X-linked agammaglobulinemia (X-LA) is the prototypic disorder of humoral immunity. Male patients with this disease have severe panhypogammaglobulinemia, with little or no humoral immune function, but they have normal cell-mediated immunity. These patients have B-lymphocyte precursors (pre–B cells), but do not have mature B lymphocytes or plasma cells. T lymphocytes and all other components of the immune system are normal.

X-LA is caused by a mutation of the gene encoding a cytoplasmic tyrosine kinase (Bruton’s tyrosine kinase). This protein is essential for the process by which B cells differentiate, and the absence of Bruton’s tyrosine kinase results in a developmental arrest of B-lymphocyte maturation at the pre–B cell stage. The defective gene has been mapped to the X chromosome and, interestingly, an effect on B-lymphocyte differentiation is observed in female carriers of X-LA, all of whom are immunologically normal. Generally, the inactivation of one X chromosome occurs at random in female cells. However, among carriers for X-LA, all mature B lymphocytes have inactivated the abnormal X chromosome, because lack of expression of the normal gene blocks B-cell differentiation. In fact, an analysis of X chromosome activation patterns of peripheral blood can be used to determine carrier status.

The differential diagnosis of panhypogammaglobulinemia in infancy includes transient hypogammaglobulinemia of infancy, common variable immunodeficiency, immunoglobulin deficiency with increased IgM, combined immunodeficiency disorders, and rare cases of human immunodeficiency virus (HIV) infection. A quantitation of B and T lymphocytes in peripheral blood helps distinguish among these possibilities. Boys with X-LA have normal numbers of T lymphocytes but have no detectable B lymphocytes. In contrast, infants with transient hypogammaglobulinemia or common variable immunodeficiency generally have normal numbers of B and T lymphocytes; children with severe combined immunodeficiency have decreased numbers of T lymphocytes with normal, decreased, or increased numbers of B cells; and children with HIV infection have decreased numbers of CD4⁺ T lymphocytes.

Boys with X-LA usually are protected by transplacentally acquired maternal IgG for the first 3 to 4 months of life. Thereafter, chronic and recurrent infections are the predominant clinical manifestation of X-LA. Otitis media, pneumonia, diarrhea, and sinusitis occur most often, usually in combination. Clues to the diagnosis of immunodeficiency include the chronic or recurrent nature of infections and the occurrence of those infections at more than one anatomic site. S. pneumoniae, H. influenzae, and Staphylococcus aureus are the most frequently identified bacterial pathogens, but nontypeable, unencapsulated H. influenzae, Salmonellae, Pseudomonas, and Mycoplasma infections occur with increased frequency, as do certain specific viral infections. Infections are not limited to mucosal surfaces. Bacterial meningitis, sepsis, and osteomyelitis occur in as many as 10% to 15% of untreated patients. Other sentinel symptoms that should prompt consideration of X-LA include the presentation of oligoarticular arthritis or dermatomyositis in a young boy. A helpful sign on physical examination, related to the absence of B lymphocytes, is the finding of hypoplastic or absent tonsils, adenoids, and lymph nodes.

Enterovirus infections are a particularly difficult problem in patients with X-LA. This group of viruses (coxsackie, enteric cytopathogenic human orphan [ECHO], and polio) tends to cause chronic diarrhea, hepatitis, pneumonitis, and meningoencephalitis in patients with X-LA. In some instances, the infection takes the form of a dermatomyositis-like syndrome consisting of rash, edema of subcutaneous tissue, and muscle weakness. Enterovirus infections often are fatal in patients with X-LA, although therapy with extremely high doses of gamma globulin containing virus-specific antibodies has been helpful.

The management of patients with X-LA includes the use of gamma globulin prophylaxis and an aggressive approach to the diagnosis and therapy of febrile or inflammatory illnesses. Early recognition of the disease and adequate gamma globulin replacement leads to a good prognosis in most patients. Although no controlled studies exist, gamma globulin prophylaxis appears to be most effective in patients who have not yet incurred structural damage to target organs of the respiratory or gastrointestinal tract, and when trough IgG levels are in the physiologic range. Nevertheless, chronic infections of paranasal sinuses and/or the lungs develop in approximately 50% of X-LA patients, particularly those who had severe, recurrent, or chronic infections before the recognition of immune deficiency and initiation of gamma globulin prophylaxis. Gamma globulin therapy should allow normal or near-normal growth velocity. Persistently impaired linear growth should prompt an evaluation of growth hormone levels because X-LA has occurred in association with growth hormone deficiency in a few kindreds. Most reported deaths of X-LA patients are attributed to recurrent lower respiratory tract infections with resulting chronic pulmonary disease or to chronic enterovirus infections. Early diagnosis is critical, so that gamma globulin therapy can be initiated before the onset of any of these problems and to provide families with appropriate genetic counseling. Bone marrow stem-cell transplants without a preparative regimen generally have not been successful.

The phrase common variable immunodeficiency (CVID) describes a heterogeneous group of disorders characterized by hypogammaglobulinemia. In distinction from X-LA, B lymphocytes frequently are found in the peripheral blood of patients with CVID, and the hypogammaglobulinemia may be less profound. Additional immunologic abnormalities, such as T-cell dysfunction and autoimmune diseases, are expressed variably. Many patients with CVID appear to have defects intrinsic to the B lymphocyte, but other patients have excessive T-lymphocyte suppressor function, inadequate T-lymphocyte helper function, or anti–B-lymphocyte antibodies. Most patients do not manifest symptoms until after the first decade of life, but some patients present in early childhood or infancy. It has long been assumed that patients with CVID have acquired hypogammaglobulinemia, although only a few reports exist in which the transition from normal gamma globulin levels to hypogammaglobulinemia is documented. No recognizable pattern of inheritance exists in most patients, but other disorders of humoral immunity (e.g., IgA deficiency and transient hypogammaglobulinemia of infancy) occur at higher frequency among family members of patients with CVID than among the general population.

It has become increasingly apparent that the clinical phenotype of CVID can be the result of a wide variety of immunologic abnormalities. For example, genetic analyses have identified mutations of Btk (the gene causing XLA), SH2D1A (the gene causing the X-linked lymphoproliferative syndrome) and ICOS (the “inducible stimulator” on activated T cells) among small numbers of individuals previously identified as having CVID. It is likely that such analyses will help to define subgroups of CVID patients who differ in presentation and outcome, and perhaps lead to novel therapies.

As in X-LA, the most frequent manifestations of CVID are chronic or recurrent infections of the upper and lower respiratory tracts. Recurrent pneumonia, chronic bronchitis, and sinusitis occur in the majority of patients and some eventually develop chronic pulmonary dysfunction. Most of the identified respiratory tract pathogens are encapsulated bacteria. An almost equal incidence of obstructive and restrictive lung disease occurs. Somewhat in contrast to patients with X-LA, in patients with CVID, disease of the gastrointestinal tract occurs with almost equal frequency as disease of the respiratory tract. As many as 30% to 60% of patients with CVID have chronic diarrhea. An infectious agent is identified in approximately one-half of patients; many of the others have idiopathic inflammatory bowel diseases. The most frequently documented gastrointestinal pathogen is Giardia lamblia. Bacterial overgrowth of the small bowel is an important cause of chronic diarrhea in patients with CVID; enteroviruses are a problem less frequently.

Patients with CVID have a variety of associated disorders for which no infectious etiology has been established. These disorders may be the result of infections caused by unidentified pathogens, but many are believed to be autoimmune in origin, perhaps the result of the same disordered immunoregulation that is presumed to be responsible for the development of hypogammaglobulinemia. Gastrointestinal and hematologic disorders predominate. Chronic idiopathic diarrhea is the single biggest problem. Intestinal biopsy samples typically demonstrate nodular lymphoid hyperplasia as well as villous blunting and epithelial atrophy in the small bowel. Inflammatory bowel diseases, achlorhydria, and pernicious anemia occur with significant frequency. Hematologic abnormalities include the development of persistent splenomegaly, immune thrombocytopenia, leukopenia, and autoimmune hemolytic anemia. Curiously, a few patients have developed a clinical picture typical of sarcoidosis, with granulomatous lesions and elevated angiotensin-converting enzyme levels, although without the hypergammaglobulinemia typically found in patients with sarcoidosis. Patients who present with CVID in infancy and early childhood often have particularly severe problems with autoimmune and chronic inflammatory disorders, resulting in a mortality rate that exceeds 50%. An increased susceptibility to malignancy (particularly thymoma and lymphoma) is present in adults with CVID, but the risk in children is not known.