IKAROS-how many feathers have you lost: mild and severe phenotypes in IKZF1 deficiency.

Heterozygous germline variants in human IKZF1 encoding for IKAROS define an inborn error of immunity with immunodeficiency, immune dysregulation and risk of malignancy with a broad phenotypic spectrum. Growing evidence of underlying pathophysiological genotype-phenotype correlations helps to improve our understanding of IKAROS-associated diseases. We describe 6 patients from 4 kindreds with two novel IKZF1 variants leading to haploinsufficiency from 3 centers in Germany. We also provide an overview of first symptoms to a final diagnosis including data from the literature.

One gene to rule them all - clinical perspectives of a potent suppressor of cytokine signaling - SOCS1.

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.

[Juvenile localized scleroderma]. / Zirkumskripte Sklerodermie im Kindesalter.

Juvenile scleroderma, often referred to as juvenile localized scleroderma or "morphea", is a rare inflammatory disease of the skin and skin-related structures, accompanied by local sclerosis and tissue fibrosis. Depending on the clinical manifestation, four different subtypes can be defined: limited, generalized, linear, and mixed. To prevent possible sequelae of the disease, the diagnosis should be made as early as possible and therapy should be initiated at specialized centers in multiprofessional pediatric and dermatologic collaboration. In this review, we present the main clinical, laboratory, and therapeutic characteristics of juvenile localized scleroderma and summarize recommendations.

The Medical Action Ontology: A tool for annotating and analyzing treatments and clinical management of human disease.

BACKGROUND: Navigating the clinical literature to determine the optimal clinical management for rare diseases presents significant challenges. We introduce the Medical Action Ontology (MAxO), an ontology specifically designed to organize medical procedures, therapies, and interventions. METHODS: MAxO incorporates logical structures that link MAxO terms to numerous other ontologies within the OBO Foundry. Term development involves a blend of manual and semi-automated processes. Additionally, we have generated annotations detailing diagnostic modalities for specific phenotypic abnormalities defined by the Human Phenotype Ontology (HPO). We introduce a web application, POET, that facilitates MAxO annotations for specific medical actions for diseases using the Mondo Disease Ontology. FINDINGS: MAxO encompasses 1,757 terms spanning a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. These terms annotate phenotypic features associated with specific disease (using HPO and Mondo). Presently, there are over 16,000 MAxO diagnostic annotations that target HPO terms. Through POET, we have created 413 MAxO annotations specifying treatments for 189 rare diseases. CONCLUSIONS: MAxO offers a computational representation of treatments and other actions taken for the clinical management of patients. Its development is closely coupled to Mondo and HPO, broadening the scope of our computational modeling of diseases and phenotypic features. We invite the community to contribute disease annotations using POET (https://poet.jax.org/). MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO). FUNDING: NHGRI 1U24HG011449-01A1 and NHGRI 5RM1HG010860-04.

Rapid and sustained response to JAK inhibition in a child with severe MDA5 + juvenile dermatomyositis.

BACKGROUND: Juvenile dermatomyositis (jDM) is the most common idiopathic inflammatory myopathy of childhood. Amyopathic or hypomyopathic courses have been described. CASE PRESENTATION: We present the case of a 4-year-old patient with MDA5 antibody positive jDM and interstitial lung disease. In our patient, typical symptoms of jDM with classical skin lesions, arthritis, proximal muscle weakness, and ulcerative calcifications were observed. Due to the severity of the disease and the pulmonary changes, therapy with the Janus kinase (JAK) inhibitor ruxolitinib was added to the therapy with corticosteroids, intravenous immunoglobulins (IVIG) and hydroxychloroquine leading to a fast and sustained remission. CONCLUSION: While there is growing evidence that JAK inhibition is a promising therapeutic option in jDM our case report shows that this approach may also be effective in MDA5-positive jDM with high risk features.

The Medical Action Ontology: A Tool for Annotating and Analyzing Treatments and Clinical Management of Human Disease.

Navigating the vast landscape of clinical literature to find optimal treatments and management strategies can be a challenging task, especially for rare diseases. To address this task, we introduce the Medical Action Ontology (MAxO), the first ontology specifically designed to organize medical procedures, therapies, and interventions in a structured way. Currently, MAxO contains 1757 medical action terms added through a combination of manual and semi-automated processes. MAxO was developed with logical structures that make it compatible with several other ontologies within the Open Biological and Biomedical Ontologies (OBO) Foundry. These cover a wide range of biomedical domains, from human anatomy and investigations to the chemical and protein entities involved in biological processes. We have created a database of over 16000 annotations that describe diagnostic modalities for specific phenotypic abnormalities as defined by the Human Phenotype Ontology (HPO). Additionally, 413 annotations are provided for medical actions for 189 rare diseases. We have developed a web application called POET (https://poet.jax.org/) for the community to use to contribute MAxO annotations. MAxO provides a computational representation of treatments and other actions taken for the clinical management of patients. The development of MAxO is closely coupled to the Mondo Disease Ontology (Mondo) and the Human Phenotype Ontology (HPO) and expands the scope of our computational modeling of diseases and phenotypic features to include diagnostics and therapeutic actions. MAxO is available under the open-source CC-BY 4.0 license (https://github.com/monarch-initiative/MAxO).

Update of evidence- and consensus-based guidelines for the treatment of juvenile idiopathic arthritis (JIA) by the German Society of Pediatric and Juvenile Rheumatic Diseases (GKJR): New perspectives on interdisciplinary care.

BACKGROUND: New therapeutic strategies for juvenile idiopathic arthritis (JIA) have evolved within the past ten years, and as a result, an update of the 2011 recommendations of the German management guidelines was initiated. METHODS: A systemic literature review was performed, overarching principles were proposed and pre-selected via an online survey followed by two multidisciplinary consensus conferences. Pharmacological and non-pharmacological treatments were discussed, statements were proposed and ultimately agreed upon by nominal group technique (NGT). RESULTS: 12 overarching therapeutic principles, as well as 9 recommendations on pharmacological and 5 on non-pharmacological treatments for JIA were agreed upon. CONCLUSION: This report summarizes the recent update of the interdisciplinary, consensus-based German guidelines on the management of JIA. The multi- and interdisciplinary participation of all caregivers was central for this patient-focused update. With these guidelines, physicians can choose an evidence-based approach, which allows better tailored treatment in this vulnerable cohort of children and adolescents.

Touch aversion in patients with interpersonal traumatization.

BACKGROUND: Interpersonal touch is a key aspect of human interaction and a usually very comforting experience. For patients suffering from posttraumatic stress disorders (PTSD) caused by interpersonal traumatization, such touch is affectively ambiguous. METHODS: In two studies, we investigated the experience and neural processing of various types of interpersonal and impersonal touch in patients as compared with healthy controls. RESULTS: Patients strongly disliked show, interpersonal skin-to-skin stroking, while controls appreciated this kind of touch. No group differences were observed for ratings of impersonal touch. Similarly, the neural activation differed between groups for interpersonal, but not for impersonal touch. The interpersonal touch aversion in patients was accompanied by enhanced blood-oxygen-level-dependent response in the superior temporal gyrus and by a pronounced reduction of response in the hippocampus. This reduction was significantly correlated to symptoms of negative alterations and arousal within the patients. CONCLUSION: We interpret the hippocampal suppression as an attempt to control traumatic memories, evoked by interpersonal touch. This mechanism may maintain the aversion of interpersonal touch in patients with interpersonal trauma-related PTSD.

Deactivation of default mode network during touch.

Interpersonal touch possesses a strong affective component, which immediately evokes attention. The neural processing of such touch is moderated by specialized C-tactile nerve fibers in the periphery and results in central activation of somatosensory areas as well as regions involved in social processing, such as the superior temporal gyrus (STG). In the present functional neuroimaging investigation, we tested the hypothesis that the attention grasping effect of interpersonal touch as compared to impersonal touch is reflected in a more-pronounced deactivation of the default mode network (DMN). Using functional magnetic resonance imaging, we investigated the neural processing of interpersonal relative to impersonal touch conditions that were furthermore modulated by stroking velocity in order to target c-tactile nerve fibers to a different extent. A sample of 30 healthy participants (19 women, mean age 40.5 years) was investigated. In the impersonal touch, participants were stroked with a brush on the forearm. In the interpersonal touch condition, the experimenter performed the stroking with the palm of his hand. Interpersonal touch was rated as more pleasant and intense than impersonal touch and led to a stronger blood oxygen level dependent (BOLD) signal increase in the somatosensory cortex SII extending to the superior temporal cortex. Over all touch conditions, this activation was coupled in time to the deactivation of prominent nodes of the DMN. Although deactivation of the DMN was most pronounced for interpersonal touch conditions, the direct comparison did not show significant differences in DMN deactivation between interpersonal and impersonal touch or between different stroking velocities. We therefore conclude that all applied touch conditions deactivate the DMN and the strong connection to areas which code the contextual and social characteristics of affective touch may explain the attention grasping effect of touch.

Reduced olfactory bulb volume in depression-A structural moderator analysis.

BACKGROUND: Removal of the olfactory bulb (OB) leads to depression like behavior in rodents. A link between depression and olfactory function is also established in humans. We hypothesized that the human OB volume relates to depressive state and tested whether such a potential coherence is moderated by structural alterations in other brain regions. METHODS: Eighty-three participants (32 patients with major depression and 51 matched healthy controls) underwent structural MR scanning. Individual OB volumes were compared between patients and controls and the impact of depression and comorbidity was analyzed with multiple regression analysis. Whole-brain voxel-based morphometry revealed structures co-varying with both depressive state and OB volume. RESULTS: The OB volume of patients was significantly reduced and this reduction averaged out at 17% compared to the controls. The OB volume was correlated to the volume of the insula, superior temporal cortex, and amygdala. The independent variables of depression (ß = -.37), age (ß = -.25), and gender (ß = -.40) explained the individual OB volume variation (R2 = .37). The correlation between OB volume and depression was moderated by volumetric reductions in a cluster including the insula and superior temporal gyrus (STG). CONCLUSIONS: The OB volume relates to depression in humans and to the volume of structures which are critical for salience detection. We assume that a reduced OB volume causes diminished neural olfactory input which facilitates volume reduction in the insula and STG. The OB volume may hence constitute a factor of vulnerability to depression. Olfactory-based deep brain stimulation is discussed as a future therapeutic approach.