• Donata Orioli
  • Miria StefaniniEmail author


Trichothiodystrophy (TTD) is a rare autosomal recessive multisystem disorder characterized by hair abnormalities and a wide spectrum of clinical manifestations including physical and mental retardation, ichthyosis, proneness to infections, signs of premature ageing and, in about half of the reported cases, cutaneous photosensitivity. Both the photosensitive and the non-photosensitive form of TTD show similar clinical outcome and include patients who differ in type and severity of symptoms. Here we discuss the cellular and genetic defects associated with TTD, the functions of the disease genes identified so far and the genotype-phenotype relationships. The three genes responsible for the photosensitive form of TTD encode distinct subunits of the general transcription factor TFIIH, which plays a key role also in DNA repair. Subtle defects in transcription can easily explain the spectrum of TTD clinical symptoms except for clinical and cellular photosensitivity that, however, in TTD does not result in increased carcinogenesis. The recent finding that alterations in the β-subunit of the basal transcription factor TFIIE result in the non-photosensitive form of TTD highlights the relevance of transcriptional alterations for the TTD pathological phenotype. Besides reporting recent research advances, we discuss how alterations in distinct pathways may result in specific TTD clinical manifestations, namely, cutaneous photosensitivity, lack of skin cancer, ageing signs and neurological alterations.



We acknowledge patients and their families as well as referring clinicians for their fundamental contribution to our knowledge of TTD. We thank all the members of our team at the IGM CNR Pavia for their contribution to the research over the years. Our studies mentioned in the text have been supported by grants from the Associazione Italiana per la Ricerca sul Cancro (AIRC IG 13537 and 17710), the European Community, the Cariplo Foundation and the Italian Ministry of University and Research.


  1. 1.
    Price VH, Odom RB, Ward WH, Jones FT. Trichothiodystrophy: sulfur-deficient brittle hair as a marker for a neuroectodermal symptom complex. Arch Dermatol. 1980;116:1375–84.CrossRefGoogle Scholar
  2. 2.
    Itin PH, Sarasin A, Pittelkow MR. Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes. J Am Acad Dermatol. 2001;44:891–920; quiz 921–4. Scholar
  3. 3.
    Faghri S, Tamura D, Kraemer KH, Digiovanna JJ. Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations. J Med Genet. 2008;45:609–21. Scholar
  4. 4.
    Stefanini M, Ruggieri M. Trichothiodystrophy. New York: Springer; 2008. p. 821–45.Google Scholar
  5. 5.
    Tamura D, Merideth M, DiGiovanna JJ, et al. High-risk pregnancy and neonatal complications in the DNA repair and transcription disorder trichothiodystrophy: report of 27 affected pregnancies. Prenat Diagn. 2011;31:1046–53. Scholar
  6. 6.
    Tamura D, Khan SG, Merideth M, et al. Effect of mutations in XPD(ERCC2) on pregnancy and prenatal development in mothers of patients with trichothiodystrophy or xeroderma pigmentosum. Eur J Hum Genet. 2012;20:1308–10. Scholar
  7. 7.
    Moslehi R, Signore C, Tamura D, et al. Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development. Clin Genet. 2010;77:365–73. Scholar
  8. 8.
    Moslehi R, Kumar A, Mills JL, et al. Phenotype-specific adverse effects of XPD mutations on human prenatal development implicate impairment of TFIIH-mediated functions in placenta. Eur J Hum Genet. 2012;20:626–31. Scholar
  9. 9.
    Kraemer KH, Patronas NJ, Schiffmann R, et al. Xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome: a complex genotype-phenotype relationship. Neuroscience. 2007;145:1388–96. Scholar
  10. 10.
    Brooks BP, Thompson AH, Clayton JA, et al. Ocular manifestations of trichothiodystrophy. Ophthalmology. 2011;118:2335–42. Scholar
  11. 11.
    Botta E, Nardo T, Orioli D, et al. Genotype-phenotype relationships in trichothiodystrophy patients with novel splicing mutations in the XPD gene. Hum Mutat. 2009;30:438–45. Scholar
  12. 12.
    Kuschal C, Botta E, Orioli D, et al. GTF2E2 mutations destabilize the general transcription factor complex TFIIE in individuals with DNA repair-proficient trichothiodystrophy. Am J Hum Genet. 2016;98:627–42. Scholar
  13. 13.
    Viprakasit V, Gibbons RJ, Broughton BC, et al. Mutations in the general transcription factor TFIIH result in beta-thalassaemia in individuals with trichothiodystrophy. Hum Mol Genet. 2001;10:2797–802.CrossRefGoogle Scholar
  14. 14.
    Stefanini M, Botta E, Lanzafame M, Orioli D. Trichothiodystrophy: from basic mechanisms to clinical implications. DNA Repair (Amst). 2010;9:2–10. Scholar
  15. 15.
    Weeda G, Rossignol M, Fraser RA, et al. The XPB subunit of repair/transcription factor TFIIH directly interacts with SUG1, a subunit of the 26S proteasome and putative transcription factor. Nucleic Acids Res. 1997;25:2274–83.CrossRefGoogle Scholar
  16. 16.
    Giglia-Mari G, Coin F, Ranish JA, et al. A new, tenth subunit of TFIIH is responsible for the DNA repair syndrome trichothiodystrophy group A. Nat Genet. 2004;36:714–9. Scholar
  17. 17.
    Moriwaki S, Saruwatari H, Kanzaki T, et al. Trichothiodystrophy group A: a first Japanese patient with a novel homozygous nonsense mutation in the GTF2H5 gene. J Dermatol. 2014;41:705–8. Scholar
  18. 18.
    Takeichi T, Tomimura S, Okuno Y, et al. Trichothiodystrophy, complementation group A complicated with squamous cell carcinoma. J Eur Acad Dermatol Venereol. 2017;32:e75–7. Scholar
  19. 19.
    Nakabayashi K, Amann D, Ren Y, et al. Identification of C7orf11 (TTDN1) gene mutations and genetic heterogeneity in nonphotosensitive trichothiodystrophy. Am J Hum Genet. 2005;76:510–6. Scholar
  20. 20.
    Botta E, Offman J, Nardo T, et al. Mutations in the C7orf11 (TTDN1) gene in six nonphotosensitive trichothiodystrophy patients: no obvious genotype-phenotype relationships. Hum Mutat. 2007;28:92–6. Scholar
  21. 21.
    Heller ER, Khan SG, Kuschal C, et al. Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype. J Invest Dermatol. 2015;135:734–41. Scholar
  22. 22.
    Corbett MA, Dudding-Byth T, Crock PA, et al. A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A. J Med Genet. 2015;52:269–74. Scholar
  23. 23.
    Theil AF, Mandemaker IK, van den Akker E, et al. Trichothiodystrophy causative TFIIEβ mutation affects transcription in highly differentiated tissue. Hum Mol Genet. 2017;26:4689–98. Scholar
  24. 24.
    Kleijer WJ, Laugel V, Berneburg M, et al. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair (Amst). 2008;7:744–50. Scholar
  25. 25.
    Marteijn JA, Lans H, Vermeulen W, Hoeijmakers JHJ. Understanding nucleotide excision repair and its roles in cancer and ageing. Nat Rev Mol Cell Biol. 2014;15:465–81. Scholar
  26. 26.
    Spivak G. Transcription-coupled repair: an update. Arch Toxicol. 2016;90:2583–94. Scholar
  27. 27.
    Lainé J-P, Egly JM. When transcription and repair meet: a complex system. Trends Genet. 2006;22:430–6. Scholar
  28. 28.
    Lehmann AR, McGibbon D, Stefanini M. Xeroderma pigmentosum. Orphanet J Rare Dis. 2011;6:70. Scholar
  29. 29.
    Stefanini M, Lagomarsini P, Arlett CF, et al. Xeroderma pigmentosum (complementation group D) mutation is present in patients affected by trichothiodystrophy with photosensitivity. Hum Genet. 1986;74:107–12.CrossRefGoogle Scholar
  30. 30.
    Stefanini M, Vermeulen W, Weeda G, et al. A new nucleotide-excision-repair gene associated with the disorder trichothiodystrophy. Am J Hum Genet. 1993;53:817–21.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Stefanini M, Kraemer KH. Xeroderma pigmentosum. New York: Springer; 2008. p. 771–92.Google Scholar
  32. 32.
    Jia N, Nakazawa Y, Guo C, et al. A rapid, comprehensive system for assaying DNA repair activity and cytotoxic effects of DNA-damaging reagents. Nat Protoc. 2015;10:12–24. Scholar
  33. 33.
    Emmert S, Slor H, Busch DB, et al. Relationship of neurologic degeneration to genotype in three xeroderma pigmentosum group G patients. J Invest Dermatol. 2002;118:972–82. Scholar
  34. 34.
    Brickner JR, Soll JM, Lombardi PM, et al. A ubiquitin-dependent signalling axis specific for ALKBH-mediated DNA dealkylation repair. Nature. 2017;551:389–93. Scholar
  35. 35.
    Compe E, Egly JM. TFIIH: when transcription met DNA repair. Nat Rev Mol Cell Biol. 2012;13:343–54. Scholar
  36. 36.
    Compe E, Egly JM. Nucleotide excision repair and transcriptional regulation: TFIIH and beyond. Annu Rev Biochem. 2016;85:265–90. Scholar
  37. 37.
    Radu L, Schoenwetter E, Braun C, et al. The intricate network between the p34 and p44 subunits is central to the activity of the transcription/DNA repair factor TFIIH. Nucleic Acids Res. 2017;45:10872–83. Scholar
  38. 38.
    Li X, Urwyler O, Suter B. Drosophila Xpd regulates Cdk7 localization, mitotic kinase activity, spindle dynamics, and chromosome segregation. PLoS Genet. 2010;6:e1000876. Scholar
  39. 39.
    Yeom E, Hong S-T, Choi K-W. Crumbs interacts with Xpd for nuclear division control in Drosophila. Oncogene. 2015;34:2777–89. Scholar
  40. 40.
    Fishburn J, Tomko E, Galburt E, Hahn S. Double-stranded DNA translocase activity of transcription factor TFIIH and the mechanism of RNA polymerase II open complex formation. Proc Natl Acad Sci U S A. 2015;112:3961–6. Scholar
  41. 41.
    Luo J, Cimermancic P, Viswanath S, et al. Architecture of the human and yeast general transcription and DNA repair factor TFIIH. Mol Cell. 2015;59:794–806. Scholar
  42. 42.
    Orioli D, Compe E, Nardo T, et al. XPD mutations in trichothiodystrophy hamper collagen VI expression and reveal a role of TFIIH in transcription derepression. Hum Mol Genet. 2013;22:1061–73. Scholar
  43. 43.
    Nonnekens J, Perez-Fernandez J, Theil AF, et al. Mutations in TFIIH causing trichothiodystrophy are responsible for defects in ribosomal RNA production and processing. Hum Mol Genet. 2013;22:2881–93. Scholar
  44. 44.
    Theil AF, Hoeijmakers JHJ, Vermeulen W. TTDA: big impact of a small protein. Exp Cell Res. 2014;329:61–8. Scholar
  45. 45.
    Zhang Y, Tian Y, Chen Q, et al. TTDN1 is a Plk1-interacting protein involved in maintenance of cell cycle integrity. Cell Mol Life Sci. 2007;64:632–40. Scholar
  46. 46.
    Tanaka A, Akimoto Y, Kobayashi S, et al. Association of the winged helix motif of the TFIIEα subunit of TFIIE with either the TFIIEβ subunit or TFIIB distinguishes its functions in transcription. Genes Cells. 2015;20:203–16. Scholar
  47. 47.
    Bradsher J, Coin F, Egly JM. Distinct roles for the helicases of TFIIH in transcript initiation and promoter escape. J Biol Chem. 2000;275:2532–8.CrossRefGoogle Scholar
  48. 48.
    Broughton BC, Steingrimsdottir H, Weber CA, Lehmann AR. Mutations in the xeroderma pigmentosum group D DNA repair/transcription gene in patients with trichothiodystrophy. Nat Genet. 1994;7:189–94. Scholar
  49. 49.
    Takayama K, Salazar EP, Broughton BC, et al. Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy. Am J Hum Genet. 1996;58:263–70.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Takayama K, Danks DM, Salazar EP, et al. DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a trichothiodystrophy patient. Hum Mutat. 1997;9:519–25.<519::AID-HUMU4>3.0.CO;2-X.CrossRefPubMedGoogle Scholar
  51. 51.
    Taylor EM, Broughton BC, Botta E, et al. Xeroderma pigmentosum and trichothiodystrophy are associated with different mutations in the XPD (ERCC2) repair/transcription gene. Proc Natl Acad Sci U S A. 1997;94:8658–63.CrossRefGoogle Scholar
  52. 52.
    Botta E, Nardo T, Broughton BC, et al. Analysis of mutations in the XPD gene in Italian patients with trichothiodystrophy: site of mutation correlates with repair deficiency, but gene dosage appears to determine clinical severity. Am J Hum Genet. 1998;63:1036–48. Scholar
  53. 53.
    Boyle J, Ueda T, Oh K-S, et al. Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 (XPD) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy. Hum Mutat. 2008;29:1194–208. Scholar
  54. 54.
    Zhou X, Khan SG, Tamura D, et al. Brittle hair, developmental delay, neurologic abnormalities, and photosensitivity in a 4-year-old girl. J Am Acad Dermatol. 2010;63:323–8. Scholar
  55. 55.
    Usuda T, Saijo M, Tanaka K, et al. A Japanese trichothiodystrophy patient with XPD mutations. J Hum Genet. 2011;56:77–9. Scholar
  56. 56.
    Pehlivan D, Cefle K, Raams A, et al. A Turkish trichothiodystrophy patient with homozygous XPD mutation and genotype-phenotype relationship. J Dermatol. 2012;39:1016–21. Scholar
  57. 57.
    Zhou X, Khan SG, Tamura D, et al. Abnormal XPD-induced nuclear receptor transactivation in DNA repair disorders: trichothiodystrophy and xeroderma pigmentosum. Eur J Hum Genet. 2013;21:831–7. Scholar
  58. 58.
    Schäfer A, Gratchev A, Seebode C, et al. Functional and molecular genetic analyses of nine newly identified XPD-deficient patients reveal a novel mutation resulting in TTD as well as in XP/CS complex phenotypes. Exp Dermatol. 2013;22:486–9. Scholar
  59. 59.
    Shin S, Kim J, Kim Y, et al. Analysis of mutations in the XPD gene in a patient with brittle hair. Ann Clin Lab Sci. 2013;43:323–7.PubMedGoogle Scholar
  60. 60.
    Brauns B, Schubert S, Lehmann J, et al. Photosensitive form of trichothiodystrophy associated with a novel mutation in the XPD gene. Photodermatol Photoimmunol Photomed. 2016;32:110–2. Scholar
  61. 61.
    Miguet M, Thevenon J, Laugel V, et al. Mutations in the ERCC2 (XPD) gene associated with severe fetal ichthyosis and dysmorphic features. Prenat Diagn. 2016;36:1276–9. Scholar
  62. 62.
    Vermeulen W, Rademakers S, Jaspers NG, et al. A temperature-sensitive disorder in basal transcription and DNA repair in humans. Nat Genet. 2001;27:299–303. Scholar
  63. 63.
    van de Ven M, Andressoo JO, van der Horst GTJ, et al. Effects of compound heterozygosity at the Xpd locus on cancer and ageing in mouse models. DNA Repair (Amst). 2012;11:874–83. Scholar
  64. 64.
    Horibata K, Kono S, Ishigami C, et al. Constructive rescue of TFIIH instability by an alternative isoform of XPD derived from a mutated XPD allele in mild but not severe XP-D/CS. J Hum Genet. 2015;60:259–65. Scholar
  65. 65.
    Dubaele S, Proietti De Santis L, Bienstock RJ, et al. Basal transcription defect discriminates between xeroderma pigmentosum and trichothiodystrophy in XPD patients. Mol Cell. 2003;11:1635–46.CrossRefGoogle Scholar
  66. 66.
    Lehmann AR. XPD structure reveals its secrets. DNA Repair (Amst). 2008;7:1912–5. Scholar
  67. 67.
    Fan L, Fuss JO, Cheng QJ, et al. XPD helicase structures and activities: insights into the cancer and aging phenotypes from XPD mutations. Cell. 2008;133:789–800. Scholar
  68. 68.
    Liu H, Rudolf J, Johnson KA, et al. Structure of the DNA repair helicase XPD. Cell. 2008;133:801–12. Scholar
  69. 69.
    Wolski SC, Kuper J, Hänzelmann P, et al. Crystal structure of the FeS cluster-containing nucleotide excision repair helicase XPD. PLoS Biol. 2008;6:e149. Scholar
  70. 70.
    Swagemakers SMA, Jaspers NGJ, Raams A, et al. Pollitt syndrome patients carry mutation in TTDN1. Meta Gene. 2014;2:616–8. Scholar
  71. 71.
    Pode-Shakked B, Marek-Yagel D, Greenberger S, et al. A novel mutation in the C7orf11 gene causes nonphotosensitive trichothiodystrophy in a multiplex highly consanguineous kindred. Eur J Med Genet. 2015;58:685–8. Scholar
  72. 72.
    Shah K, Ali RH, Ansar M, et al. Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP. BMC Med Genet. 2016;17:13. Scholar
  73. 73.
    de Boer J, de Wit J, van Steeg H, et al. A mouse model for the basal transcription/DNA repair syndrome trichothiodystrophy. Mol Cell. 1998;1:981–90.CrossRefGoogle Scholar
  74. 74.
    Wijnhoven SWP, Beems RB, Roodbergen M, et al. Accelerated aging pathology in ad libitum fed Xpd(TTD) mice is accompanied by features suggestive of caloric restriction. DNA Repair (Amst). 2005;4:1314–24. Scholar
  75. 75.
    de Boer J, van Steeg H, Berg RJ, et al. Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition. Cancer Res. 1999;59:3489–94.PubMedGoogle Scholar
  76. 76.
    Andressoo JO, Mitchell JR, de Wit J, et al. An Xpd mouse model for the combined xeroderma pigmentosum/Cockayne syndrome exhibiting both cancer predisposition and segmental progeria. Cancer Cell. 2006;10:121–32. Scholar
  77. 77.
    D’Errico M, Teson M, Calcagnile A, et al. Differential role of transcription-coupled repair in UVB-induced response of human fibroblasts and keratinocytes. Cancer Res. 2005;65:432–8.PubMedGoogle Scholar
  78. 78.
    Lenart P, Krejci L. DNA, the central molecule of aging. Mutat Res. 2016;786:1–7. Scholar
  79. 79.
    Ribezzo F, Shiloh Y, Schumacher B. Systemic DNA damage responses in aging and diseases. Semin Cancer Biol. 2016;37–38:26–35. Scholar
  80. 80.
    Park JY, Cho M-O, Leonard S, et al. Homeostatic imbalance between apoptosis and cell renewal in the liver of premature aging Xpd mice. PLoS One. 2008;3:e2346. Scholar
  81. 81.
    Bateman JF, Boot-Handford RP, Lamandé SR. Genetic diseases of connective tissues: cellular and extracellular effects of ECM mutations. Nat Rev Genet. 2009;10:173–83. Scholar
  82. 82.
    Arseni L, Lanzafame M, Compe E, et al. TFIIH-dependent MMP-1 overexpression in trichothiodystrophy leads to extracellular matrix alterations in patient skin. Proc Natl Acad Sci U S A. 2015;112:1499–504. Scholar
  83. 83.
    Byers PH, Pyott SM. Recessively inherited forms of osteogenesis imperfecta. Annu Rev Genet. 2012;46:475–97. Scholar
  84. 84.
    Moslehi R, Ambroggio X, Nagarajan V, et al. Nucleotide excision repair/transcription gene defects in the fetus and impaired TFIIH-mediated function in transcription in placenta leading to preeclampsia. BMC Genomics. 2014;15:373. Scholar
  85. 85.
    Compe E, Drané P, Laurent C, et al. Dysregulation of the peroxisome proliferator-activated receptor target genes by XPD mutations. Mol Cell Biol. 2005;25:6065–76. Scholar
  86. 86.
    Traboulsi H, Davoli S, Catez P, et al. Dynamic partnership between TFIIH, PGC-1α and SIRT1 is impaired in trichothiodystrophy. PLoS Genet. 2014;10:e1004732. Scholar
  87. 87.
    Compe E, Malerba M, Soler L, et al. Neurological defects in trichothiodystrophy reveal a coactivator function of TFIIH. Nat Neurosci. 2007;10:1414–22. Scholar
  88. 88.
    Cameroni E, Stettler K, Suter B. On the traces of XPD: cell cycle matters – untangling the genotype-phenotype relationship of XPD mutations. Cell Div. 2010;5:24. Scholar
  89. 89.
    Liu J, Fang H, Chi Z, et al. XPD localizes in mitochondria and protects the mitochondrial genome from oxidative DNA damage. Nucleic Acids Res. 2015;43:5476–88. Scholar
  90. 90.
    Houten BV, Kuper J, Kisker C. Role of XPD in cellular functions: to TFIIH and beyond. DNA Repair (Amst). 2016;44:136–42. Scholar
  91. 91.
    Schultz P, Fribourg S, Poterszman A, et al. Molecular structure of human TFIIH. Cell. 2000;102:599–607.CrossRefGoogle Scholar
  92. 92.
    Kleijer WJ, de Weerd-Kastelein EA, Sluyter ML, et al. UV-induced DNA repair synthesis in cells of patients with different forms of xeroderma pigmentosum and of heterozygotes. Mutat Res. 1973;20:417–28.CrossRefGoogle Scholar
  93. 93.
    Cleaver JE, Bootsma D, Friedberg E. Human diseases with genetically altered DNA repair processes. Genetics. 1975;79(Suppl):215–25.PubMedGoogle Scholar
  94. 94.
    Lehmann AR, Bootsma D, Clarkson SG, et al. Nomenclature of human DNA repair genes. Mutat Res. 1994;315:41–2.CrossRefGoogle Scholar

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© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Istituto di Genetica Molecolare CNRPaviaItaly

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