Trichothiodystrophy 5, Nonphotosensitive

A number sign (#) is used with this entry because of evidence that nonphotosensitive trichothiodystrophy-5 (TTD5) is caused by mutation in the RNF113A gene (300951) on chromosome Xq24. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of trichothiodystrophy, see TTD1 (601675).

Clinical Features

Corbett et al. (2015) described 2 male cousins, born of 2 sisters, who had intrauterine growth restriction, progressive microcephaly with profound intellectual disability, genital anomalies that included absent or rudimentary testes and microphallus, and severe linear growth failure despite normal growth hormone (GH1; 139250) production. On MRI, they both exhibited partial absence of the posterior portion of the corpus callosum, cerebellar hypoplasia, and a Dandy-Walker malformation. Both were social and engaging, but their expressive vocabulary consisted of only a few words in the second decade of life. Shared physical features included minimal muscle mass, reduced subcutaneous fatty tissue with an aged facial appearance, high forehead, broad mouth with widely spaced primary teeth, prominent chin, and very ataxic broad-based gait. Both had minimal body hair, with no evidence of pubertal change, as well as sparse, brittle, and slow-growing scalp hair and eyebrows. Polarizing light microscopy revealed a characteristic tiger-tail pattern, and hair amino acid content analysis showed sulfur deficiency, diagnostic of trichothiodystrophy. One cousin also had major structural anomalies, including a very short esophagus with thoracic stomach as well as ureteric obstruction, both requiring surgical correction. Both cousins had recurrent infections, and 1 showed evidence of an IgG1 subclass deficiency; the latter patient also had panhypopituitarism. In addition, ophthalmic examination in this patient at age 14 years revealed bilateral retinal dystrophy, optic nerve hypoplasia, and photosensitivity. Experiments with patient lymphoblasts showed no evidence of nucleotide excision repair (NER) deficiency. All 3 obligate carrier females in the family had 100% skewed X chromosome inactivation, and all exhibited short stature. One carrier female had delayed walking and speech as well as learning difficulties. She also had slow-growing hair with some patchiness, although no tiger-banding was observed.

Mapping

By linkage analysis in a family in which 2 male cousins had nonphotosensitive trichothiodystrophy, Corbett et al. (2015) obtained a peak lod score of 1.02 between markers DXS8055 and DXS1212, spanning a 7.85-Mb region on Xq23-q25 (chrX:114,654,888-122,487,070, GRCh37).

Molecular Genetics

In 2 male cousins with nonphotosensitive trichothiodystrophy mapping to chromosome Xq23-q25, who were negative for mutation in 4 known TTD-associated genes, Corbett et al. (2015) confirmed the presence of a nonsense mutation in the RNF113A gene (Q301X; 300951.0001), which was previously detected in the proband (family 581) as part of the IGOLD sequencing project (Tarpey et al., 2009). The mutation, which segregated with disease in the family, was not found in 1,391 control X chromosomes, in 1,122 unrelated probands with X-linked mental retardation, or in the dbSNP (build 137), Exome Aggregation Consortium, or 1000 Genomes Project databases. Analysis of the RNF113A gene in 12 additional male patients with NER-proficient TTD, who were also negative for mutation in known TTD-associated genes, revealed no mutations.