Identifying the best predictive diagnostic criteria for psoriasis in children (< 18 years): a UK multicentre case-control diagnostic accuracy study (DIPSOC study).

BACKGROUND: In children, psoriasis can be challenging to diagnose. Difficulties arise from differences in the clinical presentation compared with adults. OBJECTIVES: To test the diagnostic accuracy of previously agreed consensus criteria and to develop a shortlist of the best predictive diagnostic criteria for childhood psoriasis. METHODS: A case-control diagnostic accuracy study in 12 UK dermatology departments (2017-2019) assessed 18 clinical criteria using blinded trained investigators. Children (< 18 years) with dermatologist-diagnosed psoriasis (cases, N = 170) or a different scaly inflammatory rash (controls, N = 160) were recruited. The best predictive criteria were identified using backward logistic regression, and internal validation was conducted using bootstrapping. RESULTS: The sensitivity of the consensus-agreed criteria and consensus scoring algorithm was 84·6%, the specificity was 65·1% and the area under the curve (AUC) was 0·75. The seven diagnostic criteria that performed best were: (i) scale and erythema in the scalp involving the hairline, (ii) scaly erythema inside the external auditory meatus, (iii) persistent well-demarcated erythematous rash anywhere on the body, (iv) persistent erythema in the umbilicus, (v) scaly erythematous plaques on the extensor surfaces of the elbows and/or knees, (vi) well-demarcated erythematous rash in the napkin area involving the crural fold and (vii) family history of psoriasis. The sensitivity of the best predictive model was 76·8%, with specificity 72·7% and AUC 0·84. The c-statistic optimism-adjusted shrinkage factor was 0·012. CONCLUSIONS: This study provides examination- and history-based data on the clinical features of psoriasis in children and proposes seven diagnostic criteria with good discriminatory ability in secondary-care patients. External validation is now needed.

Novel and recurrent mutations in keratin 1 cause epidermolytic ichthyosis and palmoplantar keratoderma.

Mutations in keratin genes underlie a variety of epidermal and nonepidermal cell-fragility disorders, and are the genetic basis of many inherited palmoplantar keratodermas (PPKs). Epidermolytic PPK (EPPK) is an autosomal dominant disorder that can be due to mutations in the keratin 1 gene, KRT1. Epidermolytic ichthyosis (EI), the major keratinopathic ichthyosis, is characterized by congenital erythroderma, blistering and erosions of the skin. Causative mutations in KRT1 and KRT10 have been described, with PPK being present primarily in association with the former. We report four unrelated cases (one with sporadic EI and three with autosomal dominant PPK), due to two novel and two recurrent KRT1 mutations. Mutations in KRT1 are not only scattered throughout the keratin 1 protein, as opposed to being clustered, but can result in a range of phenotypes as further confirmed by these mutations, giving a complex genotype/phenotype pattern.

Reactivity to autologous serum skin test and relationship with complement levels in chronic idiopathic urticaria and angio-oedema.

BACKGROUND: A role for complement in autoantibody-mediated histamine release in urticaria has been suggested but not proven in vivo. Aim. To study serum complement levels in patients with chronic idiopathic urticaria (CIU) and to determine whether there was a relationship with autologous serum skin test (ASST) reactivity. METHODS: We recruited 35 patients with CIU. Complement (C3, C4) levels and ASST were measured in all patients; additional investigations were undertaken dependent on history and examination. RESULTS: Complement concentrations were outside the population reference intervals in 19/35 patients, with low C3 noted in 3/35 and low C4 in 18/35. Of 12 patients with a positive ASST, 7 had low complement levels, and 12/23 with a negative ASST had low complement levels. Patients with a positive ASST had a median C3 of 1.24 g/L (range 0.35-1.51) compared with a median of 1.25 g/L in those with a negative ASST (P = 0.36), and a median C4 of 0.20 g/L (range 0.185-0.452) in those with a positive ASST compared with 0.18 g/L in those with a negative ASST (P = 0.88). CONCLUSIONS: We conclude that both a reduction in C4 and positive ASST are common in CIU and although these immunological abnormalities often coexist, there is no clear relationship between them. Other components of the complement system may be worth exploring.

Indication for linkage of the human OB gene region with extreme obesity.

Obesity is one of the most significant risk factors for hypertension, coronary heart disease, and NIDDM (Frayn KN, Coppack SW: Insulin resistance, adipose tissue and coronary heart disease. Clin Sci 82:1-8, 1992; Kaplan NM: The deadly quartet: upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med 149:1514-1520, 1989). While family segregation, adoption, and twin studies have indicated that degree of adiposity has a significant genetic component (Stunkard AJ, Harris JR, Pedersen NL, McClearn GE: The body-mass index of twins who have been reared apart. N Engl J Med 322:1483-1487, 1990; Bouchard C, Despres J-P, Mauriege P: Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 14:72-93, 1993), the genes and predisposing mutations remain poorly understood. This is in contrast to several well-defined genetic models for obesity in rodents, particularly the mouse obese (ob) gene, in which loss-of-function mutations cause severe obesity. Recent studies have demonstrated a substantial reduction in body fat when recombinant ob protein (leptin) is administered to mice. To test the relevance of these observations to human obesity, the location of the human homologue (OB) was established by radiation hybrid mapping and eight microsatellite markers spanning the OB gene region (7q3l.3) were genotyped in 101 obese French families. Affected-sib-pair analyses for extreme obesity, defined by BMI >35 kg/m2, revealed suggestive evidence for linkage to three markers located within 2 cM of the OB gene (D7S514, D7S680, and D7S530). The OB gene is therefore a candidate for genetic predisposition to extreme obesity in a subset of these families.

Identification of novel mutations in basic hair keratins hHb1 and hHb6 in monilethrix: implications for protein structure and clinical phenotype.

Monilethrix is an hereditary hair dystrophy recently shown to be due to mutations in the helix termination motif of two type II (basic) human hair keratin genes, hHb1 and hHb6. It has been suggested that mutation in hHb1 produces a less severe phenotype. We have studied hair keratin genes and clinical features in 18 unrelated pedigrees of monilethrix from Germany, Scotland, Northern Ireland, and Portugal, in 13 of which mutations have not previously been identified. By examining the rod domains of hHb1, hHb3 and hHb6, we have identified mutations in nine of the new pedigrees. We again found the glutamine-lysine substitution (E413K) in the helix termination motif of hHb6 in two families, and in another, the corresponding E413K substitution in the hHb1 gene. In four families a similar substitution E402K was present in a nearby residue. In addition two novel mutations within the helix initiation motif of hHb6 were found in Scottish and Portuguese cases, in whom the same highly conserved asparagine residue N114 was mutated to histidine (N114H) or aspartic acid (N114D) residues, respectively. In four other monilethrix pedigrees mutations in these domains of hHb1, hHb3, and hHb6 were not found. The mutations identified predict a variety of possible structural consequences for the keratin molecule. A comparison of clinical features and severity between cases with hHb1 and hHb6 mutations does not suggest distinct effects on phenotype, with the possible exception of nail dystrophy, commoner with hHb1 defects. Other factors are required to explain the marked variation in clinical severity within and between cases.

An analysis of relative costs and potential benefits of different policies for antenatal screening for beta thalassaemia trait and variant haemoglobins.

AIMS: To investigate the costs and potential benefits of different policies for antenatal screening for haemoglobinopathies in two multiethnic London communities. METHODS: 1000 consecutive antenatal patient samples referred to each of two London teaching hospital laboratories for haemoglobinopathy testing were investigated using the standard procedures of the laboratory in question. When the standard procedures did not include high performance liquid chromatography (HPLC), this technique was added, in order to assess its diagnostic value and cost-effectiveness. A comparison was made between the costs and potential benefits of universal testing for variant haemoglobins and beta thalassaemia trait using HPLC and the costs and potential benefits of universal testing for variant haemoglobins and selective testing for beta thalassaemia trait using the mean cell haemoglobin (MCH) as a screening test and less automated techniques than HPLC for definitive diagnosis. RESULTS: The costs of the two policies were found to be comparable, as the higher reagent/instrument costs of HPLC were offset by the lower labour costs. Universal testing of 2000 consecutive samples did not disclose any extra cases of beta thalassaemia trait which would not have been detected by universal screening and selective testing. However, six patients were found to have a haemoglobin A2 variant which can interfere with the diagnosis of beta thalassaemia trait. CONCLUSIONS: The introduction of universal testing by HPLC into British laboratories could be cost neutral and has potential benefits. If a higher cost is accepted then the greater degree of automation could be used to release skilled staff for other tasks within the laboratory.

Point-of-care method for total white cell count: an evaluation of the HemoCue WBC device.

Point-of-care testing (POCT) is becoming an important adjunct to haematology laboratory practice. An important component of the blood count is the total white cell count (WBC). Previously, this required laborious microscopic cell counting, but it can now be performed by means of automation; however, in many under-resourced countries, costly automated counters are only available in very few central hospitals. Moreover, neither method is practical in most POCT situations. The HemoCue WBC has been developed as a simplified alternative method, consisting of a reagent pre-loaded disposable cuvette together with basic image analysis technology. This report describes an assessment of its utility. The WBC of 500 routine blood samples from the hospital were tested in parallel by the HemoCue WBC and by a reference analyser to assess accuracy and utility of the former. The tests included precision, linearity, type of blood sample and anticoagulant and potential interfering substances in blood specimens. In the tests for accuracy, 192 of the 200 showed percentage difference from the NEQAS reference of <10% whilst the remaining eight samples differed by <12%, thus meeting the requirements of Clinical laboratory improvement amendments (CLIA)-88 regulations. Of the samples tested with potential interfering substances only those with >2% normoblasts or reticulocytosis showed significant differences from the reference measurements. The HemoCue WBC is reliable for WBC counts within the analytical range of 0.4-30.0 x 10(9)/l, except in samples where there are significant numbers of normoblasts or reticulocytes. It is simple to use and provides a valuable advance in the facilities available for POCT in haematology.

Narrowband ultraviolet B (UVB) phototherapy in children.

BACKGROUND: While narrowband ultraviolet B (UVB) phototherapy is a well-established treatment for a range of skin conditions in adults, there is little in the literature about its use in children and data regarding its long-term carcinogenic potential are lacking. AIM: We undertook a retrospective review of the use of narrowband UVB phototherapy in a paediatric population attending two Glasgow Hospitals. METHODS: Phototherapy case notes for all children aged 16 years and under at time of treatment were reviewed at two hospital sites between 1996 and 2002. RESULTS: In total, 77 children had been treated (median age 12 years, range 4-16). The conditions treated most frequently were psoriasis (45%) and atopic eczema (32%). Other dermatoses treated included alopecia areata, acne, hydroa vacciniforme and polymorphic light eruption. Treatment courses for atopic conditions were longer than those required for psoriatic conditions: median number of treatments 24 for atopic eczema (range 3-46), and 17.5 for psoriasis (range 9-35). By the end of treatment, 68% of the atopic patients and 63% of the patients with psoriasis had cleared. The adverse event profile was similar to that in adults, with erythema, herpes simplex reactivation and PLE all recorded. Anxiety was a problem for five patients. CONCLUSION: We conclude that narrowband UVB phototherapy is a useful and well-tolerated treatment for children with severe or intractable inflammatory skin disease, but concerns remain regarding long-term side-effects.

A randomized trial of topical 5% 5-fluorouracil (Efudix cream) in the treatment of actinic keratoses comparing daily with weekly treatment.

BACKGROUND: Topical 5-fluorouracil (5-FU) cream is widely used in the treatment of actinic keratoses (AKs) but the optimum treatment regimen that provides efficacy while minimizing side-effects remains unclear. OBJECTIVES: A randomized trial to compare the efficacy and side-effects of daily vs. weekly application of 5% 5-FU in the treatment of AKs of the scalp and face. PATIENTS/METHODS: Twenty patients were recruited and randomized to two groups. Group 1 (13 patients) applied 5% 5-FU twice daily for 3 weeks, group 2 (seven patients) applied 5% 5-FU twice daily for 1 day per week for 12 weeks. Patients were reviewed at weeks 3, 12, 24 and 52. At each review a lesion count and lesion map were completed and patients were asked to score efficacy and inflammation. RESULTS: At week 0 the median lesion count was the same in both groups, 17.5 lesions. At 12 weeks the median lesion count in group 1 had fallen to 0 where it remained for the duration of follow-up. In group 2 the median lesion count fell to 6 at 12 weeks, 5.5 at 24 weeks and was 3 at 52 weeks. The difference in the lesion count was significant at all time points after week 0: P < 0.05 at weeks 12 and 52, and P < 0.01 at week 24. The mean inflammation score was higher in patients clear of AKs at 12 weeks compared with those who had not cleared, 3.8 compared with 1.9. This difference was statistically significant (P < 0.05) suggesting that inflammation is necessary for efficacy. CONCLUSIONS: We conclude that daily application of 5% 5-FU cream is more effective than weekly application at clearing AKs from the scalp and face. Our results also suggest that inflammation is likely to be required to achieve a therapeutic effect.

Rising levels of serum S100 protein precede other evidence of disease progression in patients with malignant melanoma.

BACKGROUND: Several serum markers may be useful in the detection of metastatic melanoma, but none is in routine clinical use. OBJECTIVE: To assess the validity of S100 protein as a serum marker of melanoma progression. METHODS: Serum S100 protein levels were measured in 496 serum samples from 214 melanoma patients, using the Sangtec luminescence immunoassay. There were 75 patients with stage 1 melanoma, 66 initially with stage 2 melanoma, 49 initially with stage 3 melanoma and 24 with stage 4 melanoma. RESULTS: Serum S100 protein levels were < 0.2 microg L-1 in 71 of 75 (95%) stage 1 patients. One patient who had a normal level developed local recurrence. Fifty-eight of 66 (88%) stage 2 patients also had normal serum S100 protein levels. One with elevated levels progressed to stage 3 melanoma and five with elevated levels progressed to stage 4 disease. The remaining two with elevated serum S100 protein remained well. Thirty-five of 49 (71%) stage 3 patients had normal levels and, of these, two have progressed to stage 4 disease. Three patients with stage 3 disease had an elevated serum S100 protein level on one occasion but remained well. Eleven of 13 patients who developed stage 4 melanoma during the study had rising levels of serum S100 protein > 0.2 microg L-1 5-23 weeks before detection of melanoma progression by conventional means. Twenty-two of 24 patients with stage 4 disease throughout the study had consistently elevated serum S100 protein levels, and the two patients with normal levels were clinically disease free after surgery and chemotherapy. None of 14 control subjects with atypical naevi had elevated S100 protein levels, and only one of 11 healthy normal controls had an elevated level. CONCLUSIONS: Thus, rising levels of serum S100 protein are a specific and sensitive clinically relevant marker of tumour progression in melanoma patients, which precedes other evidence of melanoma recurrence.

The clinical photography of Herbert Brown: a perspective on early 20th Century dermatology.

Herbert Brown was Consultant Dermatologist to the Victoria Infirmary, Glasgow during the first half of the 20th Century. He was a keen amateur photographer, and his large archive of photographs illustrates comprehensively the work of a clinical dermatologist in that era.

G6PD Mediterranean accounts for the high prevalence of G6PD deficiency in Kurdish Jews.

The Jews of Kurdistan are a small inbred population with a high incidence of beta-thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Recently, it was reported that the beta-thalassaemia in this population shows an unusual mutational diversity; 13 different mutations were identified, of which 4 had not previously been observed in any other population. In contrast, we now report that the G6PD deficiency, which has the highest known incidence in the world, and which affects about 70% of males, is almost entirely attributable to a single widespread mutation, G6PD Mediterranean.

Candidate gene approach of familial morbid obesity: linkage analysis of the glucocorticoid receptor gene.

BACKGROUND: Morbid obesity is a multifactorial disease, with a strong but almost unknown genetic component. Familial linkage studies using the candidate gene approach have been shown to be powerful tools for identifying susceptibility genes for inherited diseases. AIM OF THE STUDY: We have investigated the role of the Glucocorticoid Receptor gene (GRL) in morbid obesity. SUBJECTS: Eighty obese families were recruited through a multimedia campaign (42 families, sample 1) or from the department of nutrition of the Hotel Dieu hospital in Paris (38 families, sample 2). METHODS: A multipoint linkage analysis with markers on chromosome 5q placed the GRL gene between D5S658 and D5S436 at genetic distances of 3.5 and 5 centimorgans, respectively. Using this map, we have chosen seven polymorphic microsatellite markers located in the vicinity of the GRL gene locus for sib pair linkage analysis. In addition to the obesity status, different quantitative phenotypes associated with obesity and insulin resistance were used for analysis. RESULTS: In sample 1, the results show a tendency towards linkage between three markers (one bc/1 intragenic RFLP and two microsatellite markers) in the GRL region and obesity characterised by a BMI > 27. However, using this phenotype, we failed to replicate the results in the second set of families. When using a more precise phenotype (the individual coefficient of variation of the BMI compared to a sex and age matched French reference population (pop) defined as the Zscore (indBMI-popBMI/SD of popBMI), a tendency for linkage was found for one marker in sample 2 as well as in the whole sample. No linkage was found when using quantitative traits associated with obesity. CONCLUSION: The GRL locus does not appear to be a major locus for obesity, but we cannot exclude that this gene or gene located nearby may have some minor effects on the obese phenotype or may be involved in some subtypes of obesity. Larger cohorts of families are probably necessary to improve the power of such linkage analysis in this heterogeneous disease.