Trichothiodystrophy: Photosensitive, TTD-P, TTD, Tay syndrome.

Although the term, "trichothiodystrophy" (TTD) refers to the hair anomalies in this group of patients, this is a heterogeneous, multisystem disease in which any or every organ in the body may be affected. Neuroectodermal derived tissues are particularly likely to be involved. This term was introduced by Price et alin 1980 to designate patients with sulfur-deficient brittle hair, which they recognized as a marker for this complex disease and designated it as a "neuroectodermal symptom complex". Patients with TTD have brittle hair and nails (associated with reduced content ofcysteine-rich matrix proteins), ichthyotic skin and physical and mental growth retardation. Ichthyosis is usually apparent at birth but much less so after the first few weeks of life. Other frequently associated features include ocular cataracts, infections and maternal complications related to pregnancy. Atrophy of subcutaneous fat may also be present. TTD occurs in a pattern of inheritance consistent with an autosomal recessive condition. The disease is extremely heterogeneous in severity and extent, with some patients showing no neurological deficiency. Others show severe, multisystem disease. Many patients die at a young age, most commonly due to infectious disease. TTD is part of a more broadly defined group of diseases identified as IBIDS (ichthyosis, brittle hair, impaired intelligence, decreased fertility and short stature). Photosensitive cases are also identified as PIBIDS (photosensitivity with IBIDS). Cases without manifest ichthyosis are also identified as PBIDS. These syndromes defy rigorous definition because of clinical variation between patients. The original two cases were described by Tay in oriental siblings, whose parents were first cousins; thus the disease is also known as Tay syndrome. The hairs in patients with TTD have a distinctive, diagnostically useful appearance on polarized light microscopy consisting of alternating light and dark bands known as the "tiger tail" anomaly. Diagnosis may be confirmed by sulfur content analysis ofhair shafts, which shows decreased sulfur and cysteine content. Approximately half of patients with TTD have photosensitivity, which correlates with a nudeotide excision repair (NER) defect. These patients are designated as having trichothiodystrophy-photosensitive (TTDP). Non-photosensitivepatients are designated as having trichothiodystrophy-nonphotosensitive (TTDN). Skin cancer is very rare in sun-sensitive TTD.

New clinico-genetic classification of trichothiodystrophy.

Trichothiodystrophy (TTD) is a congenital hair dysplasia with autosomal recessive transmission. Cross banding pattern under polarized light plus trichoschisis and a low sulfur content of hair shafts define the disorder, which is associated with variable and neuroectodermal symptoms. So-called photosensitive forms of TTD (with low level of in vitro UV-induced DNA repair, not constantly associated with marked clinical photosensitivity) are caused by mutations in genes encoding subunits of the transcription/repair factor IIH (TFIIH). Ten percentage of nonphotosensitive patients are known to have TTDN1 mutations, the specific role of which is unknown. We studied nine patients recruited at our institution and reviewed 79 with molecular analysis out of 122 TTD patients reported in literature with the aim to collect systematically the clinical findings in TTD patients and establish genotype-phenotype correlations. The frequency of congenital ichthyosis, collodion-baby type, was significantly higher in the TFIIH mutated group. Hypogonadism was significantly more frequent in the non-photosensitive group. There was no statistical difference regarding osseous anomalies. Mutations in TFIIH sub-units leading to abnormal expression in genes involved in epidermal differentiation could explain the particular dermatological changes seen in photosensitive cases of TTD. We suggest a new clinico-genetic classification of TTD, which may help clinicians confused by the current acronyms used (IBIDS, PIBIDS...). Understanding the TTD ichthyotic phenotype could lead to therapeutic advances in the management of TTD and other types of ichthyoses.

Sabinas syndrome in monozygotic twins.

A pair of 2-year-old female monozygotic twins presented with short and brittle hair. There was marked reduction in hair density, and excessive curving of the eyelashes. Onychodystrophy was also evident. They also had developmental delay in verbal and motor skills. Neither their parents nor other relatives were known to be affected, and there was no history of consanguinity. Examination of the hair shaft under light microscopy showed trichoschisis, which was more evident under electron microscopy. Under polarized light, the hair shafts showed the pathognomonic 'tiger-tail' pattern. The level of sulphur in the hair was low. Both patients were negative for TTDN1 mutation. Clinical correlation was performed and the diagnosis of Sabinas syndrome was made. Sabinas syndrome is a very rare autosomal recessive disorder first described in a group of patients from a small community in north-eastern Mexico. It is diagnosable at birth, and its major symptoms include brittle hair, mental retardation and nail dysplasia. Structural hair abnormalities are seen by both light and electron microscopy.

Structural basis for group A trichothiodystrophy.

Patients with the rare neurodevelopmental repair syndrome known as group A trichothiodystrophy (TTD-A) carry mutations in the gene encoding the p8 subunit of the transcription and DNA repair factor TFIIH. Here we describe the crystal structure of a minimal complex between Tfb5, the yeast ortholog of p8, and the C-terminal domain of Tfb2, the yeast p52 subunit of TFIIH. The structure revealed that these two polypeptides adopt the same fold, forming a compact pseudosymmetric heterodimer via a beta-strand addition and coiled coils interactions between terminal alpha-helices. Furthermore, Tfb5 protects a hydrophobic surface in Tfb2 from solvent, providing a rationale for the influence of p8 in the stabilization of p52 and explaining why mutations that weaken p8-p52 interactions lead to a reduced intracellular TFIIH concentration and a defect in nucleotide-excision repair, a common feature of TTD cells.