Primary Immune Deficiencies

Background: \- Researchers are interested in studying disorders that make individuals more susceptible to fungal infections, specifically infections with the Candida yeast. These disorders are often related to problems with the immune system and may have genetic factors, which suggests that researchers should study not only the individual with the disorder, but also his or her first- and second-degree relatives (such as parents, siblings, children, and first cousins). To provide material for future research, individuals with immune disorders and their first- and second-degree relatives will be asked to provide blood and other samples for testing and comparison with samples taken from healthy volunteers with no history of immune disorders. Objectives: \- To collect blood and other biological samples to study immune disorders that make individuals more susceptible to fungal infections. Eligibility: * Individuals of any age who have abnormal immune function characterized by recurrent or unusual fungal infections, recurrent or chronic inflammation, or other types of immune dysfunction. * First- or second-degree genetically related family members (limited to mother, father, siblings, grandparents, children, aunts, uncles, and first cousins). * Healthy volunteers at least 18 years of age (for comparison purposes). Design: * Participants will provide blood samples and buccal (cells from the inside of the mouth near the cheek) samples. * Participants with immune disorders will also be asked to provide urine samples, saliva or mucosal samples, or skin tissue biopsies, and may also have imaging studies (such as x-rays) to collect information for research. * Samples may be collected at the National Institutes of Health or at other clinical locations for the samples to the sent to the National Institutes of Health. * No treatment will be provided as part of this protocol.

Primary immunodeficiencies (PIDs) are a heterogeneous group of inborn errors of immunity characterized not only by increased susceptibility to infections but also by immune dysregulation. Among immune dysregulation manifestations, lymphoproliferative disorders represent a frequent and clinically challenging complication. These manifestations may involve secondary lymphoid organs (lymphadenopathy, splenomegaly) as well as extranodal organs such as lungs, liver, and gastrointestinal tract, often with lymphocytic and/or granulomatous infiltration. In some patients, lymphoproliferation may progress to lymphoma or other malignancies. Despite increasing knowledge about specific genetic subtypes of PIDs and the development of targeted therapies (e.g., PI3Kδ inhibitors, CTLA4 pathway modulation, mTOR inhibitors), the natural history and long-term prognosis of lymphoproliferative manifestations across unselected PID populations remain poorly defined. Most available studies focus on selected molecular subgroups or treatment responses, while real-world longitudinal data on broader PID cohorts are lacking. The PID-LP study is a multicenter retrospective longitudinal study conducted in three tertiary care centers in France. It aims to describe the initial characteristics and long-term outcomes of patients with PIDs who develop lymphoproliferative manifestations. The primary objective is to evaluate the occurrence of major clinical events during follow-up, defined as death (all causes), occurrence of lymphoma or other malignancy, or clinically significant organ dysfunction attributable to lymphoproliferation. Secondary objectives are to describe the longitudinal evolution of systemic lymphoproliferation (lymph node size, splenomegaly), the progression of organ involvement (pulmonary, hepatic, gastrointestinal), and to identify clinical, biological, genetic, radiological, and therapeutic factors at diagnosis that may predict major complications. Approximately 60 pediatric and adult patients diagnosed between 2014 and 2025 and followed for at least 12 months after diagnosis of lymphoproliferation will be included. Data will be retrospectively collected from medical records. This study is expected to improve the understanding of prognosis and disease trajectories in PID-associated lymphoproliferation, inform follow-up strategies, and generate hypotheses for future prospective interventional studies.