DISEASE CARD

Disease group DNA repair disorders
DISEASE NAME TRICHOTHIODYSTROPHY
Synonymous Amish brittle hair brain syndrome, (P)IBIDS - photosensitivity, ichthyosis, brittle hair, intellectual impairment, decreased fertility, short stature, Pollit syndrome, Sabinas brittle hair syndrome, Tay syndrome
Estimated prevalence The incidence of the photosensitive form has been established at 1.2 per million livebirths in West-Europe and at 1.1 per million livebirths in the autochthonic Western Europe population (Kleijer et al., DNA Repair 7:744-750, 2008).
OMIM 601675, 211390, 275550, 234050, 300953, 616943
Inheritance Autosomal recessive, X-linked (1 family)
Gene (s) TTDA/GTF2H5 (608780), XPB/ERCC3 (133510), XPD/ERCC2 (126340) TTDN1/MPLKIP (609188), RNF113A (300951), GTF2E2 (189964)

Defintion

Trichothiodystrophy (TTD) is a term introduced by Price et al. (1980) to describe a rare autosomal recessive multisystem disorder whose defining feature is sulphur-deficient brittle hair caused by a reduced level of cysteine-rich matrix proteins. Associated clinical symptoms include physical and mental retardation of different severity, small stature, ichthyotic skin, nail dysplasia, decreased fertility, proneness to infections, unusual facial features and some features of premature ageing. Approximately half of the patients with TTD exhibit cutaneous photosensitivity but premalignant skin lesions and cutaneous tumours have never been described. Photosensitive TTD cases show an altered cellular response to UV light due to a defect in nucleotide excision repair (NER), as a consequence of mutations in one of three genes, namely XPB/ERCC3, XPD/ERCC2 and TTDA/GTF2H5. The non-photosensitive cases have instead a normal cellular response to UV. The large majority of these cases are still unsolved. The three genes so far associated with non-photosensitive TTD, namely TTDN1/MPLKIP, RNF113A and GTF2E2, indeed account for only about 20% of the patients.

 

Clinical Description

All TTD patients exhibit sparse, dry and easily broken hair associated with low sulfur and cysteine content (10–50% of normal). Scalp hair anomalies which extend to eyebrows and eyelashes, are associated with a wide spectrum of clinical symptoms that usually affect organs of ectodermal and neuroectodermal origin. Other typical features are mental and growth retardation, face characterized by receding chin, small nose, large ears and microcephaly, nail dysplasia and ichthyosis. At birth, children often present with ichthyosiform erythroderma, and they may be encased in a collodion-like membrane. The disorder is characterized by a wide variation in the severity of the clinical features. A few mild cases have been described with hair abnormalities but without physical and mental impairment. Other patients show a pathological phenotype of moderate severity with short stature, delayed puberty, mental development at pre-school or primary school level, axial hypotonia, reduced motor coordination and survival beyond early childhood. The most severe form is characterized by very poor mental and motor performance and speech, failure to thrive and death during early childhood. Numerous patients suffer from repeated and severe infectious illnesses, mainly of the gastrointestinal and respiratory tract. In addition, osteoporosis, hearing loss, cataracts, dental caries, and other features of premature ageing have been reported. Forty to 50% of patients show an abnormal sun reaction on minimal sun exposure with blistering and persistent erythema. In the photosensitive TTD patients, the definition of the disease-gene and of the causative mutation(s) might be informative for the prognosis. The five known TTD-A cases are moderately affected and the two cases mutated in XPB have a very mild phenotype. The cases defective in XPD (more than 80% of the photosensitive TTD patients) show a wide variety in the severity of the pathological phenotype depending on the nature of the mutated XPD alleles. Among the non-photosensitive TTD patients, about 15% of the cases are mutated in the TTDN1 gene. They show different degrees of disease severity. Recently, deep phenotyping of a cohort of thirty-six patients exhibiting the clinical features of TTD has uncovered a distinct genotype-phenotype relationship in the TTDN1-defective cases. As compared with patients mutated in XPD, TTDA or unidentified genes, delayed bone age and seizures were over-represented in the TTDN-1 group. In contrast, other typical TTD features including pregnancy complications, low birth weight, collodion membrane at birth, reduced height, cataracts, thalassemia-like changes and imaging findings of brain dysmielination were under-represented or absent (Heller et al., Journal of Investigative Dermatology 135:734-741, 2015). In addition, typical TTD features associated with a heart-specific failure, i.e. mitral regurgitation, were observed in the affected members of three consanguineous Pakistani families carrying a peculiar splicing variant of TTDN1 (Shah et al., BMC Medical Genetics 17:13, 2016). RNF113A is mutated in only two Australian male cousins both showing severe clinical features. They presented with an extended phenotype including cutis marmorata, panhypopituitarism and congenital short oesophagus (Corbett et al., Journal of Medical Genetics 52:269-274, 2015). Differently, the five reported patients with mutations in GTF2E2 all show a moderate phenotype (Kuschal et al., American Journal of Human Genetics 98:627-642, 2016; Theil et al. Human Molecular Genetics 23:4689-4698, 2017).

 

Pathogenesis

Photosensitive TTD is caused by mutations in the XPB, XPD or TTDA genes. These genes encode distinct subunits of TFIIH, a multifunctional protein complex. TFIIH participates to DNA repair through the process of NER and is also a general transcription factor essential in the transcription process. All mutations identified in photosensitive TTD patients impact on the stability and functionality of the TFIIH complex thus affecting its role in both NER and transcription. However, the observation that non-photosensitive TTD patients (who are NER-proficient) share with photosensitive cases all the clinical features except cutaneous photosensitivity indicates that the DNA repair defect may not be the main determinant of the wide spectrum of symptoms of the disease. Ongoing research is indeed highlighting the contribution of transcriptional impairments in the etiopathogenesis of the TFIIH-related photosensitive form of TTD. In addition, the recent finding of non-photosensitive TTD cases associated with mutations in GTF2E2 encoding the beta subunit of the transcription factor TFIIE strongly supports the proposition that TTD is a “transcription syndrome”. It cannot however be ruled out that the accumulation of unrepaired DNA lesions may enhance the consequences of transcriptional deficiencies in the photosensitive cases.

 

Diagnosis

The main diagnostic criteria of TTD are brittle hair, mental and growth retardation, face characterized by receding chin, small nose, large ears and microcephaly, nail dysplasia and ichthyosis. The hair abnormalities are considered the key factors in the recognition of the disorder. Scalp hair, eyebrows, and eyelashes are short, thin, brittle and dry. Light microscopy reveals irregular hair surface and diameter, trichoschisis, a decreased cuticular layer with twisting, and a nodal appearance that mimics trichorrhexis nodosa. Polarisation microscopy of the hair typically shows alternating light and dark bands that confer a "tiger tail" pattern. The photosensitive form of TTD can be conclusively diagnosed by analyzing patient’s cells for the appropriate DNA repair defect. Specific functional assays on in vitro cultured skin fibroblasts from the patients (obtained from small skin biopsies) are available to evaluate the cellular response to UV light and to define the gene responsible for the DNA repair defect. Definition of the molecular defect may be informative for the prognosis. In patients with the non-photosensitive form of TTD, no cellular assays are available for diagnosis confirmation. In these cases, sequencing of the TTDN1, RNF113A and GTF2E2 genes might be informative.

 

Treatment

Management issues are: 1) comprehensive baseline evaluation and serial monitoring; 2) symptomatic care. Baseline evaluation includes measurement of growth, developmental assessment, dental evaluation, dermatologic, ophthalmologic and audiologic evaluations, brain MRI, skeletal X-rays to document the presence of skeletal dysplasia, EMG to document the presence of a demyelinating neuropathy, yearly reassessment for known potential complications such as declining vision and hearing. Symptomatic care includes an individualized educational program, assistive devices, and assessment of safety in the home for developmental delay and gait disturbances, physical therapy to prevent contractures and maintain ambulation, feeding gastrostomy tube placement to prevent malnutrition, medication for spasticity, management of hearing loss, cataracts, and other ophthalmologic complications, dental care to minimize dental caries.