous manifestations of epidermal nevus syndromes, such as the treatment of seizures and orthotics for limb length discrepancies
Nevus Comedonicus Syndrome
Becker Nevus Syndrome
The prognosis of each of the epidermal nevus syndromes (ENS) is based on the degree of extracutaneous involvement. Neurologic manifestations can be debilitating. Conversely, isolated epidermal nevi that lack other significant findings are usually of cosmetic concern with low malignant potential. Various extracutaneous malignancies are reported in associated with the ENS, and with rapidly evolving guidelines, screening should be based on a case by case basis as evaluated by genetics.
The development of malignant tumors, i.e., basal cell carcinoma, within a nevus sebaceous is a reported complication occurring in less than 1% of these lesions. Other non-malignant basaloid proliferations likely occur with higher frequency. Biopsy of any suspicious growths within this epidermal nevus should be performed and interpreted by an experienced dermatopathologist to avoid unnecessary invasive procedures. Other extracutaneous malignancies should be screened based on symptoms and risk factors.
Patients and their family members should be counseled on the low malignant potential of some isolated epidermal nevi and their potential association with extracutaneous findings. Referral for additional workup should be sought out in appropriate cases.
Epidermal nevus syndromes are a group of related disorders consisting of an epidermal nevus in association with varying extracutaneous findings. The diagnosis, management, and treatment of each of these associated disorders require a multidisciplinary approach. Successful integration of a care team, including pediatricians, geneticists, endocrinologists, dermatologists, psychiatrists, neurologists, and beyond, may be required to manage patients optimally. Social and emotional implications also need to be strongly considered in patients growing up with an ENS.
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