Table 5.

Summary Table: Primary/Congenital Immunodeficiencies

Primary immunodeficiencies can be functionally subdivided into four clinicopathologic categories: immune dysregulation, DNA repair defect, low immunoglobulin, and combined immunodeficiency types.

Immune dysregulation–type primary immunodeficiencies are characterized by defects in T-cell and/or natural killer–cell signaling or apoptosis, expansion of T-cell subsets and/or virally transformed B cells, and predisposition to hemophagocytic lymphohistiocytosis.

Examples of immune dysregulation–type primary immunodeficiencies include autoimmune lymphoproliferative syndrome, Chédiak-Higashi syndrome, and Ras-associated leukoproliferative disorder.

DNA repair defects–type primary immunodeficiencies have pleiotropic effects on development and directly predispose to various forms of malignancy.

Examples of DNA repair defect–driven primary immunodeficiencies include ataxia telangiectasia, Nijmegen breakage syndrome, and congenital mismatch repair deficiency.

Low immunoglobulin–type primary immunodeficiencies are associated with a T-cell repertoire abnormality; failure to repress self-reactive clones may lead to autoimmunity, and failure to inhibit clonal outgrowth may predispose to Epstein-Barr virus–transformed or other B-cell lymphoproliferations.

Examples of low immunoglobulin–type primary immunodeficiencies include common variable immunodeficiency and immunoglobulin subset deficiency.

Combined immunodeficiencies manifest symptoms of both B- and T-cell deficiencies, with a combination of infectious and autoimmune complications and predisposition to lymphoproliferative disorders.

Examples of combined-type primary immunodeficiencies include severe combined immunodeficiency and Down syndrome, which is associated with a mild polygenic combined immunodeficiency.

Expansions of T-cell subsets in the primary immunodeficiency setting can mimic lymphoma.

Double-negative T-cell expansions in autoimmune lymphoproliferative syndrome have a high proliferative index, monomorphic appearance, and CD4/CD8 double-negative, cytotoxic T-cell immunophenotype; both α-β or less commonly γ-δ T-cell expansions can occur.

Cytotoxic T-cell expansions occur in common variable immunodeficiency and manifest as intrasinusoidal lymphocytosis in the liver and marrow and as large granular lymphocytosis in the peripheral blood; clonal T-cell gene rearrangements may be present.

The full spectrum of immunodeficiency-related B-cell lymphoproliferative disorders seen in other immunodeficiency settings also occurs in primary immunodeficiency, ranging from hyperplasias to mucocutaneous ulcer to polymorphic B-cell lymphoproliferative disorders and Hodgkin and non-Hodgkin lymphomas.