Trichothiodystrophy

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.^[2]

Trichothiodystrophy
Other names	Amish brittle hair syndrome, BIDS syndrome, brittle hair–intellectual impairment–decreased fertility–short stature syndrome[1]
This condition is inherited in an autosomal recessive manner.[1]
Specialty	Dermatology, medical genetics

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.^[3] 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,^[4] is an autosomal recessive^[5] inherited disease. It is nonphotosensitive. BIDS is characterized by brittle hair, intellectual impairment, decreased fertility, and short stature.^[6]: 501 There is a photosensitive syndrome, PBIDS.^[7]

BIDS is associated with the gene MPLKIP (TTDN1).^[8] 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.^[9] (Chong Hai Tay was the Singaporean doctor who was the first doctor in South East Asia to have a disease named after him.^[10]) Tay syndrome should not be confused with the Tay–Sachs disease.^{[6]: 485 [11][12][13]} It is an autosomal recessive^[14] congenital disease.^{[6]: 501 [15]} In some cases, it can be diagnosed prenatally.^[16] IBIDS syndrome is nonphotosensitive.

Cause

The photosensitive form is referred to as PIBIDS, and is associated with ERCC2/XPD^[11] and ERCC3.^[17]

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.^[18] These type of defects can result in other rare autosomal recessive diseases like xeroderma pigmentosum and Cockayne syndrome.^[19]

DNA repair

Currently, mutations in four genes are recognized as causing the TTD phenotype, namely TTDN1, ERCC3/XPB, ERCC2/XPD and TTDA.^[20] 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^[21] (see DNA damage theory of aging).

Non-Photosensitive forms

The non-photosensitive forms are caused by AARS1, CARS1, TTDN1, RNF113A, TARS1 and MARS1 genes.^[22] The function of AARS1, CARS1 and TARS1 gene are to charge tRNAs with amino acid.^[23] According to one study, the TTDN1 gene plays role in mitosis.^[24] Some study suggests that the RNF113A gene is a part of spliceosome and it can terminate CXCR4 pathway through CXCR4 Ubiquitination.^[25][26][27]

RNF113A causes X-linked recessive form of TTD.^[28]

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:^[29]

• 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.^[30] Patients with Photosensetive forms should be provided with sun protection.^[30][31]

See also

• Skin lesion
• List of cutaneous conditions