Trichothiodystrophy

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| synonyms = Amish brittle hair syndrome, BIDS syndrome, brittle hair–intellectual impairment–decreased fertility–short stature syndrome

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Trichothiodystrophy (TTD) is an autosomal recessive inherited disorder characterised by brittle hair and intellectual impairment. The word breaks down into tricho – "hair", thio – "sulphur", and dystrophy – "wasting away" or literally "bad nourishment". TTD is associated with a range of symptoms connected with organs of the ectoderm and neuroectoderm. TTD may be subclassified into four syndromes: Approximately half of all patients with trichothiodystrophy have photosensitivity, which divides the classification into syndromes with or without photosensitivity; BIDS and PBIDS, and IBIDS and PIBIDS. Modern covering usage is TTD-P (photosensitive), and TTD.{{Cite book |last=Lambert WC, Gagna CE, Lambert MW |title=Diseases of DNA Repair |year=2010 |isbn=978-1-4419-6447-2 |series=Advances in Experimental Medicine and Biology |volume=685 |pages=106–10 |chapter=Trichothiodystrophy: Photosensitive, TTD-P, TTD, Tay Syndrome |doi=10.1007/978-1-4419-6448-9_10 |pmid=20687499}}

Presentation

Features of TTD can include photosensitivity, ichthyosis, brittle hair and nails, intellectual impairment, decreased fertility and short stature. A more subtle feature associated with this syndrome is a "tiger tail" banding pattern in hair shafts, seen in microscopy under polarized light.{{Cite journal |last1=Liang |first1=Christine |last2=Kraemer |first2=Kenneth H. |last3=Morris |first3=Andrea |last4=Schiffmann |first4=Raphael |last5=Price |first5=Vera H. |last6=Menefee |first6=Emory |last7=DiGiovanna |first7=John J. |date=February 2005 |title=Characterization of tiger tail banding and hair shaft abnormalities in trichothiodystrophy |journal=Journal of the American Academy of Dermatology |volume=52 |issue=2 |pages=224–232 |doi=10.1016/j.jaad.2004.09.013 |pmid=15692466}} The acronyms PIBIDS, IBIDS, BIDS and PBIDS give the initials of the words involved. BIDS syndrome, also called Amish brittle hair brain syndrome and hair-brain syndrome,{{OMIM|234050}} is an autosomal recessive{{Cite journal |last1=Baden |first1=H. P. |last2=Jackson |first2=C. E. |last3=Weiss |first3=L. |last4=Jimbow |first4=K. |last5=Lee |first5=L. |last6=Kubilus |first6=J. |last7=Gold |first7=R. J. |date=Sep 1976 |title=The physicochemical properties of hair in the BIDS syndrome |journal=American Journal of Human Genetics |volume=28 |issue=5 |pages=514–521 |pmc=1685097 |pmid=984047}} inherited disease. It is nonphotosensitive. BIDS is characterized by brittle hair, intellectual impairment, decreased fertility, and short stature.Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. {{ISBN|0-07-138076-0}}.{{rp|501}} There is a photosensitive syndrome, PBIDS.Hashimo S, and Egly JM. Trichothiodystrophy view from the molecular basis of DNA repair transcription factor TF11H.www.oxfordjournals.org/content/18/R2/R224

BIDS is associated with the gene MPLKIP (TTDN1).{{Cite journal |vauthors=Nakabayashi K, Amann D, Ren Y, etal |date=March 2005 |title=Identification of C7orf11 (TTDN1) gene mutations and genetic heterogeneity in nonphotosensitive trichothiodystrophy |journal=Am. J. Hum. Genet. |volume=76 |issue=3 |pages=510–6 |doi=10.1086/428141 |pmc=1196401 |pmid=15645389}} IBIDS syndrome, following the acronym from ichthyosis, brittle hair and nails, intellectual impairment and short stature, is the Tay syndrome or sulfur-deficient brittle hair syndrome, first described by Tay in 1971.{{Cite journal |last=Tay CH |year=1971 |title=Ichthyosiform erythroderma, hair shaft abnormalities, and mental and growth retardation. A new recessive disorder |journal=Arch Dermatol |volume=104 |issue=1 |pages=4–13 |doi=10.1001/archderm.104.1.4 |pmid=5120162}} (Chong Hai Tay was the Singaporean doctor who was the first doctor in South East Asia to have a disease named after him.https://www.sma.org.sg/UploadedImg/files/Publications%20-%20SMA%20News/4506/Interview.pdf) Tay syndrome should not be confused with the Tay–Sachs disease.{{rp|485}}{{OMIM|601675}}{{Cite book |last1=Rapini, Ronald P. |title=Dermatology: 2-Volume Set |last2=Bolognia, Jean L. |last3=Jorizzo, Joseph L. |publisher=Mosby |year=2007 |isbn=978-1-4160-2999-1 |location=St. Louis}}Hashimoto S, and Egly JM, www.oxfordjournals.org/content/18/R2/R224 It is an autosomal recessive{{Cite journal |last1=Stefanini M |first1=B. E. |last2=Botta |first2=E. |last3=Lanzafame |first3=M. |last4=Orioli |first4=D. |date=January 2010 |title=Trichothiodystrophy: from basic mechanisms to clinical implications |journal=DNA Repair |volume=9 |issue=1 |pages=2–10 |doi=10.1016/j.dnarep.2009.10.005 |pmid=19931493}} congenital disease.{{rp|501}}{{Cite book |last1=James, William |url=https://archive.org/details/andrewsdiseasess00mdwi_659 |title=Andrews' Diseases of the Skin: Clinical Dermatology (10th ed.) |last2=Berger, Timothy |last3=Elston, Dirk |publisher=Saunders |year=2005 |isbn=978-0-7216-2921-6 |page=[https://archive.org/details/andrewsdiseasess00mdwi_659/page/n585 575] |url-access=limited}} In some cases, it can be diagnosed prenatally.{{Cite journal |vauthors=Kleijer WJ, van der Sterre ML, Garritsen VH, Raams A, Jaspers NG |date=Dec 2007 |title=Prenatal diagnosis of xeroderma pigmentosum and trichothiodystrophy in 76 pregnancies at risk |journal=Prenat. Diagn. |volume=27 |issue=12 |pages=1133–1137 |doi=10.1002/pd.1849 |pmid=17880036 |s2cid=23534246}} IBIDS syndrome is nonphotosensitive.

Cause

The photosensitive form is referred to as PIBIDS, and is associated with ERCC2/XPD and ERCC3.{{OMIM|616390}}

=Photosensitive forms=

All photosensitive TTD syndromes have defects in the nucleotide excision repair (NER) pathway, which is a vital DNA repair system that removes many kinds of DNA lesions. This defect is not present in the nonphotosensitive TTD's.Hashimoto S, and Egly JM http://www.oxfordjournals.org/content/18/R2/R224{{Dead link|date=July 2018 |bot=InternetArchiveBot |fix-attempted=no }} These types of defects can result in other rare autosomal recessive diseases like xeroderma pigmentosum and Cockayne syndrome.{{Cite journal |last1=Peserico |first1=A. |last2=Battistella, P. A. |last3=Bertoli, P. |date=1 January 1992 |title=MRI of a very rare hereditary ectodermal dysplasia: PIBI(D)S |journal=Neuroradiology |volume=34 |issue=4 |pages=316–317 |doi=10.1007/BF00588190 |pmid=1528442 |s2cid=31063628}}

=DNA repair=

Currently, mutations in four genes are recognized as causing the TTD phenotype, namely TTDN1, ERCC3/XPB, ERCC2/XPD and TTDA.{{Cite journal |vauthors=Theil AF, Hoeijmakers JH, Vermeulen W |year=2014 |title=TTDA: big impact of a small protein |journal=Exp. Cell Res. |volume=329 |issue=1 |pages=61–8 |doi=10.1016/j.yexcr.2014.07.008 |pmid=25016283}} Individuals with defects in XPB, XPD and TTDA are photosensitive, whereas those with a defect in TTDN1 are not. The three genes, XPB, XPD and TTDA, encode protein components of the multi-subunit transcription/repair factor IIH (TFIIH). This complex factor is an important decision maker in NER that opens the DNA double helix after damage is initially recognized. NER is a multi-step pathway that removes a variety of different DNA damages that alter normal base pairing, including both UV-induced damages and bulky chemical adducts. Features of premature aging often occur in individuals with mutational defects in genes specifying protein components of the NER pathway, including those with TTD{{Cite journal |vauthors=Edifizi D, Schumacher B |year=2015 |title=Genome Instability in Development and Aging: Insights from Nucleotide Excision Repair in Humans, Mice, and Worms |journal=Biomolecules |volume=5 |issue=3 |pages=1855–69 |doi=10.3390/biom5031855 |pmc=4598778 |pmid=26287260 |doi-access=free}} (see DNA damage theory of aging).

= Non-Photosensitive forms =

The non-photosensitive forms are caused by AARS1, CARS1, TTDN1, RNF113A, TARS1 and MARS1 genes.{{Cite web |title=Orphanet : Diseases |url=https://www.orpha.net/en/disease/gene/list/33364?mode=name |access-date=2025-02-27 |website=www.orpha.net}} The function of AARS1, CARS1 and TARS1 gene are to charge tRNAs with amino acid.{{Cite journal |last=Delarue |first=Marc |date=1995-02-01 |title=Aminoacyl-tRNA synthetases |url=https://www.sciencedirect.com/science/article/abs/pii/0959440X9580008O |journal=Current Opinion in Structural Biology |volume=5 |issue=1 |pages=48–55 |doi=10.1016/0959-440X(95)80008-O |pmid=7773747 |issn=0959-440X}} According to one study, the TTDN1 gene plays role in mitosis.{{Cite journal |last1=Zhang |first1=Y. |last2=Tian |first2=Y. |last3=Chen |first3=Q. |last4=Chen |first4=D. |last5=Zhai |first5=Z. |last6=Shu |first6=H.-B. |date=2007-03-01 |title=TTDN1 is a Plk1-interacting protein involved in maintenance of cell cycle integrity |journal=Cellular and Molecular Life Sciences |language=en |volume=64 |issue=5 |pages=632–640 |doi=10.1007/s00018-007-6501-8 |issn=1420-9071 |pmc=11138413 |pmid=17310276}} Some study suggests that the RNF113A gene is a part of spliceosome and it can terminate CXCR4 pathway through CXCR4 Ubiquitination.{{Cite journal |last1=Lear |first1=Travis |last2=Dunn |first2=Sarah R. |last3=McKelvey |first3=Alison C. |last4=Mir |first4=Aazrin |last5=Evankovich |first5=John |last6=Chen |first6=Bill B. |last7=Liu |first7=Yuan |date=November 2017 |title=RING finger protein 113A regulates C-X-C chemokine receptor type 4 stability and signaling |journal=American Journal of Physiology-Cell Physiology |volume=313 |issue=5 |pages=C584–C592 |doi=10.1152/ajpcell.00193.2017 |pmid=28978524 |pmc=5792167 |issn=0363-6143}}{{Cite journal |last1=Zhang |first1=Xiaofeng |last2=Yan |first2=Chuangye |last3=Zhan |first3=Xiechao |last4=Li |first4=Lijia |last5=Lei |first5=Jianlin |last6=Shi |first6=Yigong |date=March 2018 |title=Structure of the human activated spliceosome in three conformational states |journal=Cell Research |language=en |volume=28 |issue=3 |pages=307–322 |doi=10.1038/cr.2018.14 |pmid=29360106 |issn=1748-7838|pmc=5835773 }}{{Cite journal |last1=Shostak |first1=Kateryna |last2=Jiang |first2=Zheshen |last3=Charloteaux |first3=Benoit |last4=Mayer |first4=Alice |last5=Habraken |first5=Yvette |last6=Tharun |first6=Lars |last7=Klein |first7=Sebastian |last8=Xu |first8=Xinyi |last9=Duong |first9=Hong Quan |last10=Vislovukh |first10=Andrii |last11=Close |first11=Pierre |last12=Florin |first12=Alexandra |last13=Rambow |first13=Florian |last14=Marine |first14=Jean-Christophe |last15=Büttner |first15=Reinhard |date=2020-03-09 |title=The X-linked trichothiodystrophy-causing gene RNF113A links the spliceosome to cell survival upon DNA damage |journal=Nature Communications |language=en |volume=11 |issue=1 |pages=1270 |doi=10.1038/s41467-020-15003-7 |pmid=32152280 |pmc=7062854 |bibcode=2020NatCo..11.1270S |issn=2041-1723}}

RNF113A causes X-linked recessive form of TTD.{{Cite journal |last1=Corbett |first1=Mark A. |last2=Dudding-Byth |first2=Tracy |last3=Crock |first3=Patricia A. |last4=Botta |first4=Elena |last5=Christie |first5=Louise M. |last6=Nardo |first6=Tiziana |last7=Caligiuri |first7=Giuseppina |last8=Hobson |first8=Lynne |last9=Boyle |first9=Jackie |last10=Mansour |first10=Albert |last11=Friend |first11=Kathryn L. |last12=Crawford |first12=Jo |last13=Jackson |first13=Graeme |last14=Vandeleur |first14=Lucianne |last15=Hackett |first15=Anna |date=2015-04-01 |title=A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A |url=https://jmg.bmj.com/content/52/4/269 |journal=Journal of Medical Genetics |language=en |volume=52 |issue=4 |pages=269–274 |doi=10.1136/jmedgenet-2014-102418 |issn=0022-2593 |pmid=25612912}}

Diagnosis

The diagnosis of TTD can by made by showing low sulfur content by biochemical assay of hair shafts, also, it can by following findings:{{Cite journal |last1=Hashimoto |first1=Satoru |last2=Egly |first2=Jean Marc |date=2009-10-15 |title=Trichothiodystrophy view from the molecular basis of DNA repair/transcription factor TFIIH |url=https://academic.oup.com/hmg/article-abstract/18/R2/R224/605065?redirectedFrom=fulltext&login=false |journal=Human Molecular Genetics |volume=18 |issue=R2 |pages=R224–R230 |doi=10.1093/hmg/ddp390 |pmid=19808800 |issn=0964-6906}}

Trichoschisis (broken or split hairs)
Alternating light and dark bands called 'tiger-tail pattern' are found in the hair shaft, which can be detected by polarised light microscopy or trichoscopy.
A severely damaged or absent hair cuticle can be seen by electron microscopy scanning.

Treatment

This disease doesn't have a cure, although it can be managed symptomatically.{{Cite journal |last1=Faghri |first1=S. |last2=Tamura |first2=D. |last3=Kraemer |first3=K. H. |last4=DiGiovanna |first4=J. J. |date=2008-10-01 |title=Trichothiodystrophy: a systematic review of 112 published cases characterises a wide spectrum of clinical manifestations |url=https://jmg.bmj.com/content/45/10/609.long |journal=Journal of Medical Genetics |language=en |volume=45 |issue=10 |pages=609–621 |doi=10.1136/jmg.2008.058743 |issn=0022-2593 |pmid=18603627|pmc=3459585 }} Patients with Photosensetive forms should be provided with sun protection.{{Cite web |title=Orphanet: Trichothiodystrophy |url=https://www.orpha.net/en/disease/detail/33364 |access-date=2025-02-27 |website=www.orpha.net}}