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Biomedical subjects

M J Tidman

Publications and source records attributed to M J Tidman.

At least 37 records · Page 2Linked to original sources
PubMed1998

A recurrent glycine substitution mutation, G2043R, in the type VII collagen gene (COL7A1) in dominant dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the type VII collagen gene (COL7A1). Nearly all cases of dominant DEB are caused by glycine substitution mutations occurring within the triple helical region of type VII collagen, and most of the mutations are unique to individual families. In this study, we identified a patient of Hispanic-Mexican origin with a mild form of DEB, which resulted from a de novo dominant glycine substitution, G2043R, in exon 73 of COL7A1. We also investigated a Scottish family with a three-generation pedigree of dominant DEB, in whom the same glycine to arginine substitution mutation was demonstrated. This particular mutation has also been detected previously in three other families with dominant DEB: one Italian, one Hungarian and one Norwegian. Given the widespread geographical distribution of this mutation and the demonstration of its occurrence as a de novo event, G2043R therefore represents the first example of a mutational hotspot in dominant DEB. Interestingly, although both the Mexican and Scottish families we studied had some clinical features in keeping with the Pasini form of the disorder, there was considerable interfamilial variability as well as intrafamilial diversity in the affected individuals.

Adult↗
PubMed1998

Pyloric atresia-junctional epidermolysis bullosa syndrome: mutations in the integrin beta4 gene (ITGB4) in two unrelated patients with mild disease.

Junctional epidermolysis bullosa associated with pyloric atresia (EB-PA; OMIM 226730) is a rare autosomal recessively inherited disease in which mucocutaneous fragility is associated with gastrointestinal atresia. This disease is usually fatal within the first few weeks or months of life even following surgical correction of the intestinal obstruction. Recently, mutations in the genes encoding the epithelial integrin alpha6beta4 (ITGA6 and ITGB4) have been identified in several patients with EB-PA. We report two unrelated patients with this disease who have survived into early childhood with mild cutaneous involvement, in whom we have identified pathogenetic mutations in ITGB4. The first patient was a compound heterozygote for a splice site mutation in exon 30 (3793 + 1G-to-A) and a non-sense mutation in exon 36 (W1478X), and the second was a compound heterozygote for a missense mutation in exon 3 (C38R) and a 1 bp deletion in exon 36 (4776delG). Although the non-sense and deletion mutations are predicted to result in markedly reduced beta4 integrin mRNA levels, the presence of the missense or splice site mutation on the second allele may enable the synthesis of some functional, albeit perturbed, beta4 polypeptide. Determination of the molecular mechanisms in these two cases increases our understanding of EB-PA and may enable correlation between genotype and phenotype.

Antigens, CD↗
PubMed1998

Hemidesmosomes show abnormal association with the keratin filament network in junctional forms of epidermolysis bullosa.

Junctional epidermolysis bullosa is a group of hereditary bullous disorders resulting from defects in several hemidesmosome-anchoring filament components. Because hemidesmosomes are involved not only in keratinocyte-extracellular matrix adherence, but also in normal anchorage of keratin intermediate filaments to the basal keratinocyte membrane, we questioned whether this intracellular function of hemidesmosomes was also perturbed in junctional epidermolysis bullosa. We used quantitative electron microscopic methods to assess certain morphologic features of hemidesmosome-keratin intermediate filaments interactions in skin from normal subjects (n = 11) and from patients with different forms of junctional epidermolysis bullosa (n = 13). In addition, skin from patients with autosomal recessive epidermolysis bullosa simplex with plectin defects (n = 3) or with autosomal recessive dystrophic epidermolysis bullosa (n = 4) were included as controls. Values were expressed as a percentage of the total number of hemidesmosomes counted. In normal skin 83.3% +/- 3.3 (SEM) hemidesmosomes were associated with keratin intermediate filaments and 90.1% +/- 1.9 had inner plaques. In Herlitz junctional epidermolysis bullosa (laminin 5 abnormalities, n = 4) these values were reduced to 45.3% +/- 11.5 (p < 0.001; analysis of variance) and 50.3% +/- 12.8 (p < 0.001), respectively. In junctional epidermolysis bullosa with pyloric atresia (alpha6beta4 abnormalities, n = 3) the values were also reduced [41.8% +/- 7.0 (p < 0.001) and 44.5% +/- 5.7 (p < 0.001), respectively]. In the non-Herlitz group (laminin 5 mutations, n = 3) the counts were 66.7% +/- 7.1 (p > 0.05) and 70.5% +/- 8.5 (p < 0.05), and in skin from patients with bullous pemphigoid antigen 2 mutations (n = 3) the counts were 54.3% +/- 13.8 (p < 0.01) and 57.1% +/- 13.9 (p < 0.01). In epidermolysis bullosa simplex associated with plectin mutations the values were 31.9% +/- 8.9 (p < 0.001) for keratin intermediate filaments association and 39.9% +/- 7.1 (p < 0.001) for inner plaques. Findings in recessive dystrophic epidermolysis bullosa patients' skin were indistinguishable from normal control skin with inner plaques (90.5% +/- 2.5) and keratin intermediate filaments attachment (86.3% +/- 2.1). These findings suggest that the molecular abnormalities underlying different forms of junctional epidermolysis bullosa appear to affect certain critical intracellular functions of hemidesmosomes, such as the normal connections with keratin intermediate filaments. This may have important implications for the maintenance of basal keratinocyte integrity and resilience in junctional epidermolysis bullosa.

Adolescent↗
PubMed1998

Severe palmo-plantar hyperkeratosis in Dowling-Meara epidermolysis bullosa simplex caused by a mutation in the keratin 14 gene (KRT14).

Mutant keratins 5 or 14 are implicated in the etiology of epidermolysis bullosa simplex (EBS). The catalog of mutations has established certain patterns of mutation clusters from which it may be possible, along with associated biochemical data, to predict phenotypic severity. It is becoming apparent that some of these assumptions may now require modification. We report a mutation in the gene encoding keratin 14 (KRT14) that changes the predicted amino acid at position 119, at the start of the helix initiation motif, from methionine to threonine (K14 M119T) in a patient with an EBS Dowling-Meara phenotype with severe palmo-plantar hyperkeratosis. This demonstrates that the three major types of EBS can arise from missense mutations in the same codon. The findings suggest that the specific nature of the missense mutation, in the context of the protein sequence, can contribute far more to the clinical severity than previously thought. The different EBS subtypes should be viewed as gradations of clinical severity rather than distinct genetic diseases.

Adult↗
PubMed1997

Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex.

Pachyonychia congenita (PC) is a group of autosomal dominant ectodermal dysplasias in which the main phenotypic characteristic is hypertrophic nail dystrophy. In the Jackson-Lawler form (PC-2), pachyonychia is accompanied by multiple pilosebaceous cysts, natal teeth, and hair abnormalities. By direct sequencing of genomic PCR products, we report heterozygous K17 missense mutations in the same conserved protein motif in a further five PC-2 families (K17 N92S in one familial and three sporadic cases; K17 Y98D in one familial case) confirming that mutations in this gene are a common cause of PC-2. We also show heterozygous missense mutations in K17 (N92H and R94H) in two families diagnosed as steatocystoma multiplex. Mild nail defects were observed in some but not all of these patients on clinical re-evaluation of these families. All the K17 mutations reported here were shown to co-segregate with the disease in the pedigrees analyzed and were excluded from 100 unaffected, unrelated chromosomes by restriction enzyme analysis of K17 genomic PCR products. We conclude that phenotypic variation is observed with K17 mutations, as is the case with other keratin disorders.

Cysts↗
PubMed1997

Measurement of quality of life in atopic dermatitis: correlation and validation of two different methods.

Atopic dermatitis is a chronic relapsing condition that can have considerable effects on the lives of sufferers. It is apparent that good, valid measures of life quality are necessary for quantifying the patients' perspective of the severity of their disease and the Dermatology Life Quality Index is often employed in clinical research. In a community study of atopic dermatitis we have assessed disability using the Dermatology Life Quality Index and the Patient Generated Index and compared the results from both indices. The results were significantly correlated and reflected the range of disability in patients in the community. Some items of the Dermatology Life Quality Index were not relevant for atopic dermatitis patients in the community and others, including swimming and sleep loss, were often cited in the Patient Generated Index but are not included in the Dermatology Life Quality Index. The Patient Generated Index is a novel, flexible approach to quality of life measurement that may be suitable for reflecting the wide variety of disability that is experienced by dermatological patients.

Activities of Daily Living↗
PubMed1997

The prevalence of epidermolysis bullosa in Scotland.

The prevalence of epidermolysis bullosa (EB) in Britain and most other countries is unknown. Patients suffering from the inherited forms of EB and living in Scotland have been traced. Two hundred and fifty-nine affected people from 76 families have been identified, of whom 211 were clinically assessed. One-third of these Scottish EB sufferers had never been seen by a dermatologist. In Lothian, where there appears to be a relatively high prevalence of EB, 75% of patients were unknown to their general practitioners. The point prevalence of all forms of EB at the outset of the study was 49.0 per million, comprising EB simplex 28.6 per million and dystrophic EB 20.4 per million. Extrapolation of accurate data available for the Lothians suggests that the point prevalence of all forms of EB in Scotland is in excess of these figures.

Adolescent↗
PubMed1996

Lipoatrophy with human insulin.

We describe a case of lipoatrophy that was secondary to human insulin. The patient had only ever been treated with human insulin, and the lipoatrophy appeared to partially resolve with continued use of the same insulin preparations. Possible underlying pathogenic mechanisms are discussed.

Adipose Tissue↗
PubMed1996

An histological and ultrastructural study of the 'dirty neck' appearance in atopic eczema.

The 'dirty neck' appearance is a characteristic disorder of pigmentation, which has previously been found to affect approximately 2% of adult atopics. This disorder results in a rippled pattern of hyperpigmentation similar to that seen in macular amyloidosis. Biopsy specimens from affected skin of three patients were examined by histological and electron microscopical techniques. In addition to eczematous changes, marked pigmentary incontinence was observed. Amyloid-like material was detected by electron microscopy but not by light microscopy in all three specimens. Some deposition of amyloid occurs in this condition but the pigmentary changes are attributable to melanin incontinence. In 1987, two separate groups, Manabe et al. and Colver et al., described a distinctive type of hyperpigmentation, found particularly on the neck in some patients with chronic atopic eczema. Manabe's group found that 1.7% of 700 patients with atopic eczema showed this clinical characteristic, and that only adolescents and adults were affected. This condition has been called the 'dirty neck' appearance or 'ripple pigmentation of the neck in atopic dermatitis'. The clinical features are a rippled pattern of hyperpigmentation seen particularly on the anterior and lateral aspects of the neck (Fig. 1). We have also observed the same appearance in the inguinal areas. A number of factors could contribute to the development of hyperpigmentation in chronic atopic eczema. It is possible that the 'dirty neck' appearance is a form of post-inflammatory pigmentation due to previous eczema, ultraviolet exposure or even the application of photosensitizing products, and that the rippled appearance is related to the cutaneous anatomy of the neck. The pathogenesis of the 'dirty neck' is obscure, but in common with previous authors, we have noted that the rippled appearance of the hyperpigmentation resembles that seen in macular amyloidosis. In order to determine whether deposition of amyloid contributes to the development of this type of pigmentation in atopic dermatitis, an histological and ultrastructural examination of skin biopsies from three patients with the condition was undertaken.

Adult↗
PubMed1996

Prevalence of atopic eczema in the community: the Lothian Atopic Dermatitis study.

An epidemiological study of atopic eczema (AE), based on a semirural community in Scotland, using sound diagnostic criteria, has yielded prevalence data for all age groups including infants and adults. The overall 1-year period prevalence, age-standardized to the Scottish population, was 2.3%. The 1-year period prevalence was highest in the under 2s (9.8%), and showed a continuous reduction with increasing age. Over the age of 40, AE was found to be relatively rare, with a 1-year period prevalence of 0.2%. Adults over 16 years made up 38% of all patients with AE.

Adolescent↗
PubMed1996

The cost of atopic eczema.

Atopic eczema affects 2.3% of the U.K. population. We have carried out a community study in a semi-rural area to assess its economic impact. One hundred and fifty-five patients with atopic eczema were identified and expenditure was assessed over a 2-month period. The mean personal cost to the patient was pounds 25.90, while the mean cost to the health service was pounds 16.20. There were 58 lost working days and 17 lost school days. A cohort of 10 severely affected patients attending the Royal Infirmary of Edinburgh were studied; each patient spent, on average, pounds 325 in 2 months, and lead to a mean health service expenditure per patient of pounds 415, in 2 months. If these results were extrapolated to the U.K. population, the annual personal cost to patients with atopic eczema would be pounds 297m, the cost to the health service would be pounds 125m, and the annual cost to society of lost working days would be pounds 43m, making the total expenditure on atopic eczema pounds 465m.

Adolescent↗
PubMed1994

Primary nodular cutaneous amyloidosis--long-term follow-up and treatment.

A case of facial primary nodular cutaneous amyloidosis is reported. This illustrates: the striking appearance of this unusual condition; the investigations appropriate to establish the diagnosis and to exclude underlying systemic amyloidosis or a condition which might contribute to amyloidosis; and the difficulty of successful management. Initial investigation failed to reveal any evidence of systemic amyloidosis or an associated internal illness. Two amyloid nodules were excised, but 7 years later the patient developed further nodules on the adjacent facial skin and again sought dermatological advice. He was reinvestigated and again no underlying condition was found. A trial of cryotherapy was unsuccessful, but curettage and cautery produced a cosmetically acceptable result.

Adult↗