Epidermal nevus syndromes

Disease/Disorder

Also known as: Feuerstein and Mims syndrome, Solomon's syndrome

Anatomy or system affected: All

Definition: A group of systemic diseases that have in common pigmented spots on the skin.

Key terms:

dysdiadochokinesis: inability to perform rapid movements

hamartoma: a benign tumor that results from overgrowth of mature tissues

hemiparesis: weakness on one side of the body

hypertrichosis: excessive hair growth

hypoplasia: incomplete development or underdevelopment of an organ

keratinocytes: predominant cell type in the epidermis of the skin

nevus: a pigmented spot on the skin

phacomatosis: any condition characterized by hamartomas

Causes and Symptoms

Approximately one in one thousand people have birthmarks or beauty marks. Birthmarks, or nevi (singular: nevus), are noncancerous growths (hamartomas) of pigmented skin cells. They appear flat or raised, smooth or velvety, and tend to thicken and darken as they age. Nevi appear at birth or develop during childhood and typically form along the routes cells take during development, known as lines of Blaschko.

Many different types of skin cells can form nevi, including cells from hair follicles, cells from sebaceous glands (glands in the skin that secrete oils that protect the skin and hair), and keratinocytes (epidermal skin cells). Nevi that consist solely of keratinocytes are called non-organoid epidermal nevi, while nevi that consist of hair-follicle or sebaceous-gland cells are organoid epidermal nevi.

Often, people have epidermal nevi and no other associated conditions. However, some people with epidermal nevi also have problems in other body systems. Epidermal nevus syndromes are a group of disorders that affect multiple organs and are characterized by the presence of epidermal nevi. These disorders include congenital hemidysplasia with ichthyosiform erythroderma and limb defects, or CHILD syndrome for short; nevus comedonicus syndrome; Schimmelpenning syndrome, also known as linear nevus sebaceous syndrome; angora hair nevus syndrome, also known as Schauder syndrome; Proteus syndrome; phakomatosis pigmentokeratotica; type 2 segmental Cowden disease; García-Hafner-Happle syndrome, also known as fibroblast growth factor receptor 3 epidermal nevus syndrome; and Becker nevus syndrome, also known as pigmentary hairy epidermal nevus.

Symptoms of Proteus syndrome include patchy overgrowth of multiple tissues; blood-vessel malformations; nevi in the lower layer of the skin (dermis) and connective tissue; asymmetric growth of the limbs, skull, vertebrae, and ears; lung cysts; fatty tumors; ovarian cysts; and salivary gland tumors. Proteus syndrome is caused by a mutation in the AKT1 gene. It occurs in fewer than one person per million.

Patients with phakomatosis pigmentokeratotica have a sebaceous gland nevus in combination with a peculiar epidermal nevus called nevus spilus (a.k.a. speckled lentiginous nevus), which resembles sesame seeds scattered on a dirty tablecloth. Other symptoms include developmental disability, epilepsy, hemiatrophy (atrophy on one side of the body) or hemiparesis (weakness on one side of the body), dysesthesia (abnormal sensation), hyperpathia (exaggerated pain reaction), scoliosis, strabismus (misalignment of the eyes), and hyperhidrosis (excessive sweating). Patients with this disease are prone to develop vitamin D–resistant rickets, also known as hypophosphatemia or hypophosphatemic rickets, and their sebaceous nevi can develop into basal cell carcinomas. Phakomatosis pigmentokeratotica is caused by mutations in the HRAS gene that occur after conception. It is extremely rare, affecting fewer than one in one million people.

CHILD syndrome results from mutations in the X-linked NSDHL gene, which encodes an enzyme involved in cholesterol synthesis (3β-hydroxysteroid dehydrogenase). Patients with CHILD syndrome have inflammatory epidermal nevi that have a tendency to form at skin folds and may resemble psoriasis in their appearance. These lesions tend to only form on one side of the body. The nails of the fingers and toes thicken and may form large strawberry-like lesions. Skeletal, heart, limb, and neurological defects can also occur. Only about sixty cases of CHILD syndrome have been reported.

Type 2 segmental Cowden disease is caused by spontaneous mutations in the PTEN gene that occur after conception. The PTEN gene encodes a tumor-suppressor protein that downregulates cell proliferation. Besides a thick, wart-like nevus (linear Cowden nevus), the symptoms and signs of this disease include limb overgrowth, scarring in the kidneys, macrocephaly (abnormally large head), seizures, intestinal polyps, ballooning of the toes, lymphatic tumors, vascular and connective-tissue nevi, varicose veins in the legs, breast and thyroid cancer, Lhermitte-Duclos disease (a slow-growing tumor of the cerebellum), and fatty tumors. The prevalence of this disease is unknown.

Nevus comedonicus syndrome causes atrophy of skin follicles and a pitted, acne-like appearance. Additional symptoms include cataracts and erosion of the corneas, hand skeleton deformities, scoliosis and other vertebral deformities, and neurological abnormalities. The causes and incidence of this disease are unknown.

Schimmelpenning syndrome characteristically shows sebaceous gland nevi (nevus sebaceous). Additionally, patients may have face and skull defects, spine and limb deformities, dislocation of the hips, hypophosphatemic rickets, intellectual deficits, seizures, brain abnormalities, or defects of the eye and optic nerve. The incidence of malignancy of sebaceous nevi in the case of Schimmelpenning syndrome is low. While the causes of this condition is not known for certain, research suggests it may be due to post-zygotic mutations in the HRAS and KRAS genes. The prevalence is unknown.

Becker nevus syndrome manifests differently in males and females because the organoid nevus in males show hypertrichosis, or excessive hair growth, at the site of the nevi, whereas the same nevi in females do not. Female patients characteristically show hypoplasia (underdevelopment) of one breast. Nevi in this syndrome exhibit a kind of checkerboard distribution throughout the body. Other symptoms include extra nipples, extra scrotum in males, skeletal defects, tooth abnormalities, and poor growth of the muscles of the shoulder girdle. One study showed that 0.52 percent of men have Becker nevus syndrome.

Angora hair nevus syndrome manifests as broad, band-like areas covered with long, smooth, white hair. Additional symptoms include macrocephaly, epilepsy, intellectual deficits, brain structural anomalies, weakness, dysdiadochokinesis (inability to perform rapid movements), facial defects, and eye abnormalities. The incidence of this disease is unknown.

García-Hafner-Happle syndrome is caused by a mosaic R248C mutation in the FGFR3 gene, which encodes one of the receptors for fibroblast growth factor. This specific mutation has been identified in approximately one-third of all keratinocytic nevi. In the case of García-Hafner-Happle syndrome, this mutation is found not just in small skin patches but in large portions of the patient's body. The symptoms of this disease include soft, velvety nevi; brain defects; seizures; and facial defects. The incidence of this disease is unknown.

Treatment and Therapy

Diagnosis of epidermal nevus syndromes remains as much an art as a science. Magnetic resonance imaging (MRI) studies of the brain and other internal organs can properly evaluate brain anomalies, internal growths, and other abnormalities. Electroencephalogram (EEG) readings of the brain can be helpful, since they tend to be abnormal in the majority of epidermal nevus syndrome patients. Skin biopsies of the nevi followed by histological studies of the nevus tissue can also provide diagnostic information. Genetic testing of abnormal tissue can give definitive answers as to the diagnosis of these conditions in particular cases.

Treating these diseases is challenging. Epidermal nevi tend to not respond to topical steroids, retinoids, and other agents. Topical calcipotriol may be effective in some cases, but this agent is not approved for children under the age of twelve in the United States. Calcipotriol works as a vitamin D₃ analog, inhibiting epidermal proliferation and promoting the differentiation of keratinocytes. Surgical excision of epidermal nevi is an option in some cases, but removal by cryosurgery or electrodesiccation shows high rates of recurrence.

In those who suffer seizures, antiseizure medicines can quell epileptic episodes. In some cases, the seizures may not respond to medication, and the only option left may be to surgically sever the connection between the two cerebral hemispheres, a procedure known as hemispherectomy.

Nevus comedonicus patients with cataracts require consultation with an ophthalmologist, as do all patients with eye defects.

Phakomatosis pigmentokeratotica and patients should consult an oncologist if diagnosed with basal cell carcinoma. All epidermal nevus syndrome patients should be under the care of a dermatologist.

Perspective and Prospects

In 1957, Gustav Schimmelpenning, while training in psychiatry and neurology at the University of Kiel, described in some detail a case of a seventeen-year old patient who had a “phacomatosis,” which refers to any disease characterized by benign tumors derived from mature cells. In 1962, two California physicians, R. C. Feuerstein and L. C. Mims, reported two cases of what they referred to as “linear nevus sebaceus with convulsions and mental retardation.” Unfortunately, they were unaware of Schimmelpenning's earlier precise clinical description. From that time on, a host of published cases describing similar syndromes led to a morass of different names for very similar conditions or the same names for extremely different conditions. In 1968, Lawrence M. Solomon and colleagues coined the phrase “epidermal nevus syndrome” as an umbrella for all these related but distinct conditions.

In order to better understand the epidermal nevus syndromes, further embryological and molecular genetic studies are necessary to uncover the precise cause of each particular disease. Better diagnosis and treatments should proceed from a greater understanding of the mechanisms behind these diseases.

Bibliography

Barnhill, Raymond L., Michael W. Piepkorn, and Klaus J. Busam, eds. Pathology of Melanocytic Nevi and Melanoma. Heidelberg: Springer, 2014. Print.

Boente, María del Carmen, et al. “Angora Hair Nevus: A Further Case of an Unusual Epidermal Nevus Representing a Hallmark of Angora Hair Nevus Syndrome.” Journal of Dermatological Case Reports 7.2 (2013): 49–51. Web. 17 Mar. 2015.

Desai, Soaham Dilip, Rita Vora, and Sheela Bharani. "Garcia-Hafner-Happle Syndrome: A Case Report and Review of a Rare Sub-type of Epidermal Nevus Syndrome." Journal of Pediatric Neurosciences 9.1 (2014): 66–69. Print.

Groesser, Leopold, et al. "Postzygotic HRAS and KRAS Mutations Cause Nevus Sebaceous and Schimmelpenning Syndrome." Nature Genetics 44.7 (2012): 783–87. Print.

Happle, Rudolf. “The Group of Epidermal Nevus Syndromes, Part I: Well-Defined Phenotypes.” Journal of the American Academy of Dermatology 63.1 (2010): 1–22. Print.

Happle, Rudolf. Mosaicism in Human Skin: Understanding Nevi, Nevoid Skin Disorders, and Cutaneous Neoplasia. Heidelberg: Springer, 2014. Print.

Solomon, Lawrence M., David F. Fretzin, and Ronald L. Dewald. "The Epidermal Nevus Syndrome." Archives of Dermatology 97.3 (1968): 273–85. Print.

Weinberg, Jeffrey M. "Epidermal Nevi." Treatment of Skin Disease: Comprehensive Therapeutic Strategies. Ed. Mark G. Lebwohl et al. 4th ed. Philadelphia: Saunders, 2014. 204–7. Print.