Alan Evans

Loss-of-function mutations in the gene encoding filaggrin cause ichthyosis vulgaris.

Ichthyosis vulgaris (OMIM 146700) is the most common inherited disorder of keratinization and one of the most frequent single-gene disorders in humans. The most widely cited incidence figure is 1 in 250 based on a survey of 6,051 healthy English schoolchildren. We have identified homozygous or compound heterozygous mutations R501X and 2282del4 in the gene encoding filaggrin (FLG) as the cause of moderate or severe ichthyosis vulgaris in 15 kindreds. In addition, these mutations are semidominant; heterozygotes show a very mild phenotype with incomplete penetrance. The mutations show a combined allele frequency of ∼4% in populations of European ancestry, explaining the high incidence of ichthyosis vulgaris. Profilaggrin is the major protein of keratohyalin granules in the epidermis. During terminal differentiation, it is cleaved into multiple filaggrin peptides that aggregate keratin filaments. The resultant matrix is cross-linked to form a major component of the cornified cell envelope. We find that loss or reduction of this major structural protein leads to varying degrees of impaired keratinization.

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (χ2 test: P = 2.12 × 10−51; Fishers exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9–11.3), and homozygote OR = 151 (95% c.i. = 20–1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.

Incidence of and survival from malignant melanoma in Scotland: an epidemiological study

BACKGROUND We aimed to assess the incidence and survival for all patients with invasive primary cutaneous malignant melanoma diagnosed in Scotland, UK, during 1979-98. METHODS The Scottish Melanoma Group obtained data for 8830 patients (3301 male and 5529 female) first diagnosed with invasive cutaneous malignant melanoma. FINDINGS Age-standardised incidence rose from 3.5 in 1979 to 10.6 per 10(5) population in 1998 for men, and from 7.0 to 13.1 for women, a rise of 303% and 187%, respectively. After 1995, the rate of increase levelled in women younger than 65 years at diagnosis. Melanoma incidence increased most in men on the trunk, head, and neck and in women on the leg. 5-year survival rose from 58% to 80% for men diagnosed in 1979 and 1993, respectively, and from 74% to 85% for women; improvements of 38% (p<0.001) and 15% (p<0.001), respectively. Most improvement was attributable to a higher proportion of thinner tumours. Male mortality from melanoma was 1.9/10(5) population per year at the start and end of the study, whereas mortality for men younger than 65 years at diagnosis rose from 1.2 to 1.35 (p=0.24). For all women, mortality fell slightly from 1.9 to 1.85/10(5) population per year (p=0.61), whereas for women younger than 65 years at diagnosis, mortality fell from 1.3 to 1.15 (p=0.62). INTERPRETATION Interventions aimed at both primary and secondary prevention of melanoma are justified. Specialist tumour registers for entire countries can be used to plan and monitor public health interventions.

Cutaneous malignant melanoma in Scotland: incidence, survival, and mortality, 1979-94. The Scottish Melanoma Group.

Abstract Objective: To determine the changing incidence of and mortality from cutaneous malignant melanoma in Scotland from 1979 to 1994. Design: Detailed registration of clinical and pathological features, surgical and other treatment, and follow up of all cases of cutaneous malignant melanoma diagnosed from 1979 to 1994 and registered with specialist database for Scotland. Setting: Scotland. Subjects: 6288 patients with invasive primary cutaneous malignant melanoma diagnosed between 1 January 1979 and 31 December 1994. Results: The annual age standardised incidence of cutaneous malignant melanoma rose significantly from 3.5 to 7.8 per 100 000 per year in men and from 6.8 to 12.3 per 100 000 per year in women (P<0.001 for both). World standardised rates increased from 2.7 to 6.0 per 100 000 per year in men and 4.6 to 8.50 per 100 000 in women. The incidence of melanoma continued to increase significantly in men of all ages during the study, but the rate stabilised in women after 1986. Mortality from cutaneous malignant melanoma was 1.3 per million per annum in men in 1979, rising to 2.3 per million per annum in 1994 (P<0.01); it was 2.4 per million per annum in women in 1979, falling to 1.9 per million per annum in 1994 (P=0.09). The underlying mortality trends showed a continuing rise for men but a downward trend for women that was not significant (P=0.09). In men, melanoma free survival was 69% at 5 years and 61% at 10 years; in women the corresponding rates were 82% and 75%. Younger patients had higher survival rates, which were not entirely explained by thinner tumours. Over the 15 year period, survival rates improved by 12% overall, only partly owing to thinner tumours. Conclusions: In Scotland the incidence of melanoma in women has stabilised, while mortality associated with melanoma in women shows a downward trend. Key messages Data from Scotland based on 6288 patients with primary invasive cutaneous malignant melanoma show a rise overall in the incidence of melanoma over 15 years but a stabilisation in the incidence of melanoma in women under 65 since 1986 Mortality associated with melanoma is now falling in women of all ages, especially in women under 65 Survival prospects remain strongly related to tumour thickness at the time of diagnosis: disease free survival at 5 years for patients with melanoma thinner than 1.5 mm was 96% in women and 91% in men, while for those with tumours thicker than 3.5 mm survival was 54% and 42% respectively

Cutaneous malignant melanoma, Scotland, 1979-89

Abstract The Scottish Melanoma Group (SMG) was established in 1979 to assess mortality from and incidence, features, pathological data, and management of cutaneous malignant melanoma in Scotland. Incidence during the first five years and five-year survival have already been reported. We now have data about incidence and mortality over eleven years in relation to anatomical site and pathological types. From 1979 to 1989, 1354 male and 2459 female patients with primary cutaneous malignant melanomas were first diagnosed in Scottish residents. The incidence rate per 100 000 population per year has increased from 3·4 in 1979 to 7·1 in 1989 for men, and from 6·6 to 10·4 for women. The overall increase over eleven years is 82% (7·4% per year). The greatest rates of increase are seen in lesions of the superficial spreading histogenetic type, arising on the female leg and the male trunk. Following public education programmes started in 1985, the proportion of all melanomas less than 1·5 mm thick has shown a sustained and significant increase. Mortality data for 1661 patients for whom a minimum of five-year follow-up is available shows five-year survival of 71o6% overall (77·6% for women, 58·7% for men). The survival advantage for women persists when appropriate statistical adjustment is made for thickness, ulceration, and histogenetic type. These data are useful in designing public education programmes aimed at both primary and secondary prevention of melanoma and in auditing changes in trends that might result from such education.

Cutaneous expression of cytochrome P450 CYP2S1: individuality in regulation by therapeutic agents for psoriasis and other skin diseases

BACKGROUND Treatment of common skin diseases such as psoriasis is complicated by differences between individuals in response to topical drug treatment and photochemotherapy. Individuality in hepatic expression of drug-metabolising enzymes is an important determinant of systemic drug handling; we investigated whether similar variation in cutaneous gene expression contributes to individuality in response to topical therapies. METHODS We used quantitative real-time RT-PCR to demonstrate the expression in skin of a recently identified cytochrome P450, CYP2S1, in healthy volunteers (n=27) and patients with psoriasis (n=29). We also investigated regulation of CYP2S1 by ultraviolet radiation, psoralen-ultraviolet A (PUVA), and topical drugs used to treat psoriasis. FINDINGS We found that CYP2S1 is expressed in skin and showed pronounced individuality in constitutive expression of the enzyme and its induction after ultraviolet irradiation or topical drug treatment. Cutaneous expression of CYP2S1 was induced by ultraviolet radiation, PUVA, coal tar, and all-trans retinoic acid; expression was significantly higher in lesional psoriatic skin than in adjacent non-lesional skin (geometric mean 3.38 [95% CI 2.64-4.34] times higher; p<0.0001), which implies that topical drugs are differentially metabolised in psoriatic plaque and non-lesional skin. We showed that all-trans retinoic acid is metabolised by CYP2S1, which has higher cutaneous expression than CYP26, previously described as the specific cutaneous P450 retinoic-acid-metabolising enzyme. INTERPRETATION These findings increase our understanding of the interaction between therapeutic agents and the skin and suggest a functional role for CYP2S1 in the metabolism of topical drugs and in mediating the response to photochemotherapy in psoriasis.

Specific Filaggrin Mutations Cause Ichthyosis Vulgaris and Are Significantly Associated with Atopic Dermatitis in Japan

Mutations in the gene encoding filaggrin (FLG) have been identified as the cause of ichthyosis vulgaris (IV) and shown to be major predisposing factors for atopic dermatitis (AD). However, these studies have been mainly carried out in European populations. In early 2007, we identified two Oriental-specific FLG mutations in four Japanese families with IV and reported that filaggrin mutations were also significant predisposing factors for AD in Japan. However, the frequency of FLG mutations observed in our Japanese AD cohort (5.6%), was much lower than that seen in Europeans (up to 48%). Here, we studied a further seven Japanese families with IV and identified two additional nonsense mutations in FLG, S2889X, and S3296X. We found that more than 20% of patients in our Japanese AD case series carry FLG mutations, and there is significant statistical association between the four mutations and AD (chi(2) P=8.4 x 10(-6); heterozygote odds ratio 7.57, 95% CI 2.84-23.03). These data emphasize that skin-barrier impairment due to reduced filaggrin expression plays an important role in the pathogenesis of AD and sheds further light on the genetic architecture of atopy in Japan.

A pilot study of treatment of lentigo maligna with 5% imiquimod cream.

Background  Lentigo maligna (LM) is an in situ form of malignant melanoma, and surgical excision is often unsatisfactory. Imiquimod cream is an immune response modifier and induces a predominantly T‐helper 1 type response.

K15 Expression Implies Lateral Differentiation within Stratified Epithelial Basal Cells

Keratins are intermediate filament proteins whose expression in epithelial tissues is closely linked to their differentiated state. The greatest complexity of this expression is seen in the epidermis and associated structures. The critical basal (proliferative) cell layer expresses the major keratin pair, K5 and K14, but it also expresses an additional type I keratin, K15, about which far less is known. We have compared the expression of K15 with K14 in normal, pathological, and tissue culture contexts; distinct differences in their expression patterns have been observed that imply different regulation and function for these two genes. K15 appears to be preferentially expressed in stable or slowly turning over basal cells. In steady-state epidermis, K15 is present in higher amounts in basal cells of thin skin but in lower amounts in the rapidly turning over thick plantar skin. Although remaining high in basal cell carcinomas (noninvasive) it is suppressed in squamous cell carcinomas (which frequently metastasize). Wounding-stimulated epidermis loses K15 expression, whereas K14 is unchanged. In cultured keratinocytes, K15 levels are suppressed until the culture stratifies, whereas K14 is constitutively expressed throughout. Therefore, unlike K14, which appears to be a fundamental component of all keratinocytes, K15 expression appears to be more tightly coupled to a mature basal keratinocyte phenotype.

Pulmonary sarcoidosis presenting as a granulomatous tattoo reaction

Summary A 29‐year‐old man presented with nodular skin lesions localized to areas of navy‐blue pigmentation within a tattoo. Light microscopy demonstrated well‐defined epithelioid granulomata in close relation to blue and black pigment. Although the patient was asymptomatic, a chest X‐ray showed bilateral pulmonary shadowing, and histology of a transbronchial biopsy specimen showed features compatible with a diagnosis of sarcoidosis. X‐ray energy dispersive spectroscopy identified copper and titanium in the tattoo pigment. These elements were not found in tissue from the lung biopsy. The cutaneous eruption resolved with oral steroid therapy. Our observations suggest that the granulomatous reaction in the tattoo was a manifestation of sarcoidosis. Rather than a specific reaction to pigment.