Trichothiodystrophy 4, Nonphotosensitive

A number sign (#) is used with this entry because of evidence that nonphotosensitive trichothiodystrophy-4 (TTD4) is caused by homozygous mutation in the C7ORF11 gene (MPLKIP; 609188) on chromosome 7p14.

Description

Trichothiodystrophy 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 (summary by Faghri et al., 2008).

Sabinas brittle hair syndrome (211390) is another form of nonphotosensitive TTD.

For a discussion of genetic heterogeneity of trichothiodystrophy, see 601675.

Clinical Features

Pollitt et al. (1968) described a brother and sister with microcephaly, mental and physical retardation, and trichorrhexis nodosa, associated with reduction in the content of high-sulfur protein in hair. Cystine content of the hair was about half normal (Pollitt and Stonier, 1971).

Among the Amish, Allen (1971) and subsequently Jackson et al. (1974) delineated a syndrome characterized by short stature, intellectual impairment, brittle hair, and decreased fertility. Twenty-five cases in an autosomal recessive pedigree pattern were identified. Impairment of linear growth and intellect was relatively mild in most. Microscopically, hairs showed an irregular, grooved surface lacking in scales. The sulfur content of the hair was about half normal.

Baden et al. (1976) referred to the disorder as the BIDS syndrome. Although they did not define the acronym, it presumably derives from brittle hair, intellectual impairment, decreased fertility and short stature. They presented data they interpreted as indicating that the hair of affected persons has normal alpha proteins, but a markedly reduced content of cystine-rich matrix proteins. Nails showed the same chemical abnormality. Inquiry showed that the nails break easily and do not grow long.

In a consanguineous Moroccan family, Przedborski et al. (1990) observed a brother and 2 sisters with trichothiodystrophy, mental retardation, short stature, ataxia, and gonadal dysfunction. Their discussion of the various syndromes associated with TTD indicated the complexity of nosology in this area. The association of hypogonadism was of interest because of the hypergonadotropic hypogonadism observed in Norwegian cases of Marinesco-Sjogren syndrome (248800), which had been interpreted as indicating linkage of 2 loci.

Rizzo et al. (1992) described the case of a 3-year-old girl with TTD and severe nervous system involvement, manifested by hypotonia, mental retardation, and partial agenesis of the corpus callosum.

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

Brooks et al. (2011) reported the ocular manifestations of the largest cohort to that time of patients with photosensitive or nonphotosensitive TTD or with TTD and xeroderma pigmentosum (XP/TTD; 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 that was likely due to abnormalities in basal transcription of critical genes, patients with TTD or XP/TTD might also have a degenerative course.

Mapping

In 3 interrelated families with trichothiodystrophy from the consanguineous Amish kindred previously reported by Jackson et al. (1974), Seboun et al. (2005) performed a genome scan and obtained a multipoint lod score of 5.5 for linked markers D7S484-D7S510-D7S519-D7S502 on chromosome 7p14.1. Further analysis yielded a maximum multipoint lod score of 6 for a 17.2-cM linkage interval flanked by markers D7S484 and D7S2422, which was confirmed by 2-point linkage analysis. Homozygosity mapping narrowed the critical interval to a 4.81-cM (3.42-Mb) region defined by markers D7S2497 and D7S691.

Molecular Genetics

In 2 affected members of a consanguineous family with nonphotosensitive trichothiodystrophy mapping to chromosome 7p14.1, from the Amish kindred previously reported by Jackson et al. (1974), Nakabayashi et al. (2005) sequenced 7 candidate genes and identified homozygosity for a missense mutation in the C7ORF11 gene (M144V; 609188.0001) that segregated with disease in the family. Analysis of 11 affected and 21 unaffected members of 4 more consanguineous families from the Amish kindred confirmed that only affected individuals were homozygous for M144V, and the mutation was not found in 148 controls, 48 of whom were unrelated Amish individuals. In the 2 sibs of Moroccan origin with nonphotosensitive trichothiodystrophy, reported by Przedborski et al. (1990), Nakabayashi et al. (2005) found a 2-bp homozygous deletion in exon 1 of the C7ORF11 mRNA, which predicted a 57-amino acid truncated protein (609188.0002). In another case, an Italian patient with nonphotosensitive trichothiodystrophy and severe nervous system impairment (Rizzo et al., 1992), homozygous deletion of part of exon 1 and the entire exon 2 were found (609188.0003). These patients were suspected of being genetically null for C7ORF11, which may explain their more severe neurologic phenotype in comparison with the Amish patients. In 10 other cases of nonphotosensitive TTD, including 2 cases of Sabinas syndrome (211390), no mutations were found in the 2 exons of the C7ORF11 gene and 5-prime upstream region.

Botta et al. (2007) evaluated the involvement of C7ORF11 in 44 unrelated nonphotosensitive TTD cases of different geographic origin and with different disease severity. Mutations were found in 6 patients, 5 of whom were homozygotes and 1 of whom was a compound heterozygote (see, e.g., 609188.0004 and 609188.0005). The severity of the clinical features did not correlate with the type of mutation, indicating that other factors besides C7ORF11 mutations influence the severity of the disorder. Because only a small number of the analyzed cases had mutations in C7ORF11, Botta et al. (2007) concluded that the nonphotosensitive form of TTD is genetically heterogeneous.

By whole-genome diploid sequencing in a sister and brother with trichorrhexis nodosa and mental and physical retardation, originally reported by Pollitt et al. (1968) and in whom Nakabayashi et al. (2005) did not find a mutation in the C7ORF11 gene, Swagemakers et al. (2014) identified homozygosity for a 1-bp deletion in C7ORF11 (609188.0004). Conventional sequencing confirmed the deletion, which was present in heterozygosity in the unaffected parents. The same mutation had previously been detected in a Dutch girl and an Italian girl with nonphotosensitive trichothiodystrophy (Botta et al., 2007), suggesting that the deletion originated from a common founder.