Clinical Information

Severe combined immunodeficiency (SCID) is characterized by the absence or dysfunction of T lymphocytes, which affects both cellular and humoral adaptive immunity. This absence or dysfunction of T cells results in a severe form of inherited primary immunodeficiency that may be life-threatening. SCID typically presents in infancy with persistent respiratory and gastrointestinal infections, failure to thrive, or graft-versus-host disease (due to engraftment of maternal T cells). The absence of lymphoid tissue, immunoglobulins, and B lymphocytes may also be noted.

Critically, having low T-cell numbers is not on its own sufficient for a diagnosis of SCID because other non-SCID disorders, such as thymic defects, may also present with significant T-cell lymphopenia. SCID results from genetic causes of hematopoietic stem cell intrinsic defects in T-lymphocyte development. Primary thymic function defects should be differentiated from SCID because hematopoietic stem cell transplantation is unlikely to be curative for thymic function defects, as the defect is in thymic stromal cell development, not in hematopoietic stem cells.

SCID is suspected when the patient has fewer than 300 autologous CD3 T cells per microliter and additional suggestive features, such as having less than 20% of CD4+ cells with naive cell surface markers, an abnormal SCID newborn screen, a family history of SCID, recurrent or opportunistic infections, or features of Omenn syndrome. An important diagnostic criterion for typical SCID is having less than 50 autologous CD3 T cells per microliter in blood, which requires immediate medical intervention. Other diagnostic criteria may include the identification of a disease-causing variant or variants in a gene whose product is known to be essential for T-cell development and having no alternate explanation for low T-cell count and low to undetectable TREC (T cell receptor excision circles) or <20% of CD4 T cells with naive cell surface marker CD45RA. Alternatively, the presence of maternal T cells in peripheral blood due to failure to reject transplacentally transferred cells is a pathognomonic finding.

Atypical or "leaky" SCID is the term used for patients with partial defects in T-cell number and function. Leaky SCID tends to present in patients older than 12 months of age with recurrent, severe, and prolonged viral infections, bronchiectasis, failure to thrive, and autoimmune manifestations, including cytopenias. Patients may display partial or restricted antigen-specific antibody responses. Leaky SCID is often caused by hypomorphic variants in genes normally associated with typical SCID. Leaky SCID can be diagnosed based on the following: low T-cell number for age; oligoclonal T cells; abnormal TREC or <20% of CD4+ T cells that are naive; the identification of disease-causing variants identified in a gene whose product is known to be essential for T-cell development; reduced T-cell proliferation tests (defined as a proliferative response to phytohemagglutinin, anti-CD3, or anti-CD3/CD28); and the exclusion of other SCID or combined immunodeficiency conditions with a known genotype, thymic disorder, and other disorders associated with low T-cell numbers.

Omenn syndrome, a form of leaky SCID that typically presents in infancy, is characterized by erythroderma, alopecia, hepatosplenomegaly, and lymphadenopathy. Laboratory findings may include elevated IgE, eosinophilia, and lymphocytosis. While RAG1 and RAG2 hypomorphic variants are most often associated with leaky SCID or Omenn syndrome, patients may have variants affecting other genes and the proteins they produce, such as Artemis or interleukin-7 receptor (IL-7R) alpha. There are forms of leaky SCID with hypomorphic variants in these genes that do not have the associated Omenn syndrome phenotype.

SCID can be classified as T-B- or T-B+ SCID, with further subdivision possible based on the presence or absence of natural killer (NK) cells. T-B- SCID is typically caused by a defect in V(D)J recombination, the process that creates the antigen receptor diversity critical to the adaptive immune system. However, T-B- SCID may also be caused by certain enzyme deficiencies, such as adenosine deaminase deficiency, which results in accumulation of metabolic by-products that are toxic to lymphocytes. Reticular dysgenesis-the most severe form of combined immunodeficiency-is caused by a deficiency of the enzyme adenylate kinase 2 and genetic variants in the AK2 gene. Reticular dysgenesis is characterized by a T-B-NK- phenotype, congenital agranulocytosis, lymphopenia, lymphoid and thymic hypoplasia, and bilateral sensorineural deafness.

T-B+ SCID is characterized by impaired development of mature T-cells and the presence of nonfunctional B cells. It is most often caused by genetic variants that affect cytokine-mediated signaling. X-linked T-B+ SCID is due to variants in the IL2RG gene, which encodes the common gamma chain that is a part of the IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors. Autosomal recessive forms of T-B+ SCID due to variants in JAK3 or IL7R also disrupt cytokine signaling. Genetic variants in one of the four CD3 genes (CD3G, CD3D, CD3E, and CD247[CD3Z]) inhibit CD3 signaling and cause T-B+ SCID.

The T-B+ cellular phenotype may also be caused by thymic defects that must be differentiated from T-B+ SCID to guide treatment decisions as stated above. Causes of these thymic defects include coronin-1A deficiency, which causes disruption of thymic egress of T cells and defective T-cell locomotion, and CD45 deficiency caused by variants in the PTPRC gene. Thymic defects with additional congenital anomalies may be observed in DiGeorge syndrome (represented on this panel by TBX1), CHARGE (coloboma, heart defects, atresia choanae [also known as choanal atresia], growth retardation, genital abnormalities, and ear abnormalities) syndrome (due to variants in CHD7 or SEMA3E), and patients with genetic variants in FOXN1.