In approximately one third of common keratinocytic nevi, the same R248C heterozygous mutation in the FGFR3 oncogene can be found.25,26FGFR3 mutations are responsible for a relatively long list of syndromes and also neoplasms such as urinary bladder cancer, uterine cervical cancer, colorectal cancer, and spermatocytic seminoma. Although many cases of urinary tract cancer have been reported in patients with keratinocytic nevi,27,28 there is no proof to date that the nevus and neoplasm share the same mutation in any patients. In 2 patients with epidermal nevus and urothelial cancer in whom the FGFR3 gene was studied, both the hamartoma and neoplasm were wild type.29 Mosaic mutations in FGFR3 have been reported in some patients with mental retardation and epilepsy. When this occurs, the condition is known as the FGFR3 syndrome or García-Hafner-Happle syndrome.30,31

Another gene often affected is the PIK3CA gene. The same E545G mosaic mutation of PIK3CA has been implicated in keratinocytic nevi, seborrheic keratosis, and colorectal cancer.32PIK3CA mutations have also been associated with lipomatous growth and vascular and skeletal abnormalities, grouped in a syndrome known as congenital lipomatous overgrowth with vascular, epidermal and skeletal anomalies (CLOVES), Online Mendelian Inheritance in Man (OMIM) #612918.33 This syndrome was described in a series of 7 patients previously diagnosed with Proteus syndrome who had certain differential characteristics: progressive and mixed complex vascular malformations on the trunk, adipose tissue abnormalities, variable degrees of scoliosis, and elongated bones without progressive overgrowth and without bone distortion characteristic of Proteus syndrome.34 Subsequently, patients were described with malformations of the central nervous system and epilepsy.35 Unlike patients with Proteus syndrome, they did not develop connective tissue nevus (elastoma, collagenoma).36 Linear keratinocytic nevus is, in contrast, a characteristic lesion in CLOVES syndrome. The lesions tend to grow and become more verrucous until adolescence, and are stable thereafter.

Approximately 40% of keratinocytic nevi are the result of RAS mutations. In a study of 72 lesions, the HRAS gene was the most frequently affected, followed by NRAS and KRAS.37 RAS genes are important oncogenes and carry mutations in up to 30% of neoplasms in humans and in multiple syndromes (RASopathies). In the group of epidermal nevi, mosaic mutations in this group of genes may give rise to both keratinocytic nevi and organoid nevi and are an example of discordance between genotype and phenotype. Nevus marginatus, which has a central area rich in sebaceous glands and a more papular peripheral area with acanthosis and papillomatosis more similar to a keratinocytic nevus, is caused by mutations in RAS genes present in both components.38 Recently, the case has been reported of a girl with multiple nevoid lesions, some of which were consistent with keratinocytic nevus on the trunk and others with nevus sebaceous in the craniofacial region.39 The patient also showed delayed tooth development, cerebral arachnoid cyst, and optical atrophy. In both types of nevus, the same KRAS mutation was found. This mutation was not present in healthy skin or in peripheral blood of her parents. The syndromic forms associated with mutations in RAS genes will be covered in greater detail in the review of sebaceous nevus.

Some keratinocytic nevi with RAS mutations have been associated with the development of malignant neoplasms that carry the same mutation. This occurred for example in the case of a girl who presented a keratinocytic nevus and developed uterovaginal rhabdomyosarcoma at the age of 6 months.40 Both the hamartoma and the neoplasm showed the same KRAS mutation, which was not present in other tissues of the same patient. Another case is a 49-year-old man with extensive keratinocytic nevus who developed urothelial cancer in which the same mosaic HRAS mutation was detected in both lesions.41

Very recently, abnormalities have been described in the FGFR2 oncogene, whose mutation would explain 5% to 10% of keratinocytic nevi.42 The recent description of 2 fetuses with sebaceous nevi that carry mutations of this gene has been the source of debate, as some authors consider that these are keratinocytic nevi.43,44

In 2011, Antonio Torrelo et al.45 described a new form of epidermal nevus with specific clinical and histological features, corresponding to solitary or multiple, congenital lesions or lesions with onset soon after birth, with a papular appearance and smooth or papillomatous surface, forming plaques that are rounded or with form of a comma, measuring 0.3 to 1.5cm with a random distribution. Only one case has been reported in which the lesions followed a Blaschkoid distribution.46 Histologically, they present regular epidermal acanthosis with thickened and rectangular epidermal crests, with orthokeratotic hyperkeratosis. The most characteristic finding is that the basal cell layer is arranged in a cobblestone pattern, with an empty eosinophilic region between the nuclei of the basal layer and the first keratinocytes of the stratum spinosum (Fig. 5).

Figure 5.

Two PENS in the same patient. A and B, Two plaques, of 8mm and 5mm, with rounded form in the first case and polygonal somewhat linear form in the second. C, Hematoxylin-eosin (HE), 4x: biopsy showed epidermal hyperplasia with thickened and merged crests, with papillomatosis and compact hyperkeratosis. D, HE, 10x: at higher magnification, the basal cell layer in the epidermis can be seen with a cobblestone appearance.

(0.69MB).

PENS syndrome is manifest in the form of mental retardation and mild delay in development of psychomotor skills and epilepsy in the first year of life.47 These manifestations usually improve or even remit as the child gets older. Other findings include characteristic facies, shortened Achilles heel tendon, hypospadias, and curved penis.48,49

The genetic mutation responsible for this disorder and the mode of transmission are not known. In the original description, FGFR3 and PIK3CA mutations were ruled out.45 Generally, the lesions are sporadic, although families have been reported with more than one member affected.47,50

Proteus syndrome (OMIM #176920) is characterized by asymmetric tissue overgrowth caused by lethal, nonhereditary, mutations of the AKT1 gene that survive in mosaic form.51 The most characteristic changes are macrodactyly and hypertrophy of the limbs. Vascular malformations, lipomas, aplasia cutis congenita and connective tissue nevus, lung disease, parotid adenoma, ovarian cystadenoma and breast cancer, endometrial cancer, and testicular cancer may also be present. Up to 50% of patients present with epidermal nevi. These are flattened solitary or multiple plaques with a velvety surface, following the Blaschko lines. Histologically, acanthosis and hyperkeratosis are observed. Unlike other tumors associated with Proteus syndrome, epidermal nevus does not grow over time.52

Before the discovery of AKT1 mutations, Proteus-like syndrome due to mutations in the PTEN gene, with autosomal dominant transmission, has led to some confusion. Currently, it is thought that all these patients have Cowden disease along with an epidermal nevus (see the next section).53,54 All cases of Proteus syndrome are sporadic.

Cowden syndrome (OMIM #158350) is a multisystemic disorder characterized by the appearance of multiple hamartomas and tumors, including breast cancer, endometrial cancer, thyroid cancer, and colon cancer. Tumors of the skin include trichilemmomas, oral papillomas, fibromas (including sclerotic fibroma or storiform collagenoma, which seems to be quite a specific finding), mucocutaneous neuromas, acral keratosis, genital lentiginosis, malformations, and vascular tumors and lipomas. It is produced by a mutation in the PTEN gene, a tumor suppressor gene of autosomal dominant transmission, although mutations have been reported in other genes.55

The lesion has also been called Cowden nevus or PTEN (used here as the acronym for papillomatous, thick, epidermal, nonorganoid nevus), and refers to the appearance of erythematous, hyperkeratotic and papillomatous papules that coalesce to form linear plaques following the Blaschko lines in patients with Cowden syndrome. It is caused by loss of heterozygosity in the PTEN gene (type 2 Happle mosaicism).54,56 It has also been called type 2 segmental Cowden disease,54 segmental overgrowth, lipomatosis, arteriovenous malformation and epidermal nevus syndrome.57 The lesion can be distinguished from the epidermal nevus characteristic of Proteus syndrome because of its more keratotic and papillomatous appearance and because it presents with other manifestations of Cowden syndrome.

Congenital hemidysplasia, ichthyosiform erythroderma, and limb defects (CHILD) syndrome (OMIM #308050) is characterized by an epidermal nevus in association with ipsilateral skeletal aplasia or hypoplasia, punctiform calcifications in bone ends, ipsilateral defects in the brain, lungs, heart, or kidney. It is transmitted according to an X-linked dominant pattern although most cases are sporadic. Clinical expression is very variable, even within the same family, and members may have very subtle lesions that hinder diagnosis.58 The disease arises as a result of mutation of the NSDHL gene,59 which participates in cholesterol metabolism. The mutation is very often lethal in male embryos, although cases have been described in males.60

CHILD nevus is often confused with an inflammatory disease, particularly psoriasis, in cases with more limited involvement.61 It presents as linear erythematous plaques or yellowish, scaling, psoriasiform or ichthyosiform plaques, following a Blaschkoid distribution. The most extensive lesions have a well-defined border at the midline. Interestingly, the great majority of patients described have involvement of the right half of the body. There is a particular predilection for folds (ptychotropism).62 Histologically, the disease is characterized by psoriasiform dermatitis with neutrophil exocytosis. In parakeratosis, it has been noted that the nuclei that persist are more rounded compared with those that are seen in psoriasis.61 We often see accumulations of histiocytes carrying lipid vacuoles that express CD68 and adipophilin in the papillary dermis, which under a papillomatous epidermis, may lead to suspicion of a verruciform xanthoma. These findings, in the context of a congenital Blaschkoid, lateral lesion, with ptychotropism, should lead to suspicion of CHILD syndrome.

This lesion is a linear plaque with an inflammatory appearance and erythema and scaling. It tends to present on the legs. In 25% of cases, the lesions are present at birth, a further 50% present during the first 6 months, and the remaining lesions can present up until the patient is 4 years of age. Histologically, we see a psoriasiform dermatitis, with epidermal hyperplasia and areas of parakeratosis on an epidermis without a granular layer, alternating with orthokeratosis over hypergranulosis. Areas with a more spongiotic appearance with lymphocyte exocytosis have been described. The disease can present in the form of type 1 or type 2 mosaicism in patients with generalized psoriasis.63 Several cases have been reported with good response to treatments for psoriasis (topical agents, phototherapy, systemic agents, biologics). Apart from an anecdotic association with arthropathy,64 extracutaneous manifestations have not been described in patients with linear epidermal verrucous inflammatory nevus. The genetic mutations responsible for the mosaicism giving rise to this nevus are not known, and, like psoriasis, it could be a polygenic disease.

This disease correponds to a mosaic form of epidermolytic ichthyosis or epidermolytic hyperkeratosis (OMIM #113800). It is due to dominant mutations in keratin 1 or 10 (KRT 1 o KRT10).65,66 These are somewhat pigmented verrucous lesions following a linear Blaschkoid distribution. They may be present at birth as a solitary lesion or multiple lesions, on any part of the body. The flexural lesions often become moist and malodorous. Histologically, they present hyperkeratosis, acanthosis, papillomatosis, and acantholysis in the granular layer. These findings are consistent with epidermolytic ichthyosis. Cases of type 2 mosaicism have been reported, with linear areas of greater involvement on an individual with this disease.67 Several families have been reported with parents affected with the nevoid form and children who present a complete form of epidermolytic ichthyosis.68–70 It is suspected that transmission occurs through gonadal mosaicism. In patients in whom this nevus is diagnosed, germinal involvement should be ruled out and genetic counselling made available.

As in the previous nevus, most authors consider this nevus a mosaic form of a monogenic disease, although there is certain disagreement on this point. In this case, it would correspond to nevoid forms of Darier disease (OMIM #124200) or more rarely Hailey-Hailey disease (OMIM #169600). Numerous cases of segmental or linear Darier disease have been reported in the literature such as segmental or linear Darier disease.71–75 Clinically, these are linear keratotic crusty lesions that appear at puberty or later (Fig. 6). Exacerbations are characteristic and often associated with sweating and exposure to sunlight. Mucosal manifestations and lesions on the limbs, including palms, soles, and nails, characteristic of Darier disease, are not usually seen in nevoid forms. Furthermore, the lack of a family history of Darier disease is characteristic.

Figure 6.

Segmental Darier disease. A and B, Clinical images of the submammary and left dorsal lesion in a female patient without any additional skin lesions. C, Hematoxylin-eosin (HE), 4x: biopsy showed epidermal acanthosis with minimal orthokeratotic hyperkeratosis, suprabasal acantholysis, and formation of an intraepidermal blister. D, HE 10x: at higher magnification, the dyskeratotic changes can be appreciated better, with presence of rounded bodies and spots. The patient was diagnosed with segmental Darier disease.

(0.64MB).

Histologically, we see the presence of a hyperkeratotic and parakeratotic epidermis in which we observe intraepidermal cleavage that contains acantholytic and dyskeratotic keratinocytes, with presence of corps ronds and grains (Fig. 6). In some cases of acantholytic and dyskeratotic epidermal nevus, a mutation has been found in ATP2A2, characteristic of the disease.76,77

Some authors affirm, however, that acantholytic and dyskeratotic epidermal nevus and segmental Darier disease are not the same entity.78–80 The examples presented are congenital lesions (instead of lesions developing after puberty), in which mutation in the ATP2A2 gene has not been demonstrated or it is possible to confirm expression of SERCA2 (the expression product of ATP2A2) by immunohistochemistry.

Nevoid forms of Hailey-Hailey disease are rare. One case has been published of type 1 segmental involvement,81 and another case with presentation at 3 months of age with a relapsing linear lesion that subsequently developed symmetric lesions characteristic of the disease.82 In this patient, loss of heterozygosity was demonstrated in the area affected earliest (type 2 mosaicism).83 Histologically, suprabasal acantholysis is observed with lymphocytes and eosinophils. Dyskeratosis can be present, although it is not usually as evident as in Darier disease and rounded bodies or grains are not usually observed. Diagnosis of Hailey-Hailey disease usually requires immunofluorescence to rule out an autoimmune blistering disease, particularly, pemphigus vulgaris.