Nevi or nests of cells may be made up of a variety of cell types. The cell types that live in the epidermis include epidermal cells or keratinocytes, sebaceous glands, hair follicles, apocrine and eccrine glands, and smooth muscle cells. This article discusses epidermal or keratinocyte nevi, nevus sebaceous, nevus comedonicus, smooth muscle hamartomas, and inflammatory linear verrucous epidermal nevi. Syndromes associated with epidermal nevi are also reviewed.
Nevi or nests of cells may be made up of a variety of cell types. The cell types that live in the epidermis include epidermal cells or keratinocytes, sebaceous glands, hair follicles, apocrine and eccrine glands, and smooth muscle cells. This article discusses epidermal or keratinocyte nevi, nevus sebaceous, nevus comedonicus, smooth muscle hamartomas and inflammatory linear verrucous epidermal nevi. Syndromes associated with epidermal nevi are also reviewed.
Epidermal nevi
Epidermal nevi are noted at birth or within the first year as a linear tan patch or thin plaque. The linear pattern often follows Blaschko lines, which are believed to represent patterns of epidermal migration during embryogenesis ( Figs. 1 and 2 ). Rarely, epidermal nevi do not develop until later in childhood. Initially, they may present as flat tan soft or velvety plaques. The natural history of epidermal nevi is that, around the time of puberty, they tend to become thicker, verrucous, and hyperpigmented.
Although epidermal nevi may affect some of the population as an isolated finding, they may occur in association with certain syndromes or represent mosaic forms of genetically inherited conditions. Therefore, the clinician must be cognizant of the associated syndromes and conditions when presented with a patient with an epidermal nevus. The finding of an epidermal nevus warrants a full physical examination to evaluate for other features that may been seen in association with epidermal nevi, such as Proteus syndrome and others that are described in more detail in this article. Rarely, extensive epidermal nevi may present with extensive cutaneous involvement alone. The terms that may be seen in the literature to describe the presentation of extensive epidermal nevi are systematized epidermal nevus or nevus unius lateralis.
Histologically, epidermal nevi reveal hyperkeratosis and papillomatosis. The microscopic findings are the same as seen in seborrheic keratoses, therefore the specimen must be labeled with the clinical suspicion or the morphologic features of the plaque noted in order for the histopathologist to render a clinically relevant diagnosis. Thirty-three percent of epidermal nevi of keratinocyte differentiation have been found to have a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Acquired seborrheic keratoses have also been found to have a mutation in the FGFR3 receptor. It is also important to distinguish the histologic features of epidermolytic hyperkeratosis (EHK). EHK is associated with mutations in the keratin gene. Patients with cutaneous epidermal nevi revealing EHK histology may transmit this gene to their offspring with widespread cutaneous involvement, as discussed later in this article. The potential for malignant transformation of epidermal nevi is low, but is higher in certain subtypes of nevi, such as nevus sebaceous.
Treatment of epidermal nevi may be difficult. Topical therapies such as off-label use of topical retinoids, and destructive modalities such as electrodessication or cryotherapy may temporally improve the appearance of the lesion, but recurrence is the rule. Definitive treatment involves full-thickness excision, which may not be possible in large or extensive lesions. Carbon dioxide laser is an alternative option; however, scarring and pigmentary alteration are potential permanent complications, especially in patients with darker skin types.
Nevus sebaceous
Nevus sebaceous, also referred to as nevus sebaceus of Jadassohn, is a common hamartoma of the epidermis, hair follicles and sebaceous and apocrine glands. Nevus sebaceous usually presents at birth as a yellow-orange to pink, finely papillomatous, alopecic plaque that is often oval or linear ( Fig. 3 ). The size may vary from less than a centimeter to several centimeters in length, and a patient can rarely have multiple lesions. There are a few reports of unusually large and exophytic lesions for which histopathology was consistent with nevus sebaceous. There is a predilection for the scalp, but the next most common location is the face, and they may also occur on the neck, trunk, or, rarely, elsewhere on the body. These lesions generally grow proportionately with the child. During puberty, they have a tendency to become more raised, verrucous, and greasy, at least in part because of androgen stimulation of sebaceous glands.
There is debate about the risk of developing benign and malignant tumors within nevus sebaceous. Because studies are based on retrospective slide reviews of excised lesions, the true incidence and lifetime risk of malignancy is unknown. Early reports suggested a high rate of developing basal cell carcinomas. More recent studies have suggested that trichoblastoma and syringocystadenoma papilliferum are the most common neoplasms to develop in nevus sebaceous, usually in adulthood. Several retrospective slide reviews of a series of excised lesions found malignant neoplasms in 0% to 2.7% of cases. Jaqueti and colleagues reviewed previously published reports and concluded that many of the neoplasms previously diagnosed as basal cell carcinomas would have been better interpreted as trichoblastomas or primitive follicular induction. Multiple other benign neoplasms have been reported to arise in nevus sebaceous, including viral warts, sebaceoma, trichilemmoma, apocrine hidrocystoma or cystadenoma, keratoacanthoma, seborrheic keratosis and melanocytic nevus.
There are reports of more unusual or aggressive malignant neoplasms arising in adults with nevus sebaceous, including squamous cell carcinoma, apocrine carcinoma, sebaceous carcinoma, eccrine porocarcinoma, adenocarcinoma and mucoepidermoid (adenosquamous) carcinoma.
There are a few retrospective studies specifically about nevus sebaceous in children. Barkham and colleagues reviewed 63 cases of nevus sebaceous evaluated at a children’s hospital, of which 50% were excised, none of which had malignant change, only 1 had a benign neoplasm. Cribier and colleagues reported benign neoplasms in 1.9% of lesions excised from prepubertal children and 11.6% from pubertal children. Rosen and colleagues reviewed 651 excised lesions in children and found that 0.8% had basal cell carcinomas (the youngest at 9.7 years of age), and 2.2% had benign neoplasms. There are a few additional reports of basal cell carcinoma developing in nevus sebaceous in children less than 16 years of age. There are rare reports of squamous cell carcinomas arising within nevus sebaceous in an 11 year old and a 15 year old.
Nevus sebaceous has been theorized to arise from genetic mosaicism. Most cases of nevus sebaceous are sporadic, but there are a few reports of familial cases. It has been hypothesized that paradominant inheritance, whereby postzygotic loss of heterozygosity results in a mosaic homozygous or hemizygous state may explain the rare familial cases of nevus sebaceous. Carlson and colleagues found a high prevalence (82%) of human papillomavirus (HPV) DNA in nevus sebaceous. They postulated that HPV infection of fetal epidermal stem cells could play a role in the pathogenesis of nevus sebaceous. Xin and colleagues found that 8 of 20 (40%) cases of nevus sebaceous exhibited loss of heterozygosity for the human homolog of the Drosophilia patched ( PTCH ) gene, the tumor suppressor gene implicated in basal cell nevus syndrome. This may help explain the risk of development of basal cell carcinomas within nevus sebaceous.
Histopathology of a nevus sebaceous reveals variable epidermal hyperplasia with hyperkeratosis, acanthosis, or papillomatosis that may become more prominent in time. Sebaceous glands may be hyperplastic and numerous, but may also be diminished or even absent. They may be located high in the dermis and unrelated to a hair follicle, sometimes communicating directly with the epidermis. Hair follicles are usually decreased, absent, or immature. Ectopic apocrine glands may be present in the lower dermis.
Removal of a nevus sebaceous is best done by surgical excision, but the necessity and timing of excision is controversial. Some investigators have argued that because the incidence of malignant neoplasms in nevus sebaceous is extremely rare, early excision is not necessary. Other investigators have argued that prophylactic excision is still warranted because malignant transformation can occur and even benign growths often require surgical intervention. Some patients or their families also desire excision for cosmetic concerns. Optimal timing for excision may depend on various factors, including size and location of the lesion, and the risks and benefits of general anesthesia versus local anesthesia. Local anesthesia is often being an option for less extensive lesions when the patient is older.
Carbon dioxide laser and photodynamic therapy have been used to treat nevus sebaceous for cosmetic reasons, but these modalities do not completely remove the lesion, leaving a risk of recurrence and development of secondary neoplasms.
Nevus sebaceous
Nevus sebaceous, also referred to as nevus sebaceus of Jadassohn, is a common hamartoma of the epidermis, hair follicles and sebaceous and apocrine glands. Nevus sebaceous usually presents at birth as a yellow-orange to pink, finely papillomatous, alopecic plaque that is often oval or linear ( Fig. 3 ). The size may vary from less than a centimeter to several centimeters in length, and a patient can rarely have multiple lesions. There are a few reports of unusually large and exophytic lesions for which histopathology was consistent with nevus sebaceous. There is a predilection for the scalp, but the next most common location is the face, and they may also occur on the neck, trunk, or, rarely, elsewhere on the body. These lesions generally grow proportionately with the child. During puberty, they have a tendency to become more raised, verrucous, and greasy, at least in part because of androgen stimulation of sebaceous glands.
There is debate about the risk of developing benign and malignant tumors within nevus sebaceous. Because studies are based on retrospective slide reviews of excised lesions, the true incidence and lifetime risk of malignancy is unknown. Early reports suggested a high rate of developing basal cell carcinomas. More recent studies have suggested that trichoblastoma and syringocystadenoma papilliferum are the most common neoplasms to develop in nevus sebaceous, usually in adulthood. Several retrospective slide reviews of a series of excised lesions found malignant neoplasms in 0% to 2.7% of cases. Jaqueti and colleagues reviewed previously published reports and concluded that many of the neoplasms previously diagnosed as basal cell carcinomas would have been better interpreted as trichoblastomas or primitive follicular induction. Multiple other benign neoplasms have been reported to arise in nevus sebaceous, including viral warts, sebaceoma, trichilemmoma, apocrine hidrocystoma or cystadenoma, keratoacanthoma, seborrheic keratosis and melanocytic nevus.
There are reports of more unusual or aggressive malignant neoplasms arising in adults with nevus sebaceous, including squamous cell carcinoma, apocrine carcinoma, sebaceous carcinoma, eccrine porocarcinoma, adenocarcinoma and mucoepidermoid (adenosquamous) carcinoma.
There are a few retrospective studies specifically about nevus sebaceous in children. Barkham and colleagues reviewed 63 cases of nevus sebaceous evaluated at a children’s hospital, of which 50% were excised, none of which had malignant change, only 1 had a benign neoplasm. Cribier and colleagues reported benign neoplasms in 1.9% of lesions excised from prepubertal children and 11.6% from pubertal children. Rosen and colleagues reviewed 651 excised lesions in children and found that 0.8% had basal cell carcinomas (the youngest at 9.7 years of age), and 2.2% had benign neoplasms. There are a few additional reports of basal cell carcinoma developing in nevus sebaceous in children less than 16 years of age. There are rare reports of squamous cell carcinomas arising within nevus sebaceous in an 11 year old and a 15 year old.
Nevus sebaceous has been theorized to arise from genetic mosaicism. Most cases of nevus sebaceous are sporadic, but there are a few reports of familial cases. It has been hypothesized that paradominant inheritance, whereby postzygotic loss of heterozygosity results in a mosaic homozygous or hemizygous state may explain the rare familial cases of nevus sebaceous. Carlson and colleagues found a high prevalence (82%) of human papillomavirus (HPV) DNA in nevus sebaceous. They postulated that HPV infection of fetal epidermal stem cells could play a role in the pathogenesis of nevus sebaceous. Xin and colleagues found that 8 of 20 (40%) cases of nevus sebaceous exhibited loss of heterozygosity for the human homolog of the Drosophilia patched ( PTCH ) gene, the tumor suppressor gene implicated in basal cell nevus syndrome. This may help explain the risk of development of basal cell carcinomas within nevus sebaceous.
Histopathology of a nevus sebaceous reveals variable epidermal hyperplasia with hyperkeratosis, acanthosis, or papillomatosis that may become more prominent in time. Sebaceous glands may be hyperplastic and numerous, but may also be diminished or even absent. They may be located high in the dermis and unrelated to a hair follicle, sometimes communicating directly with the epidermis. Hair follicles are usually decreased, absent, or immature. Ectopic apocrine glands may be present in the lower dermis.
Removal of a nevus sebaceous is best done by surgical excision, but the necessity and timing of excision is controversial. Some investigators have argued that because the incidence of malignant neoplasms in nevus sebaceous is extremely rare, early excision is not necessary. Other investigators have argued that prophylactic excision is still warranted because malignant transformation can occur and even benign growths often require surgical intervention. Some patients or their families also desire excision for cosmetic concerns. Optimal timing for excision may depend on various factors, including size and location of the lesion, and the risks and benefits of general anesthesia versus local anesthesia. Local anesthesia is often being an option for less extensive lesions when the patient is older.
Carbon dioxide laser and photodynamic therapy have been used to treat nevus sebaceous for cosmetic reasons, but these modalities do not completely remove the lesion, leaving a risk of recurrence and development of secondary neoplasms.
Nevus comedonicus
Nevus comedonicus is a developmental anomaly of the pilosebaceous unit that typically presents at birth or during childhood. Clinically, a nevus comedonicus presents as a linear array or cluster of dilated follicular orifices plugged with keratin, resembling comedones. Larger lesions typically follow Blaschko lines and extensive involvement of half the body has been described. Nevus comedonicus seems to have a predilection for the face, neck, or trunk, but can involve the extremities, scalp, or genitalia. Although usually unilateral, there are reports of bilateral lesions. Inflammatory variants with pustules, cysts, secondary bacterial infections, and scarring can occur. Malignant change is rare, but there are reports of basal cell carcinoma and squamous cell carcinoma arising within nevus comedonicus.
It has been hypothesized that nevus comedonicus arises from a developmental defect in the mesodermal component of the pilosebaceous unit, where in the resulting follicular structure is only able to produce accumulating soft keratin. Others have suggested that nevus comedonicus is a variant of epidermal nevus involving the hair follicle. Munro and Wilkie identified a somatic mutation in fibroblast growth factor receptor 2 (FGFR2), in an acneiform nevus. The severe acne found in certain patients with craniosynostosis and FGF mutations led to the search for the association. An immunohistochemical study found increased filaggrin, but not cytokeratin, expression in closed comedones of nevus comedonicus. Further studies are needed to elucidate the role of filaggrin in the pathogenesis of nevus comedonicus.
Histopathology of nevus comedonicus reveals cystically dilated hair follicles forming epidermal invaginations filled with lamellar keratin. EHK has been described in the keratinocytes of the follicular epithelial wall. There is a report of a child with generalized EHK (also known as bullous congenital ichthyosiform erythroderma), whose father had 2 small patches of nevus comedonicus on his neck and back with biopsies from his back revealing histopathologic features of EHK within the nevus comedonicus.
Cosmetically concerning or inflammatory lesions warrant treatment. Smaller, localized lesions may be excised. Larger, more extensive lesions can be challenging to treat. Potential topical therapies include ammonium lactate and other keratolytics, topical retinoids, calcipotriene, or tacalcitol. Inflammatory lesions may be treated with oral antibiotics or intralesional corticosteroids. Oral isotretinoin has limited efficacy, but may decrease formation of suppurative cystic lesions. Hormonal therapy has been used with some benefit. Other reported treatment options include manual extraction of keratin plugs, dermabrasion, and the erbium:yyttrium-aluminum-garnet (YAG) laser. A commercially available pore strip was successfully used to remove keratin plugs in 2 patients with nevus comedonicus.
Becker nevus
Becker nevus, also referred to as Becker melanosis or pigmented hairy epidermal nevus, is a common type of epidermal nevus that occurs most frequently on the trunk or proximal upper extremities of young men ( Fig. 4 ). Studies of young male military recruits in France and Italy found a prevalence ranging from 0.25% to 2.1%. Many more cases have been reported in males than females, but the true male/female ratio is unknown. Becker nevus typically presents as a hyperpigmented patch with irregular borders that gradually enlarges for a few years then remains stable. Hypertrichosis within the lesion is common, but not universal. It can also be associated with acneiform eruptions. A Becker nevus may become more elevated when stroked or rubbed because of piloerection, referred to as pseudo-Darier sign. Although they usually appear during adolescence, there are reports of Becker nevi occurring at birth or during early childhood. Some congenital lesions may be better classified as congenital smooth muscle hamartomas. Lesions are typically located on the trunk or proximal upper extremities, but they can occur elsewhere, including the face and lower extremities. Most are solitary and unilateral, although multiple and bilateral Becker nevi have been reported.
There have been rare reports of familial Becker nevus. Happle and others have hypothesized that paradominant inheritance (postzygotic loss of heterozygosity occurring at an early stage of development) best explains the usually sporadic occurrence and mosaic distribution of these lesions. Increased androgen receptors have been found in Becker nevi by ligand-binding assays, protein expression, and immunohistochemisty. It has been suggested that increased sensitivity to androgens plays a role in pathogenesis of these lesions. Androgen stimulation may help explain clinical and histopathological features such as onset during puberty, hypertrichosis, acneiform eruptions, acanthosis, and dermal thickening.
Histopathological findings may be subtle, with acanthosis, elongation of rete ridges, variable hyperkeratosis, and basal layer hyperpigmentation. There is no proliferation of melanocytes. The dermis may or may not contain smooth muscle hyperplasia. The common dermoscopic features have been described as the presence of a network, hair follicles, and vessels, with focal, skin furrow, and perifollicular hypopigmentation.
Becker nevi are not generally considered to have malignant potential. There are few isolated reports of skin cancers developing within Becker nevi, namely malignant melanoma, Bowen disease, and basal cell carcinoma, with the small number of reports suggesting a chance association. Fehr and colleagues reported 9 patients with Becker nevi who developed malignant melanoma, although only 1 occurred within the Becker nevus. The investigators suggested that patients with a Becker nevus may have a higher incidence of other pigmented lesions such as malignant melanoma, but a true association has not been established.
Some patients seeking medical attention for these lesions only require reassurance that this is a benign condition, whereas others desire treatment because of cosmetic concerns. Excision is not generally an acceptable option, and laser treatment has had variable efficacy. Various lasers have been used to lighten the pigmentation and decrease associated hypertrichosis. A comparative study suggested that 1 treatment with an erbium:YAG laser was more effective than 3 treatments with a Q-switched Nd:YAG laser. Another study suggested good to excellent response in 7 of 11 patients after multiple (2–12) treatments with a long-pulse alexandrite laser. Success has also been reported with multiple (5–6) fractional resurfacing treatments using the 1550-nm wavelength erbium-doped fiber laser in 2 patients.
Inflammatory linear verrucous epidermal nevus
Inflammatory linear verrucous epidermal nevus (ILVEN) is a type of epidermal nevus characterized by pruritic erythematous scaly papules and plaques. They may be present at birth or develop during early childhood. The differential diagnosis includes linear psoriasis, lichen striatus, linear lichen planus, and epidermal nevus with verrucous changes. The prognosis is variable, often waxing and waning with time. Treatment options that have been described as leading to temporary improvement include topical or intralesional steroids, topical retinoids, 5-fluorouracil, calcineurin inhibitors, and calcipotriol. Surgical options for localized lesions may be successful.
Porokeratotic eccrine ostial and dermal duct nevus
Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) is a rare malformation often classified as an eccrine hamartoma. Clinically, it presents as hyperkeratotic papules and plaques with comedo-like punctuate pits, often filled with keratin plugs. Lesions are usually in a linear pattern, most commonly located on the palms or soles. There are several cases with widespread unilateral or bilateral lesions distributed along Blaschko lines. Although most of these lesions are present at birth, there are reports of later onset, usually in early childhood.
There are reports of linear psoriasis in 2 patients with PEODDN. Multiple squamous cell carcinomas were found in a patient with widespread PEODDN. There is another report of Bowen disease arising within a PEODDN on the sole. Rarely, extracutaneous abnormalities have been described in patients with PEODDN, including seizure disorder, hemiparesis, and scoliosis in one patient, developmental delay with hearing loss in another patient, and ipsilateral breast hypoplasia in a recent report.
Histopathology reveals epidermal invagination with a parakeratotic column resembling a cornoid lamella, overlying a dilated eccrine acrosyringium and dermal duct. Immunohistochemical staining for carcinoembryonic antigen is positive along the cuticle of the eccrine dermal duct and acrosyringium through the channel within the parakeratotic column.
Treatment with topical steroids, tar, phototherapy, and cryotherapy have offered little benefit. Topical or oral retinoids have unclear efficacy. Carbon dioxide laser therapy has been used successfully. Small, localized lesions may be excised. There are isolated case reports of gradual improvement over years in patients with widespread involvement.
Syndromes associated with epidermal nevi
Epidermal Nevus Syndrome
Several syndromes may be associated with epidermal nevi. The term epidermal nevus syndrome has been used to describe the association of an epidermal nevus with systemic features potentially affecting multiple organs including neurologic, ocular, skeletal, and in rare cases, cardiac and renal anomalies. Even small epidermal nevi, especially in the setting of other cutaneous findings may be associated with syndromes or warrant further consideration for neurocutaneous, genetic, or metabolic disorders such as hypophosphatemic vitamin D–resistant rickets. Syndromes associated with epidermal nevi are discussed below.
Proteus Syndrome
Linear epidermal nevi are commonly found in patients with Proteus syndrome. Proteus syndrome is characterized by patchy or mosaic overgrowth of multiple tissues. The overgrowth is irregular, progressive, and usually asymmetric, most often involving a limb, but can involve any body part. In addition to epidermal nevi, vascular malformations (most commonly cutaneous capillary malformations) are frequent cutaneous manifestations in Proteus syndrome. Cerebriform connective tissue nevi are less common, but fairly specific for Proteus syndrome. These are usually located on the soles of the feet and, rarely, on the hands or elsewhere, and are generally not present at birth, but evolve slowly over time. Dysregulation of fatty tissue with overgrowth and/or atrophy is often present. Several tumors have been reported in patients with Proteus syndrome, but the most specific seem to be monomorphic adenomas of the parotid glands and bilateral ovarian cystadenomas.
The diagnosis of Proteus syndrome can be challenging and controversial. Consensus criteria for the diagnosis were proposed after a conference at the National Institutes of Health in 1998. General criteria required for diagnosis were defined as mosaic distribution of lesions, sporadic occurrence, and progressive course. To make the diagnosis, the patient then has to meet specific criteria ( Box 1 ), which were later revised and clarified. Application of these criteria to 205 cases of reported Proteus syndrome in the literature found that only 97 cases (47.3%) met diagnostic criteria, suggesting a high rate of misdiagnosis. The differential diagnosis for Proteus syndrome includes neurofibromatosis type 1, Klippel-Trenaunay syndrome, hemihyperplasia and multiple lipomatosis syndrome, and other undefined overgrowth syndromes.
General Criteria (all 3 required for diagnosis)
Mosaic distribution of lesions
Sporadic occurrence
Progressive course
Specific Criteria (either category A, or 2 from category B, or 3 from category C)
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Cerebriform connective tissue nevus a
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Linear epidermal nevus
Asymmetric, disproportionate overgrowth of limbs, skull, external auditory canal, vertebrae, or viscera b
Bilateral ovarian cystadenomas or parotid monomorphic adenoma (before second decade)
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Dysregulated adipose tissue (unencapsulated lipomas or lipohypoplasia)
Vascular malformations (capillary, venous, or lymphatic)
Lung cysts
Facial phenotype (dolichocephaly, long face, downslanting palpebral fissures, and/or minor ptosis, low nasal bridge, wide or anteverted nares, open mouth at rest) c
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a Skin lesions characterized by deep grooves and gyrations.
b Distinguished from asymmetric, proportionate overgrowth.
c Facial phenotype found in patients who have mental deficiency and, in some cases, seizures and/or brain malformations.
The cutaneous manifestations of Proteus syndrome were reported in a cohort of 24 consecutive patients evaluated at the National Institutes of Health. The most common findings were lipomas (92%), vascular malformations (88%), plantar cerebriform connective tissue nevi (83%), epidermal nevi (67%), partial lipohypoplasia (38%), and patchy dermal hypoplasia (21%). Patients with a greater number of cutaneous abnormalities tended to have more extracutaneous abnormalities.
Controversy exists regarding the genetic basis of Proteus syndrome. It has been hypothesized that the syndrome results from somatic mosaicism, with an underlying genetic mutation that would be lethal in a nonmosaic state. Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, allelic multiple hamartoma syndromes, have been associated with autosomal dominant germline PTEN mutations, with a unifying designation as PTEN hamartoma tumor syndrome. PTEN (phosphatase and tensin homolog) is a tumor suppressor gene that encodes a protein tyrosine phosphatase that antagonizes the phosphoinositol-3-kinase/Akt pathway. There have been reports of patients diagnosed with Proteus syndrome or Proteus-like syndrome who were found to have PTEN germline mutations, which has led to debate in the literature. Some investigators have argued that the patients found to have PTEN mutations were likely misdiagnosed and that the use of the term Proteus-like syndrome is misleading. There have been several series of patients with Proteus syndrome who were not found to have germline or somatic PTEN mutations. Happle suggested that cases of Proteus syndrome and Proteus-like syndrome caused by PTEN mutations should be more accurately categorized as a type 2 segmental manifestation of Cowden syndrome, caused by loss of the heterozygosity of the PTEN allele at an early stage in development. Although this debate may continue, the genetic cause in most, if not all, patients with Proteus syndrome remains unknown at this time.
Complications of Proteus syndrome include orthopedic issues from limb overgrowth, with severe functional and cosmetic consequences. Limited mobility, vascular malformations, and/or surgical intervention predispose these patients to deep venous thrombosis and pulmonary embolism, which can result in early death. Perioperative anticoagulant prophylaxis, but not chronic anticoagulation, has been recommended. Although various tumors have been reported in patients with Proteus syndrome, there are no clear screening guidelines. Evaluation of patients with suspected or confirmed Proteus syndrome should include skeletal surveys, and magnetic resonance imaging (MRI) or computed tomography (CT) imaging of the brain, chest, abdomen, and any other clinically affected areas. Management of these patients requires a multidisciplinary approach, with specialty consultations as needed. The psychosocial effects of this disfiguring and debilitating condition should also be addressed.
Linear Cowden (or PTEN) Nevus
Happle proposed the terms linear Cowden nevus or linear PTEN nevus to describe a nonorganoid (ie, purely keratinocytic) epidermal nevus caused by loss of heterozygosity in a germline PTEN mutation. He suggested that this is a cutaneous feature of type 2 segmental Cowden syndrome (see earlier discussion), and is distinct from the epidermal nevus seen in Proteus syndrome. Happle distinguished between the 2 types of epidermal nevi based on clinical features, describing the linear Cowden nevus as thicker and more papillomatous than the soft, velvety linear nevus seen in Proteus syndrome. However, he noted that most nonorganoid epidermal nevi are not associated with any particular syndrome.
Segmental Overgrowth, Lipomatosis, Arteriovenous Malformation, and Epidermal Nevus Syndrome
Caux and colleagues described 2 patients from different families who had a constellation of findings for which they proposed the acronym SOLAMEN syndrome (segmental overgrowth, lipomatosis, arteriovenous malformation, and epidermal nevus). Each of these patients had other family members who presented with classic manifestations of Cowden syndrome, and the families were found to have germline PTEN mutations. The 2 depicted patients had some features that were unusual for Cowden syndrome and were more reminiscent of manifestations of Proteus syndrome, including progressive overgrowth, lipomatosis, and vascular malformations, but they did not meet criteria for Proteus syndrome. The investigators suggested that the 2 proband patients had segmental exacerbation of Cowden disease. The investigators hypothesized that the findings in their 2 specified patients may be explained by germline PTEN mutations with mosaic inactivation of the wild-type PTEN allele resulting in homozygous loss of PTEN function in specific lesions. These 2 patients could also be categorized as having type 2 segmental Cowden disease as proposed by Happle.
CLOVE Syndrome
Sapp and colleagues delineated a syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (CLOVE syndrome) based on 7 patients who did not meet criteria for Proteus syndrome. These patients all had congenital bilateral overgrowth of the feet, and congenital, complex, truncal vascular malformations, although only 4 had linear epidermal nevi. Overgrowth in these patients was described as proportionate or ballooning, in contrast to progressive and distorting overgrowth in Proteus syndrome, with bony distortion in CLOVE syndrome only after major surgery. All 7 patients had negative PTEN mutation analysis. Gucev and colleagues subsequently described another patient with features of CLOVE syndrome, who also had central nervous system malformations including hemimegalencephaly with agenesis of the corpus callosum; a similar case was previously reported in the literature. Alomari proposed expanding the name to CLOVES syndrome to emphasize associated scoliosis and skeletal and spinal anomalies, when he reported 18 cases characterized by truncal lipomatous masses, vascular malformations, and acral deformities. Prenatal imaging and perinatal findings of a patient with CLOVE(S) syndrome have also been reported.
Nevus Sebaceous Syndrome
Almost all children with nevus sebaceous are otherwise healthy, but an association with neurologic, ocular, skeletal, or other extracutaneous manifestations defines nevus sebaceous syndrome, sometimes referred to as linear nevus sebaceous syndrome. It has also been referred to by various eponyms including Shimmelpenning syndrome, Shimmelpenning-Feuerstein-Mims syndrome, Solomon syndrome, and Jadassohn syndrome. Although there are several subtypes of epidermal nevus syndromes, as discussed in this article, some cases of nevus sebaceous syndrome in the literature are simply referred to as epidermal nevus syndrome.
A review of 196 consecutive patients with nevus sebaceous found that 7% had clinical neurologic abnormalities including mental retardation and seizures, and 2% had ocular abnormalities including colobomas and choristomas. Large size and centrofacial location were more common in patients with neurologic abnormalities, but 9 patients with extensive nevi and 4 patients with centrofacial nevi had no associated abnormalities. Neuroimaging was normal in 6 of 8 patients with neurologic abnormalities.
The most frequent extracutaneous manifestation of nevus sebaceous syndrome is central nervous system involvement, including seizures, developmental delay, and sometimes structural brain abnormalities. Ophthalmologic abnormalities are also common. A range of musculoskeletal, cardiovascular, and urogenital manifestations have been described. There can be associated endocrine abnormalities, including hypophosphatemic rickets and precocious puberty. Intraoral lesions and neoplasm in other organs may also develop.
There are several cases of aplasia cutis congenita occurring in nevus sebaceous syndrome. Happle and Konig proposed the term didymosis aplasticosebacea to refer to this association. They hypothesized that it reflects twin spotting, when somatic recombination causes a heterozygous cell to give rise to 2 different homozygous daughter cells.
Nevus sebaceous syndrome is believed to result from mosaicism of a lethal autosomal dominant gene. It has been hypothesized that the timing of the mutation during embryogenesis and the resulting extent of mosaicism may determine the phenotype of patients with nevus sebaceous. A mutation occurring late in embryogenesis could result in an isolated nevus sebaceous, whereas a mutation early in embryogenesis could have more deleterious consequences manifesting as nevus sebaceous syndrome. As discussed earlier, Carlson and colleagues found a high incidence of HPV DNA in nevus sebaceous. They theorized that HPV infection of a pluripotent stem cell at an early stage of embryogenesis could play a role in the pathogenesis of nevus sebaceous syndrome with involvement of skin, brain, eye, and skeletal and/or other structures.
Workup for a patient with suspected nevus sebaceous syndrome should include a thorough neurologic and ophthalmogical examination, with consideration of electroencephalography, neuroimaging (CT or MRI), skeletal radiography, and analysis of liver and renal function as well as serum and urine calcium and phosphate levels.
Phacomatosis Pigmentokeratotica
The term phacomatosis pigmentokeratotica was proposed by Happle and colleagues in 1996 to refer to the association of an organoid epidermal nevus, usually with sebaceous differentiation, and a speckled-lentiginous nevus (SLN), or nevus spilus. This condition is considered by some to be one of the epidermal nevus syndromes. Various extracutaneous abnormalities have been reported, including neurologic, ophthalmologic, musculoskeletal, and endocrine findings, although some patients do not have extracutaneous manifestations.
The distribution of the epidermal nevus usually follows Blaschko lines, whereas the SLN is arranged in a checkerboard pattern. The epidermal nevus and SLN can be contralateral or ipsilateral, or both can be bilateral. Different types of melanocytic neoplasms can develop within the SLN, including malignant melanoma. Malignancies, namely basal cell carcinomas, have been reported to develop in the nevus sebaceous. In addition, there are a few reports of internal neoplasms in patients with phacomatosis pigmentokeratotica.
Although the pathogenesis of phacomatosis pigmentokeratotica is unknown, it is hypothesized to result from twin spotting or didymosis, whereby somatic recombination during early embryogenesis causes a heterozygous stem cell to give rise to 2 different populations of daughter cells, each homozygous for a recessive mutation.
Nevus Comedonicus Syndrome
Although often occurring in isolation, nevus comedonicus can be associated with other developmental anomalies, referred to as nevus comedonicus syndrome. Reported extracutaneous manifestations include skeletal abnormalities (scoliosis, other spinal deformities, and limb defects), ocular abnormalities (cataracts), and central nervous system abnormalities (brain dysgenesis). Nevus comedonicus has been reported as a marker of occult spinal dysraphism. Happle proposed that nevus comedonicus syndrome results from mosaicism of a lethal autosomal mutation.
Becker Nevus Syndrome
Happle and Koopman proposed the term Becker nevus syndrome to refer to patients with a Becker nevus and other associated developmental defects. There are multiple reports of associated ipsilateral breast hypoplasia, mainly in female patients, but also in male patients. Various musculoskeletal anomalies have been described, including scoliosis, hemivertebrae, spina bifida occulata, limb asymmetry, fused or accessory cervical ribs, pectus excavatum, pectus carinatum, bilateral internal tibial torsion, ipsilateral shoulder girdle hypoplasia, ipsilateral absence of the pectoralis major muscle, umbilical hernia, and segmental odontomaxillary dysplasia. Associated soft tissue and cutaneous abnormalities include supernumary nipples, ipsilateral patchy extramammary fatty tissue hypoplasia, hypoplasia of the contralateral labium minus, accessory scrotum, sparse hair of the ipsilateral axilla, and depression of the ipsilateral temporal region.
Paradominant inheritance, or postzygotic loss of heterozygosity occuring at an early stage of embryogenesis resulting in mosaicism, has been proposed as the genetic basis of Becker nevus and Becker nevus syndrome. This may explain the typically sporadic occurrence as well as rare familial aggregation.
Epidermolytic Hyperkeratosis
The clinician should also be aware that an epidermal nevus may have features of EHK, both clinically and histologically. This type of nevus represents a mosaic form of EHK. EHK is a genetic disorder of keratinization with a clinical phenotype that varies from birth to adulthood. A newborn with EHK is born with bullae and the disorder has also been known as bullous congenital ichthyosiform erythroderma (BCIE). A feature distinguishing this condition from other newborn disorders of keratinization is that the bullae may be macerated. In time, the skin becomes thickened, hence the hyperkeratosis. Older children have a palmoplantar keratoderma and may have velvety thickening of skin folds. The flexural areas are often prominently involved with thick hyperkeratotic brown scales. The genetic defect is in keratin 1 or 10. It affects approximately 1 in 300,000 individuals. Fifty percent are dominantly inherited, and 50% are sporadic or new mutations.
Mosaic forms have been described in which adults may have a blaschkoiform strip of affected skin and their offspring present with full systemic findings. Adults suspected of a mosaic form of EHK should receive genetic counseling regarding the condition.
For patients with epidermal nevi who have been found to be carriers of the genetic mutation for EHK, a skin biopsy of an epidermal nevus may show the histologic features of marked hyperkeratosis with lysis of the epidermal cells above the basal layer.
Ichthyosis bullosa of Siemens tends to be a milder form of EHK and may also present with epidermal-type nevi, in which the blistering occurs more superficially in the epidermal layer. The genetic defect has been described in the gene encoding K2e, which is not expressed until the mid portion of epidermal maturation.
Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects Syndrome
The cutaneous features of congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) syndrome may mimic the skin lesions of inflammatory epidermal nevi. They are referred to as a unilateral ichthyosiform erythroderma, which is congenital or appears in the first few months after birth. Ptychotrophism, or the inflammatory nevi affecting intertrigineous areas, is a feature of CHILD syndrome. Skeletal features and hemihypoplasia of the affected side is a feature of the syndrome. The genetic defect has been described in the NSDHL gene encoding 3β-hydrosteroid dehydrogenase. There is a case of a boy with CHILD syndrome considered to be secondary to early postzygotic mosaicism.
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