natural history study of scid disorders

Conditions: Severe Combined Immunodeficiency (SCID); Leaky SCID; Omenn Syndrome; Reticular Dysgenesis; ADA SCID; XSCID

Summary: 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.

this study follows participants with scid prospectively, meaning the study enrolls participants where there is a plan to receive a blood and marrow transplant, enzyme therapy, or gene therapy in the future. participants are then followed according to a schedule set out by the study protocol after the procedure. there are no experimental therapies on this study. the goal of this study is to learn more about: (1) outcomes from the treatment of scid in the modern era of medicine (2) what factors lead to the best long-term outcomes, such as best donor, conditioning regimen, timing of transplant, etc., and (3) what impact newborn screening and the early diagnosis of scid has had on the long-term outcomes following bmt or gene therapy. information is also being gathered on how and when the immune system recovers after bone marrow transplant (bmt), quality of life for long-term survivors, and about whether children develop normally after treatment. this natural history study is the largest coordinated prospective study of participants with scid ever performed. information that investigators will learn, both now and in the future, will help doctors and other health professionals to better treat children with scid.

Eligibility criteria:
inclusion criteria: 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. exclusion criteria: -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.

Keywords: severe combined immunodeficiency (scid) natural history study scid treatment