Random Dermatology MCQ - Trichothiodystrophy

A 2-year-old child with severe developmental delay, ichthyotic skin, and brittle hair is evaluated. The hair is sparse, short, and easily broken. Under polarizing light microscopy, the hair shafts demonstrate a distinctive alternating pattern of light and dark bands, known as "tiger tail" striations. What is the fundamental biochemical defect and the most consistent associated laboratory finding in this condition?

A. Defect in copper metabolism; low serum copper and ceruloplasmin.
B. Defect in DNA repair due to mutations in nucleotide excision repair (NER) pathway genes; associated with photosensitivity and low sulfur content of hair.
C. Defect in cholesterol synthesis; elevated 7-dehydrocholesterol.
D. Defect in zinc absorption; low serum zinc levels.
E. Defect in melanin synthesis; hair bulb agenesis on trichogram.

Correct Answer: B. Defect in DNA repair due to mutations in nucleotide excision repair (NER) pathway genes; associated with photosensitivity and low sulfur content of hair.

Answer and Explanation

The correct answer is B. This question describes the classic features of trichothiodystrophy (TTD). The key clues are the brittle hair with the pathognomonic "tiger tail" banding under polarizing microscopy, combined with neurodevelopmental abnormalities and ichthyosis. TTD is fundamentally a disorder of DNA repair and transcription. Most patients have mutations in genes involved in the nucleotide excision repair (NER) pathway, specifically affecting the transcription factor IIH (TFIIH) complex. A hallmark biochemical finding is a deficiency of sulfur-rich matrix proteins in the hair, leading to low sulfur/cystine content, which causes the hair brittleness. Many, but not all, patients exhibit photosensitivity due to the defect in NER.

Why the Other Options are Incorrect:

• A. Defect in copper metabolism: This describes Menkes disease, which features pili torti (twisted hair), neurologic degeneration, and connective tissue abnormalities, not tiger tail banding or ichthyosis.

• C. Defect in cholesterol synthesis: This describes Smith-Lemli-Opitz syndrome, characterized by microcephaly, syndactyly, genital abnormalities, and failure to thrive, not the specific hair findings of TTD.

• D. Defect in zinc absorption: This describes acrodermatitis enteropathica, which presents with periorificial and acral dermatitis, diarrhea, and alopecia, but not tiger tail hair or ichthyosis.

• E. Defect in melanin synthesis: This is not specific. Hair bulb agenesis is not a typical finding in TTD.

Additional High-Yield Information for Exams:

• Pathogenesis: Mutations in genes encoding subunits of the TFIIH complex (e.g., XPD, XPB, TTDA) disrupt its dual roles in DNA repair (NER) and gene transcription. This leads to the multisystem phenotype.

• Clinical Features (The "Brittle Hair" Syndromes): TTD is highly variable. The mnemonic "IBIDS" or "PIBIDS" summarizes the spectrum:

  • Ichthyosis

  • Brittle hair

  • Intellectual impairment

  • Decreased fertility

  • Short stature

  • Photosensitivity (when present)

• Diagnostic Features:

  • Hair Microscopy: The "tiger tail" pattern under polarized light is diagnostic. Under light microscopy, hair may show trichoschisis (clean transverse fractures), irregular diameter, and absent cuticle.

  • Biochemical Analysis: Low sulfur/cystine content of hair (<50% of normal) is a consistent finding.

• Differential Diagnosis: Other causes of brittle hair and intellectual disability include Menkes disease (pili torti, low copper), argininosuccinic aciduria (trichorrhexis nodosa), and uncombable hair syndrome (distinct microscopic appearance, no neurologic issues).

• Associated Conditions & Prognosis:

  • Photosensitivity: Present in about 50% of cases. These patients have defective NER. Those without photosensitivity have defects only in the transcriptional role of TFIIH.

  • Prognosis: Variable depending on severity. Life expectancy can be reduced due to infections, neurological complications, and failure to thrive. There is no increased risk of skin cancer (unlike in xeroderma pigmentosum, another NER disorder), as the defect is primarily in transcription, not repair of UV-induced damage in basal cells.

• Management & Rationale:

  • Rationale: Management is entirely supportive and symptomatic, as there is no cure for the underlying defect.

  • First-line: Multidisciplinary care involving dermatology, neurology, pediatrics, and physical/occupational therapy.

  • Specific Measures:

    • Dermatologic: Emollients for ichthyosis, gentle hair care to minimize breakage.

    • Neurologic/Developmental: Early intervention programs, seizure management.

    • Sun Protection: Strict photoprotection for photosensitive patients.

    • Surveillance: Regular assessments for growth, development, and intercurrent infections.