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The incidence of epidermal nevus (EN) (isolated finding or as a syndrome) is estimated at 1-3/1,000 live births, with nevus sebaceous (NS) estimated at half of the total. Nevus sebaceous syndrome (NSS) is rare; the exact prevalence and incidence in the general population is unknown.

NSS is the association of NS with extracutaneous manifestations. NS presents typically at birth as hairless yellow-pink, salmon-colored Blaschkoid plaque(s), but nevi may not appear clinically until later in infancy or early childhood. NS are found on the head and neck in two-thirds of cases, and large extensive nevi or a centrofacial location is more associated with NSS. In puberty, NS thicken and can become verrucous in appearance. Later in life, benign neoplasms may grow within the NS; rarely do malignant neoplasms grow, and the risk specifically for basal cell carcinoma is less than 1%. Central nervous system (CNS) findings are the most common extracutaneous anomalies, notably intellectual disability (nearly 80%) and seizures (57%, generalized tonic, tonic-clonic, focal motor, infantile spasms). While structural brain anomalies may occur (hemiatrophy, vascular anomalies, hemimegalencephaly, gyral or posterior fossa abnormalities), 75% of patients with CNS findings have normal imaging. Many other organ systems may also be involved in this syndrome, most commonly ophthalmologic (strabismus, lipodermoids, retinal anomalies, coloboma, cataracts, corneal vascularization) and skeletal (frontal bossing, skeletal hypoplasia, scoliosis and kyphoscoliosis, vitamin D-resistant rickets, hypophosphatemia). Other rare findings have included endocrine, cardiovascular and urogenital systems and oral anomalies (including rare neoplasms of ameloblastoma ,odontoma, giant cell granuloma).

NSS is a sporadic disease. EN syndromes are the result of post-zygotic mutations. Mutations in KRAS, HRAS , and NRAS have been described in both isolated NS and NSS. Mutations in these same genes are seen in keratinocytic EN (KEN).

Evaluation should include prenatal, developmental, and family histories. Cutaneous examination should evaluate all skin including areas covered by hair, mucosa, eyes (especially the conjunctiva, sclerae, and extra-ocular eye movements). Careful neurologic and ophthalmologic exams should be performed. Any child with NS on the head or neck and developmental delay should have brain imaging. Skeletal exam should evaluate for kyphoscoliosis, gait and limb length. Skin biopsies and relevant laboratory studies (serum/urine calcium and phosphate, liver and renal function tests) as appropriate. Referral to specialists guided by the above is recommended.

Differential diagnosis includes cutaneous-skeletal hypophosphatemia syndrome, nevus comedonicus syndrome, Becker nevus syndrome, phakomatosis pigmentokeratotica, CHILD syndrome, the spectrum of PIK3CA-related overgrowth syndrome, SOLAMEN (segmental outgrowth-lipomatosis-arteriovenous malformation-epidermal nevus syndrome), and CLOVES syndrome.

NSS occurs sporadically due to a postzygotic mutation. They do not appear to be heritable, as the severity of the mutations are thought to be incompatible with life when present in the germline.

NSS management is individualized and multidisciplinary based on the involved organ systems and degree of impairment. NS are no longer prophylactically excised in infancy, given low risk of malignant potential. In puberty, patients may opt for removal of the thickened lesions for cosmetic reasons. Biopsy is recommended for any growths that may occur within lesions. Tissue should be sent to an experienced dermatopathologist to prevent misdiagnosis of basal cell carcinoma.

The prognosis depends on the severity of the clinical manifestations and the extent of the multisystem involvement.