Nevus sebaceus and nevus sebaceus syndromes

INTRODUCTION — Nevus sebaceus, also called nevus sebaceus of Jadassohn or organoid nevus, is a benign hamartoma of the skin, characterized by hyperplasia of the epidermis, immature hair follicles, and sebaceous and apocrine glands. Lesions are usually present at birth and appear as waxy, yellow-orange or tan, hairless plaques (picture 2C). They have a tendency to thicken and become more verrucous over time, especially around the time of puberty [1].

Nevus sebaceus and the nevus sebaceus syndrome, also called Schimmelpenning syndrome, will be reviewed in this topic. The linear epidermal nevus and epidermal nevus syndrome are discussed separately. (See "Epidermal nevus and epidermal nevus syndrome".)

EPIDEMIOLOGY — Nevus sebaceus occurs in approximately 0.3 percent of newborns, without sex predilection. It is usually sporadic, but familial cases have been reported [2,3].

PATHOGENESIS — Nevus sebaceus and nevus sebaceus syndrome (Schimmelpenning syndrome) are thought to be caused by postzygotic mosaic mutations in the HRAS or KRAS genes [4], although isolated cases due to mosaic mutations in NRAS and FGFR2 have also been reported [5,6]. Along with phacomatosis pigmentokeratotica (PPK), cutaneous skeletal hypophosphatemia syndrome (CSHS), keratinocytic epidermal nevi, and some melanocytic nevi, they are included in the group of the so-called mosaic RASopathies [7,8]. (See 'Phacomatosis pigmentokeratotica' below.)

RAS promotes cell growth through activation of multiple pathways, including the mitogen-activated protein kinase (MAPK) signal-transduction pathway. Activating germline mutations in this gene family are involved in the pathogenesis of several inherited malformation syndromes (eg, Costello syndrome, Noonan syndrome, neurofibromatosis 1, Legius syndrome), some of which are associated with an increased risk of cancer. (See "Causes of short stature", section on 'Noonan syndrome' and "Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis".)

An analysis of tissue samples from 65 individuals with nevus sebaceus and two with Schimmelpenning syndrome found an HRAS c.37G>C mutation in 59 sebaceous nevi (91 percent) but not in the adjacent normal epidermis [4]. An HRAS c.37G>C mutation and a KRAS c.35G>A mutation were found in lesional tissue samples from the two patients with nevus sebaceus syndrome. In another study, an HRAS c.37G>C mutation was found in a patient with Schimmelpenning syndrome and in 24 of 31 isolated sebaceous nevi but in none of six patient-matched normal skin samples [9]. In a whole-exome sequencing study of paired DNA from blood and sebaceous nevus tissue from five individuals with nevus sebaceus, recurrent somatic mutations in HRAS (p.Gly13Arg) and KRAS (p.Gly12Asp and p.Gly12Val) were identified in the epidermis and sebaceous lobules but not in the dermis or blood [10].

Taken together, these findings support the hypothesis that mosaic genetic mutations in the HRAS and KRAS genes are involved in the pathogenesis of nevus sebaceus. Extensive mosaicism for activating mutations involving the skin and skeletal, ocular, and central nervous systems may be the underlying genetic cause of Schimmelpenning syndrome [11].

HISTOPATHOLOGY — In nevus sebaceus, the epidermis shows varying degrees of acanthosis and papillomatosis (picture 1) [12,13]. In early lesions, sebaceous glands may be underdeveloped and decreased in number. The presence of immature hair follicles is characteristic and diagnostic. After puberty, the epidermis shows prominent papillomatous hyperplasia. Sebaceous glands are abundant and sometimes situated at an abnormally high level in the dermis. Ectopic apocrine glands can be seen in most lesions, sometimes deep in the dermis, beneath the sebaceous glands.

CLINICAL FEATURES — In most cases, nevus sebaceus is apparent at birth and presents as a well-defined, thin, yellow-orange or tan, oval, round, or linear plaque (picture 2A). Sometimes lesions are not noticed until later in childhood or after puberty. Most commonly, nevus sebaceus occurs on the scalp and is associated with a well-defined, localized area of alopecia (picture 2C). In older children and adults, lesions tend to be more elevated, verrucous, or nodular (picture 2A-C) [12]. The size ranges from one to several centimeters.

CLINICAL COURSE AND COMPLICATIONS — In infancy and childhood, nevus sebaceus remains mostly unchanged, due to the quiescence of sebaceous glands. At puberty, under hormonal influences, lesions thicken and become verrucous or nodular (picture 3A-B). Rapid, circumscribed enlargement or ulceration should arouse suspicion for malignant transformation. (See 'Risk of malignancy' below.)

Risk of malignancy — A variety of benign and malignant epithelial neoplasms may arise within sebaceous nevi. Benign tumors include viral warts, trichoblastoma, syringocystadenoma papilliferum, tricholemmoma, sebaceoma, nodular hidradenoma, hidrocystoma, and eccrine poroma [1,12-14]. Malignant neoplasms include basal cell carcinoma, apocrine carcinoma, trichilemmal carcinoma, sebaceous carcinoma, microcystic adnexal carcinoma, porocarcinoma, and squamous cell carcinoma. There are isolated reports of melanoma arising in a sebaceous nevus [15,16]. (See "Microcystic adnexal carcinoma" and "Sebaceous carcinoma".)

The exact incidence and the lifetime risk of malignancy arising in nevus sebaceus are unknown. In a review of nearly 5000 cases, benign and malignant tumors (mainly basal cell carcinomas) developed in 16 and 8 percent of patients, respectively [17]. However, the incidence of basal cell carcinoma may have been overestimated, due to misinterpretation of trichoblastoma. Large case series published after 1990 report rates of basal cell carcinoma of <1 percent [18-20].

The risk of malignancy increases with age, but basal cell carcinomas have also been reported in children. In a series of 631 patients, 5 (0.8 percent) had an associated basal cell carcinoma and 14 (2.2 percent) had a benign tumor [20]. Four basal cell carcinomas occurred in children younger than 14 years.

In another series of 706 patients aged 0 to 95 years, secondary neoplasms were found in 159 (22.5 percent) [21]. In 19 percent of specimens, the associated lesion was a benign tumor (including trichoblastoma, syringocystadenoma papilliferum, apocrine/eccrine adenoma, and trichilemmoma). Eighteen specimens (2.5 percent) contained a malignant tumor, including eight basal cell carcinomas, four squamous cell carcinomas, and three sebaceous carcinomas. One case of apocrine carcinoma and one of microcystic adnexal carcinoma were also observed.

In a series of 450 patients with nevus sebaceus, secondary tumors were found in 38 (8.5 percent) [22]. Eighty percent of the tumors were benign, with syringocystadenoma papilliferum being the most common tumor (2.7 percent), followed by trichoblastoma (1.6 percent) and trichilemmoma (1.6 percent). Basal cell carcinoma was found in 0.9 percent of the cases.

There are several reports of multiple different tumors arising simultaneously in the same sebaceous nevus [23,24].

NEVUS SEBACEUS SYNDROMES

Schimmelpenning syndrome — Described for the first time in 1957, nevus sebaceus syndrome (MIM #163200; also called Schimmelpenning syndrome or Schimmelpenning-Feuerstein-Mims syndrome) is defined by the association of a linear nevus sebaceus, which is often extensive and distributed along the lines of Blaschko, with cerebral, ocular, or skeletal defects [2,25].

The syndrome is caused by an autosomal dominant, lethal mutation in HRAS or KRAS genes that survives by somatic mosaicism [26]. Thus, all reported cases are sporadic.

Involvement of the central nervous system is frequently associated with large sebaceous nevi located on the face or scalp. Neurologic abnormalities include developmental delay, seizures, and hemimegalencephaly [27]. Ocular choristomas and colobomas are the most common ocular findings associated with nevus sebaceus syndrome [28-30].

Skeletal defects include craniofacial defects, hypoplastic bones, short stature, and vitamin D-resistant hypophosphatemic rickets [31,32].

Phacomatosis pigmentokeratotica — First described in 1996, phacomatosis pigmentokeratotica (PPK; also called phacomatosis spilosebacea) is an epidermal nevus syndrome characterized by the co-occurrence of a linear nevus sebaceus with a papular nevus spilus (also called speckled lentiginous nevus) [33,34]. PPK is caused by postzygotic HRAS mutations in a multipotent progenitor cell that gives rise to both a sebaceous and a melanocytic nevus [35].

In neonates and infants, the presentation of a papular nevus spilus is that of a large café-au-lait macule, as the typical papular and macular speckles will develop later in life [36]. Extracutaneous features are usually present, although rare cases without systemic involvement have been reported [37,38]. They include neurologic (seizures, cognitive disability, hemiparesis, muscular weakness), ocular, musculoskeletal, endocrine, and vascular abnormalities [36,39,40].

Similarly to patients with Schimmelpenning syndrome, patients with PPK are predisposed to develop vitamin D-resistant hypophosphatemic rickets [41,42]. Patients with PPK also have an increased risk of cutaneous and internal malignancies, including basal cell carcinoma, melanoma, rhabdomyosarcoma, and nephroblastoma [43-45].

Cutaneous skeletal hypophosphatemia syndrome — Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a multisystem skin and bone disorder characterized by elevated circulating levels of fibroblast growth factor-23 (FGF23) [8,46]. FGF23 is a 30kDa phosphatonin, a bone-derived hormone that regulates phosphorus homeostasis and vitamin D metabolism at the level of the renal proximal tubule cell [46]. Patients present with widespread epidermal or melanocytic nevi and hypophosphatemic rickets. Somatic activating mutations in HRAS and NRAS have been found in both cutaneous lesions and dysplastic bone of patients with CSHS, suggesting that the syndrome is part of the mosaic RASopathy spectrum [8].

DIAGNOSIS — The diagnosis of nevus sebaceus is usually made clinically, based upon the finding of a circumscribed, slightly raised, yellow-orange plaque located on the scalp or face (picture 2A-C). If the diagnosis is in question, a tissue biopsy should be performed for histologic confirmation. Typical histopathologic findings include immature hair follicles; hyperplastic, immature sebaceous glands; dilated apocrine glands; and epidermal hyperplasia [13]. (See 'Histopathology' above.)

No additional evaluation is needed for children presenting with a small, solitary nevus sebaceus. However, in patients with large or extensive lesions and suspected nevus sebaceus syndrome, a thorough neurologic and ophthalmologic examination should be performed. Additional evaluation is based upon clinical findings and may include electroencephalography, neuroimaging studies with magnetic resonance imaging (MRI), skeletal radiography, and analysis of liver and renal function, including urine calcium and phosphate levels [47].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of nevus sebaceus includes:

●Aplasia cutis congenita – Aplasia cutis congenita is a focal absence of the skin. It typically presents with a sharply demarcated, ulcerated plaque or patch that may be covered by a tense epidermal membrane, giving the appearance of a fluid-filled bulla (picture 4). The lesion usually reepithelializes over several months, resulting in a hypertrophic or atrophic scar. Rare instances of association of aplasia cutis congenita and sebaceous nevus in the same patient have been reported [48,49]. (See "Aplasia cutis congenita".)

●Juvenile xanthogranuloma – Juvenile xanthogranuloma is a rare, benign, proliferative histiocytic disorder of dermal dendrocytes. It typically presents in infants as reddish to yellow papules, plaques, or nodules, most often on the head and neck and upper trunk (picture 5A-B). Histology reveals a mixed dermal infiltrate of mononuclear cells, multinucleated giant cells with or without the features of Touton giant cells. (See "Juvenile xanthogranuloma (JXG)".)

●Epidermal nevus – Epidermal nevi are benign hamartomas of the skin, presenting at birth or in the first year of life as linear plaques of skin-colored or brown, verrucous papules that follow the lines of Blaschko (picture 6A-D). They are usually located on the trunk and limbs and are uncommon on the face (picture 7) or scalp. Histology shows orthokeratotic hyperkeratosis and flat-topped papillary projections (picture 8). On the head, epidermal (keratinocyte) nevi show linear or localized, woolly hair. (See "Epidermal nevus and epidermal nevus syndrome".)

●Syringocystadenoma papilliferum – Syringocystadenoma papilliferum is a rare, benign adnexal tumor of infants and children. It presents as an asymptomatic, solitary, firm, pink papule or plaque most often located on the scalp (picture 9). It may be seen alone or in association with other adnexal tumors, including nevus sebaceus. Histologic examination of the excised lesion shows epidermal cystic invaginations lined by papillae lined with a double layer of columnar epithelium, which shows an apocrine pattern of secretion (picture 10). (See "Cutaneous adnexal tumors", section on 'Syringocystadenoma papilliferum'.)

●Solitary mastocytoma – Cutaneous mastocytosis may present as a red, pink, or yellowish plaque or nodule in infancy or early childhood (picture 11). The lesion tends to blister if rubbed, and rubbing may induce attacks of flushing. Nearly all solitary mastocytomas involute spontaneously in the first years of childhood. A skin biopsy may be necessary to confirm the clinical diagnosis. Histology reveals a large number of dermal mast cells in clusters or in a band-like pattern. (See "Mastocytosis (cutaneous and systemic) in adults: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

●Nevus psiloliparus – Nevus psiloliparus is a type of mesodermal nevus occurring on the scalp and is characterized by the absence or paucity of hair and presence of an excessive amount of fatty tissue [48]. It presents as a round or oval, soft alopecic patch located on one side of the parietal or frontoparietal area of the scalp. Histopathologic features include the absence or paucity of hair follicles and increased lipomatous or fibrolipomatous tissue. Nevus psiloliparus is the hallmark of encephalocraniocutaneous lipomatosis, a rare congenital neurocutaneous syndrome characterized by ocular anomalies, subcutaneous fatty masses, and intracranial and intraspinal lipomas [50].

It may be difficult to differentiate among the various mosaic RASopathies, including the nevus sebaceus syndrome, epidermal nevus syndrome, phacomatosis pigmentokeratotica (PPK), and cutaneous skeletal hypophosphatemia syndrome (CSHS), due to considerable overlap in their cutaneous and extracutaneous features (table 1) [7].

MANAGEMENT — The definitive treatment of nevus sebaceus is full-thickness excision. However, the necessity and timing of excision to prevent possible future malignancy are still debated [17,19,20,51].

The decision to excise the lesion should be made in individual patients, based upon age, extension and location of the lesion, and the patient's or parents/caregivers' concern about the cosmetic appearance and/or risk of malignancy. Since the risk of malignant transformation appears to be lower than previously believed, observation may be reasonable for lesions that do not cause cosmetic concern.

Alternatives to surgical excision include photodynamic therapy, carbon dioxide laser resurfacing, and dermabrasion. However, since these treatment modalities do not completely remove the lesion, the risk of recurrence and potential for neoplasm development remains [1,13].

For children with Schimmelpenning syndrome and phacomatosis pigmentokeratotica (PPK), a multidisciplinary approach is needed, depending upon the type and extent of organ involvement, and may require the coordination of different specialists such as a dermatologist, pediatric neurologist, ophthalmologist, orthopedic surgeon, plastic surgeon, and psychologist [25].

SUMMARY AND RECOMMENDATIONS

●Definition and pathogenesis – Nevus sebaceus is a rare, benign hamartoma of the skin, characterized by hyperplasia of the epidermis, immature hair follicles, and sebaceous and apocrine glands. Nevus sebaceous and the nevus sebaceous syndromes, including Schimmelpenning syndrome, phacomatosis pigmentokeratotica (PPK), and cutaneous skeletal hypophosphatemia syndrome (CSHS), are caused by postzygotic mosaic mutations in the HRAS or KRAS genes and are considered part of the so-called mosaic RASopathies. (See 'Pathogenesis' above.)

●Clinical presentation – In most cases, nevus sebaceus is apparent at birth and presents as a well-defined, thin, yellow-orange or tan, linear plaque usually located on the scalp (picture 2C). In older children and adults, lesions tend to be more elevated, verrucous, or nodular (picture 2A-C). (See 'Clinical features' above.)

Schimmelpenning syndrome, one of the nevus sebaceus syndromes, is defined by the association of a nevus sebaceus with cerebral, ocular, or skeletal defects. (See 'Schimmelpenning syndrome' above.)

●Associated tumors – A variety of benign and malignant epithelial neoplasms may arise within sebaceous nevi, including trichoblastoma, syringocystadenoma papilliferum, and basal cell carcinoma. (See 'Risk of malignancy' above.)

●Diagnosis – The diagnosis of nevus sebaceus is usually based upon the clinical presentation. A biopsy for histopathologic confirmation may be warranted if the diagnosis is uncertain. For patients with suspected nevus sebaceus syndrome, a thorough neurologic and ophthalmologic examination should be performed. Additional evaluation includes electroencephalography, neuroimaging studies, and skeletal radiography. (See 'Diagnosis' above.)

●Management – The definitive treatment of nevus sebaceus is full-thickness excision. The decision to excise should be made in individual patients, based upon age, extension and location of the lesion, and the patient's or parents/caregivers' concern about the cosmetic appearance and/or risk of malignancy. Since the risk of malignant transformation appears to be lower than previously believed, observation may be reasonable for lesions that do not cause cosmetic concern. (See 'Management' above.)