IntroductionSchimmelpenning syndrome is a rare multisystem disorder characterized by sebaceous nevus associated with other abnormalities outside the skin which most commonly affect the brain, eyes and bones. The skin lesions associated with this disorder are called nevus sebaceus(also referred to as sebaceous nevi) because they consist of an increased number ofmalformed sebaceous glands (small oil-producing glands in the skin) along with an overgrowth (hyperplasia) of the epidermis. Nevus sebaceous 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 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 affecting the brain such as seizures or intellectual impairment, the eyes such as clouding (opacity) of the cornea or partial absence of tissue of the iris or retina (coloboma), and the skeleton such as spinal malformations, craniofacial defects, and deformities of the arms and legs. Schimmelpenning syndrome occurs randomly for no apparent reason (sporadically) during the formation and development of the embryo (embryogenesis), most likely due to a mutation of a gene that occurs after fertilization (postzygotic mutation) and is present in only some of the cells of the body (mosaic pattern).
SummaryIn the past, the term "epidermal nevus syndrome" was used to describe Schimmelpenning syndrome. Some authors still use these terms interchangeably. 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 Schimmelpenning syndrome include nevus sebaceus syndrome, Schimmelpenning-Feuerstein-Mims syndrome, linear sebaceous nevus sequence, nevus sebaceous of Jadassohn, Jadassohn nevus phacomatosis and Jadassohn sebaceous nevus syndrome.
The specific symptoms and severity of Schimmelpenning syndrome can vary greatly from one person to another. It is important to note that affected individuals may not have all of 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 Schimmelpenning syndrome is a sebaceous nevus, which is a type of epidermal nevus. The scalp, neck and face are most often affected. The arms, legs and trunk may also be affected. Sebaceous nevi are usually salmon or yellowed colored, hairless, smooth patches. Eventually (usually around puberty) they become more pronounced and may appear scaly, warty or thickened. When the scalp is involved, large lesions may be present with associated areas of hair loss (alopecia). Sebaceous nevi may be prominent and easily noticeable at birth or be subtle and unrecognized. Sometimes, sebaceous nevi do not become apparent until after puberty when they go through the above mentioned changes. The lesions, apart from their appearance, usually do not cause additional symptoms.
Nevus sebaceusmost often occurs as isolated findingand usually is not associated with any abnormalities in other organs. However, when it occurs with additional extra-cutaneous symptoms, the terms, Schimmelpenning syndrome or nevus sebaceus syndrome, are appropriate. Some researchers have noted that central facial epidermal nevi may be more likely to be associated with malformations of the brain, eyes and cranial bones.
Neurological abnormalities often occur in individuals with Schimmelpenning syndrome including seizures, delays in attaining developmental milestones (developmental delays), intellectual impairment, damage to certain cranial nerves and abnormalities affecting certain structures of the brain. Such abnormalities include one side of the brain being larger than the other (hemimegalencephaly), malformation (dysplasia) of the certain brain vessels, absence (agenesis) of the bundle of nerves that connects the two cerebral hemispheres (corpus callosum), and defects of the folds of the brain including a smooth brain that lacks the distinctive folds (agyria), abnormally small folds (microgyria) and abnormally thickened folds (pachygyria).
Individuals with Schimmelpenning syndrome may also have Dandy-Walker malformation, a rare malformation of the brain that is present at birth (congenital). 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 Magendiand Luschka). Excessive amounts of fluid accumulate around the brain and cause abnormally high pressure within the skull, 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 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 Schimmelpenning 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), 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 (epibulbarlipodermoid). A sebaceous nevus on the face can potentially involve structures in the eye including the eyelids and the thin, clear membrane that covers the outer surface of the eye (conjunctiva).
Affected individuals may also have skeletal malformations including abnormal curvature of the spine, dislocation of the hip, and deformities of the limbs. Craniofacial defects 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).
Individuals with Schimmelpenning 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. In children, growth rates may be slow, ultimately resulting in short stature. Affected individuals may be prone to fractures.
According to the medical literature, sebaceus nevi are associated with an increased risk (approximately 25 % of affected individuals) of developing secondary benign skin tumors such as trichoblastoma or syringocystadenomapapilliferum, whereas malignant secondary tumors (basal cell carcinoma, squamous cell carcinoma, sebaceous carcinoma) arising in association with a sebaceous nevus are very rare.
The exact cause of Schimmelpenning syndrome is unknown. The disorder is believed to be caused by a mutation in a gene that occurs after fertilization of the embryo (postzygotic mutation), most likely early during embryonic development. Affected individuals have some cells with a normal copy of this gene and some cells with the abnormal gene (mosaic pattern). This may be referred to as having two distinct cell lines in the body. The variability of symptoms associated with Schimmelpenning syndrome is due in part to the ratio of healthy cells to abnormal cells and the timing during development at which the mutation occurs. When all cells have the abnormal gene, the condition is not compatible with life. Researchers believe that these postzygotic mutations occur randomly for no apparent reason (sporadically).
Recent research has identified individuals with Schimmelpenning syndrome who had postzygotic mutations of the KRAS and HRAS genes. In addition, HRAS and KRAS mutations have been found in isolated sebaceous nevus (in the absence of associated extracutaneous abnormalities More research is necessary to further explore the underlying molecular mechanisms involved in the development of Schimmelpenning syndrome.
Schimmelpenning 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 Schimmelpenning 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.
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 ophthalmologic exam, chests x-rays and specialized imaging techniques to evaluate the brain. Such 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 believe that these tests should be avoided unless there are clinical signs of central nervous system involvement.
The treatment of Schimmelpenning 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 systematically and comprehensively plan an affect child’s treatment.
The specific therapeutic procedures and interventions for individuals with Schimmelpenning 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 other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
Surgery may be performed to improve cosmetic appearance of individuals with Schimmelpenning syndrome. In the past, surgery was recommended because of the risk of malignancy. However, now that the risk of malignancy is much less than previously believed, this view is no longer advocated, especially if surgery will be disfiguring. In addition, the surgical excision of a lesion may not always be possible due to the specific location of the nevus.
Additional therapies for Schimmelpenning 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 ocular malformations may also be treated surgically. In the medical literature, several cases have been reported where neurosurgery has been used to treat individuals with Schimmelpenning syndrome and epilepsy.
Additional therapies that may be used to treat individuals with Schimmelpenning syndrome include remedial education, physical therapy and occupational therapy all of which should be individualized. Genetic counseling may be of benefit for affected individuals and their families.
KRAS and HRAS mutations in Schimmelpenning syndrome cause an activation of the RAS-RAF-MAPK signaling pathway. Molecules that target this pathway may be useful in the management of these disorders in the future.
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