Trichothiodystrophy

We describe a case of classic trichothiodystrophy occurring as an isolated disorder. This is the second reported case of trichothiodystrophy unassociated with systemic disorders, in contradistinction to other cases where there have been profound associated neuro-ectodermal abnormalities. The hair has shown the pathognomonic polarizing light-microscopic findings and the sulphur content has been confirmed to be reduced to approximately 50% by energy dispersive X-ray micro-analysis. Formal light-microscopic studies of hair cross-sectional shape using a Hardy microtome have confirmed the previous finding of a very thin or absent cuticle. An additional previously unreported finding was a 'scalloped' contour in a majority of hairs. The previously described ribbon shape could not be confirmed. Follow-up observation of the patient has shown clinical improvement with time.     

Trichothiodystrophy: progresssive manifestations

INTRODUCTION: Trichothiodystrophy is an autosomal recessive genodermatosis associating congenital dysplasia of the hair and neuroectodermal defects. Clinical expression is variable, although abnormalities are generally noted from birth. We report trichothiodystrophy in two brothers with the same phenotype who presented unusual progressive manifestations. OBSERVATIONS: Case 1: A six-year-old boy was seen for vesicular blisters due to photosensitization. Clinical examination showed dry, brittle, unmanageable hair, discrete koilonychia-type nail defects and an ichthyosiform state. The teeth were normal. In addition to psychomotor retardation, the patient presented a dysmorphic syndrome (poorly rimmed low-set ears; thick, triangular upper lip; scaphocephalic skull; short hands) and congenital bilateral cataract. The diagnosis of trichothiodystrophy was confirmed by a study of DNA repair after exposure to ultraviolet light. A repair defect was found similar to that in xeroderma pigmentosum group D. The patient experienced a worsening of psychomotor retardation and episodes of hair loss with edema and inflammation of the scalp resulting from infections. He also showed marked asthenia which resolved spontaneously within a few months. Case 2: The other brother, born as a collodion baby, presented the same clinical picture (cutaneous, exoskeletal, dysmorphic), including congenital bilateral cataract, photosensitivity and a parenchymatous blister-type pulmonary lesion probably secondary to bronchiectasis. The patient's cutaneous state progressively improved. He was seen at six years of age for an episode of inflammatory edema of the scalp with hair loss. Within six months, all of the hair redrew. The diagnosis of trichothiodystrophy was confirmed by a DNA repair defect after exposure to ultraviolet light. DISCUSSION: Trichothiodystrophy is clinically associated with photosensitivity (P), ichthyosis (I), dry, brittle hair (B), intellectual impairment (I), decreased fertility (D) and short stature (S), which accounts for the acronym PIBIDS or IBIDS syndrome, depending on whether photosensitivity is involved or not (actually in about 50 p. 100 of cases). Other possibly associated features include ungueal dysplasias, bilateral cataract, defective teeth, dysmorphic disorders predominant in the ears, neurologic disorders, pulmonary bronchiectasis and recurrent infections. The two cases presented here were thus very symptomatologically complete. The two problems of current concern are psychomotor retardation and temporary hair loss as a result of infections. The latter has only been described once in the literature. This case was similar to ours since photosensitivity was involved. Analysis of DNA repair also showed a defect after exposure to ultraviolet light similar to that found in xeroderma pigmentosum group D. Thus, episodic hair loss could be a symptom characteristic of forms of trichothiodystrophy with a DNA repair defect. However, the explanation for this hair loss is not known. Other ectodermal dysplasias can be complicated by hair loss with superinfection, such as AEC syndrome (ankyloblepharon, ectodermal dysplasia, cleft palate).     

Trichothiodystrophy: PIBIDS syndrome

Trichothiodystrophy comprises a heterogeneous group of autosomal recessive entities. This fact gives rise to different interrelated neuroectodermal disorders. From a structural point of view these features are the result of the low tissue sulfur content. We report a case of trichothiodystrophy initially classified as Tay syndrome that based on clinical features, complementary exams as well as on the disease evolution was labelled as PIBIDS syndrome.     

Trichothiodystrophy without associated neuroectodermal defects

We report a case of adult T-cell leukaemia/lymphoma (ATLL) with prurigo as a prodromal skin manifestation. The patient was a 52-year-old woman with a 2-year history of a fluctuating skin condition consisting of pruritic papules and pigmentation on her lower legs and right buttock. Prurigo was diagnosed at her first visit in October 1995, and she was found to be seropositive for human T-cell lymphotropic virus type 1 (HTLV-1). Two years later, the skin lesions had spread over the patient's forearms and dorsa of the hands, and abnormal lymphoid cells had appeared in her peripheral blood. Southern blot analysis revealed monoclonal integration of HTLV-1 provirus in the peripheral blood, but not in a skin lesion. Based on these results, a diagnosis of overt ATLL of the smouldering type was made. The findings in this case indicate that in healthy HTLV-1 seropositive carriers, prurigo requires careful follow-up as a cutaneous prodrome of ATLL.     

Trichothiodystrophy: Ultrastructural Studies of Two Patients

Abstract: An 18-month-old and an 8-year-old girl had trlchothlodystro-phy (TTD). Microscopic observation of the hair under polarized light showed typical alternation of bright and dark bands; amlno add analysis of the hair demonstrated a marked reduction of cystine levels. Both patients had skin lesions consisting In the older child of diffuse follicular keratosis since birth, and in the younger of an ichthyosiform darmatitls on the lower legs that appeared at age 4 months. Ultrastructural studies of the skin showed striking similarities in both cases: perinuclear vscuoles with a unit membrane in the keratinocytes, and dispersed, irregularty arranged bundles of tonofilaments particularly at the desmosome junction. The origin of the vacuoles is unknown; the abnormalities of the tonofilaments could be explained on the basis of a generalized abnormality in sulfur-containing proteins, reflecting a disturbance In the synthesis of keratins. These electron microscopy findings could be considered as a peculiar feature of ichthyotic skin in patients with TTD.     

Trichothiodystrophy: a morphological and biochemical study

Trichothiodystrophy is a pilar dysplasia which is characterized by the existence of brittle hair with trichoschisis, a typical pattern of transmission of polarized light and decreased levels of sulfur containing amino acids. In this report we show various aspects of the hair dysplasia and of the hair bulbs by light and scanning electron microscopy. Normal levels of cystin in the peripheral blood were associated with decreased levels of this amino acid in the hair shafts. Incorporation of radio-labelled cystine in hair follicles seemed however normal. Our results do not support the generally accepted hypothesis of a defective transport mechanism in the hair follicle. As a similar defect in other tissues (e. g. nervous system, spermatozoids...) is also thought to be responsible for the associated symptoms (e. g. nervous impairment, sterility in males...) we think it is important to lead further research in this field in order to elucidate the metabolic pathways underlying these rare clinical syndromes.     

Trichothiodystrophy Associated with Urologic Malformation and Primary Hypercalduria

Abstract: Trichothiodystrophy (TTD) is a hair abnormality that may be associated with a large number of alterations affecting the skin phenotype and skin appendages, nervous system, eyes, bones, and immune, gonadal, and endocrine systems. We report the first case of TTD associated with a urologic malformation and primary hypercaiciuria. Our patient had congenital ichthyosis, physical and mental retardation, and a dysmorphic facies associated with a complex urologic malformation and primary hypercalciuria. Characteristic features of his hair under microscopic examination (trichoschisis, alternating light and dark bands under polarizing microscopy, and a severely defective cuticle) and low sulfur content by radiographic microanalysis confirmed the diagnosis. We discuss the meaning of this new association in the spectrum of abnormalities related to TTD.     

Trichothiodystrophy: an ultrastructural study of the hair follicle

We have used detailed ultrastructural and electron histochemical techniques on both the hair shaft and anagen hair follicle to elucidate further the structural abnormalities in trichothiodystrophic hair. We have shown that protein deposition in the follicle is reduced and lacks orientation, and that the anagen follicles show an overall distortion. Both the hair cuticle and cortex high sulphur protein components are affected. The results of this study help to give a visual interpretation to detailed biochemical studies conducted by other workers thereby allowing specific localization of the site of the intrinsic keratin abnormality.     

Trichothiodystrophy: an electron-histochemical study of the hair shaft

We have used sensitive electron-histochemical methods to study the subtle ultrastructural variations of cystine incorporation into the hair shaft in trichothiodystrophy. We have shown a general reduction in the cystine (sulphur) content of both the cuticle and the cortex Discontinuity, and in some cases, complete absence of the cuticular A-layer results in premature weathering of the cuticle and weakening of the hair shaft. The ultrastructural findings support the work of Gillespie & Marshall (1981) in demonstrating the absence or re-characterization of the high sulphur matrix proteins and show further evidence for the incorporation, and abnormal distribution and deposition of sulphur-rich proteins in hair cortex and cuticle. We conclude that the similar yet different results obtained from each patient's hair sample are characteristic of trichothiodystrophy, a neuro-ectodermal symptom complex which may represent a final common pathway of more than one metabolic disturbance.     

Trichothiodystrophy Without Retardation: One Patient Exhibiting Transient Combined Immunodeficiency Syndrome

Two patients had trichothiodystrophy but did not exhibit the commonly associated findings such as mental retardation, increased sensitivity to sunlight, ichthyosis, decreased fertility in males, and short stature. One of the patients had a transient combined immunodeficiency syndrome in early childhood lasting four years, but has remained in good health untreated for four years. The association of these two rare findings in this patient should alert us to the possibility that others with trichothiodystrophy may exhibit immunodeficiency.     

A New Case of Trichothiodystrophy Associated with Autism, Seizures, and Mental Retardation

Abstract: We report a patient with trichothiodystrophy associated with autism, mental retardation, and seizures. The diagnosis was based on the presence of brittle hair, with a marked decrease in sulfur-rich amino acid content, and characteristic features such as "tiger tail" under polarizing microscopy and trichoschisis under scanning electron microscopy. Macroscopic alterations were mostly observed in the frontal and occipital hair, with only microscopic abnormalities in the occipital hair. We consider this an unusual expression of this disease.     

Trichothiodystrophy and Associated Anomalies: A Variant of SIBIDS or New Symptom Complex?

Abstract: Trichothiodystrophy is characterized by sparse, short, sulfur-deflclent hair. Numerous symptom complexes have been described in which the hair abnormaiity represents a constant feature. We report a boy with trichothiodystrophy, ichthyotic skin changes, onychodystrophy, chronic neutropenia, osteoscierosis, hypothyroidism, nystagmus, growth and mentai retardation, and microcephaiy, who developed a progressive encephalopathy with ataxia and optic atrophy at 2.5 years of age. in addition to a deficient cystine ievei identified on a hair sampie, a disturbance in the composition of other amino acids was present. Ai-though features were reminiscent of osteoscierosis, ichthyosis, brittie hair due to trichothiodystrophy, impaired inteliigence, decreased fertiiity, and short stature (SIBIDS) and couid represent a variant of this disorder, findings in our patient may refiect a new trichothiodystrophy symptom compiex that carries a poor prognosis for survivai beyond chiidhood.     

A New Variant of Trichothiodystrophy with Recurrent Infections,Failure to Thrive,and Death

Abstract: Two brothers demonstrated a severe variant of trichothiodystrophy. Both had brittle hair, developmental delay with severe failure to thrive, recurrent infections, cataracts, and angioendotheliomas of the liver at autopsy. The elder died at 12 weeks, the younger at 6 months. The younger had the typical appearance of banded hair on polarizing microscopy and a low cystine content measured by ion exchange chromatography. The history, clinical findings, and basic defects of trichothiodystrophy are discussed.     

Trichothiodystrophy and fragile hair: the distinction between diagnostic signs and diagnostic labels in childhood hair disease

Background Hair typically becomes fragile when there are structural abnormalities and/or a reduction in the sulphur‐containing amino acids cystine or methionine. This finding in the setting of a neuroectodermal complaint is usually labelled trichothiodystrophy (TTD). The spectrum of features within this diagnostic grouping tests the validity of using sulphur‐deficient hair as a central characteristic. Objectives To determine what diagnoses were found within a group of subjects with fragile hair and whether low cystine or methionine were relevant central characteristics. Methods We examined cases referred to us from 12 U.K. centres for hair microscopy over 10 years where hair fragility or clinical characteristics raised the possibility of TTD. All samples underwent amino acid analysis. This was achieved through cation exchange chromatography coupled with spectrophotometric quantification. Results Twenty‐five patients (11 male, 14 female) with a mean age of 11 years (0·3–37) were evaluated. Nineteen patients had features of hair damage. Of these, five patients had abnormalities on microscopy only and four patients had microscopic changes and tiger‐tail pattern but normal amino acid content. The remaining 10 patients had reduced cystine content, two of whom also had low methionine. All but one had the tiger‐tail pattern. Among the wide range of phenotypes there were only three cases matching a diagnosis of TTD. Conclusions Our data suggest that clinically apparent fragile hair in childhood is only rarely associated with a diagnosis of TTD. The tiger‐tail change is sensitive but not wholly specific to TTD. We propose that the term trichothiodystrophy be limited in its use to define sulphur‐deficient hair rather than as a diagnostic term in a heterogeneous and incoherent multisystem disorder, where sulphur‐deficient hair is one feature.     

Trichothiodystrophy group A: A first Japanese patient with a novel homozygous nonsense mutation in the GTF2H5 gene

Trichothiodystrophy group A (TTD‐A) is one of the three types of photosensitive TTD and is a very rare genodermatosis with deficient post‐ultraviolet (UV) DNA repair. We herein describe the first Japanese case with a novel mutation in the GTF2H5 gene responsible for TTD‐A. A 5‐year‐old male, born as a collodion baby from healthy non‐consanguineous parents, exhibited sun sensitivity, brittle hair, ichthyosis, cataracts and mental/physical retardation. He demonstrated neither neurological abnormalities nor pigmentary changes following sun exposure. The patient's primary fibroblasts were hypersensitive to killing by UV (D₀ = 1.5 J/m²), and the post‐UV unscheduled DNA synthesis was 13% of normal. A host cell reactivation complementation analysis showed a decreased DNA capacity without recovery after transfecting any xeroderma pigmentosum genes. We identified a novel homozygous mutation (c.166G>T) in the coding region of the GTF2H5 gene that resulted in a predicted amino acid change: p.E55X. Thus far, only one Japanese case of TTD with a mutation of the XPD gene had been reported. The present case is the first of TTD‐A and the second case of TTD in Japan, suggesting that it is necessary to differentiate TTD from other photosensitive disorders, although the incidence of TTD is very low in Japan compared to that observed in Western countries.     

Trichothiodystrophy: quantification of cysteine in human hair and nails by application of sodium azide-dependent oxidation to cysteic acid

The term trichothiodystrophy (TTD) covers several autosomal recessive diseases whose diagnostic hallmark is short, brittle hair low in sulfur and cystine because of impaired synthesis of high-sulfur matrix protein. Clinical symptoms associated with TTD represent a variable range of abnormalities in organs derived from ectoderm and neuroectoderm. Important laboratory tests of the hair for the diagnosis of TTD comprise polarizing microscopy (tiger-tail pattern), electron microscopy, and amino acids analysis of hydrolyzed hair with a special focus on cystine. However, only very few institutions determine the amino acid composition of human hair and nail clippings, which requires special sample preparation including hydrolysis. If no special precautions are taken, quantification of cysteine and cystine becomes inaccurate because of decomposition of these residues during hydrolysis. We therefore performed the sample work-up with azide-dependent oxidation which we have for the first time adapted for analysis of hair and nail clippings. With our control and parent data resembling published data on hair and nail samples, we obtained a decreased proportion of cysteine (half cystine, determined as cysteic acid) in materials obtained from a boy with TTD. Clearly, the method for the quantification of cysteine following sodium azide-dependent oxidation is a suitable and rather convenient approach to the quantification of cyst(e)ine and other amino acids in hair and nail proteins, and is a valuable contribution to the diagnosis of TTD.     

Trichothiodystrophy fibroblasts are deficient in the repair of ultraviolet-induced cyclobutane pyrimidine dimers and (6-4)photoproducts

A photosensitive form of trichothiodystrophy (TTD) results from mutations in the same XPD gene as the DNA-repair-deficient genetic disorder xeroderma pigmentosum group D (XP-D). Nevertheless, unlike XP, no increase in skin cancers appears in patients with TTD. Although the ability to repair ultraviolet (UV)-induced DNA damage has been examined to explain their cancer-free phenotype, the information accumulated to date is contradictory. In this study, we determined the repair kinetics of cyclobutane pyrimidine dimers (CPD) and (6-4)photoproducts (6-4PP) in three TTD cell strains using an enzyme-linked immunosorbent assay. We found that all three TTD cell strains are deficient in the repair of CPD and of 6-4PP. UV sensitivity correlated well with the severity of repair defects. Moreover, accumulation of repair proteins (XPB and proliferating cell nuclear antigen) at localized DNA damage sites, detected using micropore UV irradiation combined with fluorescent antibody labeling, reflected their DNA repair activity. Importantly, mutations of the XPD gene affected both the recruitment of the TFIIH complex to DNA damage sites and the TFIIH expression. Our results suggest that there is no major difference in the repair defect between TTD and XP-D and that the cancer-free phenotype in TTD is unrelated to a DNA repair defect.