Natural History Study of SCID Disorders
Trial ID or NCT#
This study is a prospective evaluation of children with Severe Combined Immune Deficiency (SCID) who are treated under a variety of protocols used by participating institutions. In order to determine the patient, recipient and transplant-related variables that are most important in determining outcome, study investigators will uniformly collect pre-, post- and peri-transplant (or other treatment) information on all children enrolled into this study. Children will be divided into three strata: - Stratum A: Typical SCID with virtual absence of autologous T cells and poor T cell function - Stratum B: Atypical SCID (leaky SCID, Omenn syndrome and reticular dysgenesis with limited T cell diversity or number and reduced function), and - Stratum C: ADA deficient SCID and XSCID patients receiving alternative therapy including PEG-ADA ERT or gene therapy. Each Group/Cohort Stratum will be analyzed separately.
A Prospective Natural History Study of Diagnosis, Treatment and Outcomes of Children With SCID Disorders (RDCRN PIDTC-6901)
- Stratum A: Typical SCID (formerly referred to as Classic SCID)- -Subjects who meet the following inclusion criteria and the intention is to treat with allogeneic hematopoietic cell transplant (HCT) are eligible for enrollment into Stratum A (Typical SCID) of the study: - Absence or very low number of T cells (CD3 T cells <300/microliter) AND - No or very low T cell function (<10% of lower limit of normal) as measured by response to phytohemagglutinin (PHA) OR - T cells of maternal origin present. Stratum B: Leaky SCID, Omenn Syndrome, Reticular Dysgenesis- -Subjects who meet the following criteria and the intention is to treat with HCT are eligible for enrollment into Stratum B: Leaky SCID: - Maternal lymphocytes tested for and not detected AND - Either one or both of the following (a,b) : - a.) <50% of lower limit of normal T cell function as measured by response to PHA, OR response to anti-CD3/CD28 antibody - b.) Absent or <30% of lower limit of normal proliferative responses to candida and tetanus toxoid antigens - AND at least two of the following (a through e): - a.) Reduced number of CD3 T cells - age ≤2 years: <1500/microliter - age >2 years and ≤4 years: <800/microliter - age >4 years: <600/microliter - b.) ≥80% of CD3+ or CD4+ T cells that are CD45RO+ - AND/OR >80% of CD3+ or CD4+ T cells are CD62L negative - AND/OR >50% of CD3+ or CD4+T cells express HLA-DR (at <4 years of age) - AND/OR are oligoclonal T cells - c.) Hypomorphic mutation in IL2RG in a male, or homozygous hypomorphic mutation or compound heterozygosity with ≥1 hypomorphic mutation in an autosomal SCID-causing gene - d.) Low T Cell Receptor Excision Circles (TRECs) and/or the percentage of CD4+/45RA+/CD31+ or CD4+/45RA+/CD62L+ cells is below the lower limit of normal. - e.) Functional testing in vitro supporting impaired, but not absent, activity of the mutant protein, AND - Does not meet criteria for Omenn Syndrome. Omenn Syndrome: - Generalized skin rash - Maternal lymphocytes tested for and not detected; --Note: If maternal engraftment was not assessed and ruled out, the subject is not eligible as Omenn Syndrome. - ≥80% of CD3+ or CD4+ T cells are CD45RO+ AND/OR - 80% of CD3+ or CD4+T cells are CD62L negative AND/OR - 50% of CD3+ or CD4+ T cells express HLA-DR (at <2 years of age); - Absent or low (< 30% lower limit of normal) T cell proliferation response to antigens (Candida, tetanus) to which the subject has been exposed NOTE: If proliferation to antigen was not performed, but at least 4 of the following 9 supportive criteria, at least one of which must be among those marked with an asterisk (*) below are present, the subject is eligible as Omenn Syndrome: - Hepatomegaly - Splenomegaly - Lymphadenopathy - Elevated IgE - Elevated absolute eosinophil count - *Oligoclonal T cells measured by CDR3 length or flow cytometry - *Proliferation to PHA is reduced <50% of lower limit of normal or SI <30 - *Hypomorphic mutation in a SCID causing gene - Low TRECS and/or the percentage of CD4+/45RA+/CD31+ or CD4+/45RA+/CD62L+ cells is below the lower limit of normal. Reticular Dysgenesis: - Absence or very low number of T cells (CD3 <300/µL - No or very low (<10% lower limit of normal) T cell response to PHA - Severe neutropenia (absolute neutrophil count < 200 /µL) AND - ≥2 of the following (a,b,c): - a.) Sensori-neural deafness - b.) Deficiency of marrow granulopoiesis on bone marrow examination - c.) A pathogenic mutation in the adenylate kinase 2 (AK2) gene identified. Stratum C: Subjects who meet the following criteria and the intention is to treat with therapy other than allogeneic HCT, primarily PEG-ADA ERT or gene therapy with autologous modified (gene transduced) cells, are eligible for enrollment into Stratum C: - ADA Deficient SCID with intention to treat with PEG-ADA ERT - ADA Deficient SCID with intention to treat with gene therapy - X-linked SCID with intention to treat with gene therapy - Any SCID patient previously treated with a thymus transplant (includes intention to treat with HCT, as well as PEG-ADA ERT or gene therapy) - Any SCID patient who received therapy for SCID deemed "non-standard" or "investigational", including in utero procedures.
- -Subjects who meet any of the following exclusion criteria are disqualified from enrollment in Strata A, B, or C of the study: - Presence of an Human Immunodeficiency Virus (HIV) infection (by PCR) or other cause of secondary immunodeficiency - Presence of DiGeorge syndrome - MHC Class I and MHC Class II antigen deficiency, and - Metabolic conditions that imitate SCID or related disorders such as folate transporter deficiency, severe zinc deficiency or transcobalamin deficiency.
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Matthew Porteus, MD