Publications by authors named "Catharina Schuetz"

Article Synopsis
  • Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is a rare genetic disease that disrupts the immune system, causing various symptoms that usually begin in childhood.
  • In a phase III clinical trial, a drug called leniolisib was shown to effectively reduce lymph node swelling and increase naïve B cell levels in both adolescents and adults with APDS compared to those given a placebo.
  • The study found that leniolisib was well-tolerated across age groups and suggests it could be a promising treatment option for managing APDS by addressing the underlying cause rather than just the symptoms.
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Background: Research for personalised therapies concerning the Systemic Inflammatory Response Syndrome (SIRS) in children involves the utilisation of OMICS technologies and Artificial Intelligence (AI).

Methods: To identify specific ethical challenges through the perspective of healthcare professionals, we conducted 10 semi-structured interviews. The development of interview questions for the interviews was preceded by a systematic review of the scientific literature.

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Article Synopsis
  • The GA4GH Phenopacket Schema, released in 2022 and approved as a standard by ISO, allows the sharing of clinical and genomic data, including phenotypic descriptions and genetic information, to aid in genomic diagnostics.
  • Phenopacket Store Version 0.1.19 offers a collection of 6668 phenopackets linked to various diseases and genes, making it a crucial resource for testing algorithms and software in genomic research.
  • This collection represents the first extensive case-level, standardized phenotypic information sourced from medical literature, supporting advancements in diagnostic genomics and machine learning applications.
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  • The study examines a female carrier of a genetic mutation in the IKBKG gene, which is linked to conditions like ectodermal dysplasia and ectodermal dysplasia and immunodeficiency in males and incontinentia pigmenti (IP) in females, leading to a condition called NEMO-NDAS, characterized by autoinflammatory symptoms.
  • Researchers used various techniques, including RT-PCR and nanopore sequencing, to analyze gene expression and protein levels in the patient and her mother compared to healthy controls.
  • Findings revealed that the patient exhibited autoinflammatory symptoms without immunodeficiency, attributed to a non-skewed X-inactivation, alternative splicing of the IKBKG gene, and increased levels of
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Article Synopsis
  • * A 3-year study, TRANSLATE NAMSE, analyzed data from 1,577 patients, revealing that 32% received molecular diagnoses involving 370 distinct causes, primarily uncommon.
  • * The research showed that combining next-generation sequencing with advanced phenotyping methods improved diagnostic efficiency and helped identify new genotype-phenotype associations, particularly in neurodevelopmental disorders.
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Heterozygous germline variants in human 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 variants leading to haploinsufficiency from 3 centers in Germany.

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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.

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Objective: Interim analysis of the RELIANCE registry, an on-going, non-interventional, open-label, multicentre, prospective study evaluating the long-term safety, dosing regimens and effectiveness of canakinumab in patients with cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), tumour-necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate-kinase deficiency (MKD)/hyperimmunoglobulin-D syndrome (HIDS).

Methods: From September 2017 for patients with CAPS, and June 2018 for patients with FMF, TRAPS or MKD/HIDS, the registry enrolled paediatric (aged ≥2 years) and adult patients (aged ≥18 years) receiving canakinumab as part of their routine medical care. Safety, canakinumab dose, disease activity and quality of life outcome measures were evaluated at baseline and every 6 months until end of study visit.

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The caspase activation and recruitment domain 11 (CARD11) gene encodes a scaffold protein required for lymphocyte antigen receptor signaling. Dominant-negative, loss-of-function (LOF) pathogenic variants in CARD11 result in CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease. Patients with CADINS suffer with severe atopic manifestations including atopic dermatitis, food allergy, and chronic spontaneous urticaria in addition to recurrent infections and autoimmunity.

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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.

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The Human Phenotype Ontology (HPO) is a widely used resource that comprehensively organizes and defines the phenotypic features of human disease, enabling computational inference and supporting genomic and phenotypic analyses through semantic similarity and machine learning algorithms. The HPO has widespread applications in clinical diagnostics and translational research, including genomic diagnostics, gene-disease discovery, and cohort analytics. In recent years, groups around the world have developed translations of the HPO from English to other languages, and the HPO browser has been internationalized, allowing users to view HPO term labels and in many cases synonyms and definitions in ten languages in addition to English.

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Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs), conferring a predisposition to life-threatening COVID-19 pneumonia. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52/IκBδ).

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Article Synopsis
  • Inborn errors of immunity (IEI) with dysregulated JAK/STAT signaling can lead to immune dysfunction and infections, and while hematopoietic stem cell transplantation (HSCT) is a potential cure, initial outcomes were not promising.
  • This study evaluated the effectiveness of off-label JAK inhibitors (JAKi) as a treatment option for patients with hyperactive JAK/STAT signaling disorders at various European medical centers.
  • Results showed that 87% of patients with STAT1 gain of function and 90% with STAT3 gain of function saw symptom improvement, with mild adverse events reported; a significant portion of patients continued JAKi treatment successfully, and some proceeded to HSCT, achieving a 91%
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Introduction: The diagnosis and treatment of inborn errors of immunity (IEI) is a major challenge as the individual conditions are rare and often characterized by a variety of symptoms, which are often non disease-specific. Ideally, patients are treated in dedicated centers by physicians who specialize in the management of primary immune disorders. In this study, we used the example of Activated PI3Kδ syndrome (APDS), a rare IEI with an estimated prevalence of 1:1,000,000.

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Article Synopsis
  • Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is a genetic condition characterized by overactive PI3Kδ, leading to immune issues like recurrent infections and autoimmunity.
  • Leniolisib, a targeted inhibitor of PI3Kδ, showed promise in improving immune function and reducing complications like lymphoproliferation in patients with APDS over a 12-week period.
  • An ongoing study involving 37 patients showed that most experienced mild to moderate side effects, but leniolisib significantly decreased infection rates and improved overall health, with many patients needing less immunoglobulin therapy.
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X-linked chronic granulomatous disease (XL-CGD) is an inherited disorder of superoxide production, causing failure to generate the oxidative burst in phagocytes. It is characterized by invasive bacterial and fungal infections, inflammation, and chronic autoimmune disease. While XL-CGD carriers were previously assumed to be healthy, a range of clinical manifestations with significant morbidity have recently been described in a subgroup of carriers with impaired neutrophil oxidative burst due to skewed lyonization.

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Activated PI3Kδ syndrome (APDS) is a rare inborn error of immunity (IEI) characterized primarily by frequent infections, lymphoproliferation and autoimmunity. Since its initial description in 2013, APDS has become part of the growing group of nearly 500 IEIs affecting various components of the immune system. The two subtypes of APDS - APDS1 and APDS2 - are caused by variants in the and genes, respectively.

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Background: Genetic defects in components of inflammasomes can cause autoinflammation. Biallelic loss-of-function mutations in dipeptidyl peptidase 9 (DPP9), a negative regulator of the NLRP1 and CARD8 inflammasomes, have recently been shown to cause an inborn error of immunity characterized by pancytopenia, skin manifestations, and increased susceptibility to infections.

Objective: We sought to study the molecular basis of autoinflammation in a patient with severe infancy-onset hyperinflammation associated with signs of fulminant hemophagocytic lymphohistiocytosis.

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The situation of limited data concerning the response to COVID-19 mRNA vaccinations in immunocom-promised children hinders evidence-based recommendations. This prospective observational study investigated humoral and T cell responses after primary BNT162b2 vaccination in secondary immunocompromised and healthy children aged 5-11 years. Participants were categorized as: children after kidney transplantation (KTx, = 9), proteinuric glomerulonephritis (GN, = 4) and healthy children (controls, = 8).

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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.

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Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking.

Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS.

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Background: Assessment of T-cell receptor excision circles (TRECs) in dried blood spots of newborns allows the detection of severe combined immunodeficiency (SCID) (T cells <300/μL at birth) with a presumed sensitivity of 100%. TREC screening also identifies patients with selected combined immunodeficiency (CID) (T cells >300/μL, yet <1500/μL at birth). Nevertheless, relevant CIDs that would benefit from early recognition and curative treatment pass undetected.

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Article Synopsis
  • - The TREC-based newborn screening for severe combined immunodeficiencies (SCID) was implemented in Germany in August 2019, with assessments conducted every six months for 2.5 years to evaluate its effectiveness.
  • - Out of 1.9 million newborns screened, 88 cases of congenital T-cell lymphocytopenia were identified, including 25 SCID cases, and 88% were successfully genetically diagnosed.
  • - The newly established API-CID network enhances patient tracking and treatment, showing excellent short-term outcomes from hematopoietic stem cell transplantation, but ongoing assessments will be crucial for understanding long-term results.
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