Continuing Medical EducationTrichothiodystrophy: Update on the sulfur-deficient brittle hair syndromes☆,☆☆
Section snippets
Definition and diagnosis
The term trichothiodystrophy (TTD) was coined by Price in 1979-19801, 2, 3 based on a series of cases, including the early report by Pollitt, Jenner, and Davies4 in 1968, of a family with mental and physical retardation and “trichorrhexis nodosa” with abnormal amino acid composition of the hair. Brown et al5 in 1970 specifically described the congenital hair defect, consisting of trichoschisis, “alternating birefringence,” and low-sulfur content. The designation for this unique hair shaft
New findings in light microscopy and scanning electron microscopy of hair
In patients with TTD, hair abnormalities are the only obligatory and diagnostic findings that identify the sulfur-deficient neuroectodermal dysplasias. Scalp hairs, eyebrows, and eyelashes are brittle, unruly, of variable lengths, easily broken, and generally feel dry. It is important to investigate the proximal parts of hair shafts because the distal portions often show marked weathering that may produce findings similar to TTD.103 Macroscopic alterations are observed especially in the frontal
Prenatal diagnosis
Selected types of TTD manifest significantly more severe and potentially lethal phenotypes. In these cases, prenatal diagnosis and therapeutic abortion or other interventions have been considered. Approximately 50% of patients with TTD show photosensitivity and reduced DNA repair levels similar to those found in XP.135 Under these circumstances, prenatal diagnosis based on measurement of DNA repair in trophoblasts or amniotic cells and subsequent confirmation by microscopic analysis of fetal
Cellular and molecular genetic characteristics of TTD
On treatment with DNA-damaging agents, it is possible to detect and further characterize cellular abnormalities linked to nucleotide excision repair (NER) defects with the use of end points such as reduced levels of DNA repair synthesis, decreased cell survival, decreased rates of DNA and RNA synthesis, and increased mutability.139 Cells from patients with NER defects are usually assigned to a designated complementation group by means of the somatic cell fusion assay that measures the level of
Transgenic and knockout mice
Because no animal model had been available to mimic human DNA repair-deficient diseases, transgenic mice and, subsequently, knockout animals have been produced to study the biologic consequences of repair deficiency in animals. NER-deficient mice have recently been generated, giving rise to phenotypes close to XP, CS, and TTD.124 As expected, XPA and XPC knockout or null animals were very close to the human phenotypes, showing UV sensitivity and predisposition to cancer, whereas XPD and XPB
Lack of predisposition to cancer in TTD
It is clear that during their lifetimes, patients with TTD with DNA repair deficiency as well as those with CS do not develop excess malignancies, whereas patients with classic or variant XP with similar DNA repair defects are predisposed to numerous malignancies.166, 167, 179
Vuillaume et al192 reported striking differences in cellular catalase activity between XP and TTD. In XP fibroblasts, catalase activity was 5-fold less than that in controls. Fibroblasts of patients with TTD showed a high
TTD as a transcription disease
Clinically, it is increasingly evident that TTD with photosensitivity and CS resemble each other. Overlap in neurologic, developmental, and cutaneous abnormalities and the lack of cancer predisposition are observed. NER defects can easily explain photosensitivity and a predisposition to cancer but not growth retardation, brittle hair and nails, and neurodysmyelination as found in CS and TTD. Because for some patients the cellular responses to UV in TTD and XP are very close, it can be concluded
Conclusion
In recent years, enormous progress has been made in our understanding of the NER processes and transcription factor complexes in humans and in the molecular mechanisms underlying UV-sensitive diseases such as TTD. The constellation of growth retardation, brittle hair, and neurodysmyelination has been difficult to explain by NER defects alone. There is now strong evidence that these non-XP features of TTD are due to an impairment of the transcription function of XPD and XPB gene products,
Acknowledgements
We thank Drs A. Stary and T. Magnaldo for critical reading of the manuscript and Drs A. Lehmann and J. M. Egly for providing unpublished data.
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2022, Actas Dermo-SifiliograficasA case of severe trichothiodystrophy 3 in a neonate due to mutation in the GTF2H5 gene: Clinical report
2019, European Journal of Medical GeneticsCitation Excerpt :The inheritance pattern of TTD is predominantly autosomal recessive, though a novel X-linked nonsense mutation was found within the RNF113A gene (Corbett et al., 2015). The condition was first described in 1980 by Price (Itin et al., 2001), reporting two patients with a wide range of clinical features whose hair had the alternating bright and dark banding pattern called ‘tiger tail banding’ when observed under polarised microscopy. Since then, two distinct forms of TTD have been identified and characterized by the presence or absence of clinical and cellular photosensitivity (Stefanini et al., 2010).
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2019, Helicases from All Domains of LifeTrichoscopy in Hair Shaft Disorders
2018, Dermatologic ClinicsRole of Human Xeroderma Pigmentosum Group D (XPD) Helicase in Various Cellular Pathways
2018, Helicases from All Domains of LifeAlgorithmic approach toward diagnosis of patients with congenital photosensitivity disorders and review of literature
2024, International Journal of Dermatology
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Reprint requests: Mark R. Pittelkow, Department of Dermatology, Mayo Clinic and Mayo Foundation, 200 First St SW, Rochester, MN 55905.
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J Am Acad Dermatol 2001;44:891-920