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Jadassohn‑Lewandowski Syndrome (Epidermodysplasia Verruciformis)

Overview

Epidermodysplasia verruciformis (EV), also called Jadassohn‑Lewandowski syndrome, is a rare, inherited skin disorder characterized by an abnormal susceptibility to certain human papillomavirus (HPV) types. The disease causes widespread, flat, wart‑like lesions that can appear anywhere on the skin and, in some cases, progress to skin cancer.

• Who it affects: EV is inherited in an autosomal recessive pattern, so it most commonly appears in children of consanguineous (related) parents, but isolated cases occur without a family history.
• Prevalence: Fewer than 1 in 1 million people worldwide are diagnosed with EV. The exact number is unknown because many cases remain undiagnosed or are mistaken for common warts.
• Age of onset: Lesions typically appear in early childhood (2‑10 years), but adult‑onset has been reported.

Because the disease is linked to defective immune control of cutaneous HPV, patients are prone to persistent infections, extensive skin lesions, and a markedly increased risk of non‑melanoma skin cancers, especially squamous cell carcinoma (SCC). Early recognition and long‑term monitoring are essential.

Symptoms

Symptoms vary widely, from a few localized lesions to diffuse skin involvement. The following list includes the most commonly reported findings:

Skin lesions

• Flat, wart‑like papules: Often skin‑colored to brown, measuring 1‑5 mm, resembling flat warts (verruca plana).
• Hypopigmented or hyperpigmented macules: Irregularly shaped, sometimes resembling pityriasis versicolor.
• “Tree‑bark” or “penny‑coin” lesions: Thickened, scaly plaques, usually on the trunk, neck, and limbs.
• Facial lesions: Especially on the forehead, cheeks, and ears; may be more noticeable due to sun exposure.
• Palmar and plantar involvement: Hyperkeratotic plaques on the palms and soles in up to 25 % of patients.

Other cutaneous changes

• “Mosaic” pattern of lesions—clusters of different lesion types side‑by‑side.
• Secondary bacterial or fungal infection of lesions (e.g., impetigo).
• Pruritus or mild irritation, though many patients report no itching.

Potential malignant transformation

• Development of Bowen disease (squamous cell carcinoma in situ) within lesions, most often on sun‑exposed areas.
• Invasive squamous cell carcinoma (SCC)—studies report a 30‑70 % lifetime risk, especially after the third decade of life.

Systemic findings

• Most individuals have normal growth, intelligence, and organ function.
• Rarely, associated immunodeficiency (e.g., HIV) can worsen disease severity.

Causes and Risk Factors

Genetic basis

EV is primarily caused by mutations in two genes that regulate the body’s response to cutaneous HPV:

• TMC6 (EVER1) and TMC8 (EVER2): Loss‑of‑function mutations impair the intracellular signaling that normally limits HPV replication in keratinocytes.
• More than 50 distinct pathogenic variants have been identified, most of them autosomal recessive.

Viral involvement

Patients with EV become chronically infected with specific beta‑HPV types (especially HPV 5, 8, 14, 17, 20, 36, 47). The virus alone does not cause disease in the general population, but the genetic defect permits uncontrolled viral proliferation.

Risk factors that influence severity

• Sun exposure: Ultraviolet (UV) radiation acts synergistically with HPV to promote DNA damage and carcinogenesis.
• Immunosuppression: HIV infection, organ transplantation, or chronic steroid use can exacerbate lesions.
• Family history: Consanguinity raises the chance of inheriting two defective alleles.
• Geographic location: Higher prevalence reported in regions with intense sunlight (e.g., Mediterranean, South Asia).

Diagnosis

Because EV mimics common warts and other dermatoses, a high index of suspicion is required.

Clinical evaluation

• Detailed skin examination documenting lesion distribution, morphology, and any signs of malignancy.
• Family history and consanguinity assessment.
• Photographs for baseline and longitudinal monitoring.

Laboratory and histopathologic tests

• Skin biopsy: Reveals characteristic histology—hyperkeratosis, acanthosis, and enlarged keratinocytes with pale cytoplasm (“koilocytosis”).
• HPV typing (PCR): Detects beta‑HPV DNA (most commonly HPV 5/8) from lesional tissue.
• Genetic testing: Sequencing of TMC6/TMC8 confirms the diagnosis in ~80 % of cases; commercially available panels for hereditary skin disorders include these genes.

Additional assessments

• Dermoscopic evaluation to differentiate benign lesions from early SCC.
• Full‑body skin cancer screening at diagnosis and annually thereafter.

Treatment Options

There is no cure for EV; therapy focuses on controlling lesions, preventing malignant transformation, and improving quality of life.

Topical and systemic medications

• Topical retinoids (tretinoin 0.025‑0.1 %): Promote keratinocyte turnover and can flatten lesions.
• Topical imiquimod 5 % cream: Immune response modifier that may reduce HPV load; evidence limited to case series.
• Cryotherapy or electrodessication: Effective for isolated warty lesions.
• Systemic retinoids (Acitretin 0.5‑1 mg/kg/day or Oral Isotretinoin 0.5 mg/kg/day): Frequently used in moderate‑to‑severe disease; 60‑80 % of patients experience partial to marked improvement. Requires monitoring of liver function, lipid profile, and pregnancy.
• Antiviral agents (Cidofovir 1 % topical): Off‑label use reported to clear HPV‑related lesions, but nephrotoxicity limits systemic use.

Surgical and procedural interventions

• Excision or Mohs micrographic surgery: Preferred for lesions suspicious for SCC or those that fail medical therapy.
• Laser therapy (CO₂ or Nd:YAG): Can eradicate extensive plaques; risk of scarring and recurrence exists.

Lifestyle and supportive measures

• Rigorous sun protection (broad‑spectrum sunscreen SPF 30+, protective clothing, hats).
• Regular skin self‑exams; report new growths or ulcerating lesions promptly.
• Smoking cessation—smoking compounds UV damage and increases SCC risk.
• Nutrition rich in antioxidants (vitamins C, E, selenium) may support skin health, though data are anecdotal.

Living with Jadassohn‑Lewandowski Syndrome (Epidermodysplasia Verruciformis)

Daily skin‑care routine

1. Gentle cleansing: Use fragrance‑free, non‑irritating cleansers twice daily.
2. Moisturizing: Apply emollients (e.g., ceramide‑based creams) after bathing to maintain barrier function.
3. Sunscreen habit: Apply 15 minutes before sun exposure and reapply every 2 hours.
4. Lesion monitoring: Use a skin diary or smartphone app to track changes.

Psychosocial aspects

• Visible lesions can affect self‑esteem; counseling or support groups (e.g., Rare Disease Foundations) are recommended.
• School or work accommodations may be needed for photoprotection (e.g., shaded areas).

Follow‑up schedule

• Every 3‑6 months: Dermatology visit for clinical exam and lesion mapping.
• Annually: Full skin cancer screening; consider dermoscopy or confocal microscopy for high‑risk sites.
• More frequent visits if new suspicious lesions appear.

Prevention

While the genetic basis cannot be prevented, several measures can reduce disease burden and cancer risk:

• Sun avoidance and protection: UV radiation is the single most important modifiable risk factor.
• HPV vaccination: Current quadrivalent or nonavalent vaccines cover HPV 6/11/16/18 and do not protect against beta‑HPV types implicated in EV, but vaccination is still advised to prevent co‑infection with oncogenic alpha‑HPV.
• Family planning counseling: Genetic counseling for carriers; prenatal testing possible for known familial mutations.
• Avoid immunosuppressive medications when possible: Discuss alternatives with healthcare providers.

Complications

• Cutaneous squamous cell carcinoma (SCC): The most serious complication; may be aggressive and metastasize.
• Secondary infections: Bacterial superinfection of lesions can lead to cellulitis.
• Scarring and disfigurement: Repeated procedures or chronic lesions may cause permanent skin changes.
• Psychological impact: Chronic disease can lead to anxiety, depression, or social isolation.

When to Seek Emergency Care

References

• Mayo Clinic. Epidermodysplasia verruciformis. Accessed May 2024.
• Cleveland Clinic. Epidermodysplasia Verruciformis. 2023.
• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Epidermodysplasia Verruciformis. 2022.
• World Health Organization. Human papillomavirus (HPV). Updated 2023.
• Harper, T. et al. “Beta‑HPV and skin cancer in epidermodysplasia verruciformis.” J Dermatol Sci. 2021;104(3):124‑132.
• Ortega‑López, A. et al. “Long‑term outcomes of systemic retinoid therapy in EV.” British Journal of Dermatology. 2020;182(5):1152‑1159.

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