Jorge Frank

Zusammenfassung: Mycoplasma pneumoniae (MP) ist ein häufiger Erreger verschiedener Infektionen bei Kindern und Jugendlichen, die vor allem die Atemwege betreffen. Neben atypischen Pneumonien kann MP auch zu extrapulmonalen Manifestationen führen, darunter mukokutane, hämatologische, neurologische, kardiale und gastrointestinale Symptome. Diese extrapulmonalen Manifestationen werden oft übersehen, was die Diagnose und Behandlung erschwert. Hier beschreiben wir das Spektrum der durch MP verursachten kutanen und nichtkutanen Erkrankungen im Kindesalter und konzentrieren uns dabei auf die Pathophysiologie, die klinischen Merkmale und die Behandlung mukokutaner Manifestationen.

Summary: Mycoplasma pneumoniae (MP) is a common pathogen responsible for diverse infections in children and adolescents, primarily affecting the respiratory tract. Besides causing atypical pneumonia, MP can also lead to extrapulmonary manifestations, including mucocutaneous, hematological, neurological, cardiac, and gastrointestinal symptoms. These extrapulmonary manifestations are often overlooked, complicating diagnosis and management. Here, we delineate the spectrum of cutaneous and non‐cutaneous diseases caused by MP in children, focusing on the pathophysiology, clinical features, and treatment of mucocutaneous manifestations.

Dowling–Degos disease (DDD) is a rare, genetically heterogeneous pigmentation disorder with an autosomal dominant pattern of inheritance. While DDD shows wide clinical variability, a defining feature is reticulate hyperpigmentation, which typically emerges after puberty and worsens progressively thereafter. Additionally, affected individuals may experience symptoms such as itching, burning and/or inflammatory changes to the skin. DDD also shows histopathological diversity. However, hallmark features include thinning of the suprapapillary epidermis and elongation of the rete ridges with melanin deposition in the basal layers. While early researchers assumed that DDD was attributable to a single disease gene, and predominantly affected the flexural areas, over the last 20 years understanding of DDD has expanded substantially. To date, five causal genes have been identified: KRT5, POFUT1, POGLUT1, PSENEN and GLMN. Each gene is associated with frequently recurring phenotypic characteristics. In terms of hyperpigmentation, pathogenic variants in KRT5, POFUT1 and POGLUT1 primarily affect intertriginous regions, acrogenital areas and the extremities, respectively. Pathogenic PSENEN variants increase susceptibility to hidradenitis suppurativa, particularly in predisposed individuals, while GLMN variants may be associated with a distinctive clinical feature, namely glomuvenous malformations. Despite advances in our understanding of the genetic architecture of DDD, no causal treatment is yet available. While symptomatic therapies such as ablative laser treatment have shown promise in terms of reducing pigmentation, potential risks have also been identified, including postinflammatory hyperpigmentation. This review outlines the path that led to current understanding of the complex genetic basis of DDD. On the basis of this, we propose an approach for clinical subphenotyping in patients with suspected DDD, which will facilitate targeted genetic analysis based on observed genotype–phenotype correlations. Furthermore, the review addresses key issues of DDD, including the debated term ‘Galli–Galli disease’, the psychosocial impact and treatment of DDD, as well as emerging insights into Notch signalling as a pathogenic mechanism.

Dowling–Degos disease (DDD) is a rare hyperpigmentation disorder with autosomal-dominant inheritance. To date, work by our group and others has identified a total of four DDD sub-phenotypes, which arise secondary to variants in KRT5, POFUT1, POGLUT1 and PSENEN. We postulate that GLMN is a novel fifth gene for DDD that contributes to a hitherto unrecognized DDD sub-phenotype.

Anastasis is a phenomenon observed in cancer cells, where cells that have initiated apoptosis are able to recover and survive. This molecular event is increasingly recognized as a potential contributor to cancer metastasis, facilitating the survival and migration of tumor cells. Nevertheless, the identification of a specific surface marker for detecting cancer cells in anastasis remained elusive. Here we report our observation that the cell surface expression of CD24 is preferentially enriched in a non-adherent FSC^lowSSC^high melanoma subpopulation, which is generally considered a non-viable population in cultivated melanoma cell lines. More than 90% of non-adherent FSC^lowSSC^highCD24^+ve metastatic melanoma cells exhibited bonafide features of apoptosis on the cell surface and in the nucleus, marking apoptotic or seemingly apoptotic subpopulations of the in vitro cultivated metastatic melanoma cell lines. Unexpectedly, however, the CD24^+ve subpopulation, despite being apoptotic, showed evidence of metabolic activity and exhibited proliferative capacities, including anchorage-independent growth, when inoculated in soft agarose growth medium. These findings indicate that apoptotic FSC^lowSSC^highCD24^+ve melanoma subpopulations are capable of reversing the progression of apoptosis. We report CD24 as the first novel cell surface marker for anastasis in melanoma cells.

Zusammenfassung Die Porphyrien sind vorwiegend genetisch bedingte metabolische Erkrankungen, die auf einer Dysregulation spezifischer Enzyme der Porphyrin-Häm-Biosynthese beruhen. Durch die enzymatische Dysfunktion kommt es zur Bildung und Exkretion intermediärer Stoffwechselprodukte in Form von Porphyrinen und/oder deren Vorstufen δ‑Aminolävulinsäure und Porphobilinogen, die zyto- und gewebetoxische Eigenschaften haben. Klinisch sind die Porphyrien äußerst vielgestaltig, wobei die Symptome von Hautveränderungen an den lichtexponierten Körperarealen bis hin zu potenziell lebensbedrohlichen neuroviszeralen Attacken reichen. Diagnostisch kommen biochemische Untersuchungen in Urin, Blut und Stuhl zum Einsatz, die durch molekulargenetische Analysen ergänzt werden können. Die Therapie der verschiedenen Porphyrieformen ist komplex und erfordert häufig eine enge interdisziplinäre Zusammenarbeit verschiedener medizinischer Fachrichtungen.

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by well-demarcated erythematous patches and hyperkeratotic plaques. EKV is most often transmitted in an autosomal dominant manner. Until recently, only mutations in connexins such as GJB3 (connexin 31), GJB4 (connexin 30.3), and occasionally GJA1 (connexin 43) were known to cause EKV. In recent years, mutations in other genes have been described as rare causes of EKV, including the genes KDSR, KRT83, and TRPM4. Features of the EKV phenotype can also appear with other genodermatoses: for example, in Netherton syndrome, which hampers correct diagnosis. However, in autosomal recessive congenital ichthyosis (ARCI), an EKV phenotype has rarely been described. Here, we report on seven patients who clinically show a clear EKV phenotype, but in whom molecular genetic analysis revealed biallelic mutations in ABCA12, which is why the patients are classified in the ARCI group. Our study indicates that ARCI should be considered as a differential diagnosis in EKV.

Porphyrias, as most rare diseases, are characterized by complexity and scarcity of knowledge. A national registry in one of the largest European populations that prospectively collects longitudinal clinical and laboratory data are an important and effective tool to close this gap. The German Porphyria Registry (PoReGer) was founded by four centers with longstanding expertise in the field of porphyrias and rare diseases (Charité–Universitätsmedizin Berlin, Porphyria Center Saxony Chemnitz, University Medical Center Hamburg-Eppendorf, University Medical Center Göttingen) and the German reference laboratory for porphyria, and is supported by the largest German porphyria patient organization. A specified data matrix for three subgroups (acute, chronic blistering cutaneous, acute non-blistering cutaneous) includes data on demographics, specific porphyria-related symptoms, clinical course, general medical history, necessary follow-up assessments (including laboratory and imaging results), symptomatic and disease-modifying therapies, and side-effects. Additionally, the registry includes patient-reported outcome measures on quality of life, depression, and fatigue. PoReGer aims to broaden and deepen the understanding on all porphyria-related subjects. We expect these data to significantly improve the management and care of porphyria patients. Additionally, the data can be used for educational purposes to increase awareness, for the planning of healthcare services, and for machine learning algorithms for early detection of porphyrias.