Sara Brown

Eczema Genetics: Current State of Knowledge and Future Goals

Multiple genetic as well as environmental factors interact in the pathogenesis of eczema. Increased understanding of genetic predisposition in atopy and eczema has directed interest toward key pathogenic mechanisms including skin barrier dysfunction. This review provides a succinct update on the current state of knowledge regarding eczema genetics. We discuss the relevance of loss-of-function mutations in the filaggrin gene within the context of other candidate gene studies and suggest possible applications for future research. Knowledge of genetic factors in eczema may translate into a clearer understanding of pathogenic mechanisms and hence more focused therapeutic strategies, but this remains at present a distant possibility.

Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations

Background Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD.

Filaggrin haploinsufficiency is highly penetrant and is associated with increased severity of eczema: further delineation of the skin phenotype in a prospective epidemiological study of 792 school children

Backgroundu2002 Null mutations within the filaggrin gene (FLG) cause ichthyosis vulgaris and are associated with atopic eczema. However, the dermatological features of filaggrin haploinsufficiency have not been clearly defined.

Atopic eczema and the filaggrin story.

The discovery that null mutations in the filaggrin gene (FLG) are associated with atopic eczema represents the single most significant breakthrough in understanding the genetic basis of this complex disorder. The association has been replicated in multiple independent studies during the past 2 years with the use of various methodologies, from populations in Europe, the United States, and Japan. Filaggrin plays a key role in epidermal barrier function, and its association with atopic eczema emphasizes the importance of barrier dysfunction in eczema pathogenesis. This review aims to summarize the current state of knowledge regarding the role of FLG mutations in ichthyosis vulgaris, atopic eczema, and other skin disorders, with an emphasis on potential clinical applications. Further research is needed to clarify the precise role of filaggrin in skin and systemic atopic disease, to pave the way for novel therapeutic interventions.

Are filaggrin mutations associated with hand eczema or contact allergy?--we do not know.

hidradenitis suppurativa may have affected the life of Karl Marx profoundly and thereby significantly contributed to shaping his view of the world. The disease, which affects the hair follicles of inverse areas of the body surface, has a significant impact on the lives of patients: not only through suppuration and pain, but also through increased use of medical services, sick-days and a generally lowered quality of life. In Karl Marx’s case it may have affected the quality of life of millions of people, making it a unique disease in more ways than one.

The management of skin malignancy: to what extent should we rely on clinical diagnosis?

Backgroundu2002 Cutaneous malignancy forms a major part of the dermatologists workload. Clinical diagnosis is an important factor in facilitating the urgent excision of squamous cell carcinomas (SCC) and malignant melanomas.

Pseudoxanthoma elasticum: biopsy of clinically normal skin in the investigation of patients with angioid streaks

Background Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by fragmentation and calcification of elastic fibres with resultant pathological changes in the dermis, Bruch’s membrane and blood vessels. Defects in Bruch’s membrane produce angioid streaks on the retina but this appearance is not pathognomonic of PXE. Biopsy of clinically normal skin or scar tissue in patients with angioid streaks may show the histological features of PXE.

Coma Blisters in 2 Children on Anticonvulsant Medication

Blister formation and eccrine sweat gland necrosis have been recognized to occur in states of impaired consciousness and were first reported following barbiturate intoxication. Their etiology is complex and cannot simply be explained by pressure effects. Now that barbiturates are less frequently used, clinicians are likely to be less aware of the phenomenon of coma blister formation; however, newer drugs have also been associated with the occurrence of coma blisters. We describe 2 new associations of coma blisters and anticonvulsants in children. In the first child, blisters recurred on multiple occasions along with obtundation and edema. Our aims are to alert clinicians to the occurrence of coma blisters in children sedated on anticonvulsant medications and to report the new finding of recurrent coma blisters.

Filaggrin mutations in atopic eczema: genotype-phenotype correlation

RF-1 Regional chemotherapy for inoperable limb cancer using isolated limb infusion J. Marsden, V. Samarasinghe, M. Duddy, J. Moysey, S. Sinclair, A. Howells, C. McGarr, C. Defty and J. Hopkins Skin Oncology Service, University Hospital Birmingham, Birmingham, U.K. Hyperthermic isolated limb perfusion is used to deliver regional chemotherapy for inoperable cutaneous cancers threatening limb viability or function. Isolated limb infusion (ILI) is less complex, less invasive and more easily repeatable. It requires isolation of the limb with a tourniquet then administration of very high dose chemotherapy combined with limb warming followed by drug washout. From 2002 to 2004 we treated nine patients with ILI. There was one complete response and five partial responses, but severe toxicity in one patient necessitating amputation. We report further data on 19 ILI in 16 patients (aged 43–88 y, 5 male, 11 female) using melphalan 7.5 mg L limb volume and actinomycin 75 lg L. Thirteen ILI treatments were for melanoma, four were for squamous cell carcinoma, and two for Merkel cell carcinoma. Thirteen patients were treated with a single ILI, two patients were treated with two ILI treatments and one patient was treated with one ILI to each leg. Disease was confined to the leg and thigh in 12; six had skin metastases only and in 13 disease involved fascia, muscle or bone. Four patients had inguinal node dissection immediately following ILI. Data are given as median values and ranges; tumour number was 13 (1–60), and size was 27 mm (2–175). The limb volume was 7Æ1 L (5–10Æ9). Limb temperatures in subcutaneous fat and muscle increased from 37.2 C (35Æ8– 39Æ8) and 37Æ5 C (36Æ3–38Æ9) respectively to 37Æ9 C (35Æ8–39Æ4) and 37Æ9 C (36Æ4–39Æ5). The starting pH was 7Æ3 (7Æ19–7Æ44) and at completion 7Æ1 (6Æ97–7Æ31). The recirculation volume was 2Æ4 L (1Æ4–4Æ5), and the flow rate was 72Æ0 mL min (40–136). There were five complete responses (four melanoma, one Merkel cell carcinoma), 11 partial responses, and three patients with stable or progressive disease. Toxicity was erythema only (n = 8), erythema and swelling (n = 8) and severe limb swelling requiring fasciotomy (n = 3). The peak creatinine kinase level was 1130 IU L (46–6312). The hospital stay was 12 days (8–41). Two patients developed deep vein thrombosis and two had mild neutropenia; one developed neuropathy. ILI is a safe and effective treatment, but requires great care to minimize adverse effects. The therapeutic index may be improved by using drugs with greater specificity, and ILI is well suited to Phase 1 drug investigation. RF-2 Sentinel lymph node biopsy for melanoma: audit of South East Scotland experience Jan 1999–Jun 2007 C. Leitch, V.R. Doherty, U. Chetty* and M. Butterworth Department of Dermatology, Royal Infirmary of Edinburgh, Edinburgh, U.K.; *Western General Hospital, Edinburgh, U.K. and St John’s Hospital at Howden, West Lothian, U.K. The role of sentinel lymph node biopsy (SLNB) in the management of melanoma in the U.K. remains controversial. The procedure has been undertaken in South East (SE) Scotland since 1999. Current local criteria for SLNB are a Breslow thickness of ‡ 1 mm or < 1 mm with Clark level IV. The aims of this audit were to look at the number of SLNB performed, the characteristics of this patient group and the outcomes of those with positive and negative SLNB compared to our melanoma patients as a whole. SE Scotland comprises Lothian, Fife and Borders, collectively a population of 1.2 million. All patients diagnosed with invasive cutaneous melanoma (MM) from January 1999–June 2007 were identified from a prospectively accrued database (Scottish Melanoma Group). One thousand nine hundred and fifteen patients were diagnosed with MM in SE Scotland during this period (per year from January 1999 to June 2007: 195, 179, 192, 222, 233, 254, 232, 289, 119). The average age at diagnosis was 55 (range 13–97). M : F ratio was 1 : 1.6. Of a possible 744 eligible patients 300 (40%) underwent SLNB (per year from January 1999 to June 2007: 8, 12, 14, 33, 40, 63, 45, 51, 34). The average age of patients having SLNB was 53 years (range 17–86). M : F ratio was 1 : 1Æ4. SLNB were performed in 121 of 300 (40%) for melanomas on the lower limbs, 101 of 300 (34%) on the trunk, 54 of 300 (18%) on the upper limbs, 23 of 300 (8%) on the head and neck and one for a melanoma on the genital mucosa. The mean Breslow thickness was 2.8 mm. Of 300 patients, 20 (7%) were Clark level 5, 206 (69%) were Clark level 4, 51 (17%) were Clark level 3, 3 (1%) were Clark level 2 and 20 (7%) had no Clark level which could be measured. Only 6 of 300 (2%) SLNB were performed for patients out with current selection criteria. Positive SLNB were found in 51 of 300 (17%): 4 of 8 in 1999, 2 of 12 in 2000, 1 of 14 in 2001, 2 of 33 in 2002, 5 of 40 in 2003, 16 of 63 in 2004, 7 of 45 in 2005, 5 of 51 in 2006 and 9 of 34 in the first 6 months of 2007. Of those with positive SLNB, 45 of 51 (88%) had subsequent regional lymph node dissection. Surgeon A performed 218 of 300 (73%) SLNB with 41 of 218 (19%) positive results; 74 of 300 (25%) were performed by surgeon B with 9 of 74 (12%)

Appointment of a paediatric eczema nurse reduces inpatient admissions for atopic eczema

PA-1 Appointment of a paediatric eczema nurse reduces inpatient admissions for atopic eczema S.J. Brown, S.N. Leech, F.J. Eccleston and A.E.M. Taylor Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, U.K. Atopic eczema accounts for a large proportion of the paediatric dermatology workload and its incidence appears to be increasing (Taylor B, Wadsworth J, Wadsworth M, Peckham C. Changes in the reported prevalence of childhood eczema since the 1939-45 war. Lancet 1984; 2:1255-7). The role of dermatology nurses in the education and treatment of children with eczema has been reviewed (Courtenay M, Carey N. Nurse-led care in dermatology: a review of the literature. Br J Dermatol 2006; 154:1–6). In order to meet service demands with optimal management in 2001 a paediatric eczema nurse was appointed to run eczema follow-up clinics and to provide open access for advice and outpatient treatment. To test the hypothesis that this service has reduced the number of admissions for eczema we examined the data regarding paediatric dermatology admissions in two years preceding the introduction of eczema nurse clinics (1997 and 1999) and two years following their establishment (2003 and 2005). The total number of new and review patients seen in the paediatric dermatology clinics remained static, averaging approximately 6000 per year. The overall admission rate for paediatric dermatology patients has also not changed significantly in this time (mean of 28Æ8 admissions per year). The number of eczema admissions per year has fallen from 20 to 12 within this period and as a proportion of total admissions this represents a fall from approximately 75% to 50%. To analyse this data further, the percentage of eczema admissions per month was calculated and a Kolmogorov– Smirnov test was performed. This showed that the reduction in number of eczema admissions was after the appointment of the paediatric eczema nurse was statistically significant (P 1⁄4 0Æ08). A possible confounding factor that may have contributed to this change is the introduction of 0Æ03% topical tacrolimus to the hospital formulary in May 2002. In our opinion this is unlikely to have had a significant impact on admission rates since only 5% of the paediatric eczema patients received this treatment in a twelve month period. In conclusion, this data suggests that the appointment of a paediatric eczema nurse has altered the management of atopic eczema in secondary care. There has been a reduction in the number of hospital admissions; this provides a more patient-orientated service and also has potential cost implications. PA-2 Eczema: education, education, education. Are community clinics beneficial in treating paediatric eczema? Review of a nurse led community paediatric eczema clinic 2003-2005 P.B.J. Farrant, L. Benfield and M. Price Brighton General Hospital, Brighton, U.K. In trying to address the Department of Health’s desire to treat chronic conditions in the community, and with funding from the Action Learning Set, a pilot nurse-led paediatric eczema clinic was set up in August 2003. The main aim was to assess, treat and educate children with mild to moderate eczema. A weekly community clinic was set up, open to referral from local general practitioners (GPs), health visitors and dermatologists. Patients were assessed and treated as per local protocol. A large part of the session was dedicated to patient and parent education. Although this clinic was set up as a service rather than a study, patients were given a questionnaire to assess their satisfaction, and in 2004-2005 all GPs were contacted to look at consultation rates in the 6 months before and after the intervention. In 2003–2004, 53 new patients were seen, of whom 25 were seen once only, and 28 required a follow-up appointment. Of the 53, 47 were referred from primary care and six from the dermatology consultant (four were diverted after receipt of a referral letter to secondary care but before consultation). In 2004–2005, 84 new patients were seen, and 78 follow-up appointments were given (including any necessary follow-up from the 2003–2004 cohort). Seventy-six referrals came from primary care, and eight from secondary care, six of whom were referred to the clinic instead of receiving a secondary care appointment. Two patients were referred from this clinic to secondary care. The questionnaire was filled in by 26 parents, with all finding the clinic helpful, and 21 feeling that their child’s eczema had improved. Three children stayed the same, one was unsure whether the eczema had improved or not, and one had deteriorated because of a reaction to one of the creams Twenty-seven GPs responded to their questionnaire. In the six months prior to the intervention a total of 77 skin-related consultations had occurred, which decreased to 32 in the six months after intervention,13 of which were due to the need for repeat prescriptions. The majority of GPs who responded (26 of 27) were in favour of this service. In summary there seems to be a marked decrease in the number of primary care consultations before and those after the nurse-led clinic was established. One problem has been the inability of our nurse to prescribe the treatments, which led to at least 13 follow-ups with the GPs. Only 10 of