Continuing Education Activity

Epidermal nevus syndrome is an umbrella term used to describe epidermal nevi in association with syndromic features. The first well-described syndrome was Schimmelpenning syndrome, but numerous related syndromes were described in subsequent years. These interrelated syndromes share cutaneous, neurologic, skeletal, and ophthalmologic findings. This activity highlights the role of interprofessional teams in evaluating, managing, and improving the care of patients with one of these syndromes.

Objectives:

• Outline the presentation of a patient with an epidermal nevus syndrome.

• Review the evaluation of patients with epidermal nevus syndrome.

• Describe the treatment considerations for patients with epidermal nevus syndrome.

• Summarize the importance of communication amongst the interprofessional team to enhance the care of patients with epidermal nevus syndrome.

Introduction

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 sebaceus, nevus comedonicus, Becker’s nevus, and CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) nevus. These are hamartomas of the skin, which are grouped as either organoid or keratinocytic.[1]

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 nevus syndrome are among the syndromes associated with organoid epidermal nevi. The syndromes associated with keratinocytic nevi include proteus syndrome and CHILD syndrome.[2]

Etiology

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 sebaceus 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.[2][3]

Phakomatosis pigmentokeratotica is also characterized by a nevus sebaceus 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.[2]

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.[4]

Becker 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.[5]

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 is 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.[2][6][7]

Congenital hemidysplasia, ichthyosiform erythroderma, and limb defects (CHILD) syndrome are 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 hemiplegia, 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.[8]

Epidemiology

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.

Pathophysiology

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 harbors many known mutations, including RAS, fibroblast growth factor receptor 3 (FGFR3), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and keratins.

• More specifically, both Schimmelpenning and phakomatosis pigmentokeratotica are RASopathies.[9] The RAS pathway is crucial to the regulation of several growth factor receptors. Accordingly, phacomatosis pigmentokeratotica appears to be caused by a post-zygotic HRAS mutation in a progenitor cell that is responsible for the development of both a nevus sebaceus and a papular speckled lentiginous nevus.[10]

• Fibroblast growth factor receptor 2 (FGFR2) mutations are believed to cause nevus comedonicus syndrome; however, when germline mutations in FGFR2 occur, this leads to the development of Apert syndrome.

• Interestingly, actin gene (ACTB) mutations have been identified in some smooth muscle cells of non-syndromic variants of Becker nevi more commonly than in the syndromic form.

• Proteus syndrome is well classified as a phosphoinositide 3 kinase-AKT-related overgrowth syndrome.

• CHILD syndrome is caused by a loss-of-function mutation in the gene that encodes 3-b-hydroxysteroid dehydrogenase, the NSDHL gene.[4][11]

Histopathology

Most of the epidermal nevi have some characteristic histologic findings.

• A keratinocytic epidermal nevus will show broad hyperkeratosis, papillomatosis, and acanthosis.
• Biopsy of a nevus sebaceus will show sebaceous gland development in association with acanthosis. These findings may vary based on the age of the patient due to the effects of hormonal stimulation.
• Becker’s nevi will show variable papillomatosis, hyperkeratosis, pigmentation of the basal layer, and augmentation of the smooth muscle fibers.[5]
• A nevus comedonicus will show dilated follicular ostia, which are variably filled with keratin.[12]
• Connective tissue nevi of proteus syndrome typically show hamartomas of connective tissue, fat, and blood vessels.[7]
• Acanthosis, papillomatosis, elongation of the rete ridges, and foamy, lipid-filled histiocytes in the dermal papillae are observed in CHILD syndrome.[13]

History and Physical

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.[12]

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.[2]

Evaluation

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. The evaluation should begin with a comprehensive history, including prenatal, developmental, and past medical and family history. A complete full-body skin exam, including the mucosal surfaces, should be performed by a dermatologist who is familiar with the vast majority of ENS. An astute pediatrician should perform a full skeletal assessment with a referral for imaging by radiology or a second opinion by orthopedics and endocrinology in the case of coexistent rickets. Routine imaging of the CNS is not standard unless there are developmental concerns that can be gleaned from a thorough history. Therefore, small isolated epidermal nevi usually do not require further workup and are usually an isolated finding. Epidermal nevi, which are large, dentofacial in location, or have associated neurologic symptoms such as seizures, may warrant further imaging to rule out structural brain abnormalities. Subsequent referral for a workup by neurology is recommended in case of suspected neurologic involvement. Geneticists can help to stratify the genetic basis for the syndrome in question and counsel regarding the risk of recurrence in future generations.[4]

Treatment / Management

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.

• Surgical excision can be utilized to address symptomatic epidermal nevi or for improved cosmesis. Routine full-thickness excision of nevus sebaceus is not considered the standard of care in the pediatric population and, if desired, for cosmetic purposes, can be done at an older age when challenges of administering local anesthesia are reduced. The malignant potential of nevus sebaceus is low, particularly in the pediatric age population.

• Other non-invasive treatments, including photodynamic therapy, laser ablation, and dermabrasion, can be considered on a case-by-case basis. However, these treatments may mitigate but not completely eliminate the malignant potential.

• The treatment for CHILD nevus is particularly interesting in that the affected pathway is critical in the synthesis of cholesterol. Treatment with a combination of topical lovastatin and cholesterol has been reported to result in clearance.[2][8]

Differential Diagnosis

Schimmelpenning Syndrome

• Phacomatosis pigmentokeratotica
• Nevus comedonicus syndrome
• Proteus syndrome

Phacomatosis Pigmentokeratotica

• Schimmelpenning syndrome
• Proteus syndrome

Nevus Comedonicus Syndrome

• Syndrome of segmentally arranged basaloid follicular hamartomas with ipsilateral osseous, dental, and cerebral anomalies
• Munro’s acne nevus

Becker Nevus Syndrome

• Giant congenital nevus
• Café au lait macule

 Proteus Syndrome

• Klippel-Trenaunay syndrome
• Hyperplasia with lipomatosis
• CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and scoliosis/skeletal/spinal anomalies) syndrome

CHILD Syndrome

• Inflammatory verrucous epidermal nevus
• Harlequin change of the newborn[2]

Prognosis

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 reportedly associated with the ENS, and with rapidly evolving guidelines, screening should be based on a case-by-case basis as evaluated by genetics.[4]

Complications

The development of malignant tumors, ie, basal cell carcinoma, within a nevus sebaceus 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.[4]

Deterrence and Patient Education

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.

Enhancing Healthcare Team Outcomes

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 an interprofessional team 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.