Comment
Epidermal nevus syndrome is a group of disorders characterized by both local or systematized epidermal nevi and systemic findings. Solomon et al4 first coined the term epidermal nevus syndrome more than 40 years ago; however, since then there has been confusion about how to define ENS. Epidermal nevus syndrome has been considered an umbrella term that includes more specific syndromes involving epidermal nevi, such as Proteus syndrome and Schimmelpenning syndrome; conversely, it also has been considered a term for those who do not meet the criteria for more specific syndromes.1,9 Happle1 discussed that the genetic variations found in ENS warrant recognition. Simply put, ENS is a heterogeneous group of syndromes that are similar in that they involve epidermal nevi and internal abnormalities but are genetically distinct. The list of definitive ENSs, as suggested by Happle1 and others, will likely continue to grow.3,5
The exact pathomechanism of ENS is unknown, but the clinical presentation most likely represents a lethal disorder mitigated by mosaicism.2,9 Gene defects vary depending on the specific ENS. For instance, the phosphatase and tensin homolog gene, PTEN, mutations have been associated with type 2 segmental Cowden disease. Fibroblast growth factor receptor 3, FGFR3, mutations have been linked to Garcia-Hafner-Happle syndrome.3FGFR3 mutations have been found in nonepidermolytic epidermal nevi, and some suggest that the majority of epidermal nevi exhibit mutations in FGFR3.5,10,11 On the other hand, other gene defects have not been elucidated, such as in Schimmelpenning syndrome.3
Clinically, ENS may involve nonepidermolytic verrucous nevi, sebaceous nevi, organoid nevi, linear Cowden nevi, and woolly hair nevi. Lesions may be flesh-colored, pink, yellow, or hyperpigmented plaques in a blaschkoid distribution and may be localized or systematized. Nevi typically are present at birth or develop within the first year of life.9,12,13 Other cutaneous findings may be noted apart from epidermal nevi, including melanocytic nevi, aplasia cutis congenita, and hemangiomas.13,14
Extracutaneous findings include central nervous system, skeletal, ocular, cardiac, and genitourinary defects, which are often observed in these patients.3,9,13,14 Central nervous system findings are seen in 50% to 70% of cases, with seizures and mental retardation among the most common.13-15 Genitourinary abnormalities associated with epidermal nevi, including horseshoe kidney, cystic kidney, duplicated collecting system, testicular and paratesticular tumors, and hypospadias have been documented in the literature.16 Our patient had a history of papillary transitional cell bladder carcinoma, which is rare for a patient younger than 30 years. The overall median age of diagnosis of bladder cancer is 65 years, and it is more common in men than in women.17 Transitional cell carcinomas account for approximately 90% of all bladder cancers in the United States. Other common types of bladder cancer include squamous cell carcinoma, adenocarcinoma, and rhabdomyosarcoma.16 Typically, transitional cell carcinoma is associated with smoking, exposure to aniline dyes, cyclophosphamide, and living in industrialized areas.16,17 Individuals who work with textiles, dyes, leather, tires, rubber, and/or petroleum; painters; truck drivers; drill press operators; and hairdressers are at an increased risk for development of bladder cancer.16
Interestingly, it has been shown in some studies that papillary transitional cell bladder carcinoma frequently is associated with FGFR3 mutations, which may be the missing link in the rare finding of papillary transitional cell bladder carcinoma and epidermal nevi.5,18,19 In addition, PTEN mutations also have been identified in low-grade papillary transitional cell carcinomas of the bladder, another gene linked to an ENS with type 2 segmental Cowden disease.3,20
Histopathologically, epidermal nevi have 10 different descriptions. Our patient had a nonorganoid nonepidermolytic epidermal nevus characterized by hyperkeratosis, acanthosis, papillomatosis, and elongated rete ridges. Focal acantholysis and epidermolytic hyperkeratosis also is seen in some epidermal nevi but was not seen in this case.9,21
Simple epidermal nevi occur in approximately 1 in 1000 newborns; however, when a child presents with multiple or systematized epidermal nevi, investigation should be undertaken for other possible associations.13,14 Of note, there have been several cases of squamous cell, verrucous, basal cell, and adnexal carcinomas arising in linear epidermal nevi.22-24
Epidermal nevi can be difficult to treat. Some patients are troubled by the appearance of these nevi, especially those with systematized disease. Unfortunately, for patients with multiple nevi or systematized disease, there are no consistently effective treatment options; however, there are case reports25,26 in the literature citing improvement or cure of epidermal nevi with full-thickness excision, continuous and pulsed CO2 laser, pulsed dye laser, and erbium-doped YAG laser.25 Other therapies that have been purported to help improve epidermal nevi are topical and oral retinoids, corticosteroids, topical 5-fluorouracil, anthralin, and podophyllin.26
