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Trichothiodystrophy-5 (TTD5) is an X-linked disorder characterized by sparse and brittle hair, facial dysmorphism, global developmental delays, growth deficiency...

Trichothiodystrophy-5 (TTD5) is an X-linked disorder characterized by sparse and brittle hair, facial dysmorphism, global developmental delays, growth deficiency, hypogonadism, and structural brain abnormalities (summary by Mendelsohn et al., 2020).

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.

Mendelsohn et al. (2020) reported an 11-year-old boy with severe global developmental delay, failure to thrive and growth retardation, refractory seizures with recurrent status epilepticus, hypogammaglobulinemia, hypergonadotropic hypogonadism, and duodenal strictures. He had facial and skin findings compatible with nonphotosensitive trichothiodystrophy, including sparse and brittle 'wool-like' hair, thin eyebrows, and dry skin with diffuse cutis marmorata. MRI showed hypoplasia of the corpus callosum, and hair analysis revealed focal trichorrhexis nodosa and atypical bands without tiger-tail banding. The proband's mother and maternal grandmother had short stature, with heights in the 2nd and 1st centiles, respectively. In addition, the grandmother was reported to have a history of photosensitivity. The authors also provided clinical details for a 2-year-old Saudi boy, previously published by Monies et al. (2019) as patient UKPN-2077, with a mutation in the RNF1131A gene. The boy had global developmental delay, failure to thrive, microcephaly, seizures, and ambiguous genitalia with severe hypospadias. Facial anomalies included a triangular face with broad forehead; pointed, cupped, posteriorly rotated, and low-set ears; and wide mouth. He had sparse and brittle hair, absent eyebrows and eyelashes, and mottled, dry skin. Mendelsohn et al. (2020) noted significant clinical overlap between these patients and the cousins reported by Corbett et al. (2015).

Tessarech et al. (2020) reported 2 male fetuses from a French family in which microcephaly, short or absent corpus callosum, and microphallus were evident on prenatal ultrasound. The pregnancies were terminated at 34 and 22 weeks' gestation, and autopsies showed similar abnormalities in both fetuses, including microcephaly and dysmorphic craniofacial features. In addition, they both had microphallus, absent or rudimentary testes, and adrenal hypoplasia. Both brains were decreased in size with agenesis of the posterior corpus callosum, and 1 fetus also had cerebellar hypoplasia. Their mother was of average stature and both parents were healthy.

▼ Inheritance

The transmission pattern of TTD5 in the families studied by Corbett et al. (2015) and Tessarech et al. (2020) was consistent with X-linked dominant inheritance.

▼ 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.

In an 11-year-old boy with nonphotosensitive trichothiodystrophy, Mendelsohn et al. (2020) identified hemizygosity for an 8-bp deletion in the RNF113A gene (300951.0002) that was inherited from his short-statured mother, who exhibited 100% skewed X chromosome inactivation. Mendelsohn et al. (2020) also reported clinical details for an unrelated 2-year-old Saudi boy with developmental delay and sparse brittle hair, who previously had been found to have a 2-bp deletion in RNF113A (300951.0003) by Monies et al. (2019).

In 2 male fetuses from a French family with brain and genital abnormalities, negative for mutation in the ARX (300382) and ATRX (300032) genes, Tessarech et al. (2020) performed whole-exome sequencing and identified hemizygosity for the Q301X mutation in the RNF113A gene. Their unaffected mother, who showed 100% X chromosome skewing in peripheral leukocytes, was heterozygous for the mutation, which was not found in either maternal grandparent, suggesting de novo occurrence.

Tags: Xq24