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  • Updated 03.25.2022
  • Released 01.19.1998
  • Expires For CME 03.25.2025

Epidermal nevus syndromes: neurologic phenotypes

Introduction

Overview

The term “epidermal nevus syndromes” defines a group of conditions characterized by the association of epidermal nevi with systemic manifestations. The two syndromes associated with neurologic expression due to CNS involvement that correspond to neurocutaneous syndromes are discussed in this review: keratinocytic nevus syndrome and sebaceous nevus syndrome. There are four distinctive phenotypes derived from the two principal syndromes: (1) Proteus syndrome; (2) sebaceous nevus, aplasia cutis congenita, limbal dermoid, and pigmented (melanocytic) nevus (SCALP) syndrome; (3) congenital lipomatous overgrowth, vascular malformations, epidermal (keratinocytic) nevi, scoliosis/skeletal and spinal anomalies (CLOVES) syndrome; and (4) Heide syndrome.

Other types of epidermal nevus syndromes that do not affect, or only rarely affect, the nervous system are not discussed in this article. They include Becker nevus syndrome, an epidermal nevus with hypertrichosis and “smooth muscle hamartoma” associated with shoulder, arm, and breast hypoplasia; inflammatory linear verrucous epidermal nevus (ILVEN) syndrome; and congenital hemidysplasia with ichthyosiform nevus and limb defect (CHILD) syndrome.

The area of distribution of the sebaceous or keratinocytic nevus is determined by the region of the neural crest involved.

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, the neurologic phenotypes. Another important mutation is the AKT1 gene in the Proteus syndrome subtype. The pathogenesis of skin lesions and many systemic anomalies in both phenotypes is explained by defective neural crest. The two most frequent phenotypes of epidermal nevus syndromes, 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 syndrome” (eponymous of the first patient reported with this entity), which is justified historically and medically. Frequently, one of the components of this syndrome is overlooked. Early recognition of Heide 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 has been recognized since the 19th century. It is inappropriate to rename it for a more recent author as an eponym, such as “Schimmelpenning syndrome,” due to the 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 are a spectrum of the same syndrome (60; 65; 93; 160), confirming the early interpretation by 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 (156).

Key points

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

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

• The two most frequent phenotypes, linear sebaceous nevus syndrome and keratinocytic nevus syndrome, are neurologic phenotypes. The most frequent manifestations are epilepsy and intellectual disability. These two main neurologic phenotypes are subdivided into several forms. The principal cerebral pathology 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.

• There are four distinctive phenotypes derived from the two principal syndromes: (1) Proteus syndrome; (2) sebaceous nevus, aplasia cutis congenita, limbal dermoid, and pigmented (melanocytic) nevus (SCALP) syndrome; (3) congenital lipomatous overgrowth, vascular malformations, epidermal (keratinocytic) nevi, scoliosis/skeletal and spinal anomalies (CLOVES) syndrome; and (4) Heide syndrome.

Historical note and terminology

In comparison with other neurocutaneous syndromes recognized in the 19th century with cutaneous lesions described before the neurologic findings, tuberous sclerosis in particular, the clinical neurologic picture of sebaceous nevus syndrome was described simultaneously with the skin lesions. One example is the case of a girl with ocular lesions, facial sebaceous nevus, and epilepsy as reported by Gerhardt in 1871 (57). In both conditions, the definite histopathological delineation of the cutaneous lesions and neuropathological features were defined later. The initial reports by distinguished 19th century dermatologists described in detail the clinical and histopathological characteristics of the two more frequent varieties of epidermal nevi associated with neurologic involvement: keratinocytic nevi by Von Baerensprung in 1863 (168) and sebaceous nevi by Jadassohn in 1895 (77). Other systemic involvement in sebaceous nevus syndrome, in particular ocular anomalies, was also described in the 19th century by Gerhardt in 1871 and Bogel in 1886 (57; 19). Before the detailed clinical and histopathological description of sebaceous nevus by Jadassohn, the distinction between keratinocytic nevus and sebaceous had not been established.

In the detailed clinicopathological description of sebaceous nevus made by Jadassohn (77), he cited Gerhardt’s contribution. Despite the early descriptions by Jadassohn in 1895 and others in the 19th century, as well as reports in the early 1920s and 1930s, the subtype of linear sebaceous nevus syndrome was recognized and considered a new neurocutaneous syndrome only after the early 1960s with the report of Feuerstein and Mims in 1962 and early 1970s (48; 103; 71; 163; 89). Those early reports were followed by numerous case reports and reviews of sebaceous nevi in the face, scalp, neck, trunk, and extremities. In several instances, patients presented neurologic, ocular, or other systemic features (155). Jadassohn himself recorded involvement of the CNS in some of the articles he reviewed and cited Gerhardt’s case (77; 177). 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 (133).

The first detailed report of a patient with a keratinocytic nevus syndrome with the typical neurologic picture of epilepsy and intellectual impairment was the case of a girl who had left hemifacial hyperplasia, left verrucous keratinocytic nevus in of the face, neck, and arm, associated with ipsilateral hemimegalencephaly, confirmed by autopsy (61). By disgrace, Heide, the little girl who was the subject of this report, was victim of “active euthanasia” in 1943 (136). Two years after that report, Schimmelpenning described a 17-year-old female with a sebaceous nevus located in the left side of the scalp, a nevus vasculosus on the left side of the neck (more likely part of the nevus and not hemangioma), ocular anomalies, and epilepsy under the title “Clinical contribution to symptomatology of phakomatosis” (148). Although he did not include Jadassohn’s reference in his report, Schimmelpenning did recognize Jadassohn’s contribution in the text, saying: “Jadassohn was probably the first to recognize nevus sebaceous and differentiate it from adenoma Pringle.” It was the report by Feuerstein and Mims of two children with a linear sebaceous nevus in the midline of the face (confirmed by skin biopsy) associated with epilepsy and cognitive deficit under the explicit title “Linear nevus sebaceous with convulsions and mental retardation” that drew attention from the medical community towards this “new” neurocutaneous syndrome (48). 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, renal, 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 widely accepted and encompasses the different phenotypes (156; 155; 54; 50). In their review of 60 patients, Solomon and Esterly further defined a variety of clinical presentations (155).

Happle stated that Feuerstein and Mims “rediscovered” in English the condition described by Schimmelpenning in 1957 in German, ignoring the early contributions of Gerhardt, Bogel, and Jadassohn, which were also in German, and he asserted that this syndrome should bear Schimmelpenning’s name (69). The eponym Schimmelpenning syndrome is not appropriate because Jadassohn was the first to define the histopathology and clinical features of sebaceous nevi in 1895; other authors, beginning in the 20th century, also contributed to defining the “linear sebaceous nevus syndrome” (53). Also, it is noteworthy that the two unrelated children reported by Feuerstein and Mims in 1962 represent the typical presentation of sebaceous nevi located in the midline of the face or mildly lateralized, extending from the forehead as a continuous line to the tip of the nose and corresponding to the distribution of the prosencephalic neural crest (50). The sebaceous nevi of the patient described by Schimmelpenning was located on the left side of the scalp, face, eye, and neck and arose mainly from the mesencephalic neural crest. Even though both lesions correspond to sebaceous nevi, it is important to distinguish them because the different distribution suggests a difference in neural crest 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 (89). 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 (163; 177).

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" (106; 13; 150). Jadassohn made seminal contributions to dermatology besides the first definition and correct classification of the sebaceous nevus (173).

Epidermal nevi correspond to a distinct group of congenital hamartomatous malformations of the skin; there are several types and several syndromes. They are classified based on histopathological criteria according to their predominant component (155; 121; 135; 134; 158; 167). Only two types, keratinocytic and sebaceous nevi, are associated with CNS involvement and neurologic manifestations (48, 54; 48, 50). When these nevi are associated with neurologic and systemic involvement, keratinocytic or sebaceous nevus syndromes result, and two main phenotypes are delineated: linear nevus sebaceous syndrome and keratinocytic nevus syndrome. Phakomatosis pigmentokeratotica is the coexistence of nevus sebaceous with melanocytic nevi (70; 73). In a few cases of phakomatosis pigmentokeratotica, intellectual deficit can be present but cerebral anomalies were not demonstrated (161; 56).

The incidence of epidermal nevi is approximately 1 in 1000 live births without gender predominance (155). In a study, epidermal nevi were seen in 1 of 85 pediatric dermatologic patients, and epidermal nevus syndromes showed a relative frequency of 1 in 1080 of these patients (167).

Sebaceous nevus can often be diagnosed at birth (57; 109; 95). Although the nonspecific term “epidermal nevus syndrome” is often used interchangeably with “keratinocytic nevus syndrome” and “linear nevus sebaceous syndrome,” the last two terms should be applied more specifically to avoid ambiguity. 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.

Nevus of Jadassohn in a 5-year-old boy
(A) Face of a 5-year-old boy with a typical nevus of Jadassohn in the frontal region, dorsum of the nose and neck on the left side. A continuous line extends from the forehead onto the nose. He has epilepsy and mild intellectual d...

Blaschko described the linear pattern of epidermal nevi and other dermatoses, now known as “Blaschko lines,” and other authors have confirmed the pattern (18; 68; 158; 167). Blaschko lines are traditionally thought to be pathways of embryonic and fetal skin cell development and migration (18; 108). Subsequent reconsideration of their embryology suggests that the lines of Blaschko more likely correspond to neural crest migrations to and within the dermis (144). It is important to distinguish that in epidermal nevus syndrome there are two 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.

There are four subtypes of the two main neurologic phenotypes originally described in the last century or earlier. The acronym SCALP, which stands for sebaceous nevus, central nervous system malformations, aplasia cutis congenita, limbal dermoid, and pigmented nevus (melanocytic nevus), was introduced for this particular clinical presentation (88; 74; 28). Patients identified under another acronym, CLOVES syndrome, were initially mistakenly identified as having Proteus syndrome (142). CLOVES 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 (05). CLOVES syndrome can be associated with hemimegalencephaly but only infrequently is recognized (62).

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 (31; 32; 16). Proteus syndrome is a distinctive and severe neurologic phenotype of keratinocytic nevus syndrome (54; 50). Hemimegalencephaly is the most common cause of neurologic manifestations (132; 32; 54; 50).

Heide syndrome is a congenital hemifacial hyperplasia with lipomatosis, epidermal or sebaceous nevus, and hemimegalencephaly.

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