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Quantifying the phenotypic features of rare diseases such as inborn errors of immunity (IEI) helps clinicians make diagnoses, classify disorders, and objectify the disease severity at its first presentation as well as during therapy and follow-up. Furthermore, it may allow cross-sectional and cohort comparisons and support treatment decisions such as an evaluation for transplantation. On the basis of a literature review, we provide a descriptive comparison of ten selected scores and measures frequently used in IEI and divide these into three categories: (1) diagnostic tools (for Hyper-IgE syndrome, hemophagocytic lymphohistiocytosis, and Wiskott-Aldrich syndrome), (2) morbidity and disease activity measures (for common variable immune deficiency [CVID], profound combined immune deficiency, CTLA-4 haploinsufficiency, immune deficiency and dysregulation activity [IDDA], IPEX organ impairment, and the autoinflammatory disease activity index), and (3) treatment stratification scores (shown for hypogammaglobulinemia). The depth of preclinical and statistical validations varies among the presented tools, and disease-inherent and user-dependent factors complicate their broader application. To support a comparable, standardized evaluation for prospective monitoring of diseases with immune dysregulation, we propose the IDDA2.1 score (comprising 22 parameters on a 2–5-step scale) as a simple yet comprehensive and powerful tool. Originally developed for use in a retrospective study in LRBA deficiency, this new version may be applied to all IEI with immune dysregulation. Reviewing published aggregate cohort data from hundreds of patients, the IDDA kaleidoscope function is presented for 18 exemplary IEI as an instructive phenotype–pattern visualization tool, and an unsupervised, hierarchically clustered heatmap mathematically confirms similarities and differences in their phenotype expression profiles.

Epstein-Barr virus positive (EBV ) smooth muscle tumors (SMTs) constitute a very rare oncological entity. They usually develop in the context of secondary immunodeficiency caused by human immunodeficiency virus infection or immunosuppressive treatment after solid organ transplantation. However, in a small fraction of predominantly pediatric patients, EBV SMTs may occur in patients with primary immunodeficiency disorders (PIDs), such as GATA2 and CARMIL2 deficiency. In secondary immunodeficiencies and when the underlying condition can not be cured, the treatment of EBV SMTs is based on surgery in combination with antiretroviral and reduced or altered immunosuppressive pharmacotherapy, respectively. Importantly, without definitive reconstitution of cellular immunity, long-term survival is poor. This is particularly relevant for patients with EBV SMTs on the basis of PIDs. Recently, allogeneic hematopoietic stem cell transplantation resulted in cure of immunodeficiency and EBV SMTs in a GATA2-deficient patient. We propose that in the absence of secondary immunodeficiency disorders patients presenting with EBV SMTs should be thoroughly evaluated for PIDs. Allogeneic hematopoietic stem cell transplantation should be taken into consideration, ideally in the setting of a prospective clinical trial.

Bi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78 months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning.

Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the β-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: β-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger–Huët anomaly/SOPH). We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

NOD2 polymorphisms may affect sensing of the bacterial muramyl dipeptide (MDP) and trigger perturbed inflammatory responses. Genetic screening of a patient with immunodeficiency and enteropathy revealed a rare homozygous missense mutation in the first CARD domain of NOD2 (ENST00000300589; c.160G > A, p.E54K). Biochemical assays confirmed impaired NOD2-dependent signaling and proinflammatory cytokine production in patient’s cells and heterologous cellular models with overexpression of the NOD2 mutant. Immunoprecipitation-coupled mass spectrometry unveiled the ATPase valosin-containing protein (VCP) as novel interaction partner of wildtype NOD2, while the binding to the NOD2 variant p.E54K was abrogated. Knockdown of VCP in coloncarcinoma cells led to impaired NF-κB activity and IL8 expression upon MDP stimulation. In contrast, tunicamycin-induced ER stress resulted in increased IL8, CXCL1, and CXCL2 production in cells with knockdown of VCP, while enhanced expression of these proinflammatory molecules was abolished upon knockout of NOD2. Taken together, these data suggest that VCP-mediated inflammatory responses upon ER stress are NOD2-dependent.

Background Diagnosis, treatment, and care of patients with rare diseases require multidisciplinary cooperation between medical and paramedical specialities and with patients and families. Innovative genetic diagnostics, whole exome and whole genome sequencing (WES, WGS) has enlarged the diagnostic toolkit but also increased the complexity of the endeavour. Structured multidisciplinary clinical pathways (CPW) can guide diagnosis, treatment, and care of patients with rare diseases, link scientific evidence to clinical practice and optimise clinical outcomes whilst maximising clinical efficiency. Results In contrast to the common approach of appending disease-specific CPWs to disease-specific guidelines, we suggest a generic CPW manoeuvring the patient along the way of finding the correct diagnosis by applying the best diagnostic strategy into an appropriate system of treatment and care. Available guidelines can be integrated into the generic CPW in the course of its application. The approach also applies to situations where a diagnosis remains unsolved. The backbone of the generic CPW is a set of multidisciplinary structured case conferences projecting and evaluating diagnostic and/or therapeutic steps, enforcing to integrate best scientific evidence with clinical experience. The generic CPW is stated as a flowchart and a checklist which can be used to record and document parsimoniously the structure, process and results of a patient’s pathway, but also as a data model for research. It was applied in a multicentre setting with 587 cases each with a presumptive diagnosis of a rare disease. In 369 cases (62.8%) a diagnosis could be confirmed, and multidisciplinary treatment and/or care was initiated. The median process time from first contact until confirmation of diagnosis by WES was 109 days and much shorter than diagnostic delays reported in the literature. Application of the CPW is illustrated by two case reports. Conclusions Our model is a tool to change the diagnostic odyssey into an organised and trackable route. It can also be used to inform patients and families about the stages of their individual route, to update health care providers only partially involved or attending specialised treatment and care, like the patient’s or family’s primary physician, and finally to train novices in the field.

Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity first described in 2013. With an estimated prevalence of 1-2 per 1,000,000 individuals, it is considered an ultra-rare disease. The aim of this survey was to explore the diagnostic and therapeutic challenges of patients with APDS from the patients` and physicians` perspective in Austria, Germany, and Switzerland. A qualitative case study approach was applied. Semi-structured interviews were conducted with six patients or legal guardians of children with APDS, and four clinical immunologists with direct experience in APDS care. Transcripts were analyzed using inductive content analysis. The interviews revealed a median diagnostic delay of several years, mainly due to the rarity and phenotypic heterogeneity of APDS and the involvement of multiple specialties prior to referral to an immunologist. Many patients initially received symptomatic treatment before an underlying immune disorder was suspected. Physicians emphasized the decisive role of genetic testing for confirmation, while patients frequently described the diagnosis as a \"lucky coincidence\". Both groups highlighted structural barriers including limited awareness, fragmented care, and delayed access to targeted therapy. Early recognition of APDS requires specific education across specialties, wider access to genetic testing, and the development of standardized diagnostic and disease activity tools. Strengthening interdisciplinary care pathways and timely initiation of APDS-specific therapy may substantially improve outcomes in this ultra-rare immunodeficiency.

Patients with inborn errors of immunity or DNA repair defects are at significant risk of developing malignancy and this complication of their underlying condition represents a substantial cause of morbidity and mortality. Whilst this risk is increasingly well-recognized, our understanding of the causative mechanisms remains incomplete. Diagnosing cancer is challenging in the presence of underlying co-morbidities and frequently other inflammatory and lymphoproliferative processes. We lack a structured approach to management despite recognizing the competing challenges of poor response to therapy and increased risk of toxicity. Finally, clinicians need guidance on how to screen for malignancy in many of these predisposing immunodeficiencies. In order to begin to address these challenges, we brought together representatives of European Immunology and Pediatric Haemato-Oncology to define the current state of our knowledge and identify priorities for clinical and research development. We propose key developmental priorities which our two communities will need to work together to address, collaborating with colleagues around the world.

Purpose The transition process from paediatric/adolescent to adult medical care settings is of utmost importance for the future health of adolescents with chronic diseases and poses even more difficulties in the context of rare diseases (RDs). Paediatric care teams are challenged to deliver adolescent-appropriate information and structures. Here we present a structured transition pathway which is patient-focused and adoptable for different RDs. Methods The transition pathway for adolescents 16 years and older was developed and implemented as part of a multi-centre study in 10 university hospitals in Germany. Key elements of the pathway included: assessment of patients’ disease-related knowledge and needs, training/educational and counselling sessions, a structured epicrisis and a transfer appointment jointly with the paediatric and adult specialist. Specific care coordinators from the participating university hospitals were in charge of organization and coordination of the transition process. Results Of a total of 292 patients, 286 completed the pathway. Deficits in disease-specific knowledge were present in more than 90% of participants. A need for genetic or socio-legal counselling was indicated by > 60%. A mean of 2.1 training sessions per patient were provided over a period of almost 1 year, followed by the transfer to adult care in 267 cases. Twelve patients remained in paediatric care as no adult health care specialist could be identified. Targeted training and counselling resulted in improved disease-specific knowledge and contributed to empowering of patients. Conclusion The described transition pathway succeeds to improve health literacy in adolescents with RDs and can be implemented by paediatric care teams in any RD specialty. Patient empowerment was mainly achieved by individualized training and counselling.

Purpose X-linked agammaglobulinemia (XLA) is an inborn error of immunity caused by variants in Bruton’s tyrosine kinase ( BTK ). XLA patients require lifelong immunoglobulin replacement therapy (IgRT). Only few XLA patients are indicated for allogeneic hematopoietic cell transplantation (HCT) because of severe complications. Accordingly, the published transplantation experience in XLA is minimal. We aimed to collect clinical data of XLA patients who received HCT in an international framework and to establish appropriate transplantation criteria and methods for XLA patients. Methods XLA patients were recruited through a questionnaire and a literature review. The data are on patient characteristics and transplantation methods and outcomes. Results In this study, twenty-two XLA patients who underwent HCT were recruited. The indication for HCT was recurrent or life-threatening infection in sixteen patients, malignancy in three, and other factors in three. A myeloablative conditioning, reduced toxicity myeloablative conditioning (RT-MAC), and reduced intensity conditioning (RIC) were selected in four, ten, and eight patients, respectively. Engraftment was achieved in 21 patients (95%). In all patients, 2-year overall survival (OS) and event-free survival (EFS) were 86% and 77%, respectively. In patients who received RT-MAC or RIC using treosulfan, busulfan, or melphalan, 2-year OS and EFS were 82% and 71%, respectively. Finally, twenty-one patients (95%) obtained complete or stable high-level mixed chimerism (50–95%), and the 1-year discontinuation rate of IgRT was 89%. Conclusion Based on the concept in which IgRT is the standard treatment for XLA, HCT may be an effective and safe alternative treatment option for XLA patients, and IgRT can be discontinued following transplantation. It is ideal to perform HCT in XLA patients for whom transplantation is indicated before they develop organ damage.