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Year : 2022  |  Volume : 2  |  Issue : 4  |  Page : 962-964

A rare case in a child with mild trichothiodystrophy associated with ERCC2 gene

1 Department Paediatric Ophthalmology and Adult Strabismus Services, Aravind Eye Hospital, Madurai, Tamil Nadu, India
2 Department of Genetics Aravind Medical Research Foundation, Affiliation with Department of Molecular Biology, Alagappa University, Karaikudi, Tamil Nadu, India

Date of Submission19-May-2022
Date of Acceptance21-Jun-2022
Date of Web Publication11-Oct-2022

Correspondence Address:
Dr. Rajendran Janani
Paediatric Ophthalmology and Adult Strabismus Services, Aravind Eye Hospital, Madurai, Tamil Nadu
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_1217_22

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A 7-year-old girl with bilateral cataracts, along with photosensitivity, was suspected to have xeroderma pigmentosum. Further dermatological examination confirmed the proband had dry skin, brittle hair, high-arched palate, and ichthyosis. The proband underwent bilateral cataract surgery. Her best corrected visual acuity (BCVA) improved to 6/9 in both eyes. Polarizing light microscopic observation of the proband eyebrow hair shaft resembled tiger tail-like stripes, which is an authentic clinical feature associated with trichothiodystrophy (TTD). Furthermore, on whole exome sequencing (WES) of the proband, mutations in the ERCC2 gene were found to be strongly associated with TTD1.

Keywords: ERCC2 gene, exome sequencing, ichthyosis, tiger tail-like hair shaft, trichothiodystrophy, TTD1 photosensitive

How to cite this article:
Janani R, Chermakani P, Sundaresan P, Shetty S, Rai K. A rare case in a child with mild trichothiodystrophy associated with ERCC2 gene. Indian J Ophthalmol Case Rep 2022;2:962-4

How to cite this URL:
Janani R, Chermakani P, Sundaresan P, Shetty S, Rai K. A rare case in a child with mild trichothiodystrophy associated with ERCC2 gene. Indian J Ophthalmol Case Rep [serial online] 2022 [cited 2022 Nov 30];2:962-4. Available from: https://www.ijoreports.in/text.asp?2022/2/4/962/358148

The term trichothiodystrophy (TTD) is derived from a Greek word (tricho – hair; thio – sulfur; dys – faulty; trophy – nourishment).[1] The probands are defined by six distinct clinical features, known collectively as PIBIDS (photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, and short stature).[2] Mutations in the ERCC2 gene are commonly associated with heterogenous disorders such as xeroderma pigmentosum complementation group D (XP-D), TTD1, cerebro-oculo-facio-skeletal syndrome 2 (COFS2), and mixed phenotype acute leukemia, T/myeloid (cMPAL). The XPD protein encoded by the ERCC2 gene has an important segment comprising transcriptional factor IIH (TFIIH) which activates transcription coupled nucleotide excision repair (NER) through adenosine triphosphate (ATP) dependent DNA helicase. DNA damage triggers transcription, favors the binding of TFIIH to ERCC2 gene promoter, and forms pores around the DNA lesions, eventually resulting in cutting the erroneous DNA fragment and substituting the precise DNA fragment through NER pathway.[3] TTD1 often presents in photosensitive and non-photosensitive forms. Photosensitive forms tend to have genetic mutations in ERCC2, ERCC3, and GTF2H5, while non-photosensitive forms have mutations in GTF2E2, TARS1, MPLKIP, and RNF113A. The population prevalence of TTD1 in united states is estimated to be 1 in every 1.2 Million.[4] So far, 45 missense mutations in the ERCC2 gene have been reported, and are associated with any one of the following four diseases: XP-D, TTD1, COFS2, and cMPAL. Of these, 18 missense mutations in the ERCC2 gene are exclusively involved in the pathogenesis of TTD1. To date, only two siblings from India have been reported to harbor mutations in the MPLKIP gene, a M-phase–specific PLK1-interacting protein, which causes non-photosensitive TTD4.[5] This study describes a rare case of mild TTD with ERCC2 genetic association.

  Case Report Top

A 7-year-old girl born of nonconsanguineous parents presented with bilateral cataracts, microphthalmos, and photosensitivity, which led to the clinical suspicion of xeroderma pigmentosum [Figure 1]a. Further, a dermatological observation of the proband identified dry skin, brittle hair and nails, a high-arched palate, and ichthyosis [Figure 1]b and [Figure 1]c. Ophthalmic examination of the proband displayed bilateral cataracts of the type cataracta pulverulenta, and her best corrected visual acuity (BCVA) was (6/18) in both eyes [Figure 1]d. The axial length of the intraocular lens (IOL Master 700) in the right eye (RE) was 19.75 mm and in the left eye (LE) was 19.03 mm, indicating simple microphthalmia. The posterior pole was found to be hyperopic on fundoscopy. Pedigree analysis showed the proband had no previous medical/family history of ocular and dermal anomalies [Figure 1]e.
Figure 1: Clinical presentation of the proband with bilateral cataracts and mild TTD1. (a) Proband digits exhibit brittle nails. (b) Clinical photograph of a 7 year old girl proband with brittle and stubby hair. (c) Slit lamp photograph shows cataract (cataracta pulverulenta). (d) Dermatological representation of the proband shows ichthyosis like scaly dry skin. (e) Pedigree of the proband involved in this study. Circle filled with black shade with an arrow – proband; unaffected disease carriers are unshaded. (f) The proband hair shaft displays alternate bright and dark bands, similar to a tiger tail pattern, which is a typical feature associated with TTD1. (g) Normal hair shaft lacks tiger tail like banding pattern under polarizing light microscope. TTD = trichothiodystrophy

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The proband's vision improved to 6/9 in both eyes after cataract surgery, indicating a successful outcome. Polarizing light microscopic observation of the proband's hair shaft revealed a tiger tail-like striping pattern with alternate light and dark bands, a distinguishing feature of TTD1 due to a lack of sulfur and cysteine [Figure 1]f, while the control hairs remain normal [Figure 1]g. Whole exome sequencing (WES) results identified a pathogenic homozygous missense variant in exon 21 (rs121913021) of the ERCC2 gene. A transversion mutation (NG 007067.2:g.23008C>G; c.1972C>G; resulting in the substitution of p. R658G) in helicase domain VI was likely to be associated with TTD1 [Figure 2]a and [Figure 2]b.
Figure 2: Genetic map of ERCC2 and validation of the missense variant using Sanger sequencing. (a) Genetic map of ERCC2 gene. It has four XPD domains shown as HD1 (yellow), HD2 (pink), 4 FeS (green), and Arch (red). Mutation associated with TTD1 clinical phenotype is indicated in blue colour. The missense variant identified in this study is indicated in red color (labeled with a red star). (b) Genetic validation of exon 21 in the ERCC2 gene in proband and her parents using Sanger sequencing. TTD = trichothiodystrophy

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  Discussion Top

ERCC2 gene mutations frequently impede the DNA repair mechanism, resulting in XP-D, TTD1, and Cockayne syndrome. The nucleotide sequence analysis of the ERCC2 variant with its amino acid Arg658 changed to either His or Cys in TTD cell strains showed intermediate ultraviolet (UV) sensitivity.[6] The primary fibroblast of a TTD patient with Arg658Cys mutation in the ERCC2 gene destabilizes TFIIH in an in vivo temperature-sensitive defect of transcription and DNA repair due to TFIIH thermo-instability.[7] As a result, the amino acid residue Arg658 of the ERCC2 gene was depicted as a TTD-susceptible residue. This study identified a modified homozygous missense variant (c. C1972G; p. R658G) in the ERCC2 gene that encodes a unique amino acid glycine, contributing to the clinical phenotype TTD1. Moreover, the microscopic examination of the proband hair also showed a “tiger tail-like banding pattern,” which is a definitive feature noted in TTD1 patients. Oftentimes, TTD patients with brittle hair or nails have a decreased rate of basal transcription of the ERCC2 gene.[8] The structural and molecular analysis of 15 hairs from TTD patients using confocal microscopy and Raman spectroscopy, respectively, revealed breaks and disordered disulfide conformers in the hair shafts. Additionally, this study found no correlation between disease severity and the proportion of abnormal hairs present in TTD patients.[9] In our case report bilateral cataract, microphthalmia and other clinical features of the proband, correlated with the manifestations of TTD1 or XP/TTD1 patients. In a study cohort of 32 patients, 94% of the individuals presented with some degree of visual abnormalities, of which 56% of the probands displayed infantile cataract,while microphthalmia accounted for 8%.[10] Our study concludes that this could be a milder case of TTD due to the absence of mental impairment, short stature, and repeated infections. To the best of our knowledge, this is the first report from India that describes the clinical and molecular manifestations of a milder form of TTD1 associated with ERCC2. The mutations identified in this study were strongly associated with intermediate UV sensitivity and TFIIH destabilization and are supported strongly by literature reports.

  Conclusion Top

The child has been successfully treated for bilateral cataracts. This is a unique case describing a milder form of TTD1 that is clinically and genetically linked to ERCC2. In the future, the proband may develop secondary infections associated with TTD1. So, their family members are advised to monitor the child's routine hygiene for better patient management.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Faghri S, Tamura D, Kraemer KH, Digiovanna JJ. Trichothiodystrophy: A systematic review of 112 published cases characterizes a wide spectrum of clinical manifestations. J Med Genet 2008;45:609-21.  Back to cited text no. 1
Crovato F, Borrone C, Rebora A. Trichothiodystrophy--BIDS, IBIDS and PIBIDS? Br J Dermatol 1983;108:247.  Back to cited text no. 2
Arab HH, Wani G, Ray A, Shah ZI, Zhu Q, Wani AA. Dissociation of CAK from core TFIIH reveals a functional link between XP-G/CS and the TFIIH disassembly state. PLoS One 2010;5:e11007.  Back to cited text no. 3
Kleijer WJ, Laugel V, Berneburg M, Nardo T, Fawcett H, Gratchev A, et al. Incidence of DNA repair deficiency disorders in western Europe: Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. DNA Repair (Amst) 2008;7:744-50.  Back to cited text no. 4
Pande S, Shukla A, Girisha KM. Trichothiodystrophy type 4 in an Indian family. Am J Med Genet A 2020;182:2226-9.  Back to cited text no. 5
Takayama K, Salazar EP, Broughton BC, Lehmann AR, Sarasin A, Thompson LH, et al. Defects in the DNA repair and transcription gene ERCC2(XPD) in trichothiodystrophy. Am J Hum Genet 1996;58:263-70.  Back to cited text no. 6
Vermeulen W, Rademakers S, Jaspers NG, Appeldoorn E, Raams A, Klein B, et al. A temperature-sensitive disorder in basal transcription and DNA repair in humans. Nat Genet 2001;27:299-303.  Back to cited text no. 7
Liang C, Kraemer KH, Morris A, Schiffmann R, Price VH, Menefee E, et al. Characterization of tiger-tail banding and hair shaft abnormalities in trichothiodystrophy. J Am Acad Dermatol 2005;52:224-32.  Back to cited text no. 8
Liang C, Morris A, Schlücker S, Imoto K, Price VH, Menefee E, et al. Structural and molecular hair abnormalities in trichothiodystrophy. J Invest Dermatol 2006;126:2210-6.  Back to cited text no. 9
Brooks BP, Thompson AH, Clayton JA, Chan CC, Tamura D, Zein WM, et al. Ocular manifestations of trichothiodystrophy. Ophthalmology 2011;118:2335-42.  Back to cited text no. 10


  [Figure 1], [Figure 2]


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