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Wednesday 19 November 2003

Definition: Trichothiodystrophy is a rare genetic disorder characterized by a hair dysplasia and associated with numerous symptoms affecting mainly organs derived from the neuroectoderm.

Most patients with TTD are sensitive to sunlight. However, they do not develop the severe skin problems characteristic of xeroderma pigmentosum (XP), nor the typical features of Cockayne syndrome (CS).

The primary clinical phenotype is that of brittle hair and nails owing to a deficiency in a class of sulphur-rich proteins in these tissues. Physical and mental retardation, as well as ichthyosis (scaly skin), are also prevalent. At the cellular level many, but not all, cases of TTD are defective in NER. But skin cancer has not been documented in this disease.

Genetic analysis has implicated the XPD gene in most cases. However, in one case the cellular phenotype of defective NER in vivo was complemented by microinjection of XPB complementary DNA. Defective NER in cells from yet another case was phenotypically corrected by fusion with either XPB or XPD cells, leading to the assignment of a third genetic complementation group called TTDA.


- hair shaft abnormalities
- ichthyosis
- immature sexual development
- short stature
- peculiar facies
- sensitive skin.
- brittle hair and nails.
- possible physical and mental retardation.
- normally no cancer associated
- defective nucleotide excision repair (defective DNA repair)
- four complementation groups

  • ERCC2/XPD (MIM.126340)
  • ERCC3/XPB (MIM.133510)
  • TTD-A
  • TTDN1 (7p14)

- Normal immunological responses to UV light (contrary to XP patients with mutations in the same gene)


- nonphotosensitive trichothiodystrophy (TTD).

  • TTDN1 locus at 7p14 (TTD nonphotosensitive 1) : C7orf11 mutations

- photosensititive TTD
- * About half of TTD patients exhibit photosensitivity because their nucleotide-excision repair pathway (NER) does not remove UV-induced DNA lesions efficiently. However, they do not present the skin cancer susceptibility expected from such an NER disorder. Their deficiencies result from phenotype-specific mutations in either XPB or XPD. These genes encode the helicase subunits of TFIIH, a DNA repair factor that is also required for transcription of class II genes.


- mutations in ERCC2/XPD (MIM.126340) coding for helicase subunits of transcription/repair vector TFIIH (predominant)

- mutations in ERCC3/XPB (MIM.133510) coding for helicase subunits of transcription/repair vector TFIIH (rare)

- an exceptional trichothiodystrophy complementation group designated TTD-A (Stefanini et al., 1993)

- nonphotosensitive trichothiodystrophy (TTD).

  • TTDN1 locus at 7p14 (TTD nonphotosensitive 1): C7orf11 mutations (15645389)


- Trichothiodystrophy (TTD) main symptoms are brittle hair and nails (because of a reduced content of cysteine-rich matrix proteins), ichthyotic skin, and physical and mental retardation (Stefanini et al., 1993).

- Some of the TTD patients show photosensitivity, correlated with a defective excision repair, but no cases of skin cancer have been related. The TTD are caused by mutations in three genes: TTD-A, XPB and XPD.

- Likewise CS, the TTD individuals with mutations in XPD may also have XP syndromes. The TTD is mainly a transcription disease, because the deficiency of these three groups can be restored by the micro-injection of the TFIIH factor, though none of the known TFIIH subunits is mutated in TTD-A gene (Sancar, 1996).


- Cleaver JE. Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer. 2005 Jul;5(7):564-73. PMID: 16069818

- Bergmann E, Egly JM. Trichothiodystrophy, a transcription syndrome. Trends Genet. 2001 May;17(5):279-86. PMID: 11335038