Epidermal nevus syndrome

Laura Flores-Sarnat MD (Dr. Flores-Sarnat of Alberta Children's Hospital has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.)
Originally released January 19, 1998; last updated November 14, 2016; expires November 14, 2019

This article includes discussion of epidermal nevus syndrome, linear sebaceous nevus of Jadassohn, linear nevus sebaceous syndrome, linear sebaceous nevus syndrome, organoid nevus syndrome, keratinocytic nevus syndrome, and linear epidermal nevus syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Epidermal nevus syndrome encompasses several sporadic congenital phenotypes characterized by epidermal nevi as the common denominator and associated with neurologic and other systemic involvement. Genetic somatic mutations occurring as mosaicism have been demonstrated in several subtypes; the most recent include postzygotic RAS mutations in both linear keratinocytic nevus syndrome and linear sebaceous nevus syndrome. Another important mutation is AKT1 gene in Proteus syndrome. The pathogenesis of skin lesions and of many systemic anomalies in all forms of epidermal nevus syndrome is explained by defective neural crest. The 2 most frequent phenotypes of epidermal nevus syndrome, linear keratinocytic nevus syndrome and linear sebaceous nevus syndrome are associated with neurologic manifestations, mainly epilepsy and intellectual disability. The most important cerebral anomaly that causes the neurologic picture is hemimegalencephaly, which is sometimes not recognized. The distinctive triad of facial keratinocytic or sebaceous nevus, hemifacial hyperplasia with lipomatosis, and ipsilateral hemimegalencephaly defines “Heide's syndrome” (eponymous of the first patient reported with this entity), which is justified historically and medically. Frequently, 1 of the components of this syndrome is overlooked. Recognition of Heide's syndrome can help physicians plan a multidisciplinary approach to investigation, management, and prognosis. On the other hand, the term “linear sebaceous nevus syndrome” is a well defined entity, and it is inappropriate to rename it for a new author as an eponym, such as “Schimmelpenning syndrome” after numerous previous and later contributions of so many authors over more than a century.

The discovery of activating HRAS and KRAS mutations in both keratinocytic and sebaceous nevi and their resulting phenotypes confirms the concept that they represent a spectrum of the same syndrome (Hafner et al 2012; Groesser et al 2012; Levinsohn et al 2013; Sun et al 2013), confirming the early interpretation of Solomon and colleagues that epidermal nevus syndrome is an inclusive term for congenital disorders characterized by epidermal nevi as the common denominator and is associated with neurologic and other systemic involvement (Solomon et al 1968).

Key points

 

• Epidermal nevus syndrome is an inclusive term for congenital disorders characterized by epidermal nevi as the common denominator and associated with neurologic and other multiple systemic involvement.

 

• Pathogenesis of the skin lesions and of many systemic anomalies in all epidermal nevus syndromes is explained by a defect in neural crest.

 

• The 2 most frequent phenotypes of epidermal nevus syndrome are linear sebaceous nevus syndrome and keratinocytic nevus syndrome, which are the most frequently associated with neurologic manifestations, mainly epilepsy and intellectual disability. These 2 main neurologic phenotypes are subdivided into several forms. The principal cerebral anomaly that causes the neurologic picture is hemimegalencephaly.

 

• Genetic somatic mosaic mutations in HRAS and KRAS genes cause both keratinocytic nevus syndrome and linear sebaceous nevus syndrome.

 

• Proteus syndrome, a phenotype of keratinocytic nevus syndrome, is caused by somatic mutations in the AKT1 gene.

 

• Three distinctive additional syndromes also are part of the neurologic phenotypes of epidermal nevus syndrome: CLOVES, SCALP, and Heide's syndrome.

Historical note and terminology

In comparison with other neurocutaneous syndromes recognized in the 19th century with cutaneous lesions described before the neurologic and neuropathological findings, in particular tuberous sclerosis, the clinical neurologic picture in epidermal nevus syndrome was described simultaneously with the skin lesions. One example is the case of a girl with facial sebaceous nevus and epilepsy (Gerhardt 1871). In both conditions, the definite histopathological delineation of the cutaneous lesions and neuropathological features was defined later. The initial reports by distinguished 19th century dermatologists described in detail the clinical and histopathological characteristics of the 2 more frequent varieties of epidermal nevi: keratinocytic nevi (Von Baerensprung 1863) and sebaceous nevi (Jadassohn 1895). Other systemic involvement in epidermal nevus syndrome, in particular ocular anomalies, was also described in the 19th century (Bögel 1886).

Despite early descriptions in the 19th century and reports in the early 1920s and 1930s (Flores-Sarnat 2013; Flores-Sarnat 2016), the subtype of linear sebaceous nevus syndrome was definitely recognized and considered to be a new neurocutaneous syndrome only until after the early 1960s with the report of Feuerstein and Mims in 1962 and early 1970s (Feuerstein and Mims 1962; Marden and Venters 1966; Herbst and Cohen 1971; Tripp 1971; Lansky et al 1972). Those early reports were followed by numerous case reports and reviews of sebaceous nevi in the face, scalp, trunk, and extremities. In several instances, patients presented neurologic, ocular, or other systemic features (Solomon and Esterly 1975; Flores-Sarnat 2013). Jadassohn himself recorded involvement of the CNS in some of the articles he reviewed (Jadassohn 1895; Zaremba 1978). Particularly after Robinson, many authors have used the term “nevus sebaceous of Jadassohn,” which is justified because he was the first to describe this lesion (Robinson 1932).

The first detailed report of a patient with an epidermal nevus syndrome with the typical neurologic picture of epilepsy and intellectual impairment was the case of a girl who had a verrucous (keratinocytic) nevus in the left side of the face, neck, and arm, associated with ipsilateral hemimegalencephaly, which was confirmed by autopsy (Gross and Uiberrak 1955). By disgrace, Heide, the little girl who was the subject of this report, was victim of “active euthanasia” in 1943 (Ronen et al 2009). Two years after that report, Schimmelpenning described an adult female with a sebaceous nevus located in the left side of the scalp, a nevus vasculosus on the left side of the neck, ocular anomalies, and epilepsy under the title “Clinical contribution to symptomatology of phakomatosis” (Schimmelpenning 1957). It was the report by Feuerstein and Mims of 2 children with a linear sebaceous nevus in the midline of the face (confirmed by skin biopsy) associated with epilepsy and mental retardation under the explicit title “Linear nevus sebaceous with convulsions and mental retardation” that drew attention from the medical community towards this “new” neurocutaneous syndrome (Feuerstein and Mims 1962). Soon after, the recognition of this constellation resulted in numerous reports under the designation “linear sebaceous nervus syndrome” and sometimes “Feuerstein-Mims syndrome” or “Schimmelpenning-Feuerstein-Mims syndrome” appeared, adding ocular, cardiovascular, and musculoskeletal anomalies. Solomon and colleagues reported 12 patients with epidermal nevi associated with a variety of systemic anomalies and further reviewed the syndrome. They coined the term "epidermal nevus syndrome," the rubric that remains the most widely accepted and encompasses the different phenotypes (Solomon et al 1968; Solomon and Esterly 1975; Flores-Sarnat 2015; Flores-Sarnat 2016). In their review of 60 patients, Solomon and Esterly further defined a variety of clinical presentations (Solomon and Esterly 1975).

Happle stated that Feuerstein and Mims “rediscovered” the condition described by Schimmelpenning in 1957, and he asserted that this syndrome should bear Schimmelpenning's name (Happle 2004). However, the eponym Schimmelpenning syndrome is not appropriate or justified because the large number of authors beginning in the 19th century who contributed to defining the “linear sebaceous nevus syndrome” (Flores-Sarnat 2013). Furthermore, in his single report and follow-up of 1 case, Schimmelpenning focused mainly in the cranial than in the cerebral abnormalities (Schimmelpenning 1983). Also, it is noteworthy that the 2 unrelated children reported by Feuerstein and Mims in 1962 correspond to the typical presentation of epidermal nevus syndrome with a sebaceous nevus located in the midline of the face or mildly lateralized, extending from the forehead as a continuous line to the tip of the nose. By contrast, the skin lesion of the patient described by Schimmelpenning was located in the left side of the scalp, not in the face (forehead and nose), and she had prominent exostoses of the frontal and parietal bones. Even though both lesions correspond to sebaceous nevi, it is important to distinguish them because the different distribution suggests a difference in origin. It is correct to continue using the descriptive term suggested by Feuerstein-Mims to the condition they described in 1962, including cases with other locations of the sebaceous nevus, retaining the term “linear sebaceous nervus syndrome” (coined by Lansky and colleagues) to denote the association with neurologic and other systemic anomalies described by many authors (Lansky et al 1972). When referring to either form (midfacial or lateral scalp) or other localization of sebaceous nevi, associated with systemic findings, the term “linear sebaceous nevus syndrome” should be appropriately applied.

Other authors have expressed that it is not justified to designate either Schimmelpenning or Feuerstein and Mims to the syndrome (Feuerstein and Mims did not try to give their name to the syndrome) because the large number of contributors to the description of these disorders over more than a century precludes the use of new author eponyms (Tripp 1971; Zaremba 1978).

In Jadassohn's original description, he considered sebaceous nevi as “organoid” due to the involvement of several skin adnexa; therefore, several authors have used the term "organoid nevi” and “organoid nevus syndrome" (Mehregan and Pinkus 1965; Barth et al 1977; Shields et al 1996). Jadassohn made seminal contributions to dermatology besides the first definition and correct classification of the sebaceous nevus (Weyers 2013).

Epidermal nevi correspond to a distinct group of congenital hamartomatous malformations of the skin. They are classified based on histopathological criteria according to their predominant component as keratinocytic, sebaceous, nevus comedonicus has a proliferation of hair follicle structures, apocrine, and eccrine nevi as well as other types of mixed components (Solomon and Esterly 1975; Paller 1987; Rogers et al 1989; Rogers 1992). When these nevi are associated with systemic involvement, epidermal nevus syndrome results and several phenotypes are delineated: linear nevus sebaceous syndrome, keratinocytic nevus syndrome (Sugarman 2004; Vidaurri de la Cruz et al 2004), CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defect) syndrome, Becker nevus syndrome (epidermal nevus associated with shoulder, arm, and breast hypoplasia), nevus comedonicus syndrome, phakomatosis pigmentokeratotica (coexistence of nevus sebaceous with melanocytic nevi) (Happle et al 1996), and ILVEN (inflammatory linear verrucous epidermal nevus) (Altman and Mehregan 1971). In a few cases of phakomatosis pigmentokeratotica, intellectual deficit can be present but cerebral anomalies have not been demonstrated (Tadini et al 1998; Gamayunov et al 2016).

Epidermal nevus syndrome is an inclusive term for several phenotypes characterized by the presence of epidermal nevi associated with other organ system involvement; when it includes a neurologic picture, it is considered a neurocutaneous syndrome. Happle, Rogers, and other dermatologists called this group, collectively, “epidermal nevus syndromes” (Happle 1991; Rogers 1992; Happle 1995; Sugarman and Frieden 2004). The incidence of epidermal nevi is approximately 1 in 1000 live births without gender predominance (Solomon and Esterly 1975). In a study, epidermal nevi were seen in 1 of 85 pediatric dermatologic patients, and epidermal nevus syndrome showed a relative frequency of 1 in 1080 of these patients (Vidaurri de la Cruz et al 2004).

Sebaceous nevus often can be diagnosed at birth (Mollica et al 1974). Although the terms “epidermal nevus syndrome,” “keratinocytic nevus syndrome,” and “linear nevus sebaceous syndrome” are sometimes used interchangeably, to avoid ambiguity, the terms should be applied more specifically. Linear nevus sebaceous syndrome should be restricted to those cases with sebaceous nevi; an example is the typical nevus in the midline of the forehead as a yellowish to orange or tan plaque-like nevus known as nevus sebaceous of Jadassohn.

Image: Nevus of Jadassohn in a 5-year-old boy

Blaschko described the linear pattern of epidermal nevi and other dermatoses, now known as “Blaschko lines,” and other authors have confirmed the pattern (Blaschko 1901; Happle 1995; Sugarman 2004; Vidaurri de la Cruz et al 2004). Blaschko lines are traditionally thought to be pathways of embryonic and fetal skin cell development and migration (Blaschko 1901; Miller 2004). More recent reconsideration of their embryology suggests that the lines of Blaschko more likely correspond to neural crest migrations to and within the dermis (Sarnat and Flores-Sarnat 2005). It is important to distinguish that in epidermal nevus syndrome there are 2 main neurologic phenotypes with prominent involvement of the central nervous system: the linear sebaceous nevus syndrome and keratinocytic nevus syndrome; both have characteristic clinical subtypes.

Image: Epidermal nevus syndrome in a 10-year-old boy
Image: Linear sebaceous nevus syndrome in a 16-year-old boy
There are other subtypes of the 2 main neurologic phenotypes. The acronym SCALP, that stands for sebaceous nevus, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus (melanocytic nervus), was introduced for this particular clinical presentation (Lam et al 2008). Patients identified under another acronym, CLOVE syndrome, were initially mistakenly identified as having Proteus syndrome (Sapp et al 2007). CLOVE stands for congenital lipomatous overgrowth, vascular malformations, and epidermal nevi, later expanded to CLOVES syndrome to include the association with scoliosis and skeletal and spinal anomalies (Alomari 2009). CLOVES syndrome can be associated with hemimegalencephaly but only infrequently is recognized (Gucev et al 2008).

Proteus syndrome is a complex hamartomatous disorder characterized by disproportionate, asymmetrical overgrowth of any tissue of the body, particularly the skeleton, cerebriform connective tissue nevi, epidermal nevi, vascular malformations, and dysregulated adipose tissue with multiple systemic complications (Cohen and Hayden 1979; Cohen 2005; Biesecker 2006). Proteus syndrome is a distinctive and severe neurologic phenotype of keratinocytic nevus syndrome (Flores-Sarnat 2015; Flores-Sarnat 2016). Hemimegalencephaly is the most common cause of neurologic manifestations (Rizzo et al 1990; Cohen 2005; Flores-Sarnat 2015; Flores-Sarnat 2016).

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