Dermatology MCQ - Viral Infections - Epidermodysplasia verruciformis

A 25-year-old man presents with widespread, pityriasis versicolor-like hypopigmented macules and flat, scaly papules on his trunk, neck, and face since adolescence. He also has numerous refractory plantar warts. His sister has a similar condition. Biopsy of a hypopigmented lesion shows enlarged keratinocytes with blue-gray, swollen cytoplasm and large nuclei. Which of the following genetic defects is most likely responsible for this condition?

A) Mutation in the STAT1 gene
B) Deficiency of EVER1 or EVER2 genes
C) Mutation in the CARD11 gene
D) Deficiency of IL12RB1
E) Mutation in the FOXP3 gene

Correct Answer: B) Deficiency of EVER1 or EVER2 genes

Explanation

This presentation is classic for epidermodysplasia verruciformis (EV), a rare autosomal recessive disorder characterized by abnormal susceptibility to specific human papillomavirus (HPV) types.

Key Clinical Features of Epidermodysplasia Verruciformis:

• Skin Lesions:

  • Pityriasis versicolor-like macules: Hypopigmented or reddish-brown scaly patches.

  • Flat, wart-like papules: Especially on the hands, feet, face, and trunk.

  • Refractory plantar warts are common.

• Oncogenic Risk: ~30-60% of patients develop cutaneous squamous cell carcinomas (SCC), typically on sun-exposed areas, often before age 40.

• Inheritance: Usually autosomal recessive; familial cases are common.

Genetic Defect:

• Primary Cause: Mutations in the EVER1 (TMC6) or EVER2 (TMC8) genes on chromosome 17.

• Function: These genes encode transmembrane proteins in the endoplasmic reticulum that regulate zinc homeostasis and are critical for controlling HPV infection in keratinocytes. Their deficiency allows unchecked replication of certain beta-HPV types (e.g., HPV5, HPV8).

Histopathology:

• Biopsy shows enlarged keratinocytes with blue-gray, swollen cytoplasm and large nuclei (a characteristic viral cytopathic effect).

• Cells may appear "blue" due to abundant viral particles.

Why Not the Other Options?

• (A) Mutation in the STAT1 gene: Causes gain-of-function STAT1 mutations leading to chronic mucocutaneous candidiasis and autoimmunity, not EV.

• (C) Mutation in the CARD11 gene: Causes B-cell immunodeficiency with susceptibility to bacterial and viral infections, but not specific HPV susceptibility like EV.

• (D) Deficiency of IL12RB1: Causes Mendelian susceptibility to mycobacterial disease (MSMD), not EV.

• (E) Mutation in the FOXP3 gene: Causes IPEX syndrome (enteropathy, endocrinopathy, eczema), not EV.

Management:

• Sun protection: Critical to reduce UV-induced carcinogenesis.

• Regular skin exams: For early detection of SCC.

• Treatment of warts: Topical imiquimod, 5-fluorouracil, cryotherapy, or retinoids (often refractory).

• Oral retinoids (e.g., acitretin) may reduce premalignant lesions.

Prognosis:
High risk of skin cancers; lifelong monitoring is essential.

Note: EV is a model disease demonstrating the role of innate keratinocyte immunity in controlling HPV. The EVER genes are specific to EV susceptibility.