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. Approximately half of all patients with TTD have photosensitivity, which divides the classification into syndromes with or without photosensitivity; into four syndromes: BIDS and PBIDS, and IBIDS and PIBIDS. Modern covering usage is TTD-P (photosensitive), and TTD.
Genetics
Currently, mutations in four genes are recognized as causing the TTD phenotype, namely TTDN1, XPB, XPD and TTDA. 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.
Types
| Type | Gene | OMIM | Description |
|---|---|---|---|
| TTD | - | 608780 | Includes photosensitivity, icthyosis, brittle hair and nails, intellectual impairment, decreased fertility and short stature. |
| BIDS | MPLKIP (TTDN1) | 609188 | Also called Amish brittle hair brain syndrome and hair-brain syndrome, is an autosomal recessive inherited disease; It is nonphotosensitive, characterized by brittle hair, intellectual impairment, decreased fertility, and short stature. |
| IBIDS | - | 601675 | 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. Chong Hai Tay was the Singaporean doctor who was the first doctor in South East Asia to have a disease named after him). Tay syndrome should not be confused with the Tay-Sachs disease. It is an autosomal recessive congenital disease. In some cases, it can be diagnosed prenatally. IBIDS syndrome is nonphotosensitive. |
| PIBIDS | ERCC2 ERCC3 | 278730 133510 | Photosensitive form |
Symptoms
The signs and symptoms of Trichothiodystrophy vary widely, and survival of the patient is upto only infancy or early childhood. Mild cases involve only the hair, but more severe cases can cause:
- Delayed development
- Significant intellectual disability and recurrent infections
- Dry, scaly skin (ichthyosis)
- Abnormalities of fingernails and toenails
- Clouding of lens in both eyes from birth (congenital cataracts)
- Poor coordination
- Skeletal abnormalities
- Extreme sensitivity to UV rays from sunlight, causing severe sunburn
Mothers of children with TTD may experience problems during pregnancy including:
- Pregnancy-induced high blood pressure (Pre-eclampsia)
- HELLP syndrome that damages the liver
Babies with TTD are at risk of premature birth, low birth weight and slow growth.
Diagnosis
For families with an index PIBIDS patient where the responsible genetic mutations have been demonstrated, prenatal diagnosis is possible using a test to establish a nucleotide excision repair (NER) defect. Such a test would detect unscheduled DNA synthesis (UDS) upon UV irradiation. For earlier detection, results are confirmed either with a measurement of UDS from amniotic fluid cells or with a microscopic analysis of fetal hair for TTD, which may be repeated more than once in suspected patients as TTD is not readily visible at birth and can appear several months after.
An additional DNA repair test called a Comet Assay has more recently been proposed as a more rapid, sensitive prenatal diagnosis of TTD and can typically provide results within 24 hours while avoiding radioactive substances.
Popular Citations
- Stefanini M, Botta E, Lanzafame M, Orioli D (2010). "Trichothiodystrophy: from basic mechanisms to clinical implications". DNA Repair (Amst).
- Liang C, Morris A, Schlucker S, Imoto K, Price VH, Menefee E, Wincovitch SM, Levin IW, Tamura D, Strehle KR, Kraemer KH, DiGiovanna JJ (2006). "Structural and molecular hair abnormalities in Trichothiodystrophy". J Invest Dermatol.