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.

Genotype-phenotype correlation in a large English cohort of patients with autosomal recessive ichthyosis.

BACKGROUND: Recessive forms of congenital ichthyosis encompass a group of rare inherited disorders of keratinization leading to dry, scaly skin. So far, 13 genes have been implicated, but there is a paucity of data on genotype-phenotype correlation in some populations. OBJECTIVES: We compiled an English cohort of 146 individuals with recessive ichthyosis and assessed genotype-phenotype correlation. METHODS: Deep phenotyping was undertaken by history-taking and clinical examination. DNA was screened for mutations using a next-generation sequencing ichthyosis gene panel and Sanger sequencing. RESULTS: Cases were recruited from 13 National Health Service sites in England, with 65% of patients aged < 16 years at enrolment. Pathogenic biallelic mutations were found in 83% of cases, with the candidate gene spread as follows: TGM1 29%, NIPAL4 12%, ABCA12 12%, ALOX12B 9%, ALOXE3 7%, SLC27A4 5%, CERS3 3%, CYP4F22 3%, PNPLA1 2%, SDR9C7 1%. Clinically, a new sign, an anteriorly overfolded ear at birth, was noted in 43% of patients with ALOX12B mutations. The need for intensive care stay (P = 0·004), and hand deformities (P < 0·001), were associated with ABCA12 mutations. Self-improving collodion ichthyosis occurred in 8% of the cases (mostly TGM1 and ALOX12B mutations) but could not be predicted precisely from neonatal phenotype or genotype. CONCLUSIONS: These data refine genotype-phenotype correlation for recessive forms of ichthyosis in England, demonstrating the spectrum of disease features and comorbidities, as well as the gene pathologies therein. Collectively, the data from these patients provide a valuable resource for further clinical assessment, improving clinical care and the possibility of future stratified management. What's already known about this topic? Recessive forms of ichthyosis are rare but often difficult to diagnose. Mutations in 13 genes are known to cause recessive forms of ichthyosis: ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, SULT2B1, ST14 and TGM1. Some phenotypic features may associate with certain gene mutations, but paradigms for genotype-phenotype correlation need refining. What does this study add? The genotypic spectrum of recessive ichthyosis in England (based on 146 cases) comprises TGM1 (29%), NIPAL4 (12%), ABCA12 (12%), ALOX12B (9%), ALOXE3 (7%), SLC27A4 (5%), CERS3 (3%), CYP4F22 (3%), PNPLA1 (2%) and SDR9C7 (1%). New or particular phenotypic clues were defined for mutations in ALOX12B, ABCA12, CYP4F22, NIPAL4, SDR9C7 and TGM1, either in neonates or in later life, which allow for greater diagnostic precision. In around 17% of cases, the molecular basis of recessive ichthyosis remains unknown.

Propranolol in the treatment of infantile haemangiomas: lessons from the European Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce survey.

BACKGROUND: Oral propranolol is widely prescribed as first-line treatment for infantile haemangiomas (IHs). Anecdotally, prescribing practice differs widely between centres. OBJECTIVES: The Propranolol In the Treatment of Complicated Haemangiomas (PITCH) Taskforce was founded to establish patterns of use of propranolol in IHs. METHODS: Participating centres entered data on all of their patients who had completed treatment with oral propranolol for IHs, using an online data capture tool. RESULTS: The study cohort comprised 1097 children from 39 centres in eight European countries. 76·1% were female and 92·8% had a focal IH, with the remainder showing a segmental, multifocal or indeterminate pattern. The main indications for treatment were periocular location (29·3%), risk of cosmetic disfigurement (21·1%) and ulceration and bleeding (20·6%). In total 69·2% of patients were titrated up to a maintenance regimen, which consisted of 2 mg kg(-1) per day (85·8%) in the majority of cases. 91·4% of patients had an excellent or good response to treatment. Rebound growth occurred in 14·1% upon stopping, of whom 53·9% were restarted and treatment response was recaptured in 91·6% of cases. While there was no significant difference in the treatment response, comparing a daily maintenance dose of < 2 mg kg(-1) vs. 2 mg kg(-1) vs. > 2 mg kg(-1) , the risk of adverse events was significantly higher: odds ratio (OR) 1 vs. adjusted OR 0·70, 95% confidence interval (CI) 0·33-1·50, P = 0·36 vs. OR 2·38, 95% CI 1·04-5·46, P = 0·04, Ptrend < 0·001. CONCLUSIONS: The PITCH survey summarizes the use of oral propranolol across 39 European centres, in a variety of IH phases, and could be used to inform treatment guidelines and the design of an interventional study.

Acute resistance exercise and pressure pain sensitivity in knee osteoarthritis: a randomised crossover trial.

OBJECTIVE: To determine whether a single bout of resistance exercise produces an analgesic effect in individuals with knee osteoarthritis (OA). DESIGN: Eleven participants with knee OA (65.9 ± 10.4 yrs), and 11 old (61.3 ± 8.2 yrs) and 11 young (25.0 ± 4.9 yrs) healthy adults performed separate bouts of upper and lower body resistance exercise. Baseline and post-exercise pressure pain thresholds were measured at eight sites across the body and pressure pain tolerance was measured at the knee. RESULTS: Pressure pain thresholds increased following exercise for all three groups, indicating reduced pain sensitivity. For the young and old healthy groups this exercise-induced analgesia (EIA) occurred following upper or lower body resistance exercise. In contrast, only upper body exercise significantly raised pain thresholds in the knee OA group, with variable non-significant effects following lower body exercise. Pressure pain tolerance was unchanged in all groups following either upper or lower body exercise. CONCLUSION: An acute bout of upper or lower body exercise evoked a systemic decrease in pain sensitivity in healthy individuals irrespective of age. The decreased pain sensitivity following resistance exercise can be attributed to changes in pain thresholds, not pain tolerance. While individuals with knee OA experienced EIA, a systemic decrease in pain sensitivity was only evident following upper body exercise.

Mutations in AEC syndrome skin reveal a role for p63 in basement membrane adhesion, skin barrier integrity and hair follicle biology.

BACKGROUND: AEC (ankyloblepharon-ectodermal defects-clefting) syndrome is an autosomal dominant ectodermal dysplasia disorder caused by mutations in the transcription factor p63. Clinically, the skin is dry and often fragile; other features can include partial eyelid fusion (ankyloblepharon), hypodontia, orofacial clefting, sparse hair or alopecia, and nail dystrophy. OBJECTIVES: To investigate how p63 gene mutations affect gene and protein expression in AEC syndrome skin. METHODS: We performed microarray analysis on samples of intact and eroded AEC syndrome skin compared with control skin. Changes were verified by quantitative real-time reverse transcription-polymerase chain reaction and, for basal keratinocyte-associated genes, by immunohistochemistry and analysis of microdissected skin. RESULTS: We identified significant upregulation of six genes and downregulation of 69 genes in AEC syndrome skin, with the main changes in genes implicated in epidermal adhesion, skin barrier formation and hair follicle biology. There was reduced expression of genes encoding the basement membrane proteins FRAS1 and collagen VII, as well as the skin barrier-associated small proline-rich proteins 1A and 4, late cornified envelope protein 5A, hornerin, and lipid transporters including ALOX15B. Reduced expression of the hair-associated keratins 25, 27, 31, 33B, 34, 35, 81 and 85 was also noted. We also confirmed similar alterations in gene expression for 26 of the 75 genes in eroded AEC scalp skin. CONCLUSIONS: This study identifies specific changes in skin structural biology and signalling pathways that result from mutant p63 and provides new molecular insight into the AEC syndrome phenotype.

Tenascin-X deficiency and Ehlers-Danlos syndrome: a case report and review of the literature.

Tenascin-X is a large extracellular matrix glycoprotein that is widely distributed within connective tissues and is associated with an autosomal recessive type of Ehlers-Danlos syndrome (EDS). Tenascin-X represents the first EDS susceptibility gene that does not code for a fibrillar collagen or collagen-processing enzyme. We describe a paediatric case of tenascin-X deficiency and review the literature.

Pseudoepitheliomatous, keratotic and micaceous balanitis after penile squamous cell carcinoma.

Pseudoepitheliomatous keratotic and micaceous balanitis (PKMB) is a rare form of balanitis, with only a handful of cases reported since the disease was first described. Although the condition has been described as benign, there is increasing evidence of its premalignant potential, with several of the reported cases progressing to verrucous or squamous cell carcinoma (SCC). We report a case of PKMB following penile SCC and discuss the literature on this rare condition.

Multiple primary malignancies in patients with Merkel cell carcinoma.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare malignant cutaneous tumour, the incidence of which is increasing. Second malignancies have been reported to occur with high incidence in these patients. OBJECTIVES: We report the rate and nature of multiple malignancies in patients with MCC treated over a 10 year period in Addenbrooke's Hospital in Cambridge, United Kingdom, as well as the temporal relationship of these additional malignancies to the diagnosis of MCC. RESULTS: The 27 patients had an approximately equal sex incidence with a median age at diagnosis of 79 years. Seventy percent (n=19) of patients had a second primary malignant tumour; and 7 of these patients had two or more tumours in addition to the MCC. Eighteen patients had additional cutaneous malignancies: melanoma, squamous cell carcinoma and basal cell carcinoma, and 8 patients presented non-cutaneous malignancy including colorectal, haematological and breast tumours. Of the 28 additional tumours in our patients, half were diagnosed prior to presentation of MCC, 32% within 6 months of diagnosis, and 18% between 6 months and 3 years after diagnosis. Possible reasons for the high rate of additional tumours in this population are discussed. CONCLUSIONS: Our figures reflect a higher incidence of multiple malignancies in those with Merkel cell tumour than has previously been reported. This has important implications for the care and surveillance of these patients.