Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

Biallelic mutations in the genes encoding CD27 or its ligand CD70 underlie inborn errors of immunity characterized predominantly by EBV-associated immune dysregulation, such as chronic viremia, severe infectious mononucleosis, hemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and malignancy. A comprehensive understanding of the natural history, immune characteristics and transplant outcomes has remained elusive. Here, in a multi-institutional global collaboration, we collected clinical information of 49 patients from 29 families (CD27 n=33, CD70 n=16), including 24 previously unreported individuals and identified a total of 16 distinct mutations in CD27, and 8 in CD70, respectively. The majority (90%) of patients were EBV+ at diagnosis, but only ~30% presented with infectious mononucleosis. Lymphoproliferation and lymphoma were the main clinical manifestations (70% and 43%, respectively), and 9 of the CD27-deficient patients developed HLH. Twenty-one (43%) patients developed autoinflammatory features including uveitis, arthritis and periodic fever. Detailed immunological characterization revealed aberrant generation of memory B and T cells, including a paucity of EBV-specific T cells, and impaired effector function of CD8+ T cells, thereby providing mechanistic insight into cellular defects underpinning the clinical features of disrupted CD27/CD70 signaling. Nineteen patients underwent allogeneic hematopoietic stem cell transplantation (HSCT) prior to adulthood predominantly because of lymphoma, with 95% survival without disease recurrence. Our data highlight the marked predisposition to lymphoma of both CD27- and CD70-deficient patients. The excellent outcome after HSCT supports the timely implementation of this treatment modality particularly in patients presenting with malignant transformation to lymphoma.

The nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) is a master regulator of immune and inflammatory responses.1,2 NF-κB1 belongs to the NF-κB/Rel family of transcription factors that consists of five members in humans: NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA, c-Rel, and RelB. The p105 and p100 precursors are proteolytically processed by the proteasome to generate the shorter p50 and p52 isoforms. Homo-and heterodimers are formed by p50, p52 and the Rel proteins. Unstimulated, these dimeric complexes are sequestered in the cytoplasm by inhibitory IκB proteins in an inactive state. Upon stimulation, the phosphorylation and subsequent degradation of IκB proteins is rapidly triggered, releasing the NF-κB/Rel complexes to enter the nucleus where they bind to DNA at κB sites and activate or repress the expression of their target genes. 3 Recently, heterozygous mutations affecting the NFKB1 gene were identified in three human families. Haploinsufficiency of NF-κB1 was causative for combined variable immunodeficiency (CVID) characterized by recurrent infections due to immunoglobulin deficiency (pan-IgG, IgA and/or IgM). 4 We report here on two pediatric patients from unrelated families with two novel NFKB1 gene mutations identified by whole-exome sequencing ( Figure 1A,B). Both patients had early onset of disease during their teenage years and presented in addition to hypogammaglobulinemia or selective IgA deficiency with a striking lack of specific antibodies (clinical characteristics are summarized in Table 1 and Online Supplementary Table S1).Patient 1 is a now 26-year old female who first presented with recurrent autoimmune hemolytic anemia at the age of 14. Hypogammaglobulinemia (IgG2 subclass deficiency), deficient production of specific antibodies, decreased class-switched and memory B cells, naïve CD4-positive and regulatory T cells, increased activated and double-negative T cells (DNT cells, CD4 -CD8 -TCRα/β + ), autoimmune phenomena (hemolytic anemia, thrombocytopenia and leukopenia), lymphadenopathy, and hepatosplenomegaly were observed. She developed chronic lung disease with bronchiectasis, frequent respiratory tract infections and pneumonia. Infections with viral, bacterial and fungal pathogens were frequent. She suffered from intractable abdominal pain and bloody diarrhea without evidence of infection. After a liver biopsy she developed pancolitis with subsequent sepsis and multi-organ failure and was successfully resuscitated. The patient is being treated with intravenous immunoglobulin. Steroids were intermittently given to reduce pulmonary infiltrates with partial response. Mycophenolate mofetil stabilized blood counts, but pulmonary symptoms and infections remained.To identify the genetic cause of disease whole exome sequencing was performed for the patient and her family (Online Supplementary Methods, Online Supplementary Table S2). A heterozygous de novo NFKB1 frameshift mutation was detected ( Figure 1A). The NFKB1 gene encodes two proteins: p50 and its precursor ...

Background: About one quarter of children affected with cancer die. For children and their families, the end-of-life period is highly distressing. Aim: This study focused on how end-of-life care in pediatric cancer patients changed over a period of 10 years and if changes in pediatric palliative care structures were associated with quality of care.