Dermatology MCQ - Viral Infections - EVER1/EVER2 deficiency

A 17-year-old female presents with severe, refractory anogenital and cutaneous warts that have been present since childhood. She has a history of recurrent respiratory infections and chronic lung disease. Laboratory studies show normal lymphocyte counts but absent antibody responses to tetanus and pneumococcal vaccines. Which of the following inborn errors of immunity is most likely associated with this presentation?

A) X-linked agammaglobulinemia (BTK deficiency)
B) Wiskott-Aldrich syndrome (WAS gene mutation)
C) Chronic mucocutaneous candidiasis (STAT1 gain-of-function)
D) EVER1/EVER2 deficiency
E) Hyper-IgM syndrome (CD40L deficiency)

Correct Answer: D) EVER1/EVER2 deficiency

Explanation

This presentation is classic for EVER1/EVER2 deficiency, an inborn error of immunity specifically predisposing to persistent HPV infections.

Key Clinical Features:

• Severe, Refractory HPV Infections:

  • Cutaneous and anogenital warts that are extensive, recalcitrant to treatment, and often present from childhood.

  • Increased risk of HPV-induced squamous cell carcinoma (e.g., skin, cervical).

• Recurrent Respiratory Infections: Due to comorbid immune dysfunction (e.g., hypogammaglobulinemia in some cases).

• Chronic Lung Disease: Bronchiectasis may develop from recurrent infections.

Pathogenesis:

• Genes: Mutations in EVER1 (TMC6) or EVER2 (TMC8) genes.

• Function: These genes encode endoplasmic reticulum proteins that regulate zinc homeostasis in keratinocytes and are crucial for controlling HPV infection. Deficiency allows unchecked HPV replication.

• Immunologic Profile: Patients may have mild antibody deficiency (impaired specific antibody responses) but normal lymphocyte counts.

Why Not the Other Options?

• (A) X-linked agammaglobulinemia (BTK deficiency): Presents with recurrent bacterial infections (not viral warts) due to absent B cells and antibodies. HPV is not a typical feature.

• (B) Wiskott-Aldrich syndrome (WAS mutation): Causes eczema, thrombocytopenia, and recurrent infections (bacterial/viral), but HPV is not predominant.

• (C) Chronic mucocutaneous candidiasis (STAT1 GOF): Predisposes to chronic Candida infections (not HPV), and autoimmunity.

• (E) Hyper-IgM syndrome (CD40L deficiency): Causes recurrent opportunistic infections (e.g., Pneumocystis), neutropenia, and liver disease, but not prominent HPV.

Management:

• Aggressive wart treatment: Topical/imiquimod, cryotherapy, surgery.

• Cancer surveillance: Regular skin and gynecologic exams for SCC.

• Immunoglobulin replacement if hypogammaglobulinemic.

Prognosis:
High morbidity from disfiguring warts and increased cancer risk. Early diagnosis is key to intensive management.

Note: EVER deficiency is a rare but important cause of lifelong HPV susceptibility, highlighting the role of innate keratinocyte immunity in controlling HPV.