DISEASE CARD

Defintion

Trichothiodystrophy (TTD) is a term introduced by Price et al. (1980) to describe a rare autosomal recessive neuroectodermal disorder whose primary feature is sulphur-deficient brittle hair caused by a reduced level of cysteine-rich matrix proteins. Approximately half of the patients with TTD exhibit cutaneous photosensitivity. Those cases show an altered cellular response to UV light due to a defect in nucleotide excision repair (NER), as a consequence of mutations in one of three genes, namely XPB/ERCC3, XPD/ERCC2 and  TTDA/GTF2H5.^1-4

The four genes so far associated with non-photosensitive TTD, namely TTDN1/MPLKIP, RNF113A, GTF2E2 and TARS indeed account for only about 20% of the patients.^4-7

Clinical Description

All TTD patients exhibit sparse, dry and easily broken hair associated with low sulfur and cysteine content (10–50% of normal). The scalp hair anomalies, which extend to eyebrows and eyelashes, are associated with a wide spectrum of clinical symptoms that usually affect organs of ectodermal and neuroectodermal origin.⁸

Neurologic pathologies are common (up to 86% of cases), including mental retardation, developmental delay, motor disorder and microcephaly. Nail dysplasia is a further feature, as well as ichthyosis (up to 80% of individuals show skin changes). At birth, children often present with ichthyosiform erythroderma, they even may be encased in a collodion-like membrane. Only rarely, ichthyosis manifests within the first few weeks of life. As in autosomal dominant ichthyosis, the flexures of the limbs usually are spared.⁹

The disorder is characterized by a broad variation of disease severity and extent. A few mild cases have been described with hair abnormalities but without physical and mental impairment. Other patients show a pathological phenotype of moderate severity with short stature, delayed puberty, mental development at pre-school or primary school level, axial hypotonia, reduced motor coordination and survival beyond early childhood. The most severe form is characterized by very poor mental and motor performance and speech, failure to thrive and death during early childhood, most commonly due to (pulmonary) infections that account for an increased mortality rate in affected children. In addition, osteoporosis, hearing loss, cataracts, dental caries, and other features of premature ageing (e.g. loss of facial subcutaneous fat) have been reported.⁹ Further common TTD features include small height (81%), pregnancy complications, low birth weight or collodion membrane at birth (55%), ocular anomalies (e.g. infantile cataracts,, refractive error, microcornea, nystagmus, focal retinal dystrophy) or thalassemia-like changes.^10-13. Less common are gonadal dysgenesis and abnormalities in the skeletal, cardiac, hepatic and hematologic (e.g. neutropenia) systems.⁹

Forty to 50% of patients show an abnormal sun reaction on minimal sun exposure with blistering and persistent erythema. In the photosensitive TTD patients, the definition of the disease-gene and of the causative mutation(s) might be informative for the prognosis. Individuals with mutation in GTF2H5 gene seem to be moderately affected and cases mutated in XPB were so far associated with a very mild phenotype. The cases defective in XPD (more than 80% of the photosensitive TTD patients) show a wide variety in the severity of the pathological phenotype depending on the nature of the mutated XPD alleles.

Among the non-photosensitive TTD patients, about 15% of the cases are mutated in the TTDN1 gene. They show different degrees of disease severity. Deep phenotyping of a cohort of thirty-six patients exhibiting the clinical features of TTD has uncovered a distinct genotype-phenotype relationship in the TTDN1-defective cases. As compared with patients mutated in XPD, GTF2H5 or unidentified genes, delayed bone age and seizures were over-represented in the TTDN-1 group.^{6, 9}

Typical TTD features associated with a heart-specific failure, i.e. mitral regurgitation, were observed in the affected members of three consanguineous Pakistani families carrying a peculiar splicing variant of TTDN1.¹⁴ RNF113A is mutated in only two Australian male cousins both showing severe clinical features. They presented with an extended phenotype including cutis marmorata, panhypopituitarism and congenital short oesophagus.⁶ In contrast, five reported patients with mutations in GTF2E2 all show a moderate phenotype.¹⁵

Pathogenesis

Photosensitive TTD is caused by mutations in the XPB, XPD or GTF2H5 genes. These genes encode distinct subunits of TFIIH, a multifunctional protein complex. TFIIH participates to DNA repair through the process of NER and is also a general transcription factor essential in the transcription process. All mutations identified in photosensitive TTD patients impact on the stability and functionality of the TFIIH complex thus affecting its role in both NER and transcription. However, the observation that non-photosensitive TTD patients (who are NER-proficient) share with photosensitive cases all the clinical features except cutaneous photosensitivity indicates that the DNA repair defect may not be the main determinant of the wide spectrum of symptoms of the disease. Ongoing research is indeed highlighting the contribution of transcriptional impairments in the aetiopathogenesis of the TFIIH-related photosensitive form of TTD. In addition, the finding of non-photosensitive TTD cases associated with mutations in GTF2E2 encoding the beta subunit of the transcription factor TFIIE strongly supports the proposition that TTD is a “transcription syndrome”. It cannot however be ruled out that the accumulation of unrepaired DNA lesions may enhance the consequences of transcriptional deficiencies in the photosensitive cases.¹⁶

Ichthyosis in TTD is likely linked to altered expression of LXR (Liver X receptor) responsive genes, including ABCA12 (Harlequin ichthyosis) and ABCG1 (involved in cholesterol transport in the epidermis).¹⁷

Diagnosis

The main diagnostic criteria of TTD are brittle hair, mental and growth retardation, typical facies, and ichthyosis. The hair abnormalities are considered the key factors for diagnosis. Scalp hair, eyebrows, and eyelashes are short, thin, brittle and dry. Light microscopy of pulled hair may reveal irregular hair surface and diameter, trichoschisis, a decreased cuticular layer with twisting (pili torti), and a nodal appearance that mimics trichorrhexis nodosa. Trichoscopy, as a noninvasive and easily applicable method, may display broken hair with exaggerated curls (glomerule like appearance), grains of sand appearance and wavy contour of the hair shafts. Polarisation microscopy of the hair typically shows alternating light and dark bands that confer a "tiger tail" pattern (may not be present before 3 months of age). ^{18, 19}

The photosensitive form of TTD can be diagnosed by analyzing patient’s cells for the appropriate DNA repair defect.²⁰ Specific functional assays on in vitro cultured skin fibroblasts from the patients (obtained from small skin biopsies) are available to evaluate the cellular response to UV light and to define the gene responsible for the DNA repair defect. Definition of the molecular defect may be informative for the prognosis. In patients with the non-photosensitive form of TTD, no cellular assays are available for diagnosis confirmation. In these cases, sequencing of the TTDN1, RNF113A, GTF2E2 and TARS genes might be informative. Cases of x-linked recessive forms (RFN113A mutation) have been described.⁶ RNF113A deficiency triggers cell death upon DNA damage through multiple mechanisms, including apoptosis via the destabilization of the prosurvival protein MCL-1, ferroptosis and enhances production of ROS due to altered Noxa1 expression. ²¹ Photosensitive TTD are associated with mutations in the XPB, XPD or TTDA genes.

Treatment

Baseline evaluation includes measurement of growth, developmental assessment, dental evaluation, dermatologic, ophthalmologic and audiologic evaluations, brain MRI, skeletal X-rays to document the presence of skeletal dysplasia and electromyography (EMG) to document the presence of a demyelinating neuropathy. Annually checks (esp. eyes, ears) to early identify potential complications (e.g. declining vision and hearing) are recommended.  

Symptomatic care includes an individualized educational program, assistive devices, and assessment of safety in the home for developmental delay and gait disturbances, physical therapy to prevent contractures and maintain ambulation, in severe cases feeding gastrostomy tube placement for prevention of malnutrition, treatment of spasticity, management of hearing loss, cataracts, and other ophthalmologic complications and dental care to minimize dental caries. Treatment of skin lesions includes ceramides, glucocorticoids, topical calcineurininhibitors as well as sun protection in case of photosensitivity.

In a case report, efficacy of dupilumab (IL-4/IL-13 antibody) has been shown in a boy by significantly reducing the ichthyosis, eczema and pruritus.²²

References

^{1. Takayama K, Danks DM, Salazar EP, Cleaver JE, Weber CA. DNA repair characteristics and mutations in the ERCC2 DNA repair and transcription gene in a trichothiodystrophy patient. Hum Mutat. 1997;9(6):519-525.}

^{2. Weeda G, Eveno E, Donker I, et al. A mutation in the XPB/ERCC3 DNA repair transcription gene, associated with trichothiodystrophy. Am J Hum Genet. 1997;60(2):320-329.}

^{3. 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(7):714-719.}

^{4. Theil AF, Botta E, Raams A, et al. Bi-allelic TARS Mutations Are Associated with Brittle Hair Phenotype. Am J Hum Genet. 2019;105(2):434-440}

^{5. 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(3):510-516.}

^{6. Corbett MA, Dudding-Byth T, Crock PA, et al. A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A.J Med Geent 2015;52(4):269-274.}

^{7. 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(4):627-642.}

^{8. Liang C, Morris A, Schlücker S, et al. Structural and molecular hair abnormalities in trichothiodystrophy. J Invest Dermatol. 2006;126(10):2210-2216.}

^{9. 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(10):609-621.}

^{10. Tunç U, Demir G, Kutlay A, Akbaş YB. A rare ocular manifestation of trichothiodystrophy: Focal retinal dystrophy. J Fr Ophtalmol. 2021;44(9):e547-e550.}

^{11. Brooks BP, Thompson AH, Clayton JA, et al. Ocular manifestations of trichothiodystrophy. Ophthalmology.2011;118(12):2335-2342.}

^{12. Heller ER, Khan SG, Kuschal C, Tamura D, DiGiovanna JJ, Kraemer KH. Mutations in the TTDN1 gene are associated with a distinct trichothiodystrophy phenotype. J Invest Dermatol. 2015;135(3):734-741.}

^{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(24):2797-2802.}

^{14. 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}

^{15. 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(23):4689-4698.}

^{16. Hashimoto S, Egly JM. Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH. Human molecular genetics. 2009;18(R2):R224-R230.}

^{17. Hashimoto S, Takanari H, Compe E, Egly JM. Dysregulation of LXR responsive genes contribute to ichthyosis in trichothiodystrophy. J Dermatol Sci. 2020;97(3):201-207.}

^{18. Rudnicka L, Olszewska M, Waśkiel A, Rakowska A. Trichoscopy in Hair Shaft Disorders. Dermatol Clin. 2018;36(4):421-430.}

^{19. Yılmaz MA, Nasirov V. Glomerular hair sign: New trichoscopic finding in a patient with trichothiodystrophy. 2021;34(1):e14676.}

^{20. Lehmann AR, Arlett CF, Broughton BC, et al. Trichothiodystrophy, a human DNA repair disorder with heterogeneity in the cellular response to ultraviolet light. Cancer Res. 1988;48(21):6090-6096.}

^{21. Shostak K, Jiang Z, Charloteaux B, et al. The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage. 2020;11(1):1270.}

^{22. Gruber R, Zschocke A, Zellner H, Schmuth M. Successful treatment of trichothiodystrophy with dupilumab. 2021;46(7):1381-1383.}