What are the other Names for this Condition? (Also known as/Synonyms)

• EV (Epidermodysplasia Verruciformis)
• Lewandowsky-Lutz Syndrome
• Tree Man Syndrome

What is Epidermodysplasia Verruciformis? (Definition/Background Information)

• Epidermodysplasia Verruciformis (EV) is a rare skin disorder, characterized by wart-like lesions on the skin that are caused by repeated and chronic infection with human papillomavirus (HPV). The chronic HPV infection occurs because of increased susceptibility to the virus, due to genetic mutations or reduced immunity
• The affected individuals develop warts, in small groups or clusters made up of numerous scaly structures, which resemble a tree bark. Hence, the condition is also known as Tree Man Syndrome
• Epidermodysplasia Verruciformis can either be inherited or acquired; the latter caused by suppression of immunity owing to medications, or human immunodeficiency virus (HIV) infection. When the cause is genetic, mutation(s) in the EVER1 and EVER2 genes on chromosome 17 may result in the disorder
• The diagnosis of Epidermodysplasia Verruciformis may involve clinical observations and immunohistochemical studies. Untreated or inadequately treated skin lesions may turn cancerous, generally to squamous cell carcinoma or intra-epidermal carcinoma (non-melanoma skin cancers)
• Epidermodysplasia Verruciformis disorder is managed with retinoid treatments, cryotherapy, and surgical excision of the warts. The outcome, in most cases, is typically favorable with effective treatment

Who gets Epidermodysplasia Verruciformis? (Age and Sex Distribution)

• The exact prevalence of Epidermodysplasia Verruciformis (EV) is not known. To date, over 200 cases have been reported in the medical literature
• The manifestation of EV typically occurs in childhood; although, there have been cases of individuals being affected in infancy and puberty as well
• EV can affect both male and female genders and no preference is noted
• Epidermodysplasia Verruciformis occurs without racial or ethnic predilection

What are the Risk Factors for Epidermodysplasia Verruciformis? (Predisposing Factors)

The following are some known risk factors for the development of Epidermodysplasia Verruciformis:

• A family history of the disorder
• Being born to parents who are close blood relatives (such as first cousins); about 10% of the reported cases are known to be of children born in consanguineous marriages
• Being infected with HIV
• Having undergone an organ transplant, and therefore, being on immunosuppressive drugs
• Being affected by cancers of the lymphatic system (lymphoma)

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one’s chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Epidermodysplasia Verruciformis? (Etiology)

Epidermodysplasia Verruciformis is caused by repeated infections of the skin by the human papilloma virus (HPV), predominantly HPV5 and HPV8. However, other variants of the virus can also cause the disease.

A defective immune response to HPV increases the susceptibility of the affected individuals to the virus, which may be caused by:

• Mutation(s) in the EVER1 or EVER2 genes, also known as TMC6 and TMC8 genes respectively, is responsible for about 75% the EV cases
  • Under normal circumstances, these two genes code for membrane proteins that interact with a zinc transporter protein (ZnT-1) in the intracellular structure, known as endoplasmic reticulum of skin cells called keratinocytes. Mutation(s) in these genes make the keratinocytes susceptible to HPV infections
  • The exact mechanism of how unmutated EVER1 and EVER2 gene products block HPV infection is not clear. It is theorized that intracellular equilibrium in Zn levels catalyzed by EVER + Zn protein complexes may inhibit HPV expression, or that they play a direct role in the immune response to HPV infection
• Mutations in other genes, such as RHOH, MST1 and LCK, lead to abnormalities in T-lymphocytes and T-cell receptors. These aberrations affect the functioning of the T-cells, which play a crucial role in immune responses. The diminished immune response owing to these mutations may allow the HPV particles to infect repeatedly

These genetic mutation(s) can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.

• Autosomal dominant:

Autosomal dominant conditions are traits or disorders that are present when only one copy of the mutation is inherited on a non-sex chromosome. In these types of conditions, the individual has one normal copy and one mutant copy of the gene. The abnormal gene dominates, masking the effects of the correctly function gene. If an individual has an autosomal dominant condition, the chance of passing the abnormal gene on to their offspring is 50%. Children, who do not inherit the abnormal gene, will not develop the condition or pass it on to their offspring.

• Autosomal recessive:

Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected). 

• X-linked inheritance:

X-linked conditions are traits or disorders that occur when two copies of an abnormal gene are inherited on a sex chromosome (X or Y chromosome). All X-linked recessive traits are fully evident in males, because they have only one copy of the X chromosome. This means that there is no normal gene present to mask the effects of the mutant copy. All males who are affected will pass the mutated gene onto their female offspring, because they must inherit one copy of the X chromosome from each parent. This means that they will be unaffected carriers. Females are rarely affected by X-linked recessive disorders because they have two copies of the X chromosome. In the rare case that females inherit two mutated copies of the gene, they will inherit the condition.

Any medical condition that can suppress immunity in an individual, such as HIV infection, being on immunosuppressant drugs following organ transplantation, or certain types of cancer that affect the lymphatic system, may lead to abnormal T-cell function, thereby increasing an individual’s vulnerability to HPV infections. In such instances, the condition is known as Acquired Epidermodysplasia Verruciformis.

What are the Signs and Symptoms of Epidermodysplasia Verruciformis?

The signs and symptoms of Epidermodysplasia Verruciformis typically begin in childhood, and progress as the child grows (advances in age). In some cases, the skin lesions may develop and remain unchanged. In some individuals, the lesions are known to reappear after treatment.

The common signs and symptoms of Epidermodysplasia Verruciformis may include:

• The presence of lesions on the skin that may be of the following types:
  • Wart-like flat lesions
  • Raised skin lesions
• The wart-like flat lesions may be:
  • In the form of solid papules, about 1 cm in diameter
  • Have a scaly appearance
  • Unpigmented, lightly-pigmented, or be deep pink or reddish-brown in color
  • Form a plaque due to combination of several papules
• The raised skin lesions may be:
  • Brown in color
  • Oily in appearance
  • Scaly and thick

The skin lesions may appear on the following areas of the body:

• Hands and feet
• Palms and soles
• Arms and legs, armpits
• Head and neck region including the chin and earlobes
• Trunk (chest, back, abdomen)
• External genitals

A small number of warts or lesions may be seen on the body; or, there may be hundreds of them grouped together to form clusters. This may lead to an unorganized, asymmetrical, and rough ‘bark-like’ appearance on the affected skin regions, thus earning Epidermodysplasia Verruciformis the sobriquet ‘Tree Man Syndrome’.

How is Epidermodysplasia Verruciformis Diagnosed?

The diagnosis of Epidermodysplasia Verruciformis is made using the help of the following tools:

• Thorough physical examination and assessment of symptoms
• Evaluation of family medical history
• Biopsy of the lesion/affected skin, to check for dark patches (acanthosis), thickening of the outer skin layer (hyperkeratosis), and granular cells of the skin (hypergranulosis)
• In-situ hybridization to check for HPV viral particles (using a probe to identify nucleic acid material of human papilloma virus in the skin sample)
• Immunohistochemical analysis, in which an anti-HPV antibody is used to bind the virus in the sample, which is then visualized with a microscope
• Tests, as appropriate to rule out other conditions that may have similar symptoms, such as squamous cell carcinoma

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Epidermodysplasia Verruciformis?

The potential complications of Epidermodysplasia Verruciformis may include:

• Significant disfigurement without proper and timely treatment; this can result in severe and lifelong emotional and psychological stress
• Transformation of skin lesions to cancers (typically to squamous cell or intra-epidermal carcinoma), which may take place in approximately 30-60% of the affected individuals. Such a transformation is mostly observed in individuals who are between 30-50 years of age

Metastatic carcinomas (in advanced stages) are generally rare; but if metastasis is observed, then the condition can be fatal.

How is Epidermodysplasia Verruciformis Treated?

The treatment for Epidermodysplasia Verruciformis may involve the following:

• Oral (systemic) and/or topical retinoids, and other immune modifiers, such as imiquimod, to improve the immune response of cells
• Surgery, which may consist of:
  • Cryosurgery: The use of extreme cold, such as liquid nitrogen, to destroy and remove the abnormal skin growths
  • Electrosurgery: The use of high frequency electrical current (of alternating polarity) to destroy the undesired growth
  • Laser ablation: The use of laser beam to vaporize unwanted tissue
• Experimental therapies such as
  • Interferon alpha for improving immune response
  • Vitamin D analogs, which may have anti-proliferative properties

How can Epidermodysplasia Verruciformis be Prevented?

At the present time, there are no methods or guidelines available to prevent the development of Epidermodysplasia Verruciformis (EV).

• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as EV
• In individuals with EV, exposure to sunlight (UVA and UVB lights) is reported to worsen the condition through transformation of lesions to cancers. Therefore, avoiding sunlight and protecting oneself when exposure is unavoidable may help avoid complications, and are highly recommended
• Regular medical screening at periodic intervals with tests and physical examinations are strongly recommended

What is the Prognosis of Epidermodysplasia Verruciformis? (Outcomes/Resolutions)

• Epidermodysplasia Verruciformis is a life-long and progressive disorder that needs continuous monitoring and management
• The outcome in majority of cases is favorable, if the condition is managed well
• Failure to treat the condition in a timely fashion can lead to complications, such as transformation of the lesions to cancers
• Even though malignant transformations are known to take place, metastatic tumors are not generally observed. In case of metastasis, the condition can be fatal

Additional and Relevant Useful Information for Epidermodysplasia Verruciformis:

Please visit our Skin Care Health Center for more physician-approved health information:

http://www.dovemed.com/healthy-living/skin-disorders/