Genetic heterogeneity in erythropoietic protoporphyria: a study of the enzymatic defect in nine affected families.

Erythropoietic protoporphyria (EPP) is associated with a deficiency of protohaem ferrolyase. We have used a novel assay for this enzyme based on its ability to utilize zinc as a substrate to investigate the inheritance of EPP in nine affected families. Zinc chelatase activity was markedly reduced in peripheral blood mononuclear cells from 14 EPP patients (mean, 3.3 nmol Zn protohaem/h/mg protein; range, 0.3-8.0) when compared with 41 controls (16.8 +/- 3.6) p less than 0.01. In three families with parent-to-child transmission of disease, the asymptomatic parent had an enzymatic activity within the normal range. In three pedigrees where the parents were asymptomatic, enzymatic activities were below the 95% confidence limits in both. Zinc chelatase activity was below the mean control value in 17 of the 18 parents in nine affected pedigrees, and six of seven asymptomatic offspring of patients with protoporphyria. The findings suggest that EPP is not transmitted as a simple dominant trait and that inheritance of more than one gene may be required for disease expression.

Adhesion molecule expression in polymorphic light eruption.

Endothelial leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) are cytokine-regulated cell-surface leukocyte adhesion molecules. We have investigated the in vivo kinetics and pattern of expression of these adhesion molecules in relation to tissue accumulation of leukocytes in the photodermatosis, polymorphic light eruption (PMLE), which is characterized by dense perivascular leukocytic infiltration. Immunohistology was performed on biopsies taken at varying time points from PMLE lesions induced in 11 subjects by suberythemal solar simulated irradiation. Vascular endothelial ELAM-1 expression was first observed at 5 h, maximal at 24 to 72 h, and remained elevated at 6 d. VCAM-1, minimally expressed in control skin, was induced above background levels on endothelium and some perivascular cells after 24 h and maintained at 6 d. Endothelial cell ICAM-1 expression was increased above control levels at 72 h and 6 d. Keratinocyte ICAM-1 expression, most marked overlying areas of dermal leukocytic infiltration, began at 5 h and was strong at 72 h and 6 d. In addition to lymphocytes, significant numbers of neutrophils but not eosinophils were detected in the dermal leukocytic infiltrate that appeared at 5 h and persisted at 6 d. The pattern of adhesion molecule expression that we have observed is similar to that seen in normal skin during a delayed hypersensitivity reaction. These observations support an immunologic basis for PMLE.

Immune function, mutant frequency, and cancer risk in the DNA repair defective genodermatoses xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy.

There is evidence for defective DNA repair in xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy, but for increased cancer risk only in xeroderma pigmentosum. Natural and adaptive immune surveillance and mutant frequency to 6-thioguanine resistance in circulating T-lymphocytes were studied in five patients with xeroderma pigmentosum, two with Cockayne's syndrome, and one with trichothiodystrophy. Forty-eight-hour cutaneous hypersensitivity responses to recall antigens excluded anergy and circulating CD3+, CD4+, CD8+, and CD16+ cell numbers were within normal limits in all patients tested, as were proliferative lymphocyte responses to PHA, except in the trichothiodystrophy patient. Proliferative responses to recall antigens (PPD, SKSD, and Candida) showed that all patients responded to one or more antigens. Direct natural killer cytotoxicity measured against the human erythromyeloid leukaemia cell line K562 using a 4-h 51Cr release assay was significantly reduced in xeroderma pigmentosum (specific cytotoxicity less than mean +/- SD greater than 17.4 +/- 9.4 per cent, with effector:target cell ratio of 50:1) compared to normal controls (45.8 +/- 17.8), but normal in Cockayne's syndrome and trichothiodystrophy. Generation of lymphokine activated killer cell activity was normal in the two xeroderma pigmentosum lines tested. The mutant frequency in the xeroderma pigmentosum donors was significantly increased (p less than 0.01) and was elevated in the two Cockayne's syndrome donors, taking age into account. No mutants were observed from the single trichothiodystrophy donor. These findings suggest that reduced natural killer cell activity may contribute to the greatly increased susceptibility to skin cancer in xeroderma pigmentosum.

Successful treatment of severe polymorphous light eruption with azathioprine.

Two patients with severe, disabling polymorphous light eruption, who were unable to tolerate photochemotherapy and who were unresponsive to alternative recognized therapies, are described. In both cases short-term treatment with azathioprine achieved a marked clinical improvement, confirmed by testing with an irradiation monochromator. This response suggests an immunological basis for polymorphous light eruption. Patients with polymorphous light eruption vary considerably with regard to degree of photosensitivity, and while azathioprine therapy should not be considered in the majority of sufferers, we have shown that it can be very helpful in rare patients with exceptionally severe disease.

A histological study of the evolution of solar urticaria.

The histological evolution of solar simulator-induced lesions of solar urticaria was investigated in four severely affected white patients. A series of two to 32 minimal whealing doses of radiation, each much lower than the 24-hour minimal erythema dose, was administered to separate buttock sites. Biopsy specimens were obtained from the exposed areas at five minutes and two and 24 hours later, as well as from adjacent nonexposed skin. Lesions showed a statistically significant dose-dependent increase, predominantly perivascular, in upper dermal neutrophil and eosinophil numbers at five minutes and two hours, but not at 24 hours, and at higher radiation doses in mononuclear cell numbers by 24 hours. Nonirradiated patient skin and irradiated control subject skin was not similarly affected. These changes may be associated with the pathogenesis of solar urticaria.

Elevated hprt mutant frequency in circulating T-lymphocytes of xeroderma pigmentosum patients.

The mutant frequency to 6-thioguanine resistance in circulating T-lymphocytes from 10 xeroderma pigmentosum patients (including complementation groups D and G and XP variants) has been determined. A highly significantly elevated frequency was observed, compared to age-matched, non-smoking control donors (x 2.1-fold higher than the mutant frequency in normal control donors, adjusted for age and cloning efficiency, p less than 0.001). The mutant frequency of 5 XP heterozygotes was in the normal range, when age, smoking habit and log cloning efficiency were taken into account. A number of possible factors which may account for the elevated mutant frequency seen in the XP donors (including an elevated spontaneous mutation rate, UV mutagenesis of the T-cells as they pass through the skin, an effect of environmental mutagens such as tobacco smoke, or as a consequence of immune deficiency) are discussed.

O'Brien's actinic granuloma: response to isotretinoin.

We describe a 75-year-old man demonstrating the florid clinical features of actinic granuloma of O'Brien. This rare disfiguring condition is believed to result from a granulomatous reaction of the dermis to solar-induced elastosis and is poorly responsive to topical steroids. Twelve weeks' treatment with isotretinoin prevented the development of new granulomata and produced almost complete resolution of established lesions.

ANCA associated with Behçet's disease.

Behçet's disease is a multisystem disorder affecting primarily mucocutaneous and ocular sites although the gastrointestinal, cardiovascular, central nervous and respiratory systems may also be involved. Hulusi Behçet, a Turkish dermatologist, first described Behçet's disease in 1937 and suggested a possible infectious aetiology. The pathogenesis of this condition still remains unclear although it is likely that infection acts as a trigger in genetically susceptible individuals. We report a patient with unusual cutaneous manifestations of Behçet's disease and antineutrophil cytoplasmic antibodies (ANCA) directed against the cytotoxic protein, bactericidal/permeability-increasing protein (BPI). This is the first report of Behçet's disease associated with this autoantibody.

Meningism following Salmonella virchow food poisoning.

Thirty six patients were admitted to hospital as a result of Salmonella virchow infection during an outbreak of food poisoning in Essex in 1984. Out of 12 patients with evidence of bloodstream invasion, one third presented primarily with meningism and attention is drawn to this unusual clinical picture.

Penicillamine-induced elastosis perforans serpiginosa treated successfully with isotretinoin.

Elastosis perforans serpiginosa (EPS) and the elastotic changes of pseudoxanthoma elasticum (PXE) are rare but well-recognized side-effects of long-term penicillamine therapy. A 42-year old female patient who developed both of these cutaneous side-effects following treatment with high-dose penicillamine for Wilson's disease is described; near-complete resolution of the EPS, but not the PXE was achieved by treatment with isotretinoin (0.5 mg/kg/day) for 6 weeks, despite continuation of the penicillamine.

The acute idiopathic photodermatoses.

The acute idiopathic photodermatoses are more common in females and comprise polymorphic light eruption, actinic prurigo, hydroa vacciniforme, and solar urticaria. Polymorphic light eruption occurs considerably more frequently than the others and while precise pathogenic mechanisms are still unclear, increasing evidence suggests an immunological basis for this condition. Although clinically distinct, actinic prurigo may be a variant of polymorphic light eruption, whereas solar urticaria and possibly hydroa vacciniforme are distinct entities, the former representing a type I hypersensitivity response. Polymorphic light eruption is characterized by a recurrent cutaneous reaction to ultraviolet (UV) exposure occurring after a delay of several hours that consists of pruritic erythematous papules, vesicles, or plaques on usually only some exposed sites and resolves without scarring over about a week. Actinic prurigo is differentiated from polymorphic light eruption by childhood onset and more persistent and excoriated lesions present both on sun-exposed and, to a lesser extent, non-exposed sites. Hydroa vacciniform is a rare disorder that also begins in childhood, and is characterized by recurrent crops of vesicles on sun-exposed skin and subsequent vacciniforme scarring. Solar urticaria is an uncommon condition that usually begins in the third or fourth decade and is differentiated from the other acute idiopathic photodermatoses by rapid onset of urticarial lesions within minutes of UV exposure and resolution within 1 to 2 hours.

DNA repair deficient photodermatoses.

Photosensitive genodermatoses associated with established defects of DNA repair currently include the autosomal recessive diseases xeroderma pigmentosum (XP), Cockayne's syndrome (CS), trichothiodystrophy (TTD), and Bloom's syndrome (BS). XP is a heterogeneous disorder associated with defective excision repair or daughter strand repair of ultraviolet (UV)-induced DNA damage. It is characterized by cutaneous and ocular abnormalities predominantly on sun-exposed sites and in some cases, neurological features resulting from progressive neuronal loss. Skin involvement includes easy sunburning, pigmentary abnormalities, telangiectasia, dryness, scarring, and susceptibility to multiple benign and malignant neoplasms. In CS, defective repair of actively transcribing DNA is clinically associated with acute photosensitivity, growth retardation, demyelinating neurological abnormalities, and pigmentary retinal degeneration, but without increased cancer susceptibility. TTD is characterized by sulphur-deficient brittle hair, variable growth delay, mental retardation, ichthyosis, and in some cases photosensitivity. Although in some patients there is a deficiency of DNA excision repair identical to that in certain xeroderma pigmentosum patients, no increased cancer risk is present in trichothiodystrophy. In BS, deficient cellular DNA ligase is associated with congenital telangiectasia, photosensitivity, growth retardation, immune deficiency, increased susceptibility to infection, and predominantly internal rather than cutaneous malignancy. Immunological factors may at least determine the varying susceptibility to malignancy of these conditions.

Polymorphic light eruption.

Polymorphic light eruption (PLE) describes a broad clinical spectrum including a number of different yet overlapping clinical subgroups. In the absence of an understanding of pathogenic mechanisms it remains unclear whether these subdivisions are appropriate. The action spectrum for PLE usually includes the ultraviolet A (UVA) spectrum, but a proportion of patients respond principally to UVB. This diversity in action spectra remains unexplained, as does the difficulty in artificial induction of lesions, particularly when physiologically relevant doses of UV radiation are employed. Models for the pathogenesis of PLE must explain several characteristic features of the condition, including nonuniform susceptibility of exposed skin areas, higher incidence in temperature climates, particularly in spring, and progressive tolerance during the summer months in some patients. Although unproven, an immunological mechanism is consistent with such features and is supported by immunohistological changes and keratinocyte ICAM-1 expression, similar to known type IV hypersensitivity reactions, and clinical response of severe cases to immunosuppression with azathioprine. Other recently proposed mechanisms include an abnormality in cutaneous arachidonic acid metabolism in response to UV irradiation, and excessive leukotriene B4 release by circulating leukocytes following UVA irradiation.

Actinic folliculitis--response to isotretinoin.

Two female patients with an identical facial eruption, consisting of severe outbreaks of folliculitic pustules occurring 6 to 24 h following periods of intense sun exposure and persisting for several days, are reported. Both failed to improve with standard acne treatments, but responded well to oral isotretinoin therapy.

A study of the role of house dust mite in atopic dermatitis.

Subjects with positive skin-prick tests to house dust mite (HDM) solution, including those with and without atopic dermatitis, participated in a double-blind, controlled study of the role of HDM exposure in the pathogenesis of atopic dermatitis. HDM solution and diluent control were applied daily to mildly eczematous or clinically uninvolved skin of the antecubital or popliteal fossae, without prior abrasion, for 5 days. Responses were assessed by a clinical grading system and by measurement of area of dermatitis; pruritus was recorded on visual analogue scales. The clinical grading system showed that marked or moderate delayed local reactions developed in one third of patients with atopic dermatitis in response to HDM application to both mildly eczematous and clinically uninvolved skin. Relative to control sites, significant increases in area of dermatitis and degree of pruritus were also recorded in response to HDM application to mildly eczematous sites. Application of HDM solution to normal, unabraded skin of prick test positive subjects without a history of dermatitis, produced pruritus and immediate urticarial responses which were not seen at control sites, findings which demonstrate that HDM antigen may be rapidly absorbed in normal skin. Application of vehicle or antigen solution to which subjects were negative on prick testing, produced no significant local reactions. This study provides objective evidence for a role for cutaneous HDM exposure in the pathogenesis of atopic dermatitis.

Homozygous variegate porphyria: a case report.

Homozygous variegate porphyria is described in a 14-year-old girl with a unique clinical presentation of photosensitivity from the second year of life, mental retardation, clinodactyly, and normal growth rate. The erythrocyte protoporphyrin concentration was raised with the protoporphyrin being predominantly zinc-chelated, which appears to be characteristic for all homozygous hepatic porphyrias. Protoporphyrinogen oxidase activity in lymphoblasts was decreased in both patient and parents despite the latter having normal porphyrin excretion.