We're celebrating
40 years!
Last updated:
11/17/2023
Years published: 2012, 2015, 2018, 2023
NORD gratefully acknowledges Jeffrey Sugarman, MD, PhD, Professor in Dermatology and Family Medicine, University of California, San Francisco, and Kathryn Hummel, Medical Student, Touro College of Osteopathic Medicine, for assistance in the preparation of this report.
Introduction
Nevus sebaceus syndrome is a rare multisystem disorder characterized by the presence of sebaceous nevi often distributed along the lines of Blaschko (patterns that represent the embryonic migration patterns of the skin) and accompanied by extracutaneous abnormalities. These abnormalities most commonly involve the brain, eyes and skeletal system, and less commonly affect the endocrine system, heart and kidneys. The skin lesions associated with this disorder are called nevus sebaceus—also referred to as sebaceous nevi—because they consist of an increased number of malformed sebaceous glands (small oil-producing glands in the skin) along with an overgrowth (hyperplasia) of the epidermis.
When the nevi have more sebaceous gland hyperplasia, they are referred to as sebaceous nevi and when they have few sebaceous glands and predominately epidermal overgrowth, they are referred to as epidermal nevi. Often the site of the nevus determines this, as the head and neck have more sebaceous glands, more nevus sebaceus are seen in these locations. Nevus sebaceus is the most common type of organoid epidermal nevus (which broadly encompasses abnormally formed adnexal skin elements, such as hair follicles and glands within the skin). Epidermal (including sebaceous) nevi are usually present at birth (congenital), although they might not be identified until later during childhood or after puberty. Affected individuals may also have abnormalities in other organs (nevus sebaceous syndrome). These abnormalities can include seizures, brain malformations, intellectual impairment, clouding (opacity) of the cornea or partial absence of tissue of the iris or retina (coloboma), spinal malformations, craniofacial differences, deformities of the arms and legs and endocrine abnormalities leading to hypophosphatemic (low potassium) rickets. Nevus sebaceus syndrome occurs randomly (sporadically) during the formation and development of the embryo. Research has shown this to be due changes or variants of the KRAS and HRAS genes, which occur after fertilization (postzygotic) and are present in only some of the cells of the body—referred to as a “mosaic” pattern.
Summary
The term “epidermal nevus syndrome” is used interchangeably with nevus sebaceous syndrome. However, epidermal nevus syndrome no longer refers to a single entity but rather represents a group of distinct, but related multisystem disorders. Additional terms used to describe nevus sebaceus syndrome include Schimmelpenning syndrome, Schimmelpenning-Feuerstein-Mims syndrome, nevus sebaceous of Jadassohn and Jadassohn sebaceous nevus syndrome. Nevus sebaceous syndrome is now the preferred term.
The specific symptoms and severity of nevus sebaceus syndrome can vary greatly from one person to another. It is important to note that affected individuals may not have all the symptoms discussed below. Affected individuals or their parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
The characteristic skin lesion that affects individuals with nevus sebaceus syndrome is a sebaceous nevus, which is a type of epidermal nevus. These lesions are often small, isolated lesions–but when larger–are distributed along the lines of Blaschko, with the scalp (59.3%), face (32.6%) and neck being most commonly affected. The arms, legs and trunk may also be affected. The related birthmark, keratinocytic epidermal nevus, caused by the same gene variant, is more commonly found on the trunk and extremities and contains fewer sebaceous glands. Sebaceous nevi are usually salmon-colored or yellowish hairless, smooth patches. These lesions usually become more pronounced around puberty and may appear scaly, warty or thickened. When the scalp is involved, they present with associated areas of hair loss (alopecia). Sebaceous nevi may be prominent and easily noticeable at birth or be subtle and go unrecognized. Sometimes, sebaceous nevi do not become apparent until after puberty, when they go through the above-mentioned changes because of the increase in androgenic hormones that occur during this time. The lesions, apart from their appearance, usually do not cause additional symptoms. After puberty, sebaceous nevi may develop growths within them. Although these were once thought to represent skin cancer (basal cell carcinoma), we now know that most of these growths are benign.
Nevus sebaceous lesions most often occur as an isolated finding and are not usually associated with abnormalities in other organs. However, when they occur with additional symptoms in organs other than the skin, the term “nevus sebaceus syndrome” is appropriate. Some researchers have noted that central facial epidermal (sebaceous) nevi may be more likely to be associated with malformations of the brain, eyes and cranial bones.
Neurological abnormalities are the most common finding in individuals with nevus sebaceus syndrome, affecting approximately 66% of patients. These include seizures, delays in attaining developmental milestones, intellectual impairment, damage to certain cranial nerves and abnormalities of certain structures of the brain. Such abnormalities include one side of the brain being larger than the other (hemimegaloencephaly), malformation (dysplasia) of certain brain vessels and absence (agenesis) of the bundle of nerves that connects the two cerebral hemispheres (corpus callosum). Defects in the folding of the brain have also been recorded, including the presence of a smooth brain that lacks distinctive folds (agyria), abnormally small folds (microgyria) and abnormally thickened folds (pachygyria).
Individuals with nevus sebaceus syndrome may also have Dandy-Walker malformation, a rare malformation of the brain that is present at birth. It is characterized by an abnormally enlarged space at the back of the brain (cystic 4th ventricle) that interferes with the normal flow of cerebrospinal fluid through the openings between the ventricle and other parts of the brain (foramina of Magendie and Luschka). Excessive amounts of fluid accumulate around the brain and cause abnormally high pressure within the skull, leading to swelling of the head (congenital hydrocephalus) and neurological impairment. Motor delays and learning problems may also occur. Dandy-Walker malformation is a form of “obstructive” or “internal noncommunicating hydrocephalus”, meaning that the normal flow of cerebrospinal fluid is blocked resulting in the widening of the ventricles. Dandy-Walker malformation is often associated with partial agenesis of a part of the cerebellum known as the cerebellar vermis. (For more information on this disorder, choose “Dandy-Walker” as your search term in the Rare Disease Database.)
Ocular abnormalities also occur in 59% of people with nevus sebaceus syndrome, including a partial absence of tissue (coloboma) from the colored portion of the eye (iris) or the membrane lining the back of the eyes (retina), tumor-like growths (choristomas), clouding (opacity) of the cornea, crossed eyes (strabismus), defects of the optic nerve, and scarring degeneration or detachment of the retina. Some individuals may have a benign, yellowish-white, fatty tumor on the outer portion of the eyeball (epibulbar lipodermoid). A sebaceous nevus on the face can potentially involve structures of the eye including the eyelids and the thin, clear membrane that covers the outer surface of the eye (conjunctiva). These can lead to visual disturbances effect.
Skeletal malformations exist in approximately 50% of individuals; these can include abnormal curvature of the spine, dislocation of the hip and deformities of the limbs. Craniofacial differences—such as an unusually prominent forehead (frontal bossing), underdeveloped nasal and orbital bones and asymmetry of the skull—may also occur. Additional skeletal malformations may include bone cysts, underdevelopment of the pelvis and incomplete formation of certain bony structures including the ankle, foot and bones of the spinal column (vertebrae).
Less often (10% of patients), genitourinary abnormalities may also occur, namely: hydronephrosis, a double collecting system, fusion of the kidney (horseshoe kidney), cystic kidney, misplacement of the opening of the urethra (hypospadias), failure of the testicles to descend (cryptorchidism), testicular tumors and uteropelvic junction obstruction. Individuals with nevus sebaceus syndrome may also develop vitamin D-resistant rickets, a condition characterized by bow deformities of the legs, pain in the legs and progressive softening of the bone structure due to deficiencies in calcium and phosphate. In children, growth rates may be slow, ultimately resulting in short stature. Affected individuals may be prone to fractures.
It is reported in medical literature that 12% of patients with nevus sebaceus syndrome have various types of heart malformations. These include atrial septal defect, ventricular septal defect, patent ductus arteriosus, patent foramen ovale, coarctation of the aorta, hypoplasia of the aorta, arterial flutter/fibrillation and arterial premature systoles. It has also been determined that vascular malformations occur with a higher frequency (12.6% to 33%) in patients with nevus sebaceus syndrome compared with the general population (<1%). As mentioned above, sebaceous nevi are associated with an increased risk of developing secondary benign skin tumors such as trichoblastoma, syringocystadenoma papilliferum, and other benign basaloid tumors. Malignant secondary tumors, such as basal cell carcinoma, squamous cell carcinoma and sebaceous carcinoma in association with a sebaceous nevus are very rare.
Individuals with nevus sebaceus syndrome have variants of the KRAS and HRAS genes that are not inherited but occur after fertilization of the embryo (postzygotic). HRAS and KRAS variants have also been found in people with isolated sebaceous nevi who do not have abnormalities in other organs. These gene variants are only found in the nevi and are not present in the surrounding skin.
HRAS and KRAS are two of the most extensively studied genes that encode Ras proteins, which classifies nevus sebaceus syndrome as a “RASopathy”. RASopathies include a group of disorders characterized by variants in the RAS-MAPK pathway. This signaling pathway plays a pivotal role in cell differentiation, proliferation and survival. More specifically, nevus sebaceous syndrome is classified as a mosaic RASopathy due to the presence of the variant only in the lesions associated with the syndrome and not the surrounding tissue. This fits the definition of mosaicism, which is the presence of two distinct cell populations in a single individual due to gene variants that occur after fertilization. The earlier in development the RAS variant occurs, the more widespread the nevus will be and the more likely there will be abnormalities in other organs. More research is necessary to explore further the relationship of RAS variants and the complex features seen in some affected patients.
Nevus sebaceus syndrome affects males and females in equal numbers. The exact prevalence and incidence of the disorder in the general population are unknown. Epidermal nevi—as an isolated finding or a part of a syndrome—have been reported to occur in approximately 1 to 3 per 1,000 live births.
A diagnosis of nevus sebaceus syndrome is made based upon identification of characteristic symptoms (e.g., a sebaceous nevus, along with abnormalities affecting other organ systems). A detailed patient history and a thorough clinical evaluation are crucial to the diagnosis and management of this disorder.
Clinical Testing and Work-Up
In some cases, a small sample of affected skin may be taken for microscopic study (biopsy). Additional tests may be required to detect the presence and extent of associated symptoms. Such tests include a skeletal survey, a complete eye exam, chest X-rays and specialized imaging techniques to evaluate the brain. These imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). Whether a child with a sebaceous nevus should undergo such imaging techniques is controversial. Some researchers think these tests should be avoided unless there are clinical signs of central nervous system involvement.
Treatment
The treatment of nevus sebaceus syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, pediatric neurologists, dermatologists, orthopedists, orthopedic surgeons, ophthalmologists and other healthcare professionals may need to plan an affected child’s treatment systematically and comprehensively.
The specific therapeutic procedures and interventions for individuals with nevus sebaceus syndrome will vary depending upon numerous factors, including the specific symptoms present, the extent of the disorder, an individual’s age and overall health, tolerance of certain medications or procedures, personal preference, and many other factors. Decisions concerning the use of therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based on the specifics of their case. The potential risks and benefits, including possible side effects and long-term consequences; patient preference and other appropriate factors, should be thoroughly discussed with the patient and parents.
Additional therapies for nevus sebaceus syndrome depend upon the specific abnormalities present and usually follow standard guidelines. For example, epilepsy may be treated by anti-seizure medications and certain skeletal and eye malformations may also be treated surgically. Several cases have been reported in the medical literature where neurosurgery has been used to treat individuals with nevus sebaceus syndrome and epilepsy.
Surgery may be performed to improve the cosmetic appearance of individuals with nevus sebaceus syndrome. In the past, surgery was recommended because of the risk of malignancy. However, since the risk of malignancy is much less than previously thought, this view is no longer recommended, especially if surgery will be disfiguring. In addition, the surgical excision of a lesion may not always be possible due to the location of the nevus.
For cosmetic purposes only, destructive treatments such as dermabrasion, laser therapy, electrodesiccation and cryotherapy have been suggested. However, these methods often do not destroy the RAS-affected basilar cells, which can regrow and lead to reoccurrence. Therapies that do destroy these basilar cells, such as more aggressive forms of the above therapies as well as CO2 laser therapy, may prevent recurrence but will result in scarring. Surgical excision has also been used to remove sebaceous nevi but will also result in scarring. Further research into cosmetic procedures to improve the appearance of sebaceus nevi is ongoing.
When there is multi-organ involvement, a team approach to management is mandatory. This may include neurology, ophthalmology, surgery, orthopedics, endocrinology, psychology, physical therapy and occupational therapy.
Although the condition is unlikely to be inherited, genetic counseling may be helpful for affected individuals and their families.
Burosumab, an antibody directed at the FGF23 protein, is currently being investigated for the treatment of nevus sebaceous syndrome associated with vitamin D-resistant rickets. This combination of conditions is also referred to as cutaneous skeletal hypophosphatemia syndrome (CSHS), a mosaic RASopathy wherein KRAS and HRAS variants in regions of skeletal dysplasia result in the excessive production of fibroblast growth factor 23 (FGF23). FGF23 is a hormone that regulates phosphate levels in the body. In conditions characterized by excessive FGF23 activity, such as CSHS, there is impaired renal reabsorption of phosphate, leading to low levels of serum phosphate and calcium. This can result in skeletal abnormalities, including rickets in children and osteomalacia in adults.
The current mainstay treatment for hypophosphatemic rickets is multiple daily doses of phosphorus and vitamin D analogs. This approach, however, can lead to gastrointestinal upset, hyperparathyroidism, hypercalciuria, hypercalcemia and nephrocalcinosis. Burosumab is an antibody that directly targets and inhibits FGF23, thereby preventing phosphorus deficiencies. In recent clinical trials, treatment was well-tolerated in both children and adult patients and helped treat symptoms. These results warrant further investigation of burosumab therapy in more patients with hypophosphatemic rickets who have FGF23 gene variants.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Asch S, Sugarman JL Epidermal Nevus Syndromes. Handb Clin Neurol. 132:291-316. 2015.
Sugarman, JL. Epidermal Nevus Syndromes: an overview. In: Phakomatoses & Hamartoneoplastic Syndromes. Ruggieri, Martino; Pascual Castroviejo, Ignacio; Di Rocco, Concezio (Eds.) SpringerWein, New York. 2008.
Jones KL. Ed. Smith’s Recognizable Patterns of Human Malformation. 6th ed. Elsevier Saunders, Philadelphia, PA; 2006:576.
Prayson RA. Epidermal Nevus Syndrome. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:105-106.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:484-485.
JOURNAL ARTICLES
Sugarman J, Maruri A, Hamilton DJ, et al. The efficacy and safety of burosumab in two patients with cutaneous skeletal hypophosphatemia syndrome. Bone. 2023;166:116598. https://pubmed.ncbi.nlm.nih.gov/36341949/
Linglart A, Imel EA, Whyte MP, et al. Sustained efficacy and safety of burosumab, a monoclonal antibody to FGF23, in children with x-linked hypophosphatemia. J Clin Endocrinol Metab. 2022;107(3):813-824. https://pubmed.ncbi.nlm.nih.gov/34636899/
Jafry M, Sidbury R. RASopathies. Clin Dermatol. 2020;38(4):455-461. https://pubmed.ncbi.nlm.nih.gov/32972603/
Asche S, Sugarman JL. Epidermal nevus syndromes: New insights into whorls and swirls. Pediatric Dermatology 2018;35:21–29. https://onlinelibrary.wiley.com/doi/pdf/10.1111/pde.13273
Asch S, Sugarman JL. Fifty-two words for snow: dermatologists naming epidermal naevi Br J Dermatol. 2018 Jan;178(1):296. https://www.ncbi.nlm.nih.gov/pubmed/28960256
Lim Y, Ovejero D, Sugarman JL, et al. Multilineage somatic activating mutations in HRAS and NRAS cause mosaic cutaneous and skeletal lesions, elevated FGF23 and hypophosphatemia. Human Molecular Genetics. 2014; 23(2):397-407. https://www.ncbi.nlm.nih.gov/pubmed/24006476
Wang SM, Hsieh YJ, Chang KM, Tsai HL, Chen CP. Schimmelpenning syndrome: a case report and literature review. Pediatr Neonatol. 2014;55(6):487-490. https://pubmed.ncbi.nlm.nih.gov/23597534/
Kiedrowicz M, Kacalak-Rzepka A, Królicki A, Maleszka R, Bielecka-Grzela S. Therapeutic effects of CO2 laser therapy of linear nevus sebaceous in the course of the Schimmelpenning-Feuerstein-Mims syndrome. Postepy Dermatol Alergol. 2013;30(5):320-323. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858662/
Levinsohn JL, Tian LC, Boyden LM, McNiff JM, Narayan D, Loring ES, Yun D, Sugarman JL, Overton JD, Mane SM, Lifton RP, Paller AS, Wagner AM, Antaya RJ, Choate KA. Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceous. J Invest Dermatol. 2013 Mar;133(3):827-30. doi: 10.1038/jid.2012.379. Epub 2012 Oct 25. https://www.ncbi.nlm.nih.gov/pubmed/23096712
Resende C, Araújo C, Vieira AP, Ventura F, Brito C. Schimmelpenning syndrome. Dermatol Online J. 2013;19(10):20026. Published 2013 Oct 16. https://pubmed.ncbi.nlm.nih.gov/24139367
Groesser L, Herschberger E, Ruetten A, et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet. 2012;44:783-787. https://www.ncbi.nlm.nih.gov/pubmed/22683711
Moody MN, Landau JM, Goldberg LH. Nevus sebaceous revisited. Pediatr Dermatol. 2012;29:15-23. https://www.ncbi.nlm.nih.gov/pubmed/21995782
Amato C, Elia M, Schepis C. Schimmelpenning syndrome: a kind of craniofacial epidermal nevus associated with cerebral and ocular MR imaging abnormalities. AJNR Am J Neuroradiol. 2010;31:E47-48. https://www.ncbi.nlm.nih.gov/pubmed/20299435
Happle R.The group of epidermal nevus syndromes. Part I. Well defined phenotypes. J Am Acad Derm. 2010;63:1-22.
https://www.ncbi.nlm.nih.gov/pubmed/20542174
Happle R.The group of epidermal nevus syndromes. Part II. Less well defined phenotypes. J Am AcadDerm. 2010;63:25-30. https://www.ncbi.nlm.nih.gov/pubmed/20542175
Brandling-Bennett HA, Morel KD. Epidermal nevi. Pediatr Clin North Am. 2010;57:1177-1198. https://www.ncbi.nlm.nih.gov/pubmed/20888465
Greene AK, Rogers GF, Mulliken JB.Schimmelpenning syndrome: an association with vascular anomalies. Cleft Palate Craniofac J. 2007;44:208-215. https://www.ncbi.nlm.nih.gov/pubmed/17328648
Happle R. Gustav Schimmelpenning and the syndrome bearing his name. Dermatology. 2004;209:84-87. https://www.ncbi.nlm.nih.gov/pubmed/15316159
Sugarman JL.Epidermal nevus syndromes. Semin Cutan Med Surg. 2004;23:145-157. https://www.ncbi.nlm.nih.gov/pubmed/15295924
NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.
NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.
Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.
Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.
Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/