Ocular Manifestations of Trichothiodystrophy

Abstract

Objective Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterized by sulfur-deficient brittle hair and multisystem abnormalities. Many TTD patients have a defect in known DNA repair genes. This report systematically evaluates the ocular manifestations of the largest-to-date cohort of TTD patients and xeroderma pigmentosum (XP)/TTD patients. Design Case Series Participants Thirty-two participants, ages 1 to 30 years, referred to the National Eye Institute for examination from 2001 to 2010: Twenty-five had TTD, and 7 had XP/TTD. Methods Complete, age- and developmental stage-appropriate ophthalmic examination. Main Outcome Measures Visual acuity (VA), best corrected VA, ocular motility, state of the ocular surface and corneal endothelial cell density, corneal diameter, lens assessment. Results Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataracts (56% TTD and 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected VA was present in 28% of TTD patients and 71% of XP/TTD patients. Degenerative changes included dry eye (32% TTD, 57% XP/TTD) and ocular surface disease identified by ocular surface staining with fluorescein (32% TTD), that usually are exhibited by much older patients in the general population. The two oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization. Conclusions TTD and XP/TTD study participants had a wide variety of ocular findings including refractive error, infantile cataracts, microcornea, nystagmus, and dry eye/ocular surface disease. While many of these can be ascribed to abnormal development—likely due to abnormalities in basal transcription of critical genes—patients may also have a degenerative course.

Corneal endothelium in xeroderma pigmentosum: clinical specular microscopy study

“…The age of the patients in our study is comparable with that of the case series by Okubo et al 1 (17.8±10.2 years, p=0.77) and Goyal et al 6 (15.9±13.4 years, p=0.87), the latter also having a similar gender distribution (p=0.97). The case series by Brooks et al 15 had two males and five females (p=0.08), and their visual acuities (IQR 0.00–0.10) are comparable with our study.…”

“…The range of the values (1387–2499 cells/mm 2 ) in xeroderma pigmentosum is below the representative values of the normal corneal endothelium over a lifetime 11. Brooks et al 15 assessed endothelial cell density in three individuals with xeroderma pigmentosum, and found one to have normal values, one borderline low values and the third to have low values. The average cell area, coefficient of variation of cell area and maximum cell area were much higher in patients with xeroderma pigmentosum than in the controls.…”

Disruption of TTDA Results in Complete Nucleotide Excision Repair Deficiency and Embryonic Lethality

“…Siblings TTD13PV and TTD14PV carry a homozygous mutation in the ATG start codon, aborting TTDA protein synthesis. Intriguingly, despite the rather diverse clearly severe mutations, these patients are surprisingly similar in their expression of the clinical features [15], [23], [24], consistent with the idea that they all represent null-alleles. Yeast strains with a complete Ttda deletion are viable [20], whereas complete absence of the TFIIH subunits XPB and XPD is incompatible with life in both mammals and yeast [25]–[27], likely due to their indispensable role in transcription.…”

Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novelXPD/ERCC2mutation

“…We are unsure how to interpret this, as the normal mitochondria and MRI-c contradict a dominant CS phenotype. Furthermore, the ocular findings of TTD238DOD are in line with those previously reported for XP/TTD patients, although cataract was severe and he also had iridal pigmentary changes 15 . Overall, the phenotype in the presented case is indeed that of mild XP together with a slightly altered TTD, suggestive of a beneficial interplay between the gene-products and it should be emphasized that lack of the tell-tale tiger tail pattern does not rule out TTD.…”