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Rough skin, brittle hair, and photosensitivity: a mild phenotypic variant of trichothiodystrophy
  1. * Victorian Clinical Genetics Service, Royal Children's Hospital, Melbourne, Victoria 3052, Australia
  2. Skin and Cancer Foundation, Melbourne, Victoria 3053, Australia
  3. UCSF Cancer Center, University of California, San Francisco, CA 94143-0808, USA
  1. Dr Gardner

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Editor—The trichothiodystrophies (TTD) are named primarily for the hair sulphur deficiency which is their most specific feature and which leads to brittleness of the hair. Other ectodermal tissues may be affected and typically the skin is ichthyotic and the nails dystrophic. Additionally, there may be a distinctive facies and physical and developmental retardation of varying degree of severity. Inheritance is autosomal recessive and at least three loci exist, of which two are known, the excision repair/transcription factor genes XPD/ERCC-2 andXPB/ERCC-3. We describe an 8 year old girl in whom the diagnosis of a mild and in some respects atypical form of TTD was made on the synthesis of clinical, pathological, and biochemical data. The genotypic basis of this clinical phenotype has yet to be established.

The patient was the second child of a dizygous twin pregnancy born to unrelated, healthy, white parents by emergency caesarean section at 32 weeks because of pre-eclampsia. The family history was unremarkable and her male co-twin was healthy. Birth weight was 2100 g (90th centile for this gestation). Birth length and head circumference were 51.5 cm and 32.5 cm respectively. The skin was dry and flaky from birth (but never “collodion”), and in using a towel her mother had to pat her dry, rather than to rub. Thickening of the palms and soles developed in the first year of life. The nails were brittle from birth. Hair growth has always been slow and she has never had a proper haircut, only trims. Desquamated cells from the external auditory canal failed to clear and she has required periodic syringing.

She was referred to our service at 5 years of age because of concerns related to persistent dermatitis, dermal photosensitivity suggested by easy burning in the sun, mild developmental delay, and distinctive facial appearance. We noted the following features: hair that was “wiry” in texture, fragile, and easy to extract; abnormal scalp hair distribution with temporal recession; prominent forehead with sparse eyebrows (fig 1); a generalised dryness of the skin with areas of keratoderma; and brittle, spoon shaped fingernails and toenails. The keratoderma was particularly marked on the soles and palms (fig 2) and at the popliteal and antecubital flexures. Apart from congenital absence of the second premolars, the teeth were normal. Her weight was 27 kg (90th centile), height 128 cm (97th centile), and head circumference 54 cm (98th centile). These measurements are consonant with the parental heights and weights, which were in the 90th-97th centile range. She was attending a normal school and was in the appropriate class for age, but was receiving remedial help with reading and perceptual motor skills. Her co-twin did not display any of the above features on examination and was reported to be performing satisfactorily at school. On review at the age of 8½ years, her hair was becoming thicker but the growth rate remained very slow. The keratoderma continued to be a problem and was managed by a combination of skin creams. The skin photosensitivity was being dealt with by ultraviolet barrier cream and sun protection. Formal testing with monochromatic light across the ultraviolet A and B spectra did not produce unusual erythema, indicating that the photosensitivity was of mild degree. Eye examination was difficult because of photophobia, but no abnormal retinal pigmentation was observed. She was having private tuition for reading and arithmetic.

Figure 1

Patient aged 8 years. The hair is short (has only been trimmed) and stands up irregularly. There is temporal recession.

Hair examination on polarised light microscopy showed no alternating dark and light band “tiger tail” pattern. On scanning electron microscopy, marked irregularity and flattening of hair shafts was observed. Some areas showed twisting and variation in shaft diameter. Transmission electron microscopy showed a defective A layer in the outermost cuticle cells (fig 3), a characteristic of TTD.1 The hair cysteine content of the patient and of an age and sex matched control was assessed on hair cuttings scoured as in Church et al 2 and measured according to a modification of the method in Strydom and Cohen.3 All hair shafts showed decreased cysteine content compared to the control specimens and with reference to previously published values (table 1).

Figure 3

Cross section of hair shaft on transmission electron microscopy. (Left) Normal, showing central cortex and cuticle cell layers peripherally. The cuticle cells are elongated and show a dark continuous band (A layer) on their internal border (arrow). (Right) TTD, present case. The outermost cuticular layers are disrupted and the normal architecture is lost. The A layer (arrowhead) is only intermittently discernible.

Table 1

Hair cysteine analysis results

Since the patient came from the same city as a previously reported case of TTD (TTD183ME), who was a compound heterozygote at theXPD/ERCC2 locus, we first tested the mutations identified in that case, these being a null mutation in one allele (c1381C>G, c2146del45) and a causative mutation in the other (c2173G>C).4 5 We used this occasion to test the robustness of buccal smears for diagnostic purposes. We had previously used buccal smears successfully for the diagnosis of xeroderma pigmentosum complementation group A (XPA) patients (J E Cleaver, M McDowell, unpublished data), but we expected that theXPD gene, being larger thanXPA and with more introns, might prove more difficult.5 Buccal smears were taken from the patient and her co-twin and sent by express mail from Melbourne to San Francisco. Samples were then solubilised in alkali extraction buffer and subjected to genomic amplification by PCR, using primers that flank those genomic regions in which mutations noted above had previously been identified. The PCR products were subcloned into a cloning vector and individual inserts sequenced. The unaffected co-twin had no causative mutations in the regions investigated, although there were two common neutral polymorphisms (c687G>A, c711C>T). The index case had neither of these polymorphisms and neither was the c1381C>G, c2146del45 null allele identified. We sequenced about 300 nucleotides around the region of the causative mutation (c2173G>C) and found only wild type sequences.

This child presents a mild phenotypic form of trichothiodystrophy (TTD). The scalp hair was abnormal in its texture, strength, and distribution, and the electron microscopic (but not light microscopic) picture was similar to that of the classical form of TTD. Hair cysteine content was reduced and the A layer of the cuticle cells defective, substantiating the diagnosis. Other clinical observations included keratoderma, nail dystrophy, and mild developmental delay. Linear growth was unaffected.

TTD can present with a notably wide clinical range.6In its mildest form, the disorder may be confined clinically to an abnormality of the hair.7 8 The “tiger tail” hair sign is typical but not universal,6 as indeed our case exemplifies. A further grade of affection is illustrated in our patient, with mild to moderate involvement of the ectoderm and certain of its appendages, as well as (if indeed this is causally related) a minor cognitive component. At the other end of the spectrum, TTD is a seriously disabling disease, with a severe skin affliction and mental defect and growth retardation.

The TTDs comprise one of a group of related disorders resulting from abnormalities in components of the nucleotide excision repair (NER) system, these factors having a second role as subunits of the basal transcription factor TFIIH.9 10 Three TTD complementation groups exist, corresponding to the genesXPB/ERCC-3,XPD/ERCC-2, and an uncloned geneTTDA. Xeroderma pigmentosum (XP) and a form of Cockayne syndrome (CS) with XP-like symptoms are also the result of defects in the NER/TFIIH system, and the three conditions XP, CS, and TTD overlap at a clinical and molecular level. The phenotype in XP includes photosensitivity, pigmentary abnormalities, neurodegeneration, and (unlike TTD) a predisposition to skin cancer; CS is characterised by neurodysmyelination, photosensitivity, and physical and mental retardation.

Mutations in one particular NER/TFIIH subunit,XPD/ERCC-2, account for the great majority of photosensitive TTD patients, and are seen in patients with XP complementation group D (XPD), and in patients with combined clinical features of XP and Cockayne syndrome.9 11 12 In vitro insertion of XPD/ERCC-2 in cells of the three conditions corrects the UV induced DNA damage in cells, showing a locus homogeneity with allelic heterogeneity in the three clinical phenotypes. The gene has yet to be identified in a second TTD complementation group, in which the phenotype is severe. Mutations in the gene XPB/ERCC-3, which codes for another NER/TFIIH subunit, have recently been identified in the third complementation group of TTD, characterised by a mild phenotype, and so far represented only by two sibs; the Cockayne/XP syndrome has also been associated with this locus.9 13 The two reportedXPB/ERCC-3 TTD sibs displayed a dermatological phenotype of “collodion baby”, proceeding to a residual mild ichthyosis of the trunk and a mild photosensitivity. Hair microscopy showed a “tiger tail” pattern. They were noted to be of normal intelligence and physical growth, although a “mild learning disability” was recorded in one, and this child also had growth indices at the lower limit of normal (–2 SD).

We have not been able to find an XPD/ERCC-2mutation in our patient, although this possibility is by no means excluded. The mildness of the phenotype may suggest an equivalence to the XPB/ERCC-3 sibs in Weedaet al,9 but there is a difference in that she had not presented as a collodion baby, her linear growth is not compromised, her keratoderma is more marked, and light microscopy did not show “tiger tailing”. Which, if either, locus underlies her case remains open to question.


We thank Dr Richard McNeill who referred the patient, Dr C W Chow and Professor J P Dowling who performed hair electron microscopy, Dr C Baker who did the skin light testing, and Mr Gary Corino of the Commonwealth Scientific and Industrial Research Organisation, Geelong, Australia, who did the hair sulphur analysis. We thank the patient and her family for their help in the study. JEC acknowledges NIEHS grant number 1RO1 8061 and a generous gift from the XP Society.


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