Severe epidermolysis bullosa simplex phenotype caused by codominant mutations p.Ile377Thr in keratin 14 and p.Gly138Glu in keratin 5.

Epidermolysis bullosa simplex (EBS) is a rare skin disease usually inherited in an autosomal dominant pattern. EBS is resulting from mutations in keratin 5 (KRT5) and keratin 14 (KRT14) genes encoding the keratins 5 and 14 proteins expressed in the keratinocytes of the basal layer of the epidermis. To date, seven pathogenic mutations have been reported to be responsible for EBS in the Canadian population from the province of Quebec: p.Pro25Leu, p.Leu150Pro, p.Met327Thr and p.Arg559X in KRT5; p.Arg125Ser, p.Ile377Thr and p.Ile412Phe in KRT14. Here, we present a novel French-Canadian patient diagnosed with EBS confined to the soles but presenting a severe complication form including blisters, hyperkeratosis, skin erosions and toenail abnormalities. Mutation screening was performed by direct sequencing of the entire coding regions of KRT5 and KRT14 genes and revealed the previously reported missense heterozygous mutation c. 1130T > C in KRT14 (p.Ile377Thr). Furthermore, this patient is carrying a second mutation in KRT5, c.413G > A (p.Gly138Glu), which has been linked to an increased risk of basal cell carcinoma in the literature. We suspect an impact of the p.Gly138Glu variant on the EBS phenotype severity of the studied patient. The pathogenicity and consequences of both genetic variations were simulated by in silico tools.

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell-cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell-cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.

[Occupational aspects of palmoplantar pustulosis : Discussion based on the evaluation of retrospective data]. / Berufsdermatologische Aspekte der Pustulosis palmoplantaris : Diskussionsbeitrag anhand einer retrospektiven Datenauswertung.

BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic inflammatory skin disease. Its classification as a variant of psoriasis is controversial. Exogenous factors may affect PPP. OBJECTIVES: Occupational aspects of PPP based on a retrospective evaluation of patient data are discussed. METHODS: Data from 1518 patients who took part in a tertiary prevention program (TIP) for occupational skin diseases in our department between January 2015 and June 2019 were evaluated. RESULTS: PPP was diagnosed in 30 patients (1.98%). The hands were affected in all of them, while concomitant feet involvement was found in 83.3%. The majority was female (70.0%) and reported tobacco smoking (83.3%). Systemic treatment was continued or initiated in one third of patients. In only 8 patients (26.7%) was PPP considered to be work-related. CONCLUSIONS: PPP is an endogenous disease which is influenced by nonoccupational factors (e.g., tobacco smoking). Therefore, a thorough investigation is mandatory when assessing whether occupational factors are legally essential and exceed aggravation by everyday life. For this purpose, a well-documented course of the disease and a critical appraisal of occupational and nonoccupational factors are crucial. Only if occupational causality is probable can preventive measures be provided by the statutory accident insurance and PPP can be legally recognized as an occupational disease.

A DSG1 Frameshift Variant in a Rottweiler Dog with Footpad Hyperkeratosis.

A single male Rottweiler dog with severe footpad hyperkeratosis starting at an age of eight weeks was investigated. The hyperkeratosis was initially restricted to the footpads. The footpad lesions caused severe discomfort to the dog and had to be trimmed under anesthesia every 8-10 weeks. Histologically, the epidermis showed papillated villous projections of dense keratin in the stratum corneum. Starting at eight months of age, the patient additionally developed signs consistent with atopic dermatitis and recurrent bacterial skin and ear infections. Crusted hyperkeratotic plaques developed at sites of infection. We sequenced the genome of the affected dog and compared the data to 655 control genomes. A search for variants in 32 candidate genes associated with human palmoplantar keratoderma (PPK) revealed a single private protein-changing variant in the affected dog. This was located in the DSG1 gene encoding desmoglein 1. Heterozygous monoallelic DSG1 variants have been reported in human patients with striate palmoplantar keratoderma I (SPPK1), while biallelic DSG1 loss of function variants in humans lead to a more pronounced condition termed severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome. The identified canine variant, DSG1:c.2541_2545delGGGCT, leads to a frameshift and truncates about 20% of the coding sequence. The affected dog was homozygous for the mutant allele. The comparative data on desmoglein 1 function in humans suggest that the identified DSG1 variant may have caused the footpad hyperkeratosis and predisposition for allergies and skin infections in the affected dog.

Onychomycosis, the Active Invasion of a Normal Nail Unit by a Dermatophytic Versus the Colonization of an Existing Abnormal Nail Unit by Environmental Fungus.

Onychomycosis was described by early investigators as the presence of an abnormal nail unit and a member of the order Mycota, producing the abnormality. This interpretation has caused more than 50 years of confusion in the dermatologic literature. Unquestionably, the clinician sees more abnormal toenails than fingernails, and investigators have described a multitude of fungi as the cause of the clinically abnormal toenail. In 2010, developmental scientists proved, what we have long recognized, that there is no bilateral symmetry in living organisms and, therefore, one sole is different from the other. This causes a gait asymmetry, coupled with the pressure the closed shoe exerts on toenails while walking. This produces a series of abnormalities, which are clinically identical to what has been described for dermatophytic onychomycosis. These are fungus free and result in toenail niches. These toenail abnormalities were recently described as the asymmetric gait nail unit syndrome (AGNUS). It is possible that environmental fungi can colonize these toenail niches and, therefore, were described by investigators as a new onychomycosis entity In the normal host, onychomycosis should be only used to describe the active invasion of the nail bed (NB) corneocytes by a dermatophyte, as seen in dermatophytic onychomycosis. Dermatophytes only affect those hosts who have inherited the dermatophytosis susceptibility gene, transmitted as an autosomal dominant trait. In studies encompassing 3,000 abnormal toenails, only 27%-30% were found as dermatophyte culture positive, 25% were negative and the rest environmental fungi were recovered.

Lack of association between mutation in IL36RN and palmoplantar pustular psoriasis in Chinese patients.

BACKGROUND: Palmoplantar pustulosis is considered to be a localized pustular psoriasis confined to the palms and soles. Mutation of the IL36RN gene, encoding interleukin-36 receptor antagonist (IL-36Ra), is associated with generalized pustular psoriasis, but IL36RN mutations in Chinese palmoplantar pustulosis patients have not previously been investigated. OBJECTIVE: The aim of this study was to evaluate the mutation of IL36RN in Chinese patients with palmoplantar pustulosis. METHODS: Fifty-one Han Chinese patients with palmoplantar pustulosis were recruited. All exons and exon-intron boundary sequences of IL36RN were amplified in polymerase chain reactions, and Sanger sequencing of the amplicons was performed. RESULTS: Among the 51 palmoplantar pustulosis patients, four different single-base substitutions were identified in nine patients. The mutations were c.140A>G/p.Asn47Ser in five patients, c.258G>A/p.Met86IIe in two patients, and c.115+6T>C and c.169G>A/p.Val57IIe in one patient each. All mutations were heterozygous. Comparison with the human genome database and reported literature suggested that these variants may not be pathogenic mutations causing palmoplantar pustulosis. Furthermore, there was no difference in disease severity, onset age, or disease duration between patients with these heterozygous IL36RN variants and those without (p>0.1). STUDY LIMITATION: Lack of the further evaluation of IL36Ra protein in palmoplantar pustulosis lesions. CONCLUSIONS: The four variants of IL36RN identified did not appear to be associated with the specific phenotypes of palmoplantar pustulosis.

Lack of association between mutation in IL36RN and palmoplantar pustular psoriasis in Chinese patients

Abstract Background: Palmoplantar pustulosis is considered to be a localized pustular psoriasis confined to the palms and soles. Mutation of the IL36RN gene, encoding interleukin-36 receptor antagonist (IL-36Ra), is associated with generalized pustular psoriasis, but IL36RN mutations in Chinese palmoplantar pustulosis patients have not previously been investigated. Objective: The aim of this study was to evaluate the mutation of IL36RN in Chinese patients with palmoplantar pustulosis. Methods: Fifty-one Han Chinese patients with palmoplantar pustulosis were recruited. All exons and exon-intron boundary sequences of IL36RN were amplified in polymerase chain reactions, and Sanger sequencing of the amplicons was performed. Results: Among the 51 palmoplantar pustulosis patients, four different single-base substitutions were identified in nine patients. The mutations were c.140A>G/p.Asn47Ser in five patients, c.258G>A/p.Met86IIe in two patients, and c.115+6T>C and c.169G>A/p.Val57IIe in one patient each. All mutations were heterozygous. Comparison with the human genome database and reported literature suggested that these variants may not be pathogenic mutations causing palmoplantar pustulosis. Furthermore, there was no difference in disease severity, onset age, or disease duration between patients with these heterozygous IL36RN variants and those without (p > 0.1). Study limitation: Lack of the further evaluation of IL36Ra protein in palmoplantar pustulosis lesions. Conclusions: The four variants of IL36RN identified did not appear to be associated with the specific phenotypes of palmoplantar pustulosis.

A novel de novo mutation p.Ala428Asp in KRT5 gene as a cause of localized epidermolysis bullosa simplex.

Epidermolysis bullosa is a group of inherited blistering skin diseases resulting in most cases from missense mutations in KRT5 and KRT14 genes encoding the basal epidermal keratins 5 and 14. Here, we present a patient diagnosed with a localized subtype of epidermolysis bullosa simplex caused by a heterozygous mutation p.Ala428Asp in the KRT5 gene, that has not been previously identified. Moreover, a bioinformatic analysis of the novel mutation was performed, showing changes in the interaction network between the proteins. Identification of novel mutations and genotype-phenotype correlations allow to better understanding of underlying pathophysiologic bases and is important for genetic counselling, patients' management, and disease course prediction.

Morphological characteristics and human papillomavirus genotype predict the treatment response in cutaneous warts.

BACKGROUND: Cutaneous warts have a cure rate after therapy of no more than approximately 50%. Recently, we developed and validated a standard assessment tool for warts (Cutaneous WARTS diagnostic tool, CWARTS) based on phenotypical characteristics. OBJECTIVES: To assess whether patient and morphological wart characteristics predict the human papillomavirus (HPV) type in a specific wart and whether these characteristics as well as the HPV type predict a favourable treatment response. METHODS: Photographs were used to score nine morphological wart characteristics using the newly developed CWARTS tool. Genotyping of 23 wart-associated HPV types was performed using the hyperkeratotic skin lesion-polymerase chain reaction/multiplex genotyping assay. The results were correlated with a favourable response to treatment with monochloroacetic acid, cryotherapy or a combination of cryotherapy and salicylic acid. Odds ratios were calculated using logistic regression in a generalized estimating equations model. RESULTS: Black dots (capillary thrombosis) strongly predicted the presence of any HPV type in a wart. From all characteristics tested, the HPV type most strongly predicted the treatment response when the warts were treated with monochloroacetic acid or a combination of cryotherapy and salicylic acid with a significantly decreased treatment response if the warts contained HPVs of the alpha genus (HPV2, HPV27 or HPV57). When cryotherapy alone was used for common warts, HPV type did not play a role, but cryotherapy was less effective in the presence of callus and when the wart was located deeper in the skin. CONCLUSIONS: Morphological characteristics of the warts and the HPV genotype influence treatment outcome and thus potentially influence future treatment decisions for common and plantar warts.

Mutations in AAGAB underlie autosomal dominant punctate palmoplantar keratoderma.

Punctate palmoplantar keratoderma type 1 (PPPK1) is a rare autosomal dominant inherited skin disease, characterized by multiple hyperkeratotic lesions on the palms and soles. The causative gene for PPPK1 has been identified as AAGAB, which encodes α- and γ-adaptin-binding protein p34. We describe the clinical features in three unrelated families with PPPK1, and report three recurrent causative mutations in AAGAB.

Causative Agents of Onychomycosis: A 7-Year Study.

BACKGROUND: Onychomycosis is principally caused by dermatophyte species, but nondermatophyte molds and yeasts have also been involved, causing different clinical manifestations. The aim of this investigation is to determine the clinicomycological and epidemiological profile of the etiologic agents of onychomycosis. METHODS: The study population included 9,785 suspected cases of onychomycosis referred to the Medical Mycology Reference Laboratory in Isfahan, Iran, during 2007-2014. Nail clipping was collected in sterile Petri dishes for direct microscopic examination and culture. Clinical isolates were identified by using phenotypic tests and molecular techniques. RESULTS: Of total 9,785 cases with clinical suspicion of onychomycosis comprised in the present study, 1,284 patients (13.1%) were positive by direct microscopy. Age range of patients was between 1 and 82 years. Housewives were the commonest infected population. Candida albicans was the most prevalent species isolated from patients in this study (34.9%) followed by Trichophyton interdigitale (11.7%) and Aspergillus flavus (9.1%). CONCLUSION: The pattern of causative agents and clinical signs of onychomycosis is altering region to region, so repeated epidemiological surveys of onychomycosis seems to be fundamental. The present study provides novel and appropriate epidemiologic data of onychomycosis for the better prevention and treatment of this fungal infection.

Síndrome de descamación de la piel acral: presentación de un caso y revisión bibliográfica / Acral peeling skin syndrome: a case report and literature review

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Efficacy of botulinum toxin in pachyonychia congenita type 1: report of two new cases.

Pachyonychia congenita (PC) is a rare genodermatosis caused by a mutation in keratin genes, which can lead to hypertrophic nail dystrophy and focal palmoplantar keratoderma (predominantly plantar), amongst other manifestations. Painful blisters and callosities, sometimes exacerbated by hyperhidrosis, are major issues that can have a significant impact on patient quality of life. Many alternative treatments for this condition have been applied with variable and partial clinical response, but a definitive cure for this disease has yet to be discovered. After obtaining informed consent, two patients with genetically confirmed PC type 1 were treated with plantar injections of botulinum toxin type A. Both patients showed a marked improvement in pain and blistering with an average response time of one week, a six-month mean duration of effectiveness, and a lack of any side effects or tachyphylaxis.