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 ... 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 (TTD), 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 is of interest because of the hypergonadotropic hypogonadism observed in Norwegian cases of Marinesco-Sjogren syndrome (248800) which have been interpreted as indicating linkage of 2 loci. Thus it was considered possible that a single genetic defect affecting hair, central nervous system, and gonads is involved in this category of cases and that BIDS and Marinesco-Sjogren syndrome, and perhaps as well as the disorder in the Moroccan sibs, are allelic. 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. - Nonphotosensitive Trichothiodystrophy Trichothiodystrophy was the term that Price et al. (1980) assigned to conditions of brittle hair with markedly reduced sulfur content. TTD can be associated with a spectrum of symptoms affecting organs of ectodermal and neuroectodermal origin. These include nail dystrophy, mental and growth retardation, ichthyosis, decreased fertility, and cutaneous photosensitivity, but not cancer (Bergmann and Egly, 2001). Approximately half of patients with TTD display photosensitivity. These cases are associated with defects in nucleotide excision repair due to mutations in genes encoding subunits of transcription factor II H (TFIIH); see the entry concerning this form (601675). Amish brittle hair-brain syndrome (ABHS) is a form of nonphotosensitive trichothiodystrophy. Other forms of nonphotosensitive trichothiodystrophy include Sabinas brittle hair syndrome (211390) and the disorder described as trichorrhexis nodosa with mental retardation, also known as Pollitt syndrome (275550). Brooks et al. (2011) reported the ocular manifestations of the largest cohort to that time of patients with photosensitive (601675) and nonphotosensitive TTD and with 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, likely due to abnormalities in basal transcription of critical genes, patients with TTD or XP/TTD might also have a degenerative course.
Nakabayashi et al. (2005) analyzed 7 genes in the ABHS critical region by DNA sequencing and identified 3 homozygous sequence variations in the C7ORF11 gene in affected members of 1 of the Amish families. Two of the variations ... Nakabayashi et al. (2005) analyzed 7 genes in the ABHS critical region by DNA sequencing and identified 3 homozygous sequence variations in the C7ORF11 gene in affected members of 1 of the Amish families. Two of the variations were found in either normal controls or the unaffected parents in the family. The third variant was an A-to-G transition in exon 2 of C7ORF11 causing a methionine-to-valine substitution (M144V; 609188.0001). 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) and 1 case of Pollitt syndrome (275550), no mutations were found in the 2 exons of the C7ORF11 gene and 5-prime upstream region.