Natural History Study of SCID Disorders

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.