Ruud G. L. Nellen

Skin changes in oculo-dento-digital dysplasia are correlated with C-terminal truncations of connexin 43†

Oculo‐dento‐digital dysplasia (ODDD, OMIM no.164210) is a pleiotropic disorder caused by mutations in the GJA1 gene that codes for the gap junction protein connexin 43. While the gene is highly expressed in skin, ODDD is usually not associated with skin symptoms. We recently described a family with ODDD and palmoplantar keratoderma. Interestingly, mutation carriers had a novel dinucleotide deletion in the GJA1 gene that resulted in truncation of part of the C‐terminus. We speculated, that truncation of the C‐terminus may be uniquely associated with skin disease in ODDD. Here, we describe a patient with ODDD and palmar hyperkeratosis caused by a novel dinucleotide deletion that truncates most of the connexin 43 C‐terminus. Thus, our findings support the notion that such mutations are associated with the occurrence of skin symptoms in ODDD and provide the first evidence for the existence of a genotype–phenotype correlation.

More epidermal p53 patches adjacent to skin carcinomas in renal transplant recipients than in immunocompetent patients: the role of azathioprine

Abstract:  Immunosuppressive medication in renal transplant recipients (RTR) strongly increases the risk of cancers on sun‐exposed skin. This increased risk was considered an inevitable collateral effect of immunosuppression, because UV‐induced carcinomas in mice were found to be highly antigenic. Here, we posed the question whether immunosuppression also increases the frequency of p53‐mutant foci (‘p53 patches’), putative microscopic precursors of squamous cell carcinomas. As the majority of RTR was kept on azathioprine for most of the time, we investigated whether this drug could increase UV‐induced p53 patches by immunosuppression. As azathioprine can impair UV‐damaged DNA repair under certain conditions, we also investigated whether DNA repair was affected. Archive material of RTR and immunocompetent patients (ICP), as well as azathioprine‐administered hairless mice were examined for p53 patches. DNA repair was investigated by ascertaining the effect of azathioprine on unscheduled DNA synthesis (UDS) in UV‐irradiated human keratinocytes. P53 patches were more prevalent in RTR than in ICP in normal skin adjacent to carcinomas (P = 0.02), in spite of a lower mean age in the RTR (52 vs 63 years, P = 0.001), but we found no increase in UV‐induced p53 patches in mice that were immunosuppressed by azathioprine. We found a significant reduction in DNA repair activity in keratinocytes treated with azathioprine (P = 0.011). UV‐induced UDS in humans is dominated by repair of cyclobutane pyrimidine dimers, and these DNA lesions can lead to ‘UV‐signature’ mutations in the P53 gene, giving rise to p53 patches.

Molecular genetic support for the rule of dichotomy in type 2 segmental Darier disease

realize that a ‘generic’ dermatology-specific QoL measure such as the DLQI may not be sufficient to capture the unique constellation of specific skin conditions such as CHE. For example, the number of work impairment-related items in the DLQI is under-represented. Moreover, some items may become redundant in CHE, e.g. choice of clothes. This fact is well demonstrated in studies of CHE where a score of DLQI even for severe hand disease has been < 10. For example, in a Danish study, the mean DLQI score for all patients with CHE was found to be 5Æ5, and only 7Æ8 for severe disease. With regard to psoriasis, a DLQI score in the same range as for severe CHE (i.e. 7Æ8) as found in this study would not be considered severe disease, unless it was > 10. This implies that the degree of QoL impairment measured by the DLQI for different skin conditions such as psoriasis vs. CHE may not be an accurate representation of the magnitude of actual QoL impairment caused by these individual conditions. Ideally, in order to have a comprehensive assessment of QoL impairment caused by psoriasis and CHE, a psoriasis-specific and a CHE-specific measure should be used as an adjunct to the DLQI, respectively. In contrast to psoriasis, with extensive evidence of its impact on patients’ QoL, there is a paucity of literature with regard to the impact of CHE on QoL, especially using the DLQI. Correspondingly, the amount of clinical efficacy data of different treatments used with regard to improvement in patients’ QoL and health-state utilities is much more extensive for psoriasis compared with very limited evidence for CHE treatments. This gap in the literature has the potential to affect adversely the way treatment guidelines are formulated. With the advent of expensive drugs in dermatology such as biologics, there is more pressure on the pharmaceutical industry to demonstrate efficacy and cost-effectiveness. Efficacy may be demonstrated by improvement in both the severity of disease and patients’ QoL. Cost-effectiveness may be measured in terms of direct cost reduction (e.g. reduced hospital stays, shorter duration of treatment) and indirectly by enhanced productivity (e.g. less time off work). While a number of studies have been carried out to assess the cost-effectiveness of various psoriasis treatments, especially biologics, there are limited data on cost-effectiveness of treatments used in CHE, such as alitretinoin. Due to the lack of adequate evidence and in particular utility-based QoL data, the cost-effectiveness analysis in the recent National Institute for Health and Clinical Excellence (NICE) single technology appraisal for the use of alitretinoin in CHE had to rely on a ‘mapping exercise’ to link the DLQI to EQ-5D (EuroQuol Group, Rotterdam, the Netherlands). This technique has also been used in other studies to convert the DLQI values to EQ-5D utility weights using an algorithm for cost-effectiveness analysis of biologics in psoriasis. Although mapping approaches are used quite commonly to overcome missing data, they are clearly less useful than direct elicitation of QoL in relevant randomized trials. Health policymakers are in the difficult position of having to make concrete decisions regarding reimbursement for health technologies with incomplete information. This can lead to specific judgements such as the DLQI severity criteria used by NICE for alitretinoin (i.e. score of 15) compared with criteria for most biologics for psoriasis (i.e. score of 10) in which the limited methods available are used to try to achieve access to treatment in patients for whom it should prove worthwhile and cost-effective, while avoiding excess resource consumption by limiting use in subjects for whom the outcome is less likely to be cost-effective.

Eruption of lymphocyte recovery or autologous graft-versus-host disease?

Maculopapular exanthemas have a particular high incidence among patients treated with autologous hematopoietic stem cell transplantation (HSCT). In most cases, a viral or drug induced origin is easily identified. However, the transplantation itself may also induce similar skin changes. These exanthemas are known under various names, such as autologous graft‐versus‐host disease (GVHD), engraftment syndrome (ES) or eruption of lymphocyte recovery (ELR). Given the clinical and histopathological similarities of these disorders, it can prove difficult to establish a diagnosis. Here, we describe a patient who developed a maculopapular exanthema after autologous stem cell transplantation for multiple myeloma, diagnosed as autologous GVHD. We also briefly review the current knowledge of the pathogenesis of autologous GVHD, ES, and ELR. Based on these data we would like to suggest that the latter two do not reflect own disease entities but rather different presentations of autologous GVHD.

Compound heterozygosity for ARS component B mutations in a Dutch patient with mal de Meleda

Mal de Meleda (MDM, OMIM 248300) is a rare autosomal recessive disorder of palmoplantar keratinization. Its name is derived from the isle of Mljet or Meleda, Croatia, due to the high incidence of the disease among its inhabitants. The hyperkeratosis of the palms and soles seen in MDM is progressive and transgredient, i.e. extending to the dorsal sides of the extremities. Hyperhidrosis, accompanied by a malodorous scent due to secondary infection with dermatophytes and bacteria, is invariably present. Perioral erythema, ichthyosis, pseudoainhum and nail abnormalities have also been described. MDM is caused by mutations in the ARS component B gene, encoding the secreted Ly-6 ⁄uPar related protein-1 (SLURP1). SLURP1 enhances the function of the nicotinic acetylcholine receptor a7 in epidermal keratinocytes, thereby promoting differentiation of keratinocytes in the stratum granulosum to the cells forming the cornified envelope.

Mendelian Disorders of Cornification Caused by Defects in Intracellular Calcium Pumps : Mutation Update and Database for Variants in ATP2A2 and ATP2C1 Associated with Darier Disease and Hailey-Hailey Disease

The two disorders of cornification associated with mutations in genes coding for intracellular calcium pumps are Darier disease (DD) and Hailey–Hailey disease (HHD). DD is caused by mutations in the ATP2A2 gene, whereas the ATP2C1 gene is associated with HHD. Both are inherited as autosomal‐dominant traits. DD is mainly defined by warty papules in seborrheic and flexural areas, whereas the major symptoms of HHD are vesicles and erosions in flexural skin. Both phenotypes are highly variable. In 12%–40% of DD patients and 12%–55% of HHD patients, no mutations in ATP2A2 or ATP2C1 are found. We provide a comprehensive review of clinical variability in DD and HHD and a review of all reported mutations in ATP2A2 and ATP2C1. Having the entire spectrum of ATP2A2 and ATP2C1 variants allows us to address the question of a genotype–phenotype correlation, which has not been settled unequivocally in DD and HHD. We created a database for all mutations in ATP2A2 and ATP2C1 using the Leiden Open Variation Database (LOVD v3.0), for variants reported in the literature and future inclusions. This data may be of use as a reference tool in further research on treatment of DD and HHD.

Haplotype analysis in western European patients with mal de Meleda: founder effect for the W15R mutation in the SLURP1 gene

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Penile pyoderma gangrenosum: successful treatment with colchicine

Pyoderma gangrenosum is an ulcerative skin disease with variable clinical outcomes. The diagnosis is based on clinical features and exclusion of other ulcerative diseases. To date, a specific treatment is not known. Since the disease can be destructive, aggressive treatment is preferable. Here, we present a patient with a penile pyoderma gangrenosum who was successfully treated with low‐dose colchicine.

Novel TGM5 mutations in acral peeling skin syndrome

Acral peeling skin syndrome (APSS, MIM #609796) is a rare autosomal recessive disorder characterized by superficial exfoliation and blistering of the volar and dorsal aspects of hands and feet. The level of separation is at the junction of the stratum granulosum and stratum corneum. APSS is caused by mutations in the TGM5 gene encoding transglutaminase‐5, which is important for structural integrity of the outermost epidermal layers. The majority of patients originate from Europe and carry a p.(Gly113Cys) mutation in TGM5. In this study, we report both European and non‐European families carrying other mutations in the TGM5 gene. In 5 patients, we found 3 novel mutations: c.1001+2_1001+3del, c.1171G>A and c.1498C>T. To confirm their pathogenicity, we performed functional analyses with a transglutaminase activity assay, determined alternative splicing by reverse‐transcribed PCR analysis and used databases and in silico prediction tools.

A novel mutation in SLURP1 in patients with mal de Meleda from the Indian subcontinent

Mal de Meleda, (MDM, OMIM #248300) is an autosomal recessive palmoplantar keratoderma. Its major features are progressive transgredient hyperkeratosis of the palms and soles, hyperhydrosis, malodourous scent due to microbial superinfection, and minor symptoms such as perioral erythema, hyperkeratosis on elbows and knees, pseudo-ainhum and nail abnormalities. Onset of the disease is usually in infancy, with a slowly progressive course during adult life [1]. Penetrance is complete, although symptoms are highly variable, probably caused by environmental factors such as mechanical trauma or heat [1,2]. In 2001, mutations in the SLURP1 gene, encoding the secreted Ly-6/uPar related protein-1 (SLURP1), were identified as the cause of MDM [1]. SLURP1 enhances the function of the nicotinic acetylcholine receptor a7 (nAChRa7) in epidermal keratinocytes, thereby promoting keratinocyte differentiation in the stratum granulosum [3]. Mutations in SLURP1 show a remarkable geographic distribution, with most mutations reported in Europe and the Middle East. Certain mutations are highly prevalent in societies due to a founder effect [4]. The p.Gly86Arg mutation is most often found in sporadic patients with MDM of Asian origin [5,6]. To date, no mutations in Indian patients have been described. We describe an Indian family with MDM caused by a novel splice site mutation in intron 1 and provide functional consequences of this SLURP1 mutation. A fifteen year old girl developed a diffuse palmoplantar keratoderma in the first year of life. The hyperkeratosis slowly advanced to the dorsal side of her wrists (transgrediens), hands and feet, led to loss of dermatoglyphics and sclerodactyly and developed a malodorous scent. The distal phalanges acquired a conical shape without development of pseudo-ainhum, most prominently seen in the 5th digit of both hands (Fig. 1a and b). Nail changes other than a pinkish-pale hue, perioral erythema or skin changes elsewhere were not noted. Her 6 year old brother developed similar but less severe symptoms. There was no evidence of hearing loss, eye abnormalities or dental caries in both the siblings. Their performance in school was above average. Parents were consanguineous (Fig. 1c). No other family members had similar complaints. Histopathology of palmar skin showed hyperkeratosis, acanthosis with minimal superficial dermal perivascular infiltrate, without evidence of epidermolytic hyperkeratosis. Probands and their parents gave written informed consent to further molecular analysis. Genomic DNA was extracted from whole blood (QIAamp DNA Blood Mini Kit, Qiagen). Mutation analysis of SLURP1 revealed a homozygous c.58+5G>T splice donor variation in intron 1 in both index patients (Fig. 2a and b). The parents were heterozygous for the variant. Splice site prediction software tools (integrated in Alamut 2.4) showed reduced scores of the variant splice donor site, putatively leading to aberrant RNA