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Biomedical subjects

J I Harper

Publications and source records attributed to J I Harper.

At least 55 records · Page 3Linked to original sources
PubMed1998

Palmoplantar keratoderma associated with congenital heart disease.

We report the case of a 14-month-old boy suffering from total anomalous pulmonary venous connection (TAPVC) associated with congenital diffuse palmoplantar keratoderma (PPK). An association between TAPVC and PPK has not been described previously, but PPK has been reported in association with a variety of cardiac abnormalities. Given the low frequency of both conditions, a genetic link seems likely. It is therefore advisable for dermatologists to check for heart abnormalities in children with congenital PPK.

Heart Defects, Congenital↗
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

Ichthyosiform erythroderma and cardiomyopathy: report of two cases and review of the literature.

We report two children with ichthyosiform erythroderma who at the ages of 9 weeks and 8 years, respectively, developed dilated cardiomyopathy, which was fatal in one and required heart transplantation in the other. A link between these conditions is considered likely, either as a primary genetic syndrome or secondary to micronutrient deficiency and/or infection. Owing to its insidious onset, cardiomyopathy may be overlooked, or symptoms attributed to the other conditions such as severe infections and failure to thrive that are common in these patients. We therefore recommend that children with congenital erythroderma are monitored closely, clinically and with echocardiography, for cardiomyopathy.

Cardiomyopathy, Dilated↗
PubMed1997

Genetic studies of atopy and atopic dermatitis.

Atopy and the atopic disorders are likely to result from multifactorial inheritance, with interaction between genetic and environmental factors. It has been proposed that at least two major mechanisms, non-antigen specific (total IgE levels) and antigen specific (specific IgE antibodies and skin tests), regulate the immune response to allergens in humans: firstly, a gene/genes independent of the human leucocyte antigen system which is involved in the regulation of total IgE levels, and secondly, a specific immune response gene/genes associated with major histocompatibility complex class II genes which are involved in antigen-specific mechanisms. Candidate genes have been proposed for both mechanisms and linkage has been found between atopy and at least three different gene loci. This paper reviews the evidence supporting a genetic basis for atopy and atopic dermatitis and outlines recent advances in the molecular genetic mapping of genes associated with these disorders.

Dermatitis, Atopic↗
PubMed1996

Growth of herpes simplex type 1 on skin explants of atopic eczema.

In a novel approach to looking at why some children with atopic eczema are susceptible to cutaneous herpes simplex virus (HSV) infections, this study evaluates the hypothesis that HSV replicates more easily on eczematous than normal skin. Growth of HSV on eczematous skin explants was compared with growth on explants from three control groups (psoriasis, Darier's disease and normal skin) over a 2-day period. Growth of HSV was significantly less on normal skin than in atopic eczema, psoriasis and Darier's disease. Virus replicated more quickly, and grew to higher titre within 24h, in eczematous and psoriatic explants than in normal skin. A defect in skin barrier function and host defence factors including local cytokine secretion are discussed as possible mechanisms in causing the increased susceptibility of children with atopic eczema to HSV infection.

Adolescent↗
PubMed1996

Role of the pulsed dye laser in the management of ulcerated capillary haemangiomas.

A complication of capillary haemangiomas is ulceration, which may arise after trauma and/or infection. Until recently, conservative management was the rule. However, the recent advent of the pulsed dye laser has revolutionised the treatment of vascular birthmarks and provided a new tool for the management of capillary haemangiomas. Thirteen cases of ulcerated capillary haemangiomas referred to our department were reviewed; five were treated conservatively and eight were treated with the laser. Those treated with the laser had all failed conservative management and healed completely within one to four weeks. Remarkably rapid alleviation of pain was achieved. For those haemangiomas around the mouth and perineum, laser treatment enabled early restoration of normal feeding, micturition, and defaecation. It is therefore recommended that if ulcerated capillary haemangiomas do not improve after a short period of optimal conservative treatment, laser treatment should be considered.

Female↗
PubMed1996

Confirmation of linkage of Sjögren-Larsson syndrome to chromosome 17 in families of different ethnic origins.

Linkage analysis in two consanguineous pedigrees of Pakistani and English origin and one further Indian family in which affected subjects have Sjögren-Larsson syndrome (SLS) showed linkage to chromosome 17. Linkage of SLS to D17S783 and D17S805 has been reported in Swedish pedigrees, but since those data were generated from a single ethnic group originating from a common ancestor, there remained the question of whether this disease is genetically heterogeneous. This report confirms the linkage in non-Swedish pedigrees and, therefore, provides evidence to support a single locus for SLS.

Chromosome Mapping↗
PubMed1996

Immunological studies of herpes simplex virus infection in children with atopic eczema.

This study examines the role of immune defence mechanisms in herpes simplex virus (HSV) infections in atopic eczema and whether impairment of these mechanisms explains the susceptibility of some children with atopic eczema to cutaneous HSV infections. Ten children with eczema herpeticum and 13 with atopic eczema and recurrent HSV infection affecting multiple skin sites were studied, together with relevant control groups. In all children with atopic eczema, in vitro lymphoproliferation in response to stimulation with concanavalin A (Con A) was significantly decreased and natural killer (NK) cells (CD16 + 56) were reduced compared with non-atopic controls. IL-2 receptors, a marker for lymphocyte activation, were decreased during the acute phase of eczema herpeticum, and for 1 month thereafter. A positive stimulation index (> 3) to HSV antigen, and high HSV IgG antibody titres measured by ELISA, Western blotting and neutralization assay, were seen in children with eczema herpeticum by 6 weeks, and also in children with atopic eczema and recurrent HSV infections. No evidence of an HSV-specific immune defect (either cell-mediated or humoral) was found in atopic eczema. Impairment of cell-mediated immunity in atopic eczema was suggested by the reduced response to Con A. It is likely that reduced numbers of circulating NK cells and a decrease in IL-2 receptors during early eczema herpeticum contribute to the susceptibility of children with atopic eczema to cutaneous HSV infections.

Acute Disease↗
PubMed1996

An appraisal of acitretin therapy in children with inherited disorders of keratinization.

Retinoid therapy represents the treatment of choice for severe inherited disorders of keratinization. This paper reviews our experience of acitretin, compares acitretin with etretinate and defines guidelines for treatment. Forty-six children have received acitretin since 1992 in our hospital: 29 children had either lamellar ichthyosis (nine), non-bullous ichthyosiform erythroderma (five), bullous ichthyosiform erythroderma (four), Sjögren-Larsson syndrome (three) or another rare condition (eight). The other 17 children who had psoriasis (16) and extensive viral warts (one), were excluded. Data on efficacy and tolerability of retinoid therapy were available for all but one patient. The cumulative follow-up was 472 months for acitretin. The mean (+/- standard deviation) optimal dosage for acitretin was 0.47 +/- 0.17 mg/kg per day, and this did not significantly differ between disorders. The overall improvement was considerable, with only three patients responding poorly. Mild to moderate mucocutaneous dryness was frequent. Minor abnormalities of liver function tests (four patients) and triglycerides (one patient) never led to changes of therapy. Irreversible side-effects did not occur. Acitretin therapy for children with inherited keratinization disorders is best started at 0.5 mg/kg per day. It represents a safe and effective treatment, provided that the minimal effective dose is maintained and that side-effects are carefully monitored. When switching from etretinate to acitretin, a 20% reduction is recommended if the etretinate dose is over 0.75 mg/kg per day or if side-effects are dose limiting. Otherwise the same dose can be used.

Acitretin↗
PubMed1995

Junctional epidermolysis bullosa and pyloric atresia: a distinct entity. Clinical and pathological studies in five patients.

Junctional epidermolysis bullosa (JEB) associated with pyloric atresia (PA) is a distinct entity which is inherited as an autosomal recessive disorder. We describe five patients with this association; four died in the neonatal period and one is still alive at 4 years of age. The cutaneous lesions in these patients are identical or similar to those in other JEB subtypes. Urinary tract involvement is part of the syndrome and presents a problem for long-term survival. Using the monoclonal antibody GB3 we investigated skin biopsies from three of our patients and showed normal expression in all of them, unrelated to the outcome of their disease. This indicates that the GB3 monoclonal antibody is without prognostic significance in this syndrome. It is clear that JEB with PA is a distinct entity. The molecular basis as yet is unknown.

Antigens, Surface↗
PubMed1994

Mutations in the rod 1A domain of keratins 1 and 10 in bullous congenital ichthyosiform erythroderma (BCIE).

Bullous congenital ichthyosiform erythroderma is a human hereditary skin disorder in which suprabasal keratinocytes rupture. Recent reports have implicated keratins K1 and K10 in this disease. Here we describe four diverse keratin mutations that are all significantly associated with this disease. Two of these are in the helix 1A subdomain of the type II keratin 1, giving a serine-to-proline substitution in codon 185 and an asparagine-to-serine substitution in codon 187. In the analogous region of type I keratin 10, an arginine-to-proline and an arginine-to-serine transition in codon 156 have been identified. All four mutations create restriction fragment length polymorphisms that were used exclude the mutations from 120 normal chromosomes. Insertional polymorphism (in the V2 subdomains of the non-helical tails of K1 and K10) was excluded as the cause of the phenotypic heterogeneity observed within one family.

Amino Acid Sequence↗
PubMed1994

Ichthyosis bullosa of Siemens--a disease involving keratin 2e.

Ichthyosis bullosa of Siemens (IBS) is a congenital bullous ichthyosis without erythroderma. In contrast to bullous congenital ichthyosiform erythroderma (BCIE), there is a relatively mild involvement of the skin and epidermolytic hyperkeratosis (EHK) is restricted to the upper suprabasal layers of the epidermis. Tonofilament aggregation was observed by EM in suprabasal cells from affected patients in the two families under study, indicative of a keratin abnormality. Keratin 2e is a differentiation specific type II keratin expressed suprabasally in the epidermis. Part of the K2e gene was amplified by polymerase chain reaction using genomic DNA from affected and unaffected individuals from two IBS families. Direct sequencing of polymerase chain reaction products revealed a point mutation in the highly conserved helix termination motif, producing the protein sequence change LLEGEE-LLEGKE. This mutation was found in all affected members of a five-generation kindred and also in a sporadic case in a second unrelated family. No mutation was seen in unaffected individuals. The mutation destroys a MnlI restriction site, which allowed exclusion of the mutation from a population of 50 unaffected unrelated individuals by restriction fragment analysis of K2e PCR products. This is the sixth keratin gene found to be involved in an inherited epidermal disorder.

Base Sequence↗
PubMed1994

A clinical and immunological study of Netherton's syndrome.

Netherton's syndrome is a rare genodermatosis of unknown cause, which is classified as an ichthyosiform syndrome. A clinical and immunological study of seven patients with Netherton's syndrome illustrates the clinical spectrum of this disorder, the frequent association with atopy, and the absence of consistent immunological abnormalities. Failure to thrive in infancy was a feature in six of the seven patients, and was considered to be life-threatening in three. The skin disease evolved into ichthyosis linearis circumflexa in four of the seven, and the remaining three patients suffered from persistent or recurrent ichthyosiform erythroderma.

Adolescent↗
PubMed1994

A clinical and genetic study of X-linked recessive ichthyosis and contiguous gene defects.

X-linked recessive ichthyosis (XLI) is caused by a deletion, or mutation, of the steroid sulphatase gene on the distal short arm of the X chromosome (Xp22.3). This region of the X chromosome is particularly susceptible to deletions. Such deletions can occasionally extend to involve neighbouring genes, causing a contiguous gene defect. Therefore, XLI may be associated with Kallmann's syndrome (KS), mental retardation, X-linked recessive chondrodysplasia punctata and short stature. We have reviewed 33 patients with XLI. Nine showed evidence of contiguous gene defects. A further four had neurological deficit sustained at the time of birth. This study highlights the importance of screening patients with X-linked recessive ichthyosis for neighbouring genetic disorders and, in particular, the early identification of KS, as delay in diagnosis may lead to infertility and osteoporosis. Parents should be warned about possible obstetric complications due to prolonged labour in future pregnancies.

Adult↗
PubMed1994

Quantification of stratum corneum ceramides and lipid envelope ceramides in the hereditary ichthyoses.

Ceramides (sphingolipids) are the main polar lipids of the stratum corneum and play an important role in skin barrier function, cell adhesion and epidermal differentiation. In view of the function of ceramides in normal skin, this study aimed to assess their levels in patients with various types of hereditary ichthyosis, in which epidermal homeostasis is markedly abnormal. Stratum corneum samples were collected from 80 patients and 23 normal controls, and the intercellular and lipid envelope ceramides were analysed by high-performance thin-layer chromatography. The covalently bound ceramides (ceramides A and B) of the lipid envelope were present in all patients studied, and showed no significant differences from control samples. Total ceramides (ceramides 1-6) were decreased in bullous ichthyosiform erythroderma, which is presumably a secondary phenomenon similar to that seen in patients with atopic dermatitis. Patients with non-erythrodermic lamellar ichthyosis showed a marked decrease in levels of the important acylceramide, ceramide 1, whereas those with other types of autosomal recessive ichthyosis (limited lamellar ichthyosis and non-bullous ichthyosiform erythroderma) had mean levels similar to the controls. Ceramide 1 deficiency may therefore define a subgroup within the autosomal recessive ichthyoses. Sjögren-Larsson syndrome (SLS) shows a deficiency of both acyl-ceramides (ceramides 1 and 6), which would seem likely to disrupt the normal skin barrier function. Furthermore, glucosylceramides (cerebrosides) are known to be deficient in the neural tissue of patients with SLS. The relationship of these ceramide abnormalities to the underlying fatty alcohol oxidoreductase defect remains uncertain, but they may provide an interesting link between the nerve damage and cutaneous abnormalities seen in this rare neurodermatosis.

Adolescent↗
PubMed1994

Hairy elbows syndrome (familial hypertrichosis cubiti).

Hairy elbows syndrome was first described by Beighton in 1970. An association with short stature has been suggested. A 5-year-old girl with the hairy elbows syndrome who is otherwise healthy is described. Her height is on the 25th centile and appropriate for her family, in which no other members are affected. The mode of inheritance of this disorder remains to be determined.

Body Height↗