Trichothiodystrophy 1, Photosensitive

A number sign (#) is used with this entry because of evidence that photosensitive trichothiodystrophy-1 (TTD1) is caused by homozygous or compound heterozygous mutation in the ERCC2/XPD gene (126340), which encodes a helicase subunit of transcription/repair factor TFIIH, on chromosome 19q13.

Description

Trichothiodystrophy (TTD) is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. TTD patients have not been reported to have a predisposition to cancer (summary by Faghri et al., 2008).

Genetic Heterogeneity of Trichothiodystrophy

Also see TTD2 (616390), caused by mutation in the ERCC3/XPB gene (133510); TTD3 (616395), caused by mutation in the GTF2H5 gene (608780); TTD4 (234050), caused by mutation in the MPLKIP gene (609188); TTD5 (300953), caused by mutation in the RNF113A gene (300951); TTD6 (616943), caused by mutation in the GTF2E2 gene (189964); and TTD7 (618546), caused by mutation in the TARS gene (187790).

Clinical Features

In 2 brothers and a sister, with first-cousin parents of Chinese extraction, Tay (1971) described a 'new' autosomal recessive disorder characterized by nonbullous ichthyosiform erythroderma, growth and mental retardation, somewhat progeria-like appearance, and short, sparse, lusterless hair that microscopically showed pili torti and trichorrhexis nodosa. One of the children had hypogammaglobulinemia, and one died at age 2 months of intestinal obstruction. Erythroderma was particularly striking at birth.

Price et al. (1980) introduced the term trichothiodystrophy for sulfur-deficient brittle hair. They noted that trichothiodystrophy was a marker for neuroectodermal symptoms of brittle hair and nails (because of reduced content of cysteine-rich matrix proteins), ichthyotic skin, and physical and mental retardation. Approximately half of TTD patients display photosensitivity, correlated with a nucleotide excision repair (NER) defect.

King et al. (1984) described 2 cases of what they called trichothiodystrophy-neurotrichocutaneous syndrome of Pollitt in unrelated children. The first, a boy, was born with short, woolly hair that fell out easily. At 6 months he was first seen for developmental delay. The length, weight, and head circumference were below the 3rd centile. The face was unusual with receding chin and protruding ears. The skin was ichthyotic with severe flexural eczema. The hairs of the eyebrows were stubby, but the eyelashes were normal. The nails were hypoplastic and spoon-shaped. Neurologic findings included jerky ocular pursuit movements with titubation of the head, spastic diplegia, extensor plantar reflexes, and absent deep tendon reflexes. The findings were virtually identical at age 4. In addition, the skin was highly photosensitive. The findings in the second case, in a female child, were nearly identical except that bilateral central nuclear cataracts, hyperactive deep tendon reflexes, adductor spasm, and scissoring of the lower limbs were noted. Both children were the offspring of unrelated Scottish parents. King et al. (1984) suggested that this disorder is the same as the Amish brittle hair syndrome (234050) and the Sabinas brittle hair syndrome (211390).

Happle et al. (1984) reported a patient with congenital ichthyosis with trichothiodystrophy (Tay syndrome) and reviewed 12 previously reported patients. Dysplastic nails are frequently observed. As in autosomal dominant ichthyosis vulgaris, flexural areas of the limbs may be spared. Lack of subcutaneous fatty tissue is characteristic. In women, breast tissue may be completely absent in spite of normal development of the nipples. The face has an aged appearance due to lack of subcutaneous fat. Low birth weight and short stature (below 3rd centile at all ages) are features and all patients have mental retardation.

Braun-Falco et al. (1981) reported an affected brother and sister.

Nuzzo et al. (1986) reported inbred Italian kindreds in which TTD and xeroderma pigmentosum of complement group D (278730) were found to be cosegregating, suggesting linkage of the 2 disorders. TTD features in the patients included hair shaft abnormalities, ichthyosis, immature sexual development, short stature, and peculiar facies. Nuzzo et al. (1990) checked consanguinity within and among 3 families by construction of genealogic trees, typing of blood markers, and a surname analysis. The results strengthened the hypothesis that in at least 2 of the 3 families, the genetic defects represented by the combined phenotype were of the same origin, as a consequence of remote inbreeding.

In the son of a Finnish uncle-niece marriage, Blomquist et al. (1991) observed Tay or IBIDS syndrome, which was manifested by growth and mental retardation, congenital ichthyosis, and brittle hair. The boy suffered from recurrent infections and died at the age of 3 years from pneumonia. The authors also reviewed 15 cases from the literature. A birth weight less than 2,500 grams was found in 8 of 11 cases, birth length less than 40 cm in 3 of 6, hypogonadism in 9 of 9, cataract in 7 of 8, frequent infections in 7 of 7, and microcephaly in 6 of 6; all of these features were also present in their patient.

Kleijer et al. (1994) described a female child with what Crovato et al. (1983) and Rebora and Crovato (1988) referred to as the PIBI(D)S syndrome with trichothiodystrophy. She had photosensitivity, ichthyosis, brittle hair, impaired intelligence, possibly decreased fertility, and short stature. A remarkable feature was the intermittent character of the scalp hair loss during infectious periods, such as with pneumonia. The child died unexpectedly at home during sleep at the age of 2 years and 8 months. Easy suntanning suggested photosensitivity and prompted DNA repair studies, which demonstrated reduced UV-induced DNA repair synthesis.

Takayama et al. (1997) studied a male patient with typical features of trichothiodystrophy, including brittle hair, ichthyosis, characteristic face with receding chin and protruding ears, sun sensitivity, and mental and growth retardation. The relative amount of nucleotide excision repair carried out by a fibroblast cell strain from the patient after ultraviolet exposure was approximately 65% of normal as determined by a method that converted repair patches into quantifiable DNA breaks. UV survival curves showed a reduction in survival only at doses greater than 4 joules per square meter.

Peter et al. (1998) described a 4-year-old girl with trichothiodystrophy without associated neuroectodermal defects.

Viprakasit et al. (2001) showed that the specific mutations in the ERCC2 gene that cause TTD result in reduced expression of the beta-globin (HBB; 141900) gene in affected individuals. Eleven TTD patients with characterized mutations in the XPD gene were found to have the hematologic features of beta-thalassemia trait as well as reduced levels of beta-globin synthesis and beta-globin mRNA. All of these parameters were normal in 3 patients with XPD (278730). The authors hypothesized that many of the clinical features of TTD may result from inadequate expression of a diverse set of highly expressed genes.

Faghri et al. (2008) performed a systematic literature review and identified 112 patients with trichothiodystrophy, ranging in age from 12 weeks to 47 years. In addition to hair abnormalities, common reported features were developmental delay/intellectual impairment (86%), short stature (73%), ichthyosis (65%), abnormal characteristics at birth (55%), ocular abnormalities (51%; primarily cataract), infections (46%), photosensitivity (42%), maternal pregnancy complications (28%), and defective DNA repair (37%). There were 19 deaths under the age of 10 years (13 related to infection), a 20-fold higher mortality rate than that of the general US population. The spectrum of clinical features varied from mild disease with only hair involvement to severe disease with profound developmental defects, recurrent infections, and high mortality at a young age. Faghri et al. (2008) noted that abnormal characteristics at birth and pregnancy complications were unrecognized but common features of TTD, suggesting a role for DNA repair genes in normal fetal development.

Hashimoto and Egly (2009) reviewed the clinical features and genetics of TTD, as well as the pathogenesis of nucleotide excision repair defects.

Brooks et al. (2011) reported the ocular manifestations of the largest cohort to that time of patients with photosensitive or nonphotosensitive trichothiodystrophy or with TTD and xeroderma pigmentosum (XP/TTD; see 278730). Their case series included 32 participants, aged 1 to 30 years, seen over a 10-year period: 25 had TTD and 7 had XP/TTD. Developmental abnormalities included microcornea (44% TTD), microphthalmia (8% TTD, 14% XP/TTD), nystagmus (40% TTD), and infantile cataract (56% TTD, 86% XP/TTD). Corrective lenses were required by 65% of the participants, and decreased best-corrected visual acuity 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 was usually exhibited by much older patients in the general population. The 2 oldest TTD patients exhibited clinical signs of retinal/macular degeneration. Four XP/TTD patients presented with corneal neovascularization. Brooks et al. (2011) concluded that, although many of these ocular manifestations could be ascribed to abnormal development, likely due to abnormalities in basal transcription of critical genes, patients with TTD or XP/TTD might also have a degenerative course.

Pathogenesis

Orioli et al. (2013) found that skin of TTD patients with mutations in the ERCC2 gene had reduced content of COL6A1 (120220), an abundant collagen of skin and connective tissue. In culture, dermal fibroblasts from TTD patients failed to induce COL6A1 upon achieving confluence. XPD skin and cultured XPD fibroblasts with mutations in the ERCC2 gene did not show the same defects. Transfection of wildtype ERCC2 into TTD patient fibroblasts permitted induction of COL6A1 upon confluence. In silico analysis identified a putative SREBP1 (184756)-binding site in the COL6A1 promoter, and deletion of this site resulted in increased transcriptional activity from the COL6A1 promoter. Overexpression of wildtype ERCC2 in TTD patient fibroblasts resulted in RNA polymerase II and SP1 (189906) occupancy at the COL6A1 promoter, concomitant with loss of SREBP1 binding. Removal of SREBP1 from the COL6A1 promoter was also dependent on ATP hydrolysis. Orioli et al. (2013) concluded that ERCC2 in the TFIIH helicase removes SREBP1 from the COL6A1 promoter in an ATP-dependent manner and that, in TTD fibroblasts, mutated ERCC2 fails to displace the SREBP1 repressor from the COL6A1 promoter, resulting in inability to effect COL6A1 transcriptional upregulation in response to cell confluence.

Molecular Genetics

By sequence analysis of the ERCC2 gene in a patient with trichothiodystrophy, Takayama et al. (1997) identified compound heterozygous mutations: a leu461-to-val (L461V; 126340.0001) substitution and a deletion of amino acids 716-730 on one allele and an ala725-to-pro (A725P; 126340.0003) substitution on the other allele. The L461V mutation had been reported in a patient with xeroderma pigmentosum group D by Frederick et al. (1994) and in 2 other patients with trichothiodystrophy (see Takayama et al., 1996), whereas the A725P mutation had not previously been reported.

Botta et al. (1998) determined the mutations and the pattern of inheritance of the XPD alleles in 11 cases of trichothiodystrophy identified in Italy. In all of the cases, the hair abnormalities diagnostic for TTD were associated with different disease severity but similar cellular photosensitivity. The authors identified 8 causative mutations, 4 of which had not previously been described, either in TTD or XP cases, supporting their hypothesis that the mutations responsible for TTD are different from those found in other pathologic phenotypes. The arg112-to-his (R112H; 126340.0006) mutation was the most common one found in the Italian patients, 5 of whom 5 were homozygous and 2 heterozygous, for this mutation. Microscopic study of the hair showed pili torti, trichoschisis, and trichorrhexis nodosa. Polarization microscopy revealed a typical appearance of alternating light and dark bands, giving a 'tiger tail' pattern. Photosensitivity was reported in all patients, in association with the other symptoms typical of TTD, namely, ichthyosis, delayed physical and mental development, nail dysplasia, a face characterized by receding chin, small nose, and large ears, and microcephaly. Seven patients were still alive at ages 4 to 30 years; the 4 patients who died during early infancy showed severe physical and mental retardation and suffered from frequent respiratory infections. The 3 oldest patients, all women, aged 30, 20, and 21 years, had moderate mental and physical handicaps. They developed freckles during childhood, but progression to malignancy had not been observed. They had short stature (140 cm), began to menstruate at age 18 years, and were no longer prone to infections, although they suffered moderate infections during early childhood.

Vermeulen et al. (2001) showed that an arg658-to-cys (R658C) mutation in the XPD component of the TFIIH transcription factor was responsible for thermolability of that factor and underlay the temperature-sensitive clinical disorder; see 126340.0007.

Broughton et al. (2001) identified 2 patients with some features of both XP and TTD. A 3-year-old girl with sun sensitivity and mental and physical developmental delay had compound heterozygous mutations in the ERCC2 gene (126340.0011-126340.0012). Cultured cells from this patient demonstrated barely detectable levels of nucleotide excision repair. The other patient, a 28-year-old woman with sun sensitivity, pigmentation changes, and skin cancers typical of XP, had an arg112-to-his mutation (R112H; 126340.0006) seen previously in TTD patients, and a leu485-to-pro mutation (L485P; 126340.0013) on the other allele. The level of UV damage repair in the second patient was substantially higher than that in other patients with the same mutation. With both patients, polarized light microscopy revealed a tiger-tail appearance of the hair, and amino acid analysis of the hairshafts showed levels of sulfur-containing proteins between those of normal and TTD individuals.

Animal Model

De Boer et al. (2002) found that mice with the arg722-to-trp (R722W; 126340.0014) mutation in ERCC2 had many symptoms of premature aging, including osteoporosis and kyphosis, osteosclerosis, early graying, cachexia, infertility, and reduced life span. TTD mice carrying an additional mutation in XPA (611153), which enhances the DNA repair defect, showed a greatly accelerated aging phenotype, which correlated with an increased cellular sensitivity to oxidative DNA damage. De Boer et al. (2002) hypothesized that aging in TTD mice is caused by unrepaired DNA damage that compromises transcription, leading to functional inactivation of critical genes and enhanced apoptosis.