#601675
ICD+
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| TRICHOTHIODYSTROPHY, PHOTOSENSITIVE; TTDP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ICHTHYOSIFORM ERYTHRODERMA WITH HAIR ABNORMALITY AND MENTAL AND GROWTH RETARDATION, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| TAY SYNDROME, INCLUDED TRICHOTHIODYSTROPHY WITH CONGENITAL ICHTHYOSIS, INCLUDED ICHTHYOSIS, CONGENITAL, WITH TRICHOTHIODYSTROPHY, INCLUDED IBIDS SYNDROME, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence from complementation tests by cell fusion that the phenotype can be caused by mutation in at least 2 separate genes: ERCC2/XPD (126340) and ERCC3/XPB (133510), which encode the 2 helicase subunits of transcription/repair vector TFIIH. Most patients carry mutations in XPD; mutations in XPB concern only a few patients. Besides XP groups B and D, an exceptional trichothiodystrophy complementation group designated TTD-A was identified by Stefanini et al. (1993). This form was found by Giglia-Mari et al. (2004) to be caused by mutation in the tenth subunit of TFIIH, TFB5 (608780). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Trichothiodystrophy (TTD) is a term introduced by Price et al. (1980) for sulfur-deficient brittle hair. Patients with trichothiodystrophy have brittle hair and nails (because of reduced content of cysteine-rich matrix proteins), ichthyotic skin, and physical and mental retardation. Approximately half of the patients display photosensitivity, correlated with a nucleotide excision repair (NER) defect. See 234050 for a discussion of nonphotosensitive trichothiodystrophy (TTDN). As is the situation with Cockayne syndrome (216400), no cases of skin cancer had been reported with trichothiodystrophy (Itin and Pittelkow, 1990; Stary and Sarasin, 1996). 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. Happle et al. (1984) presented a case and reviewed 12 previously reported cases. 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 third centile at all ages) are features and all patients have been mentally retarded. The hair-brain syndrome (234050), which is also known as BIDS, lacks ichthyosis; by extension, the Tay syndrome is referred to as IBIDS (Blomquist et al., 1991). In the Netherton syndrome (256500), ichthyosis is combined with brittle hair displaying the characteristic phenomenon of trichorrhexis invaginata. Braun-Falco et al. (1981) reported affected brother and sister. The syndrome has been observed in Caucasians and blacks as well as Asians (as reported by Tay, 1971). This may be the disorder present in the inbred Italian kindreds in which TTD and xeroderma pigmentosum of complement group D (278730) were found to be cosegregating (Nuzzo et al., 1986), suggesting linkage. Features were hair shaft abnormalities, ichthyosis, immature sexual development, short stature, and peculiar facies. This situation is similar to that of other rare recessives that have been observed together, apparently on the basis of close linkage, e.g., recessive cerebellar ataxia (213200) and tyrosinase-negative albinism (203100). This can be viewed as a special case of linkage disequilibrium. In some such instances, a microdeletion may have inactivated 2 closely linked loci. Such should be sought in all cases of 'double' (or 'triple') syndromes. 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. This implies that the 2 diseases are indeed at linked loci. In the son of a Finnish uncle-niece marriage, Blomquist et al. (1991) observed this disorder 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. They 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 present in their patient. Jorizzo et al. (1982) described a patient with typical symptoms of TTD: characteristic hair-shaft abnormalities with reduced sulfur content, collodion baby, short stature, ichthyosis, bilateral congenital cataracts, and asthmatic attacks. On examination at the age of 20 years, Stefanini et al. (1993) found that he had had recurrent infective exacerbations of his asthma and that he remained severely growth retarded (height and weight below the 3rd centile) and of limited intelligence but not severely mentally retarded (IQ 70-80). His ichthyosiform erythroderma continued. He had developed joint contractures of the hands due to the severe ichthyosiform involvement of the palms, but sensitivity to sunlight had been present from early childhood. There was, however, no significant freckling or other pigmentary changes, no telangiectases or actinic keratoses, and no skin tumors. Peter et al. (1998) described a 4-year-old girl with trichothiodystrophy without associated neuroectodermal defects. 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 features reported 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 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 a 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biochemical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cell fusion experiments demonstrated that in all but 3 trichothiodystrophy (TTD) cell strains examined until 1993, the repair deficiency was in the same complementation group as is the defect in xeroderma pigmentosum group D (278730), where the defect involves the ERCC2 gene (126340); see Stefanini et al. (1986, 1992, 1993). In the 3 exceptional cases (2 from related patients), complementation was observed with XPD cells. In 1 of the 3 patients, originally reported by Jorizzo et al. (1982), Stefanini et al. (1993) demonstrated that cells were able to complement the excision-repair defect in all xeroderma pigmentosum complementation groups, and they showed that complementation was not intragenic. Thus, the cell strain represented a new excision-repair complementation group. The cells were referred to as TDS1BR; one might refer to the form of trichothiodystrophy with a defect in XPD as TTD1, and the form with this second DNA repair defect as TTD2. Lehmann et al. (1994) recommended that this second complementation group be referred to as TTD-A and its gene as TTDA. Any further complementation groups characterized only in TTD patients would be designated TTD-B, TTD-C, etc. The repair-deficient form of TTD most often results from mutations in the genes XPB or XPD, encoding helicases of the transcription/repair factor TFIIH. Vermeulen et al. (2000) reported on the nature of the genetic defect in the third group, TTD-A, which is also caused by dysfunctioning TFIIH. They found that none of the TFIIH subunits carries a mutation, and TFIIH from TTD-A cells is active in both transcription and repair. Instead, immunoblot and immunofluorescence analyses revealed a strong reduction in the TFIIH concentration. Thus, the phenotype of TTD-A appears to result from sublimiting amounts of TFIIH, probably due to a mutation in a gene determining the stability of the complex. The reduction of TFIIH affects mainly its repair function and hardly influences transcription. Petrini (2000) interpreted the findings as indicating that the normal TTD-A protein modulates the proteasome-mediated degradation of TFIIH. Microinjected TFIIH is less stable in TTD-A cells. Its absence in TTD-A cells would thus decrease the half-life of TFIIH and so its abundance. It is conceivable that a threshold level of THIIH is required to switch between the transcriptional mode and the nucleotide excision repair (NER) mode. Below that threshold, the essential need for transcription functions would override the signal to switch to NER mode and DNA repair therefore would be differentially affected. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Complementation tests by cell fusion demonstrated that the NER syndromes are genetically heterogeneous and comprise 10 or more complementation groups: 7 in xeroderma pigmentosum, 2 in Cockayne syndrome, and 2 in TTD (Hoeijmakers, 1994). The TTD defects are referred to as TTD-A and XPD. The finding of additional patients combining features of xeroderma pigmentosum and Cockayne syndrome within complementation groups XPB (133510), XPD, and XPG (278780) indicated that there is considerable clinical heterogeneity with phenotypic overlap within the subsets of complementation groups. Weeda et al. (1997) identified a third TTD complementation group with demonstration of a mutation in the ERCC3/XPB gene (133510.0003), thereby extending the clinical heterogeneity associated with XP-B. The defects in TTDA and in XP-D as well as that in XP-B involve subunits of TFIIH (see 189972), a basal transcription factor which functions in DNA repair. The trichothiodystrophy patients in whom Weeda et al. (1997) identified a T119P mutation (133510.0003) in the ERCC3/XPB gene were sibs born of a first-cousin marriage. The proband, a male, had congenital ichthyosis (collodion baby). The skin condition improved within 3 weeks, leaving a mild ichthyosis of the trunk. TTD was suspected at 3 years of age, on the basis of mild ichthyosis of the trunk, with involvement of the scalp, palms, and soles; mild photosensitivity; lack of second upper incisor; and hair growing normally but coarse with a tiger-tail pattern under polarized light. The diagnosis of TTD was confirmed by analysis of the amino acid content of hair, showing a decrease in cysteine residues. An affected older sister had a similar presentation as a collodion baby with favorable outcome. A diagnosis of TTD was confirmed by hair microscopy and biochemical analysis showing low cysteine content. Both the proband and his sister were in good general health, without physical and mental impairment, at the ages of 10 and 16 years, respectively. The description of these cases resembles that of the disorder referred to as Tay syndrome, or trichothiodystrophy with congenital ichthyosis, as described earlier in this entry. Kleijer et al. (1994) described TTD with the unusual additional feature of aggravation of the abnormality during periods of fever. 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 mutation in the ERCC2 gene (see 126340.0011). 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 (126340.0006) seen previously in TTD patients, and a leu485-to-pro mutation (126340.0013) in the other allele. The level of repair of UV damage 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 ERCC2 mutation arg722-to-trp (126340.0014) 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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