Genetic and Immunological Insights in Autoimmune Lymphoproliferative Syndrome

* III.I. INITIAL EVALUATION INCLUSION CRITERIA FOR PATIENTS: In order to be eligible to enroll as a potential patient participant in the initial evaluation, an individual must meet all of the following criteria: 1. Aged 0 to 99 years (must be greater than or equal to 3 years to be seen at the NIH Clinical Center). 2. A history of chronic (\>6 months) lymphadenopathy and/or splenomegaly (exception for newborns with family history of ALPS related disorders). 3. Willingness to allow blood, tissue, and other samples to be stored. III.II. INITIAL EVALUATION INCLUSION CRITERIA FOR BLOOD RELATIVES: In order to be eligible to enroll as a relative for the screening portion of this study, an individual must meet all of the following criteria: 1. Aged 0 to 99 years (must be greater than or equal to 3 years to be seen at the NIH Clinical Center). 2. Extended family members, identified as blood relatives, of an ALPS patient. 3. Able to provide informed consent. 4. Willingness to allow blood, tissue, and other samples to be stored. III.III. INCLUSION CRITERIA FOR THE NATURAL HISTORY STUDY: In order to be eligible to participate in the natural history study as a patient with ALPS, an individual must meet all of the following criteria: 1. Aged 0 to 99 years (must be greater than or equal to 3 years to be seen at the NIH Clinical Center). 2. To be considered as having ALPS, patients must have elevated CD3+TCR alpha/beta+ CD4-8-peripheral blood DNT cells (equal to or greater than 1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) in the setting of normal or elevated lymphocyte counts. 3. A history of chronic (\>6 months), non-malignant, non-infectious lymphadenopathy and/or splenomegaly (exception for newborns with family history of ALPS related disorders). 4. Willingness to allow blood, tissue and other samples to be stored. 5. Patients with RALD who present with autoimmunity, lymphadenopathy, and/or splenomegaly, with elevated or normal DNTs and somatic mutations in NRAS and KRAS.29-32 III.IV. INCLUSION OF SPECIAL POPULATIONS: Children: Children are eligible to enroll as patients or relatives in this protocol. ALPS is primarily a disorder of childhood. The study may not hold the prospect of direct benefit for patients but may provide diagnostic information about their health, which may help guide their clinical management. Additionally, their inclusion is necessary to develop important biomedical knowledge relating to the natural history of this rare disease which cannot be obtained by any other means other than the participation of pediatric participants. Although relative participants are not expected to directly benefit from participation, they will also learn diagnostic results related to ALPS and similar conditions. Minor participants will be limited to having procedures that involve no greater than minimal risk (e.g., apheresis will not be performed in minors). No children under the age of 3 years will be seen in person at the NIH Clinical Center for this protocol. Pregnant women: Women who are pregnant or breastfeeding are eligible to enroll as probands or relatives. The study procedures may hold the prospect of direct benefit by providing insight into the woman or fetus s health risks, which may help guide clinical management during and after pregnancy. Additionally, their inclusion is necessary to develop important biomedical knowledge relating to the natural history of this rare disease which cannot be obtained by any other means other than the participation of this class of women. However, their evaluation will be limited to laboratory evaluation and physical examination so that the risk to the pregnant woman and fetus will not be greater than minimal, and may only be seen remotely if obstetric issues may pose a safety risk for travel and evaluation on-site. Eligibility for this group will be determined on a case-by-case basis by the principal investigator. This protocol is not actively seeking women who are pregnant. Neonates: Viable neonates may be enrolled in this protocol as they meet study entry criteria as patient or relative participants, although no neonates will be seen in-person at the NIH Clinical Center under this protocol. Nonviable neonates and those of uncertain viability will not be enrolled. Adults who lack decision-making capacity to consent: Adults who are unable to consent may be eligible for enrollment as patient participants in this protocol because ALPS is a rare disease that may cause severe complications, and data obtained from these individuals are necessary to answer important scientific questions for this protocol. Similarly, enrolled patient participants who permanently lose the ability to provide ongoing consent during study participation may continue in the study. The risks and benefits of participation for adults unable to consent should be the same as those described for less vulnerable participants. Safeguards in place for protecting this population are described. No adults lacking decision-making capacity to consent will be enrolled as relatives, and those who permanently lose the ability to consent will be withdrawn in accordance with NIH Human Research Protections Program (HRPP) Policy 403. NIH Staff or Family Members: NIH staff and family members of study team members may be enrolled in this study if the participant meets the study entry criteria. Neither participation nor refusal to participate as a subject in the research will have an effect, either beneficial or adverse, on the participant s employment or position at NIH. Every effort will be made to protect participant information, but such information may be available in medical records and may be available to authorized users outside of the study team in both an identifiable an unidentifiable manner. The NIH investigator will provide and request that the NIH staff member review the Frequently Asked Questions (FAQs) for Staff Who are Considering Participation in NIH Research and the Leave Policy for NIH Employees Participating in NIH Medical Research Studies (NIH Policy Manual 2300-630-3). III.V. RECRUITMENT STRATEGIES: * Patients and families are referred from NIH investigators, immunologists, hematologists, rheumatologists, general medical doctors, and clinical geneticists who learn of our studies through our scientific presentations and publications; family organizations, such as the Immune Deficiency Foundation or clinicaltrials.gov. * Clinical histories, laboratory data, and pedigrees will be reviewed for research purposes as well as screening. However, priority may be given to patients in a family with multiple individuals exhibiting symptoms suggestive of ALPS (e.g., high penetrance). Patients with unique clinical features that, in our experience, may help us to understand the phenotype better may also be considered a priority. * Up to 1200 patients and relatives of ALPS patients will be enrolled in this study as part of the initial evaluation or the natural history study if outside testing has confirmed a diagnosis of ALPS. Patients who are being screened for ALPS under the initial evaluation portion of this protocol will be invited to continue participation in the natural history study only if they meet the current eligibility requirements of the natural history study. Patients that are screened and found to be ineligible for enrollment in the natural history study will be referred to other NIAID investigators if applicable. III.VI. STUDY EXCLUSIONS: An individual who meets any of the following criteria will be excluded from participation in screening or the natural history study: 1\. Any condition that the principal investigator deems to be non-conducive to the research goals of the study.