Epidermolytic ichthyosis: Clinical spectrum and burden of disease in a large German cohort.

BACKGROUND: Keratinopathic ichthyoses are a group of hereditary skin disorders caused by pathogenic variants in keratin genes such as KRT1, KRT2 and KRT10, resulting in conditions such as epidermolytic ichthyosis (EI), autosomal-recessive EI, superficial EI and epidermal nevus. Case reports highlight the diversity of clinical manifestations, but only limited information exists regarding the quality of life and burden of disease. OBJECTIVES: The objective of this study was to assess the clinical spectrum, genotype-phenotype correlations and burden of disease in patients with epidermolytic ichthyosis in Germany. METHODS: We conducted an observational study involving 48 patients diagnosed with EI. Evaluations included the severity of skin involvement using the Investigator's Global Assessment (IGA), the modified Ichthyosis Area Severity Index (mIASI) and complications. The burden of disease was evaluated using the Dermatology Life Quality Index (DLQI) or the Children's Dermatology Life Quality Index (cDLQI). RESULTS: Based on clinical features, mIASI and IGA, EI can be categorized into localized, intermediate and severe forms. Patients with keratin 1 mutations tended to have severe EI, while the three forms were evenly distributed in those with keratin 10 mutations. The study highlights that around half of the patients with EI experienced itch and severe pain. Quality of life was affected, with daily life restrictions of 78% due to care and therapies. Reimbursement for moisturizing ointments by health insurance was insufficient for one-quarter of cases. CONCLUSIONS: The results emphasize the need for targeted interventions and comprehensive care strategies to enhance the quality of life for affected individuals.

Herpes Simplex Virus 1 Can Bypass Impaired Epidermal Barriers upon Ex Vivo Infection of Skin from Atopic Dermatitis Patients.

To infect its human host, herpes simplex virus 1 (HSV-1) must overcome the protective barriers of skin and mucosa. Here, we addressed whether pathological skin conditions can facilitate viral entry via the skin surface and used ex vivo infection studies to explore viral invasion in atopic dermatitis (AD) skin characterized by disturbed barrier functions. Our focus was on the visualization of the onset of infection in single cells to determine the primary entry portals in the epidermis. After ex vivo infection of lesional AD skin, we observed infected cells in suprabasal layers indicating successful invasion in the epidermis via the skin surface which was never detected in control skin where only sample edges allowed viral access. The redistribution of filaggrin, loricrin, and tight-junction components in the lesional skin samples suggested multiple defective mechanical barriers. To dissect the parameters that contribute to HSV-1 invasion, we induced an AD-like phenotype by adding the Th2 cytokines interleukin 4 (IL-4) and IL-13 to healthy human skin samples. Strikingly, we detected infected cells in the epidermis, implying that the IL-4/IL-13-driven inflammation is sufficient to induce modifications allowing HSV-1 to penetrate the skin surface. In summary, not only did lesional AD skin facilitate HSV-1 penetration but IL-4/IL-13 responses alone allowed virus invasion. Our results suggest that the defective epidermal barriers of AD skin and the inflammation-induced altered barriers in healthy skin can make receptors accessible for HSV-1. IMPORTANCE Herpes simplex virus 1 (HSV-1) can target skin to establish primary infection in the epithelium. While the human skin provides effective barriers against viral invasion under healthy conditions, a prominent example of successful invasion is the disseminated HSV-1 infection in the skin of atopic dermatitis (AD) patients. AD is characterized by impaired epidermal barrier functions, chronic inflammation, and dysbiosis of skin microbiota. We addressed the initial invasion process of HSV-1 in atopic dermatitis skin to understand whether the physical barrier functions are sufficiently disturbed to allow the virus to invade skin and reach its receptors on skin cells. Our results demonstrate that HSV-1 can indeed penetrate and initiate infection in atopic dermatitis skin. Since treatment of skin with IL-4 and IL-13 already resulted in successful invasion, we assume that inflammation-induced barrier defects play an important role for the facilitated access of HSV-1 to its target cells.

Short anagen hair syndrome: association with mono- and biallelic variants in WNT10A and a genetic overlap with male pattern hair loss.

BACKGROUND: Short anagen hair (SAH) is a rare paediatric hair disorder characterized by a short anagen phase, an inability to grow long scalp hair and a negative psychological impact. The genetic basis of SAH is currently unknown. OBJECTIVES: To perform molecular genetic investigations in 48 individuals with a clinical phenotype suggestive of SAH to identify, if any, the genetic basis of this condition. METHODS: Exome sequencing was performed in 27 patients diagnosed with SAH or with a complaint of short, nongrowing hair. The cohort was screened for variants with a minor allele frequency (MAF) < 5% in the general population and a Combined Annotation Dependent Depletion (CADD) score > 15, to identify genes whose variants were enriched in this cohort. Sanger sequencing was used for variant validation and screening of 21 additional individuals with the same clinical diagnosis and their relatives. Genetic association testing of SAH-related variants for male pattern hair loss (MPHL) was performed using UK Biobank data. RESULTS: Analyses revealed that 20 individuals (42%) carried mono- or biallelic pathogenic variants in WNT10A. Rare WNT10A variants are associated with a phenotypic spectrum ranging from no clinical signs to severe ectodermal dysplasia. A significant association was found between WNT10A and SAH, and this was mostly observed in individuals with light-coloured hair and regression of the frontoparietal hairline. Notably, the most frequent variant in the cohort [c.682T>A;p.(Phe228Ile)] was in linkage disequilibrium with four common WNT10A variants, all of which have a known association with MPHL. Using UK Biobank data, our analyses showed that c.682T>A;p.(Phe228Ile) and one other variant identified in the SAH cohort are also associated with MPHL, and partially explain the known associations between WNT10A and MPHL. CONCLUSIONS: Our results suggest that WNT10A is associated with SAH and that SAH has a genetic overlap with the common phenotype MPHL. The presumed shared biologic effect of WNT10A variants in SAH and MPHL is a shortening of the anagen phase. Other factors, such as modifier genes and sex, may also play a role in the clinical manifestation of hair phenotypes associated with the WNT10A locus.

Epidemiology of inherited epidermolysis bullosa in Germany.

BACKGROUND: Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity. OBJECTIVE: Epidemiological data from different countries have been published, but none are available from Germany. METHODS: In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization. RESULTS: Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries. CONCLUSIONS: Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision-making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.

[Viral exanthems in children]. / Virale Exantheme im Kindesalter.

Viral and paraviral exanthems are the most common exanthems in children and are often the reason for a medical evaluation, especially in pediatric primary care and emergency rooms. Familiarity with the various eruptions is important for early diagnosis and patient management as well as minimizing the risk of infection. In this review, we present the newly described entities reactive infectious mucocutaneous eruptions (RIME) and the pediatric inflammatory multisystem syndrome (PIMS). In addition, atypical manifestations of Gianotti-Crosti syndrome and hand, foot, and mouth disease are discussed.

Histopathology-guided mass spectrometry differentiates benign nevi from malignant melanoma.

PURPOSE: Distinguishing benign nevi from malignant melanoma using current histopathological criteria may be very challenging and is one the most difficult areas in dermatopathology. The goal of this study was to identify proteomic differences, which would more reliably differentiate between benign and malignant melanocytic lesions. METHODS: We performed histolpathology - guided mass spectrometry (HGMS) profiling analysis on formalin-fixed, paraffin embedded tissue samples to identify differences at the proteomic level between different types of benign nevi and melanomas. A total of 756 cases, of which 357 cases of melanoma and 399 benign nevi, were included in the study. The specimens originated from both biopsies (376 samples) and tissue microarray (TMA) cores (380 samples). After obtaining mass spectra from each sample, classification models were built using a training set of biopsy specimens from 111 nevi and 100 melanomas. The classification algorithm developed on the training data set was validated on an independent set of 288 nevi and 257 melanomas from both biopsies and TMA cores. RESULTS: In the melanoma cohort, 239/257 (93%) cases classified correctly in the validation set, 3/257 (1.2%) classified incorrectly, and 15/257 (5.8%) classified as indeterminate. In the cohort of nevi, 282/288 (98%) cases classified correctly, 1/288 (0.3%) classified incorrectly, and 5/288 (1.7%) were indeterminate. HGMS showed a sensitivity of 98.76% and specificity of 99.65% in determining benign vs malignant. CONCLUSION: HGMS proteomic analysis is an objective and reliable test with minimal tissue requirements, which can be a helpful ancillary test in the diagnosis of challenging melanocytic lesions.

Primary cutaneous diffuse large B-cell lymphoma, NOS and leg type: Clinical, morphologic and prognostic differences.

BACKGROUND AND OBJECTIVES: Primary cutaneous diffuse large B-cell lymphoma, NOS (PCLBCL/NOS) is a rare PCLBCL. Only few data are available for this tumor. The aim of this study was to identify clinical and/or immunohistochemical markers (in addition to Bcl-2) that characterize PCLBCL/NOS, assist in differentiating it from PCLBCL, leg type (PCLBCL/LT) and help to assess the clinical course/prognosis. PATIENTS AND METHODS: Bcl-2- PCLBCL/NOS) cases (n = 14 were compared with Bcl-2+ PCLBCL/LT cases (n = 29). RESULTS: PCLBCL/NOS patients were younger, predominantly male and had better survival rates than patients with PCLBCL/LT. Patients with PCLBCL/NOS presented more often with larger plaques limited to one or two contiguous body regions, whereas PCLBCL/LT cases often presented with disseminated lesions. Neoplastic cells had a higher proliferation rate (Ki67) in PCLBCL/LT patients. The tumor microenvironment of PCLBCL/NOS had a more prominent CD3+ infiltrate. Overall survival data for the whole cohort (n = 37) revealed that female gender and Bcl-2 expression correlated with a worse survival rate. Bcl-6 expression and centroblastic subtype correlated with better outcomes. None of the other markers studied (e.g. GCB/non-GCB subtype) correlated with survival rate. CONCLUSIONS: PCLBCL/NOS and PCLBCL/LT differ in their clinical behavior and outcomes. Bcl-2 still seems to be the best marker for discriminating between these two subgroups. Bcl-2, female gender and Bcl-6 represent prognostic markers for PCLBCL.

Report of Three Novel Germline CYLD Mutations in Unrelated Patients with Brooke-Spiegler Syndrome, Including Classic Phenotype, Multiple Familial Trichoepitheliomas and Malignant Transformation.

Brooke-Spiegler syndrome is a rare autosomal-dominant genetic disorder characterized by multiple adnexal tumors, including cylindromas, spiradenomas, spiradenocylindromas and trichoepitheliomas. It is caused by germline CYLD mutations commonly leading to a premature stop codon. We here report on 3 novel CYLD mutations in 3 unrelated BSS patients, including the classic phenotype, multiple familial trichoepitheliomas phenotype and malignant transformation. These included c.1821_1826+1delinsCT/L607Ffs*9, c.2666A>T/p.D889V and c.2712delT/p.905Kfs*8. By extending the spectrum of CYLD mutations, better understanding of the molecular mechanisms of BSS can be gained, which might later assist in finding new treatment options.

A multistep approach to the diagnosis of rare genodermatoses.

Recent advances in genetic technology have found their way into clinical dermatology. Approximately one third of all hereditary disorders show characteristic cutaneous findings. Moreover, human skin easily provides samples for studying the mechanisms of genetic mosaicism, as well as the underlying functional defects due to mutated proteins. Diagnosing hereditary skin disorders remains, however, a challenging task due to the rarity of genodermatoses and their diversity, overlapping or heterogeneous phenotypes, huge amount of new information, and complicated nomenclature and classifications. In order to support the clinicians' interest for this complex and rapidly developing field of dermatology, we are going to present a multistep approach with some useful clues for the evaluation of patients suspected of having a genodermatosis.

Ein mehrstufiger Algorithmus zur Diagnose seltener Genodermatosen.

Jüngste Fortschritte der Genforschung haben ihren Weg in die klinische Dermatologie gefunden. Nahezu ein Drittel aller Erbkrankheiten zeigt charakteristische Hautveränderungen. Zudem können Proben menschlicher Haut als Untersuchungsmaterial zur Detektion genetischer Mosaike und der zu Grunde liegenden Defekte eingesetzt werden. Die Diagnose von Genodermatosen bleibt jedoch aufgrund ihrer unterschiedlich ausgeprägten und überlappenden Phänotypen sowie ihrer Seltenheit und Vielzahl neuer Informationen wegen eine Herausforderung für die Kliniker. Um das Interesse für dieses, sich schnell entwickelnde Feld der Dermatologie zu wecken und den Blick für einige seltene Erbkrankheiten zu schärfen, stellen wir in der hiesigen Übersicht einen Algorithmus für die Diagnostik und Evaluierung von Patienten mit fraglichen Genodermatosen vor.

Two cases of primary cutaneous lymphoma with a γ/δ+ phenotype and an indolent course: further evidence of heterogeneity of cutaneous γ/δ+ T-cell lymphomas.

Cutaneous γ/δ+ T-cell lymphoma (CGD-TCL) is a rare but aggressive lymphoma associated with a poor prognosis in most patients. The clinicopathological spectrum is variable including predominantly epidermotropic infiltrates manifesting with patches and plaques or tumors with dermal and/or subcutaneous infiltrates. The diagnosis of CGD-TCL requires the demonstration of a γ/δ+ phenotype by immunohistochemistry. We report 2 patients with epidermotropic cutaneous T-cell lymphomas displaying a γ/δ+ phenotype, but exhibiting an indolent course. In one patient, the clinical presentation was similar to mycosis fungoides in patch and plaque stage, but recurrent blister formation within the lesions was observed accompanied by fever and arthralgias, whereas the second patient presented with 2 localized erosive plaques on the left temple and dense epidermotropic and dermal diffuse and folliculotropic infiltrates of atypical small-to-medium-sized lymphocytes. These cases corroborate the view that expression of a γ/δ+ phenotype in cutaneous T-cell lymphomas per se does not portend a worse prognosis and that CGD-TCL may represent a clinically and prognostically heterogeneous group.

[Inflammatory dermatoses in children and adolescents : Diagnosis and treatment of atopic dermatitis and psoriasis]. / Entzündliche Dermatosen im Kindes- und Jugendalter : Diagnostische und therapeutische Besonderheiten anhand der atopischen Dermatitis und der Psoriasis.

Atopic dermatitis (AD) and psoriasis belong to the most common inflammatory dermatoses that we treat in everyday clinical practice. AD manifests in more than 70% of cases before the age of 5 years. Approximately one-third of psoriasis patients report on onset of disease in the first two decades of life. Here, we are going to review both disorders in the light of pediatric dermatology. We are going to discuss selected subtypes and present clues for further examination with respect to the differential diagnoses and comorbidities. The article provides insight into current therapeutic developments that are relevant for the treatment of children and adolescents.

Mutational Spectrum of the ABCA12 Gene and Genotype-Phenotype Correlation in a Cohort of 64 Patients with Autosomal Recessive Congenital Ichthyosis.

Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in ABCA12, ALOX12B, ALOXE3, CERS3, CYP4F22, NIPAL4, PNPLA1, SDR9C7, SULT2B1, and TGM1. The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in ABCA12. Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in ABCA12. Our study comprises 34 novel mutations in ABCA12, expanding the mutational spectrum of ABCA12-associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.

Further characterization of ATP6V0A2-related autosomal recessive cutis laxa.

Autosomal recessive cutis laxa (ARCL) syndromes are phenotypically overlapping, but genetically heterogeneous disorders. Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type, and wrinkly skin syndrome (WSS). The ATP6V0A2 gene encodes the a2 subunit of the V-type H(+)-ATPase, playing a role in proton translocation, and possibly also in membrane fusion. Here, we describe a highly variable phenotype in 13 patients with ARCL2, including the oldest affected individual described so far, who showed strikingly progressive dysmorphic features and heterotopic calcifications. In these individuals we identified 17 ATP6V0A2 mutations, 14 of which are novel. Furthermore, we demonstrate a localization of ATP6V0A2 at the Golgi-apparatus and a loss of the mutated ATP6V0A2 protein in patients' dermal fibroblasts. Investigation of brefeldin A-induced Golgi collapse in dermal fibroblasts as well as in HeLa cells deficient for ATP6V0A2 revealed a delay, which was absent in cells deficient for the ARCL-associated proteins GORAB or PYCR1. Furthermore, fibroblasts from patients with ATP6V0A2 mutations displayed elevated TGF-ß signalling and increased TGF-ß1 levels in the supernatant. Our current findings expand the genetic and phenotypic spectrum and suggest that, besides the known glycosylation defect, alterations in trafficking and signalling processes are potential key events in the pathogenesis of ATP6V0A2-related ARCL.

Vascular congenital dermatofibrosarcoma protuberans: a new histological variant of dermatofibrosarcoma protuberans.

We describe a case of congenital dermatofibrosarcoma protuberans (DFSP) that masqueraded as a vascular tumor both clinically and histologically. Based on the infiltrative growth pattern, presence of capillary-sized vessels, and spindle cell areas with slit-like vascular spaces and numerous thin-walled vessels at the periphery of the tumor, a kaposiform hemangioendothelioma was initially diagnosed. Strong diffuse CD34 positivity and the extension into the subcutaneous fat with a sieve-like effect prompted the fluorescence in situ hybridization analysis, which demonstrated a reciprocal t(17;22) translocation. According to our knowledge, this is the first report of a vascular histological variant of DFSP. This unique variant represents a potential pitfall for dermatopathologists and underlines the importance of cytogenetic diagnostics in unusual cases of DFSP.

Occurrence of autoantibodies against skin proteins in patients with hereditary epidermolysis bullosa predisposes to development of autoimmune blistering disease.

Skin blistering disorders are associated with inherited defects in proteins involved in the dermal-epidermal adhesion or autoantibodies targeting those proteins. Although blistering in hereditary epidermolysis bullosa (EB) is pathogenetically linked to genetic deficiency of distinct proteins of the epidermis or the dermal-epidermal junction, circulating autoantibodies against these proteins have also been identified in EB patients. So far, autoantibodies have been considered bystanders in EB and active pathogenicity of them in EB has not been disclosed. In sera of a cohort of 258 EB patients, we found by ELISA in 22% of the patients autoantibodies against the bullous pemphigoid antigen BP180. The titers correlated negatively with collagen VII skin expression and positively with disease severity. Among those patients, we identified six (2.33%) with clinical features of an autoimmune bullous disorder (AIBD) and positive indirect immunofluorescence (IIF) staining. In literature, we found four more cases of EB patients developing disease-aggravating AIBD. Co-existence of these two rare skin disorders suggests that EB patients have a predisposition for the development of AIBD. Our work highlights that EB patients with increased itch or blister formation should be evaluated for additional AIBD and repeated screening for changes in autoantibody titers and skin-binding specificities is advised.

Assessment of the Genetic Spectrum of Uncombable Hair Syndrome in a Cohort of 107 Individuals.

Importance: Uncombable hair syndrome (UHS) is a rare hair shaft anomaly that manifests during infancy and is characterized by dry, frizzy, and wiry hair that cannot be combed flat. Only about 100 known cases have been reported so far. Objective: To elucidate the genetic spectrum of UHS. Design, Setting, and Participants: This cohort study includes 107 unrelated index patients with a suspected diagnosis of UHS and family members who were recruited worldwide from January 2013 to December 2021. Participants of all ages, races, and ethnicities were recruited at referral centers or were enrolled on their own initiative following personal contact with the authors. Genetic analyses were conducted in Germany from January 2014 to December 2021. Main Outcomes and Measures: Clinical photographs, Sanger or whole-exome sequencing and array-based genotyping of DNA extracted from blood or saliva samples, and 3-dimensional protein modeling. Descriptive statistics, such as frequency counts, were used to describe the distribution of identified pathogenic variants and genotypes. Results: The genetic characteristics of patients with UHS were established in 80 of 107 (74.8%) index patients (82 [76.6%] female) who carried biallelic pathogenic variants in PADI3, TGM3, or TCHH (ie, genes that encode functionally related hair shaft proteins). Molecular genetic findings from 11 of these 80 individuals were previously published. In 76 (71.0%) individuals, the UHS phenotype were associated with pathogenic variants in PADI3. The 2 most commonly observed PADI3 variants account for 73 (48.0%) and 57 (37.5%) of the 152 variant PADI3 alleles in total, respectively. Two individuals carried pathogenic variants in TGM3, and 2 others carried pathogenic variants in TCHH. Haplotype analyses suggested a founder effect for the 4 most commonly observed pathogenic variants in the PADI3 gene. Conclusions and Relevance: This cohort study extends and gives an overview of the genetic variant spectrum of UHS based on molecular genetic analyses of the largest worldwide collective of affected individuals, to our knowledge. Formerly, a diagnosis of UHS could only be made by physical examination of the patient and confirmed by microscopical examination of the hair shaft. The discovery of pathogenic variants in PADI3, TCHH, and TGM3 may open a new avenue for clinicians and affected individuals by introducing molecular diagnostics for UHS.

Mild recessive dystrophic epidermolysis bullosa associated with two compound heterozygous COL7A1 mutations.

Dystrophic epidermolysis bullosa is a group of inherited skin blistering disorders caused by mutations in the COL7A1 gene coding for type VII collagen. More than 500 different COL7A1 mutations have been detected in dystrophic epidermolysis bullosa to date. Clarification of genotype-phenotype correlations is of particular importance for the development of novel therapeutic approaches. Here we report a female patient with mild dystrophic epidermolysis bullosa harbouring two compound heterozygous COL7A1 mutations, namely the intronic splice site mutation c.3832-2A > G and the glycine substitution p.G1347W. Our data extend the current knowledge on genotype-phenotype correlations in dystrophic epidermolysis bullosa.