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Biomedical subjects

J I Harper

Publications and source records attributed to J I Harper.

At least 19 recordsLinked to original sources
PubMed2001

Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci.

We have carried out a genome screen for atopic dermatitis (AD) and have identified linkage to AD on chromosomes 1q21, 17q25 and 20p. These regions correspond closely with known psoriasis loci, as does a previously identified AD locus on chromosome 3q21. The results indicate that AD is influenced by genes with general effects on dermal inflammation and immunity.

Child↗
PubMed2001

Gene polymorphism in Netherton and common atopic disease.

Atopic dermatitis (AD) and asthma are characterized by IgE-mediated atopic (allergic) responses to common proteins (allergens), many of which are proteinases. Loci influencing atopy have been localized to a number of chromosomal regions, including the chromosome 5q31 cytokine cluster. Netherton disease is a rare recessive skin disorder in which atopy is a universal accompaniment. The gene underlying Netherton disease (SPINK5) encodes a 15-domain serine proteinase inhibitor (LEKTI) which is expressed in epithelial and mucosal surfaces and in the thymus. We have identified six coding polymorphisms in SPINK5 (Table 1) and found that a Glu420-->Lys variant shows significant association with atopy and AD in two independent panels of families. Our results implicate a previously unrecognized pathway for the development of common allergic illnesses.

Amino Acid Sequence↗
PubMed2001

The role of cutaneous dendritic cells in the immunopathogenesis of atopic dermatitis.

We review the immunology of atopic dermatitis (AD) and focus attention on the role of cutaneous dendritic cells. AD is a complex immune-mediated skin disorder characterized by the recruitment of both CD4+ and CD8+ T cells into the skin. T-helper (Th) 2-type cytokines are dominant in acute AD skin, while both Th1- and Th2-type cytokines are present in chronic AD. Cutaneous dendritic cells, which are present in increased numbers within AD skin, are believed to play a key part in the activation of T cells in the skin. They may also help to determine the pattern of cytokines produced by activated effector T cells.

CD4-Positive T-Lymphocytes↗
PubMed2001

Juvenile xanthogranuloma as a sequel to Langerhans cell histiocytosis: a report of three cases.

We report three children who had multisystem Langerhans cell histiocytosis (LCH) with cutaneous involvement and subsequently developed juvenile xanthogranuloma (JXG). JXG appeared 3--6 years after the initial manifestation of LCH. JXG lesions, which presented as yellowish papules, revealed typical Touton giant cells and were factor XIIIa positive but S100 and CD1a negative. Non-LCH histiocyte disorders, such as JXG, are known to occur as a reaction to a variety of external stimuli such as infection and trauma. It is therefore conceivable that the inflammatory reaction associated with LCH may have precipitated the development of JXG in our patients. Alternatively, one could speculate that this association might be due to a common histogenetic precursor of the cell types involved.

Child↗
PubMed2001

Cyclosporin for atopic dermatitis in children.

This paper details a UK consensus conference held in London in April 2000 to establish guidelines for the use of cyclosporin A for atopic dermatitis in children. It should be reserved for the severest refractory atopic dermatitis. In view of its potential toxicity, careful monitoring is mandatory, in particular blood pressure and renal function.

Child↗
PubMed2000

Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome.

We describe here eleven different mutations in SPINK5, encoding the serine protease inhibitor LEKTI, in 13 families with Netherton syndrome (NS, MIM256500). Most of these mutations predict premature termination codons. These results disclose a critical role of SPINK5 in epidermal barrier function and immunity, and suggest a new pathway for high serum IgE levels and atopic manifestations.

Abnormalities, Multiple↗
PubMed2000

Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy.

Cyclosporin (CyA) has been shown to be highly effective and well tolerated in the short-term treatment of severe childhood atopic dermatitis; however, there is limited experience in its longer-term use. The aim of this study was to compare multiple short courses of CyA with continuous therapy for 1 year, with respect to efficacy, safety, tolerability and quality of life. Children aged 2-16 years, with a diagnosis of severe atopic dermatitis refractory to topical steroid therapy, were randomly assigned to receive short course therapy (multiple courses of 12 weeks) or continuous therapy. The starting dose and maximum dose for all patients was 5 mg/kg per day. Disease activity was monitored using the Six Area Six Sign Atopic Dermatitis score and the 'Rule of Nines' area score. Pruritus, sleep disturbance and irritability were measured using visual analogue scales, and topical therapy was monitored. Safety measurements included monitoring of serum creatinine, blood pressure and adverse events. Forty patients were included in the efficacy analysis, 21 of whom were randomized to the short course group (of whom six were withdrawn) and 19 to the continuous group (of whom five were withdrawn). Significant improvements were seen in all efficacy parameters at every time-point. There were no significant differences between groups, although the improvement was more consistent in the continuous arm. In the short course arm, 7 out of 21 patients could be managed by at least two short courses. The remaining 14 patients includes 12 who could not be controlled by at least two short courses, one patient who failed to return after week 12 and another patient who was withdrawn at week 4 due to an adverse event. Quality of life improved for both the children and their families. Tolerability was considered good or very good in at least 80% of the patients at week 12 and at the end of the study. No clinically significant change was seen in mean serum creatinine and no change was seen in mean blood pressure in either group. CyA is effective in controlling severe atopic dermatitis in children over a 1-year period and is well tolerated. More consistent control is achieved with continuous treatment; however, short course therapy was adequate for some patients, indicating that treatment should be tailored to the individual patient's needs. Short course treatment may produce prolonged remission in some cases and reduce the cumulative exposure to the drug.

Adolescent↗
PubMed2000

Lipoatrophic panniculitis and chromosome 10 abnormality.

We report a 3-year-old girl with a 12-month history of an acquired lipoatrophy that was rapidly progressive. Her karyotype revealed additional material on chromosome 10 at the 10q26 location. The human pancreatic lipase gene maps to chromosome 10q24-26, and we postulate an association. Lipoatrophic panniculitis describes the panniculitides in which atrophy is a feature. The classification of these diseases is confusing in the literature and the precise diagnosis still relies on a combination of clinical and laboratory assessment. Our finding of a chromosomal abnormality on chromosome 10q26 has not been described previously.

Child, Preschool↗
PubMed2000

Localization of the Netherton syndrome gene to chromosome 5q32, by linkage analysis and homozygosity mapping.

Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Ialpha, the alpha subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor beta2, and the diastrophic dysplasia sulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.

Adolescent↗
PubMed2000

Radial aplasia, poikiloderma and auto-immune enterocolitis--new syndrome or severe form of Rothmund-Thomson syndrome?

A syndrome is described in three isolated patients in whom the main features are bilateral radial aplasia, short stature, an inflammatory based 'elastic' pyloric stenosis, a pan-enteric inflammatory gut disorder that appears to be due to an autoimmune process, and poikiloderma. Other features in individual cases include cleft palate, micrognathia, anal atresia, patellar aplasia/hypoplasia and sensorineural deafness. This combination may represent a severe form of Rothmund-Thomson syndrome or possibly a previously unrecognized condition.

Abnormalities, Multiple↗
PubMed2000

Long term follow up of topical mustine treatment for cutaneous langerhans cell histiocytosis.

BACKGROUND AND OBJECTIVES: Skin lesions in Langerhans cell histiocytosis (LCH) are often painful and difficult to treat. Topical application of nitrogen mustard (0.02% mechlorethamine hydrochloride, mustine), an alkylating cytostatic agent, has been shown to be effective. There is, however, concern about potentially harmful long term side effects. STUDY DESIGN: In a retrospective study 20 children with LCH (average extent of initial skin involvement: 16.4% body surface) were followed up for an average of 8.3 years after completion of topical mustine therapy. They had received a total of 34 courses (mean duration 14.2 weeks) of topical mustine. Disease status on follow up was assessed according to the Histiocyte Society classification. RESULTS: After mustine was introduced, 16 patients were able to discontinue systemic steroids and/or chemotherapy. Topical mustine was well tolerated in 18 patients, but two developed irritant dermatitis. On follow up, the disease was inactive in 10 patients. Among the children with active disease, six had mild skin disease and four had progressive disease, two of them with skin lesions unresponsive to mustine treatment. Scars confined to areas of formerly active skin disease were found in six patients. There was no evidence of premalignant or malignant skin disease in the treated areas. CONCLUSION: Topical mustine is an effective and safe treatment for skin disease in most children with LCH. Residual scarring was probably a result of the disease itself rather than to mustine. Although no evidence of skin cancer was found in this study, continued long term follow up is advisable.

Administration, Topical↗
PubMed1999

Skin fragility and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin 1.

We report a 2-year-old boy with an unusual autosomal recessively inherited skin disease comprising trauma-induced skin fragility and congenital ectodermal dysplasia affecting hair, nails and sweat glands. Skin biopsy showed widening of intercellular spaces between keratinocytes and ultrastructural findings of small, poorly formed desmosomes with reduced connections to the keratin filament cytoskeleton. Immunohistochemical analysis revealed a complete absence of staining for the accessory desmosomal plaque protein plakophilin 1 (PKP1; band 6 protein). The affected individual was a compound heterozygote for null mutations on both alleles of the PKP1 gene. Both mutations occurred within the amino terminus of PKP1, the domain which normally binds the cytoskeletal keratin filament network to the cell membrane. Apart from its localization within desmosomal plaques, PKP1 may also be present within the cytoplasm and nucleus and has putative roles in signal transduction and regulation of gene activity. The clinicopathological observations in this patient demonstrate the relevance of PKP1 to desmosome formation, cutaneous cell-cell adhesion and epidermal development and demonstrate the specific manifestations of human functional knockout mutations in this gene.

Base Sequence↗