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Background: Evidence on fumaric acid esters (FAE) in the treatment of pediatric psoriasis is scarce.Objective: Describe the effectiveness, influence on the quality of life (QoL) and safety of FAE in children with recalcitrant psoriasis in daily clinical practice.Methods: A prospective case series.Results: Fourteen patients with recalcitrant plaque-type psoriasis were described (mean age 13.7, range 8–17 years). Mean treatment duration was 48.6 weeks (range 12–124). Maximum daily dose varied between 180 and 1200 mg with a mean of 564 mg per day. Mean Psoriasis Area and Severity Index (PASI) (±SEM) at baseline was 10.5 (1.0) compared to 8.6 (1.1), 6.2 (1.6) and 4.9 (1.5) at week 12, 24 and 36, respectively. An improvement in PASI was observed in nine patients (64.3%). Mean CDLQI (±SEM) at week 0, 12, 24 and 36 was 8.9 (1.4), 6.8 (1.2), 3.7 (1.4) and 3.1 (2.0), respectively. Most common adverse events (AEs) were gastrointestinal complaints (n = 13, 92.9%) and flushes (n = 10, 71.4%). Lymphocytopenia (n = 5, 45.5%) and eosinophilia (n = 4, 36.4%) were frequently observed laboratory abnormalities. AEs were usually mild and transient. One serious adverse event, unrelated to FAE, was reported.Conclusions: FAE showed improvement of disease severity and QoL in the majority of children. Side-effects occurred frequently, but were usually mild and transient. FAE may be an alternative systemic treatment option for pediatric psoriasis, provided that also the long-term safety data are closely monitored, in particular lymphocytopenia. [ABSTRACT FROM AUTHOR]

Background: The Psoriasis Area and Severity Index (PASI) is not able to measure small affected areas in a body region which is important for assessing the performance of high-effective treatment. Objective: To present the Low PASI score, show the difference between the classic PASI and the Low PASI, evaluate the inter-observer agreement of both scores, and compare the two scores within investigators. Methods: Cross-sectional study. Two investigators independently assessed the classic PASI and the Low PASI in 10 patients with mild-to-moderate plaque psoriasis. Differences in outcome between the two scores were calculated. Intra-class correlation coefficients (ICC) were used to determine the inter-observer agreement and to compare measurements of the two scores within both investigators. Prediction limits of 95% for the errors in measurements were provided. Results: In both investigators, Low PASI was mean 1.71 and 1.76, whereas the classic PASI was mean 4.14 and 4.33. The inter-observer agreement (ICC) was excellent for both investigators in both scores (ICC classic PASI = 0.95 and Low PASI = 0.87). Conclusion: The Low PASI score allows more possible scores at lower levels of psoriasis extent (affected areas lower than 10% in a body region) compared to the classic PASI. This new score may lead to a more precise analysis of treatment responses and may have important clinical implications. [ABSTRACT FROM PUBLISHER]

Research suggests that overweight and obese youths are stigmatized in contemporary society, and are more likely than normal-weight youths to become the victims of bullying. In the current study, meta-analyses were performed to analyze to what extent overweight and obese youths are more likely than normal-weight youths to be the victims of bullying. The databases Psychinfo, ERIC and Medline were searched for relevant articles. Retrieved articles were scanned to find further articles. Language was not used as an exclusion criterion. A total of 14 articles (N=55 231) were included in a meta-analysis on bullying and overweight youths, and a total of 16 articles (N=58 520) were included in a meta-analysis on bullying and obese youths. The results suggested that both overweight and obese youths were more likely to be victims of bullying. The results were not moderated by gender, overweight and obese boys and girls were equally likely to be victimized. Results remained significant after adjustment for publication bias. Both overweight and obesity are risk factors for being a victim of bullying. [ABSTRACT FROM AUTHOR]

Focal dermal hypoplasia (FDH) is an X-linked dominant disorder caused by nonsense mutations and deletions in the PORCN gene coding for a transmembrane endoplasmic reticulum protein required for Wingless signalling. Symptoms consist mainly of linear atrophic skin defects, skeletal deformities and, in many cases, mental retardation. Osteopathia striata is a nearly constant feature. Approximately 90% of patients are women. A few instances of father-to-daughter transmission and a number of sporadic male cases presumably as a result of somatic mosaicism have been recorded. The aim of this study was to demonstrate the presence of somatic mosaicism for PORCN mutations in a male patient. We sequenced the PORCN gene in different tissues from a boy with symptoms of FDH. We demonstrate post-zygotic mosaicism for a novel deletion in the PORCN gene. A novel PORCN deletion, present in a post-zygotic mosaic, causes focal dermal hyplasia in a male patient. [ABSTRACT FROM AUTHOR]

The article discusses the implications of the Wingless (WNT) pathway towards the development of odonto-onycho-dermal dysplasia (OODD). It states that OODD is caused by the mutation of the WNT10A gene which is characterized by keratoderma, nail dystrophy and abnormal teeth. It presents the findings of a study conducted by the authors which revealed evidence for phenotypic heterogenicity associated with WNT10A genetic mutations.

Background Conradi–Hünermann–Happle syndrome [X-linked dominant chondrodysplasia punctata type 2 (CDPX2); MIM no. 302960] is an X-linked dominant disorder of cholesterol metabolism that causes a wide spectrum of skeletal abnormalities and linear ichthyosiform skin lesions. Mosaicism is probably responsible for the variability of the phenotype. Objectives To describe new mutations in patients with variable manifestations of the disease. Methods We studied three patients with CDPX2. We performed mutation analysis of the EBP (formerly known as CDPX2) gene and gas chromatography–mass spectroscopy on serum of two patients. Results We found two novel (3G→T and 419-422delTTCT) and one known mutation in the EBP gene. We demonstrated the presence of increased levels of dehydrocholesterol and 8(9)-cholestenol in the two patients with new mutations, confirming the diagnosis of CDPX2 and strongly suggesting that the mutations are indeed pathogenic. One patient had a very mild phenotype, presenting with linear alopecia and a mild symmetrical epiphyseal dysplasia. X-inactivation studies in peripheral blood of all patients showed skewing in only the most severely affected patient. Conclusions The strong phenotypic variability in our patients suggests that there is no clear genotype–phenotype correlation. [ABSTRACT FROM AUTHOR]

We describe a Dutch man suffering from a previously undescribed erythrokeratoderma associated with palmoplantar keratoderma and circular constrictions of the fingers. No mutations were identified in the genes encoding loricrin, connexin 26, 30, 30.3, 31 and 31.1, and ARS/complex B. There are some similarities between the disorder described here and other palmoplantar keratodermas and erythrokeratodermas, but assignment to a particular disease category is not possible. Hence we propose that we have delineated a novel type of keratoderma. [ABSTRACT FROM AUTHOR]

Summary We report a mother and daughter with a syndrome of hypotrichosis, striate palmoplantar keratoderma, onychogryphosis, periodontitis, acro-osteolysis and psoriasis-like skin lesions. The syndrome resembles Papillon–Lefèvre syndrome (PLS), characterized by palmoplantar keratoderma, periodontitis and psoriasis-like skin lesions, and particularly Haim–Munk syndrome, an allelic variant of PLS with acro-osteolysis. Both are caused by mutations in the cathepsin C gene (CTSC ). Our patients differ in the unique nature of the palmar keratoderma and hypotrichosis. We have sequenced CTSC in the mother without finding mutations in either coding or non-coding parts of the gene. We propose that our patients suffer from a new syndrome possibly caused by mutations in a gene that has a functional or structural relation with CTSC . [ABSTRACT FROM AUTHOR]

Summary Background Keratitis–ichthyosis–deafness (KID) syndrome is a debilitating ectodermal dysplasia that predisposes patients to develop squamous cell carcinomas in addition to leading to profound sensory deafness and erythrokeratoderma. We recently demonstrated that KID can be caused by a specific missense mutation in connexin 26 (GJB2 ). Another syndrome, called hystrix-like ichthyosis–deafnesss (HID) syndrome, strongly resembles the KID syndrome. These disorders are distinguished mainly on the basis of electron microscopic findings. We hypothesized that KID and HID syndromes may be genetically related. Objective To demonstrate by mutation analysis that HID and KID syndromes are genetically indistinguishable. Methods DNA was extracted from paraffin-embedded tissue samples of the first HID syndrome patient described in the literature. Since the KID syndrome mutation abolishes an Asp I restriction site, we were able to screen the patient's DNA by polymerase chain reaction and subsequent restriction enzyme analysis. Results Restriction analysis of the connexin 26 gene in HID syndrome demonstrated the presence of the KID syndrome mutation that we previously described. This result was confirmed by direct DNA sequencing. Conclusions We show that KID and HID syndromes are identical at the molecular level and confirm the clinical impression that these syndromes are one and the same. That previous clinical reports made a distinction may be a consequence of sampling artefacts; alternatively, genetic background effects such as the presence of concurrent mutations in other skin-expressed genes may modify the phenotype. [ABSTRACT FROM AUTHOR]

Gap junctions are intercellular channels which are permeable to ions and small molecules up to about 1 kDa in size. They are prominent in the skin, but their precise function there is largely unknown. Mutations in skin-expressed gap junction genes disrupt epidermal growth and differentiation. A relatively minor epidermal connexin, connexin 26 (Cx26), is associated with a wide variety of phenotypes, each specifically associated with a particular amino acid residue. How the different mutations in GJB2 lead to such distinctive phenotypes is poorly understood. Analysis of new GJB2 mutations can shed new light on pathogenesis and the apparently vital role of Cx26 in maintaining epidermal integrity. [ABSTRACT FROM AUTHOR]

Neonatal ichthyosis-sclerosing cholangitis (NISCh) syndrome is a rare autosomal recessive disorder associated with scalp hypotrichosis, scarring alopecia, ichthyosis and sclerosing cholangitis. It is caused by homozygous mutations in the CLDN1 gene coding for the tight junction component claudin-1. Only five patients have been reported so far: four patients from two inbred Moroccan families, all carrying a dinucleotide deletion c.200_201delTT in the CLDN1 gene and a Swiss patient with a 1-bp deletion (c.358delG) in exon 2. Here, we report on three Moroccan brothers born of consanguineous parents (first cousins) presenting with ichthyosis, hypotrichosis and congenital paucity of bile ducts. In our patients, we found the same dinucleotide deletion (c.200_201delTT) in the CLDN1 gene that had been reported previously. In our view, this is suggestive of a founder effect. Interestingly, our patients presented not with sclerosing cholangitis but with congenital paucity of bile ducts. Although the two conditions cannot always be easily distinguished, we would suggest that paucity of bile ducts could be a manifestation of NISCh. [ABSTRACT FROM AUTHOR]

The article presents a case of a 17-year-old Dutch boy who developed transgradient palmoplantar keratosis on his palms and soles shortly after birth. The patient has been diagnosed of having Mal de Meleda (MDM), based on the clinical symptoms. The finding shows that since the identification of mutations in ARS component B gene as the cause of MDM, a limited number of mutations have been identified.

A letter to the editor is presented in response to the article on the discovery of chanarin-dorfman syndrome published in the previous issue.

Discusses the medical case of a four-year-old boy with erythrokeratoderma variabilis. Clinical history; Physical examination findings; Results of the light and electron microscopic examination of the lesions; Association between mutations in connexins with the autosomal dominant skin disorder.

This article discusses two cases of palmoplantar keratoderma, a skin condition characterized by thickened and hardened skin on the palms and soles. The patients presented with linear distribution of verrucous and keratotic plaques on their hands, feet, and other areas of the body. Genetic analysis revealed pathogenic variants in the HRAS gene, which is associated with various skin disorders. The article suggests that the clinical presentation of HRAS-associated nevus (HAN) can vary widely, from isolated linear palmoplantar keratoderma to widespread lesions covering the skin in a mosaic pattern. [Extracted from the article]

This article explores the genetic and clinical aspects of autosomal recessive congenital ichthyosis (ARCI) caused by mutations in the NIPAL4 and PNPLA1 genes. The study investigates potential treatments for ARCI, including anti-interleukin therapy for cytokine dysregulation and pruritus. The authors conducted a retrospective analysis of patients with these gene mutations and evaluated their response to specific treatments. The results showed varying effects, highlighting the need for further research in this area. The article also includes a table summarizing the genetic variants and clinical features of twelve patients with different forms of ichthyosis and palmoplantar keratoderma. The study was conducted as part of the European Reference Network-SKIN subthematic group Ichthyosis and Palmoplantar Keratoderma and received ethical approval. [Extracted from the article]

A response of the author of the article "Darier Disease in Israel: Combined Evaluation of Genetic and Neuropsychiatric Aspects," that was pulished in the previous issue is presented.

Presents a response by the authors to a letter the editor about their article "A New Type of Erythrokeratoderma," in a previous issue.

Linked Comment: E. Epstein. Br J Dermatol 2022; 186:203. Plain language summary available online [ABSTRACT FROM AUTHOR]

Restrictive dermopathy (RD) is a severe neonatal inherited skin syndrome of which children die shortly after birth. Clinical features include intrauterine growth retardation, taut translucent and easily eroded skin, multiple joint ankylosis and distinct facial features. RD is usually caused by homozygous or compound heterozygous mutations in ZMPSTE24, predicted to cause loss of function of the encoded zinc metalloproteinase STE24. ZMPSTE24 is essential for the processing of the nuclear intermediate filament protein prelamin A. We report two distantly related children from the United Arab Emirates with RD. Remarkably, they lived up to 2 months, suggesting some residual function of the mutant protein. We sought to confirm the diagnosis by thorough microscopic analysis of patient skin, to identify the causative mutation and to study its functional consequences. A skin biopsy was obtained and processed for light and electron microscopy. Peripheral blood leucocytes were used for DNA and RNA isolation, and detection of prelamin A by immunofluorescence. Analysis of the skin confirmed the earlier reported densely packed collagen bundles and lack of elastin fibres. In both patients a homozygous splice site mutation c.627+1G>C in ZMPSTE24 was identified. Analysis of the ZMPSTE24 mRNA revealed an in-frame exon 5 skipping. Accumulation of prelamin A could be detected at the nuclear envelope of patient blood lymphocytes. We thus report the first splice site mutation in ZMPSTE24, which is likely to be a founder mutation in the United Arab Emirates. The accumulation of prelamin A at the nuclear periphery is consistent with defective ZMPSTE24 function. Interestingly, a regular blood sample can be used to investigate prelamin A accumulation. [ABSTRACT FROM AUTHOR]

Schnitzler's syndrome is an auto-inflammatory disorder which is characterized by two mandatory features: an urticarial rash and a monoclonal gammopathy. Although the pathophysiology of this syndrome is not yet fully understood, a role for interleukin-1 seems apparent. While this presumed link between interleukin-1 and the monoclonal gammopathy is not yet elucidated, a mutual factor in pathophysiology however seems likely. Here we present a novel hypothesis of a shared pathophysiologic mechanism between Schitzler's syndrome and monoclonal gammopathy. [ABSTRACT FROM AUTHOR]

The article presents a case study of three white patients with Brooke–Spiegler syndrome (BSS) who were initially diagnosed both clinically and histopathologically. Topics include mutation analysis of the cylindromatosis (CYLD) gene, which revealed three splice site mutations and assessment of the expression of CYLD in normal human epidermal keratinocytes (NHEK), leucocytes and peripheral blood mononuclear cells (PBMC) by quantitative reverse transcriptase (qRT)-PCR.

In a multidisciplinary outpatient clinic for hereditary skin diseases and/or syndromes involving the skin, 7% (30 of 409) of patients were found to have an abnormality involving the X chromosome, a mutation in a gene located on the X chromosome or a clinical diagnosis of an X-linked monogenetic condition. The collaboration of a dermatologist and a clinical geneticist proves to be very valuable in recognizing and diagnosing these conditions. By combining their specific expertize in counselling an individual patient, X-linked diagnoses were recognized and could be confirmed by molecular and/or cytogenetic studies in 24 of 30 cases. Mosaicism plays an important role in many X-linked hereditary skin disorders. From our experience, we extracted clinical clues for specialists working in the field of genetics and/or dermatology for considering X-linked disorders involving the skin. [ABSTRACT FROM AUTHOR]

Background Keratolysis exfoliativa (KE), also known as dyshidrosis lamellosa sicca, is a palmoplantar dermatosis characterized by air-filled blisters and collarette desquamation. It has been regarded as a subtype of dyshidrotic eczema, a fungal infection or a dermatophytid reaction. KE may also resemble acral peeling skin syndrome and localized epidermolysis bullosa simplex. Although KE is a common disorder, it is a rarely reported and is an under-recognized dermatosis. Objectives To delineate the characteristic features of KE. Methods We investigated the clinical, immunohistopathological, ultrastructural and molecular features of KE. Patients were included from the clinical records. Additional diagnostic research consisted of mutation analysis of the candidate genes TGM5, KRT5, KRT14, FLG, SPINK6 and SPINK9. Results A total of 24 patients with KE were identified, six with familial and 18 with sporadic KE. Lesions consisted of air-filled blisters only on palmoplantar skin, followed by collarette and lamellar peeling. Both light microscopy and electron microscopy showed cleavage and partially degraded corneodesmosomes within the stratum corneum, whereas immunofluorescence microscopy showed normal expression of corneodesmosomal components. No mutations were found in TGM5, KRT5/ 14 and SPINK6/ 9. There was no clear link with atopy or with FLG mutations. Conclusions Our study suggests premature corneodesmolysis as the main pathological mechanism of this palmoplantar skin disorder. We conclude that KE appears to be a distinct peeling entity. [ABSTRACT FROM AUTHOR]

Summary Background Variegate porphyria (VP) is due to a partial deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the haem biosynthetic pathway. Clinically, VP is characterized by photosensitivity and acute neurovisceral attacks that can manifest separately or together in affected individuals. The disease is inherited in an autosomal dominant fashion with incomplete penetrance and PPOX gene mutations associated with VP are usually unique to patients and their families. In South Africa, however, VP is highly prevalent as the result of a founder mutation, designated p.R59W. Previous genealogical and haplotype studies showed a link between South African and Dutch carriers of p.R59W and it was suggested that this mutation was introduced to South Africa by Dutch settlers at the end of the 17th century. Objectives To perform extended haplotype analysis in six South African and Dutch VP families with the p.R59W mutation. Methods Haplotyping of 13 microsatellite markers flanking the PPOX gene on chromosome 1q22-23 and five informative single nucleotide polymorphisms within and around the gene. Results A core haplotype cosegregated in all families studied. Conclusions Our data deliver further confirmation that the South African and Dutch VP families carrying mutation p.R59W shared a common ancestor. [ABSTRACT FROM AUTHOR]

Background Epidermolytic ichthyosis (EI), previously termed bullous congenital ichthyosiform erythroderma or epidermolytic hyperkeratosis, is a clinically heterogeneous genodermatosis caused by mutations in the genes encoding the suprabasal keratins 1 and 10. Classical EI is clinically characterized by severe neonatal erythroderma, blistering and fragile skin in infancy, quickly subsiding with subsequent development of generalized scaling hyperkeratosis. We report three Dutch families with palmoplantar keratoderma and mild blistering, but without neonatal erythroderma and generalized scaling. A novel heterozygous missense mutation in the linker L12 domain of KRT1:c.1019A>G, p.Asp340Gly was found associated with this phenotype in these families. Objectives To investigate the effects of the novel KRT1:p.Asp340Gly and the one other previously reported KRT1:p.Asp340Val mutations on keratinocyte cytoskeleton formation and stress resistance. Methods Wild-type and mutant pEGFP- KRT1 fusion constructs were transfected into HaCaT cells and exposed to hypo-osmotic shock. Haplotyping and genealogical studies were performed to investigate the possibility of a common founder for p.Asp340Gly. Results Cells transfected with either one of the keratin 1 L12 domain mutations showed significantly increased tonofilament aggregation. The haplotype around the KRT1 gene was shared in all affected family members of two families and a common founder was traced. Conclusions Our study supports the pathogenicity of the keratin 1 L12 domain mutations in vitro. These mutations are associated with a milder EI phenotype with pronounced palmoplantar keratoderma, and without neonatal erythroderma and scaling. The KRT1:p.Asp340Gly mutation in the Dutch families is likely to have arisen from a common founder. [ABSTRACT FROM AUTHOR]

Costello syndrome (CS) is a rare multiple congenital anomaly/mental retardation syndrome characterized by coarse face, loose skin and cardiomyopathy. It is often associated with benign and malignant tumors. Several groups have now demonstrated that CS is caused by recurring mutations in the HRAS gene in different ethnic groups. Here, we describe three unrelated Dutch patients and show that they all have the same mutation, G12S, in HRAS. To our knowledge, our patients are the first Dutch to be analysed. The syndrome seems to be genetically homogeneous. We discuss the pertinent nosology of the syndrome. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the prevalence of halpotype in western European patients with mal de Meleda (MDM), described as an autosomal recessive monogenic disorder defined by progressive transgradient hyperkeratosis of the palms and soles. Particular focus is given to the spectrum of mutations in SLURP1 as a cause for MDM. An ancient founder effect for p.W15R in western European population is suggested.

The article discusses the rule of dichotomy in type 2 segmental Darier disease. The disease is an autosomal dominant skin disease caused by germline mutations in the ATP2A2 gene. Researchers had distinguished the types of segmental manifestation in autosomal dominant skin disorders. Type 1 reflects heterozygosity for a de novo postzygotic mutation, while type 2 segmental manifestation was confirmed for the first time on the molecular level in Hailey-Hailey disease.

A letter to the editor is presented discussing the Bazex-Dupré-Christol syndrome and its relationship with chromosome Xq25-27.1.

The article presents a case study of a woman who had progressive cutaneous and uterine leiomyoma. Her medical history reveals that she was also diagnosed at the age of 2 years with single Wilms tumor, and was treated with surgery and chemotherapy. It notes that the development of Wilms tumor is closely related to fumarate hydratase (FH) gene dysfunction. It says that the occurrence of uterine leiomyoma with kidney cancer suggests hereditary leiomyomatosis and renal cell cancer.

A letter to the editor is presented discussing the potential of defects in DNA mismatch to signify an early-onset basal cell carcinoma.

The article presents a case study of a girl having mild phenotype of congenital ichthyosis and hypotrichosis which is linked to a new mutation in CDLN1. The hair of the patient was extremenly brittle and she did not have eyelashes or eyebrows. Her mother reported that enamel of her milk teeth was previously dysplastic.

A letter to the editor is presented is presented which discusses clinical manifestations of X-linked recessive ichthyosis in a woman caused by a homozygous interstitial 1.6-Mb deletion of Xp22.31.

NOD2/CARD15 belongs to the N-terminal caspase recruitment domain family of proteins involved in regulating NF-kB activation in response to inflammatory stimuli transduced through Toll-like receptors. Mutations and polymorphisms in the NOD2/CARD15 gene reduce antibacterial responses and are associated with granulomatous inflammatory conditions such as Blau syndrome and early-onset sarcoidosis. The polymorphism R702W (arginine to tryptophan) is strongly associated with susceptibility to Crohn’s disease in Caucasian populations. Skin abnormalities (other than cutaneous manifestations of Crohn’s disease) have not been previously associated with R702W. We report on a female patient homozygous for R702W who developed granulomatous rosacea at the age of 12 years old. From the occurrence in the context of Crohn associated with R702W, we speculate that granulomatous rosacea may be an entity distinct from other forms of rosacea, which are associated with increased production of antibacterial proteins such as cathelicidin. [ABSTRACT FROM AUTHOR]