Trichothiodystrophy (ORPHA:33364)
A rare, genetic, syndromic hair shaft abnormality disorder characterized by short, dry, sulfur-deficient, brittle hair usually associated with highly variable neuroectodermal manifestations, such as ichthyosis, photosensitivity, and intellectual disability.
Epidemiology
Although epidemiological data is limited worldwide, the prevalence at birth has been estimated at 1/830,000 in Europe.
Clinical description
TTD syndromes are numerous syndromes affecting mainly organs derived from the neuroectoderm. The clinical appearance is always characterized by brittle and fragile hair, often combined with congenital ichthyosis and nail abnormalities, growth retardation and intellectual deficit among other symptoms. The abnormalities are generally present at birth, with variable clinical expression. About half of the patients with TTD exhibit marked photosensitivity, due to abnormalities in excision repair of ultraviolet (UV)-damaged DNA. In these patients, the deficiency in DNA excision repair is indistinguishable from that observed in Xeroderma Pigmentosum type D (due to ERCC2 variants), however TTD patients do not have an increased risk of skin cancers.
Etiology
Patients with a photosensitive form of TTD carry biallelic mutations within three genes encoding distinct subunits of the multi-protein transcription initiation factor IIH (TFIIH) complex, including most frequently ERCC3, but also GTF2H5 or ERCC2. TFIIH is essential for both transcription initiation and nucleotide excision repair (NER). Seven genes have been identified in the so-called non-photosensitive form of TTD, which encode M-phase-specific PLK1 interacting protein (encoded by MPLKIP), general transcription factor IIE subunit 2 (GTF2E2), the X-linked ring finger protein 113A (RNF113A) and the recently identified cysteinyl-tRNA synthetase (CARS), threonyl-tRNA synthetase 1 (TARS1), alanyl-tRNA synthetase (AARS1) and methionyl-tRNA synthetase (MARS1).
Diagnostic methods
The diagnostic findings of TTD are short, unruly, brittle hair, with alternating dark and light bands under polarizing microscopy (tiger-tail pattern), trichoschisis (or trichorrhexis), and an absent or defective cuticle visualized by scanning electron microscopy. The amino-acid analysis of hair shafts revealed a cystine content commonly reduced to less than half of normal values. Functional testing (Unscheduled DNA synthesis) of the nucleotide excision repair system may help to identify photosensitive forms harboring DNA repair defect activity. The diagnosis may be confirmed molecularly.
Differential diagnosis
TTD is a differential diagnosis in congenital alopecias.
Antenatal diagnosis
Antenatal molecular diagnosis is possible only if the molecular diagnosis is made in the index case.
Genetic counseling
All forms of TTD are autosomal recessive disorders except for one X-linked form.
Management and treatment
There is no specific treatment. Patients should receive regular follow-ups in order to precociously detect any neurological, skin, growth delay, malformation and/or immune deficiency. Early intervention with a multidisciplinary team involving pediatricians, neurologists, physiotherapists, psychologists benefit development of the infant and quality of life. Management of ichthyosis is non-specific and mostly relies on topical application of ointments and keratolytic agents. Photoprotection is mandatory in photosensitive forms of TTD.
Prognosis
Severe infections may account for the premature death in patients with TTD, who have a higher mortality compared to the general population.

                            Last update: 
                            June 2022


                            - Expert reviewer(s): 
                            Dr Fanny MORICE-PICARD | ERN-Skin*


                                * European Reference Network