Continuing Medical Education
Trichothiodystrophy: Update on the sulfur-deficient brittle hair syndromes,☆☆

https://doi.org/10.1067/mjd.2001.114294Get rights and content

Abstract

Trichothiodystrophy (TTD) refers to a heterogeneous group of autosomal recessive disorders that share the distinctive features of short, brittle hair and an abnormally low sulfur content. Within the spectrum of the TTD syndromes are numerous interrelated neuroectodermal disorders. The TTD syndromes show defective synthesis of high-sulfur matrix proteins. Abnormalities in excision repair of ultraviolet (UV)-damaged DNA are recognized in about half of the patients. Three distinct autosomal recessive syndromes are associated with nucleotide excision repair (NER) defects: the photosensitive form of TTD, xeroderma pigmentosum, and Cockayne syndrome. The unifying feature of these conditions is exaggerated sensitivity to sunlight and UV radiation. In contrast to patients with xeroderma pigmentosum, no increase of skin cancers in patients with TTD has been observed. Genetically, 3 complementation groups have been characterized among photosensitive patients with TTD. Most patients exhibit mutations on the two alleles of the XPD gene. Rarely, mutated XPB gene or an unidentified TTD-A gene may result in TTD. In UV-sensitive TTD, the TFIIH transcription factor containing XPB and XPD helicase activities necessary for both transcription initiation and DNA repair is damaged. Beyond deficiency in the NER pathway, it is hypothesized that basal transcription may be altered leading to decreased transcription of specific genes. Depressed RNA synthesis may account for some clinical features, such as growth retardation, neurologic abnormalities, and brittle hair and nails. Therefore the attenuated expression of some proteins in differentiated cells is most likely explained by a mechanism distinct from DNA repair deficiency. The first transgenic mouse models for NER deficiencies have been generated. The TTD mouse as well as related cell models will provide important tools to understand the complex relationships between defects in DNA repair, low-sulfur hair shaft disorders, and the genotype-phenotype correlates for this constellation of inherited disorders, including the lack of predisposition to cancer in patients with TTD. (J Am Acad Dermatol 2001;44:891-920.) Learning objective: At the completion of this learning activity, participants will have a current understanding of the expanded and further defined clinical spectrum of the TTD syndromes. Participants will have gained new insight into the genetic and molecular characteristics and causes for the low-sulfur hair disorders.

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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    ☆☆

    J Am Acad Dermatol 2001;44:891-920

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