Random Dermatology MCQ - Palmoplantar keratoderma with deafness

A 16-year-old boy presents with progressive, diffuse, symmetric hyperkeratosis of his palms and soles since early childhood. He also has a history of severe bilateral sensorineural hearing loss diagnosed in infancy. On examination, there is no associated alopecia or nail dystrophy. His father has similar but milder skin findings and hearing loss. What is the most likely mode of inheritance and the implicated structural protein defect?

A. Autosomal recessive; defect in loricrin.
B. Autosomal dominant; defect in connexin 26 (GJB2).
C. X-linked recessive; defect in keratins.
D. Mitochondrial inheritance; defect in mitochondrial tRNA.
E. Autosomal dominant; defect in desmoplakin.

Correct Answer: B. Autosomal dominant; defect in connexin 26 (GJB2).

Answer and Explanation

The correct answer is B. This question describes the classic presentation of palmoplantar keratoderma with deafness, specifically Keratoderma-Ichthyosis-Deafness (KID) syndrome or the closely related Vohwinkel syndrome with deafness. The key features are the combination of diffuse palmoplantar keratoderma (PPK) and congenital sensorineural hearing loss. The presence of a similar condition in the father with male-to-male transmission strongly supports an autosomal dominant inheritance pattern. Mutations in the GJB2 gene, which encodes the gap junction protein connexin 26, are the most common cause of this phenotype. Connexin 26 is critical for cell-to-cell communication in the epidermis and the cochlea.

Why the Other Options are Incorrect:

• A. Autosomal recessive; defect in loricrin: Mutations in LOR cause progressive symmetric erythrokeratoderma or Vohwinkel syndrome (mutilating keratoderma with pseudoainhum), which can include hearing loss, but classic Vohwinkel is often autosomal dominant. More importantly, connexin 26 defects are the prototypical and most common cause of the specific PPK-deafness combination.

• C. X-linked recessive; defect in keratins: X-linked disorders would not show male-to-male transmission. While keratins are involved in other PPKs (e.g., diffuse PPK of Unna-Thost is due to KRT1), they are not classically linked with deafness.

• D. Mitochondrial inheritance: This pattern is characterized by maternal transmission only, which is not described here. Mitochondrial disorders have multisystem features (myopathy, encephalopathy) not confined to skin and hearing.

• E. Autosomal dominant; defect in desmoplakin: Mutations in DSP (desmoplakin) cause cardiocutaneous syndromes like Carvajal syndrome (striate PPK, woolly hair, and dilated cardiomyopathy) or acantholytic epidermolysis bullosa, not isolated PPK with deafness.

Additional High-Yield Information for Exams:

• Syndromes Presenting with PPK and Deafness:

  • KID Syndrome: Features Keratoderma, Ichthyosiform scaling (often spiny or verrucous), and Deafness. Can also include vascularizing keratitis, alopecia, and increased risk of squamous cell carcinoma.

  • Vohwinkel Syndrome (Mutilating Keratoderma with Deafness): Features a honeycomb PPK, pseudoainhum (constricting bands leading to autoamputation of digits), and deafness. Caused by GJB2 or LOR mutations.

  • Bart-Pumphrey Syndrome: Features knuckle pads, leukonychia, PPK, and deafness (also GJB2).

• Pathogenesis: Connexin 26 forms gap junctions, which are channels allowing direct communication between adjacent cells. Mutations disrupt ionic and metabolic coupling, affecting epidermal homeostasis and the function of the potassium-recycling pathway in the inner ear, leading to keratoderma and sensorineural hearing loss, respectively.

• Differential Diagnosis: The differential for syndromic PPK includes many entities. The combination with sensorineural deafness narrows it considerably to the connexinopathies and loricrin defects. The absence of other features like pseudoainhum or severe ichthyosis might point more towards a non-mutilating, diffuse PPK with deafness due to GJB2.

• Associated Conditions & Prognosis:

  • Hearing Loss: Typically congenital, non-progressive, and severe.

  • Ocular: Recurrent keratitis and potential visual impairment are common in KID syndrome.

  • Infections: Patients with KID syndrome are prone to recurrent bacterial and fungal skin infections, and systemic infections.

  • Malignancy: Increased risk of cutaneous squamous cell carcinoma, particularly in KID syndrome.

• Management & Rationale:

  • Rationale: Multidisciplinary management focusing on the skin, hearing, and eyes, with surveillance for complications.

  • First-line:

    • Dermatologic: Aggressive keratolysis with topical keratolytics (urea, salicylic acid), emollients, and systemic retinoids (acitretin) in severe cases.

    • Auditory: Early hearing aid fitting or cochlear implantation.

    • Ophthalmologic: Regular exams to monitor for and treat keratitis.

  • Surveillance: Regular skin exams for signs of malignancy, especially in areas of chronic inflammation. Management of recurrent infections.