BACKGROUND:Hereditary ichthyoses are rare, etiologically and clinically heterogeneous epidermal keratinization disorders that are characterized by excessive dryness with scaling of the skin and in some cases increased palmoplantar keratinization. Additional inflammation is common and there are forms associated with blistering. In terms of differential diagnosis, ichthyoses with associated erythroderma in particular must be distinguished from primary atopic diseases with immunodeficiency. AIM:The aim is to provide basic knowledge of the classification and nomenclature of ichthyoses and of current guideline-based and approved therapies. Readers should also be made aware of the difficulties of treating this rare skin disease in children and adolescents with only a few approved therapies. New and innovative treatment options are described and thereafter the reader should be able to confidently identify potential patients for approved and novel therapies. MATERIALS AND METHODS:The current guidelines as well as the current literature and expert consensus on systemic therapies for ichthyosis with a focus on pediatric patients are discussed. RESULTS:Precise phenotyping, endotyping and the inclusion of the patient's expectations with regard to therapy currently allow comprehensive treatment to alleviate symptoms with good interdisciplinary cooperation. In the absence of causal therapy options, hereditary ichthyosis usually requires lifelong symptomatic individualized therapy. The basis of therapy is local therapy. Acitretin is currently the only approved systemic therapy. Pathophysiologically driven and therefore personalized and targeted therapies, in the form of topical replacement proteins or lipids, small molecules with a variety of target structures and biologics to address inflammation, are the focus of new therapeutic options. Causal therapeutic approaches, such as gene therapies, are currently under development.

Hereditäre Ichthyosen sind seltene, ätiologisch und klinisch heterogene epidermale Verhornungsstörungen, denen eine übermäßige Trockenheit mit Schuppung der Haut und in einigen Fällen eine vermehrte palmoplantare Verhornung gemein ist. Eine damit einhergehende Inflammation ist häufig, und es gibt Formen, die mit Blasenbildung assoziiert sind. Differenzialdiagnostisch sind insbesondere die Ichthyosen mit assoziierter Erythrodermie von den primären atopischen Erkrankungen mit Immundefizienz abzugrenzen. Ziel der Arbeit ist die Vermittlung einer Grundkenntnis zur Einteilung und Nomenklatur der Ichthyosen und zu aktuellen leitliniengerechten und zugelassenen Therapien. Die Leser:innen sollen außerdem über die Schwierigkeiten der Behandlung dieser seltenen Hauterkrankung bei Kindern und Jugendlichen mit nur wenigen zugelassenen Therapien aufmerksam gemacht werden. Die Leser:innen sollten neue und innovative Therapiemöglichkeiten kennenlernen und mögliche Patient:innen für zugelassene und neuartige Therapien sicher identifizieren können. Im Folgenden wird auf die aktuellen Leitlinien sowie die aktuelle Literatur und Expert:innenkonsens zu Systemtherapien bei Ichthyose mit dem Schwerpunkt auf pädiatrischen Patient:innen eingegangen. Die genaue Phänotypisierung, Endotypisierung sowie der Einbezug der Erwartungshaltung der Patient:innen in Bezug auf die Therapie erlauben derzeit – bei guter interdisziplinärer Zusammenarbeit – eine umfassende Therapie zur Symptomlinderung. In Ermangelung kausaler Therapiemöglichkeiten ist bei hereditärer Ichthyose lebenslang eine symptomatische individualisierte Therapie notwendig. Die Basis der Therapie stellt die Lokaltherapie dar. Acitretin ist derzeit die einzige zugelassene Systemtherapie. Pathophysiologisch getriebene und damit möglichst personalisierte und zielgerichtete Therapien sind in Form von topischen Ersatzproteinen oder -lipiden, „small molecules“ mit einer Vielzahl von Zielstrukturen und Biologika zur Adressierung der Entzündung im Fokus neuer Therapieoptionen. Kausale Therapieansätze wie Gentherapien befinden sich in der Entwicklung.

Impfgranulome sind eine häufige (0,3–1

BACKGROUND:Vaccine granulomas are a common (0.3-1%) adverse event (AE) of (accidentally) subcutaneously administered vaccines and specific immunotherapies containing aluminum conjugates. The clinical symptoms with persistent itching subcutaneous nodules, predominantly affect infants and young children on the lateral thigh. AIM:To sensitize dermatologists to recognize this common and harmless vaccination AE, in order to prevent invasive diagnostics and confusion among parents and physicians. MATERIALS AND METHODS:Retrospective analysis of 13 children consulting pediatric dermatology between 2019 and 2023. Identification of diagnostic criteria and guidelines for action, based on the literature. RESULTS AND CONCLUSION:In all, 13 children (9 boys, 4 girls) with subcutaneous indolent but itching nodules at the vaccination sites (11 on the thighs, 2 on the upper arms) with a latency of weeks to months were retrospectively evaluated. The children were vaccinated according to German STIKO ("Ständige Impfkommission") recommendations. Only inactivated vaccines contain aluminum. The documented occurrence of the first vaccination granulomas was between the 12th and 36th month of life. Regarding the STIKO vaccination calendar, the third immunization with the hexavalent inactivated vaccine coincides with the first administration of the live measles, mumps and rubella (MMR) vaccine (varicella (V)). This may incorrectly lead to the assumption that the live vaccine was the cause of granuloma development. Aluminum conjugation appears to be a central trigger of the granulomas; further susceptibility factors are largely unknown. Diagnosis of sensitization to aluminum through epicutaneous testing has no practical impact and is, therefore, not routinely recommended. After weeks to years, granulomas spontaneously regress.

Background Genetic diseases leading to skin fragility are clinically and genetically heterogeneous. Dermatologists and pediatricians should be familiar with the variability of manifestations and manifestation age, in order to differentiate these rare diseases from more common causes of blistering, such as infectious (impetigo contagiosa, herpes infection) or traumatic causes (burns, scalds). This is essential to initiate appropriate diagnostic measures, provide information on treatment and prevention and to refer to specialized centers. Objectives The classification of the diseases discussed here is based on the clinical appearance, the histologic cleavage level, and genetic alterations. These diseases are all rare and pathogenetically only partially understood. Treatment methods are mostly symptomatic; causal therapies are the exception. Thanks to advances in mutation detection methods and the assumption of costs for massive parallel sequencing (since 2021) by health insurance companies, rare diseases have moved from the focus of academic research into everyday clinical practice. Due to the rarity, variability of the phenotype and, in many cases, high need for care, it is important in everyday clinical practice to be able to apply a pathway for suspected diagnoses and to work together with specialized colleagues and care centers. Materials and methods This study provides an overview of genetic diseases with skin fragility in childhood. Results and discussion Knowledge of the underlying mechanisms leading to skin fragility in childhood can help to recognize rare differential diagnoses from more common infectious and traumatic causes of blistering. This is necessary to enable adequate treatment and referral to specialized care centers and colleagues.

Biologics are approved for various dermatologic, allergic, rheumatic, and gastroenterologic inflammatory diseases, as well as for numerous malignancies. The dermatologic adverse events from treatment with biologics may resemble primary inflammatory diseases but differ in pathogenesis. In this article, we describe five different pathogenic mechanisms of dermatologic adverse events. By studying these mechanisms, we hope to gain valuable insights into the pathogenesis of primary inflammatory diseases. In addition, in this article, we provide recommendations for the treatment and management of the dermatological adverse events induced by biologics.

Genetische Erkrankungen, die zu Hautfragilität führen, sind sowohl klinisch als auch genetisch heterogen. Ein Überblick über Manifestationsformen und -alter sollte jedem Haut- und Kinderarzt geläufig sein, um diese seltenen Erkrankungen von häufigeren Ursachen für Blasenbildung wie infektiöse (Impetigo contagiosa, Herpesinfektion) und traumatische (Verbrennungen, Verbrühungen) Ursachen zu unterscheiden, entsprechende diagnostische Maßnahmen einzuleiten, zu therapeutischen oder vorbeugenden Maßnahmen zu informieren bzw. die Zuweisung zu spezialisierten Zentren vorzunehmen. Die Systematik der hier behandelten Erkrankungen basiert einerseits auf dem klinischen Erscheinungsbild abhängig von der Spaltbildungsebene, andererseits auf den bekannten genetischen Alterationen. Diese Erkrankungen sind allesamt selten und sind pathogenetisch teilweise nur zum Teil verstanden. Therapieverfahren sind meist symptomatisch, kausale Therapien sind die Ausnahme. Durch Fortschritt der Methoden zum Mutationsnachweis sowie die Kostenübernahme von massiver paralleler Sequenzierung (seit 2021) durch die Krankenkassen sind seltene Erkrankungen aus dem akademischen Forschungsfokus mehr in den klinischen Alltag gelangt. Aufgrund der Seltenheit und Variabilität des Phänotyps sowie des in vielen Fällen hohen Versorgungsbedarfs ist es wichtig, im klinischen Alltag einen Handlungspfad bei entsprechenden Verdachtsdiagnosen anwenden zu können und mit spezialisierten Kollegen und Versorgungszentren zusammenzuarbeiten. Diese Arbeit gibt einen systematischen Überblick über den „Formenkreis“ der genetischen Erkrankungen mit Hautfragilität im Kindesalter. Durch Kenntnisse der zugrunde liegenden Mechanismen, die zu Hautfragilität im Kindesalter führen, können seltene Differenzialdiagnosen von häufigeren infektiösen und traumatischen Ursachen der Blasenbildung leichter erkannt werden. Dies ist notwendig, um eine adäquate Therapie und Anbindung an spezialisierte Versorgungszentren und Kollegen zu ermöglichen.

ZusammenfassungBiologika sind für verschiedene Entzündungskrankheiten aus Dermatologie, Allergologie, Rheumatologie und Gastroenterologie sowie für zahlreiche maligne Erkrankungen zugelassen. Dermatologische unerwünschte Arzneimittelwirkungen durch Biologika können primären entzündlichen Dermatosen ähneln, unterscheiden sich von ihnen jedoch in ihrer Pathogenese. In diesem Artikel beschreiben wir die fünf verschiedenen Pathomechanismen dermatologischer, unerwünschter Arzneimittelwirkungen durch Biologika. Durch besseres Verständnis dieser Mechanismen erhoffen wir uns wertvolle Einblicke in die Pathogenese primärer Entzündungskrankheiten zu gewinnen. Außerdem geben wir in diesem Artikel Empfehlungen für die Behandlung und das Management der durch Biologika ausgelösten dermatologischen unerwünschten Arzneimittelwirkungen.

Cutaneous squamous cell carcinoma (cSCC) is a major complication of recessive dystrophic epidermolysis bullosa (RDEB) that has high morbidity and mortality rates and unmet therapeutic needs. The aim of this study was to evaluate the molecular pattern of cSCC and the clinical course of immunotherapy in 2 RDEB patients with multiple advanced cSCC. Clinical course and disease staging were evaluated retrospectively. The tumour tissues were subjected to immunohistochemical staining. DNA from the blood and cSCC samples was subjected to massive parallel sequencing, and somatic mutations were determined. Patient 1 survived for over 2 years as disease control was achieved with cemiplimab and intralesional interleukin-2. The target advanced cSCC demonstrated a high rate of somatic mutations and strong expression of the immune markers, indoleamine 2,3-dioxygenase, programmed cell death protein ligand 1, and lymphocyte-activation gene 3. The patient ultimately succumbed to complications of oesophageal carcinoma. Patient 2 had an undifferentiated cSCC on the foot, which displayed a low mutational burden and did not express immune markers. The tumour progressed quickly even with cemiplimab therapy. These 2 cases underscore the challenges of cSCC treatment for RDEB. Multiple tumours with different molecular and immune profiles occur concomitantly or sequentially, and surgical excision is not always possible because of the anatomical and tissue constraints imposed by the disease itself. In conclusion, programmed cell death protein 1 inhibitors are approved and effective in treating metastatic and locally advanced cSCC. Our experience and the literature suggest that cemiplimab is an option in patients with RDEB if surgery is not. Somatic mutations and the immune microenvironment should be characterized to predict therapeutic response, particularly in aggressive undifferentiated tumours.

Importance:Kidney-urinary tract (KUT) manifestations cause substantial morbidity in patients with junctional epidermolysis bullosa (JEB), but the spectrum of disease severity and the clinical course have been poorly characterized.Objective:To examine in a large cohort of patients with intermediate JEB the KUT manifestations, diagnostic and therapeutic procedures, genotype-phenotype correlations, and outcomes as a basis for recommendations, prognosis, and management.Design, Setting, and Participants:In this retrospective, longitudinal case series study, 99 patients with a diagnosis of JEB based on clinical and genetic findings who were treated in a single dermatology department in Freiburg, Germany, were assessed during an 18-year period (January 1, 2003, to December 31, 2021). Clinical, laboratory, and molecular genetic parameters were extracted from patients' medical records.Main Outcomes and Measures:Clinical characteristics, natural history, management of KUT manifestations, and genotype-phenotype correlations of intermediate JEB.Results:Of the 183 patients with JEB, 99 (54%) had intermediate JEB and were included in this cohort. The cohort included 49 female patients and 50 male patients. None of 49 female patients and 15 of 50 male patients had KUT involvement affecting different levels of the urinary tract, resulting in a prevalence of 30% for males; thus, the overall prevalence was 15%. The mean age at onset of KUT manifestations was 6.9 years (range, first weeks of life to 20 years; age was not available for 1 patient). Median follow-up after diagnosis of KUT involvement was 13 years (range, 3 months to 54 years). Patients with laminin 332 or integrin β4 deficiency had at least 1 missense or splice site genetic variant, leading to residual expression of laminin 332 or integrin α6β4, respectively. Severity of KUT complications did not correlate with the extent of skin involvement but with the affected protein.Conclusions and Relevance:Physicians and patients with JEB should be aware of the risk for KUT involvement in intermediate JEB, and physicians should apply interdisciplinary and individualized diagnostic and therapeutic procedures for management of these complications. Because this disorder is so rare, multicenter studies are required to make general recommendations.

We describe a case of a 65-year old patient presenting with unusual mucocutaneous melanocytic proliferations of a Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) imitating a multifocal melanoma in situ, which improved dramatically after plasmapheresis. The patient first presented at the dermatology department due to rapidly evolving brown and black macules on the glans penis. Further skin involvement of the perineal and perianal region, mamillae and oral mucosa was stated. Histology from a penile biopsy was compatible with a melanoma in situ. Due to the distribution pattern and elevated serum tumor marker S100B, metastatic melanoma was considered. Staging examinations using PET-CT scan however, revealed a lung tumor, later confirmed as a Non-small-cell lung cancer (NSCLC). Primary radio chemotherapy was initiated to treat NSCLC. Shortly after initiation of radio chemotherapy the patient developed massive vision impairment and a NSCLC-associated BDUMP was diagnosed which led to the correct classification of melanocytic skin lesions as mucocutaneous BDUMP manifestation. Plasmapheresis was started resulting in a rapid improvement of vision starting ten days after the first plasmapheresis. In contrast skin manifestations started to disappear with a marked delay 4 months after the last plasmapheresis cycle. This case highlights the importance of memorizing multiple rapidly progressing melanocytic skin and/or mucous membrane spots together with visual impairment as a possible paraneoplastic BDUMP that needs a fundamentally different therapeutic approach compared to multifocal melanoma in situ. What is already known about this topic? Bilateral Diffuse Uveal Melanocytic Proliferation (BDUMP) is a paraneoplastic syndrome with melanocytic uveal proliferation leading to vision impairment. Extraocular manifestation is rare, mainly affect the subepidermal compartment and is hard to treat. Plasmapheresis has been shown to be an effective treatment mainly for vision improvement in some but not all cases. What does this study add? Our BDUMP case with widespread skin and mucosal involvement initially mimicked a multifocal melanoma in situ and showed an excellent treatment response to plasmapheresis. Improvement of mucocutaneous lesions has not been documented well in the literature so far. We show a more than one year lasting follow up still underlining the beneficial effect of plasmapheresis in this case. In-vitro data supports the hypothesis that plasma exchange eliminates a “Cultured melanocyte elongation and proliferation (CMEP)” factor out of patient blood leading to decreased melanocyte proliferation shown numerically in-vitro and clinically in-vivo. Our case clearly indicates that before establishing a definite diagnosis and therapy in patients with rapidly evolving melanocytic skin and/or mucosal lesions BDUMP mimicking multifocal melanoma in situ should be considered making a thorough diagnostic workup mandatory.