Panhypogammaglobulinemia is characterized by low levels of all immunoglobulins (ie, immunoglobulin G [IgG], immunoglobulin A [IgA], immunoglobulin M [IgM], immunoglobulin D [IgD], immunoglobulin E [IgE]). In 1952, panhypogammaglobulinemia was first described by Colonel Ogden Bruton while examining the electrophoresis pattern of a child’s serum and noting the absence of gamma globulin. For the purpose of this section, patients with marked decreases (at least 2 standard deviations for the age-adjusted mean) in IgG levels are considered. All patients with X-linked agammaglobulinemia (ie, Bruton-type agammaglobulinemia, congenital agammaglobulinemia) and many patients with common variable immunodeficiency (CVI or CVID) meet these criteria. Other conditions that result in panhypogammaglobulinemia are also discussed.
An absence or loss in the production of all antibodies is caused by abnormalities in the development or function of plasma cells that develop from B lymphocytes. The genetic defect in X-linked agammaglobulinemia is due to mutations in the BTK gene (located on the long arm of the X chromosome at band Xq21.3 to Xq22), which codes for a tyrosine kinase (Bruton tyrosine kinase [Btk]) that is necessary for maturation of pre–B cells into B cells. Many distinct mutations of the BTK gene have been described.
Other rare causes of panhypogammaglobulinemia include mutations in the heavy mu gene, the immunoglobulin-alpha gene, the lambda-5 gene, the BLNK gene, the LRRC8 gene, and the ICOS gene. Panhypogammaglobulinemia can also occur as part of T- and B-cell–negative, severe combined immunodeficiency (SCID) syndromes such as recombinase-activating gene (RAG)-1 deficiency, RAG-2 deficiency, adenosine deaminase deficiency (ADA), and reticular dysgenesis.
The defect in CVID is variable. A few patients show lack of B-cell development similar to that found in X-linked agammaglobulinemia, but most have circulating B cells that either do not mature completely or mature into plasma cells that do not produce adequate amounts of immunoglobulin. Approximately 30% of patients have abnormalities in T-cell function.
Patients with panhypogammaglobulinemia, regardless of basis, share a predisposition to infections with encapsulated pathogenic bacterial organisms such as Streptococcus pneumoniae, meningococcus, and Haemophilus influenzae. Less often, infections develop from beta-hemolytic streptococci, Pseudomonas aeruginosa, and Staphylococcus aureus. Infections with these latter, more virulent organisms tend to occur in patients with architectural derangements such as bronchiectasis. Reports also exist of acute and chronic infection with Mycoplasma pneumoniae. Infections with more virulent organisms, such as S aureus and Pseudomonas species, tend to develop in patients with structural derangements due to bronchiectasis or sinus surgery.
Patients with X-linked agammaglobulinemia have an increased susceptibility to viral hepatitis, echovirus, and Coxsackievirus infections and may develop disseminated poliomyelitis and chronic enteroviral encephalitis. Patients with CVID have an increased incidence of tuberculosis, fungal infections, and Pneumocystis carinii infection.
The most common sites of infection are the upper and lower respiratory tract, and the most common conditions are otitis media, pharyngitis, sinusitis, bronchitis, and pneumonia. These patients are also predisposed to lymphadenitis, meningitis, septic arthritis, osteomyelitis, cellulitis, and infectious gastroenteritis. Common organisms causing infectious gastroenteritis include Giardia lamblia, Clostridium difficile, and Campylobacter, Salmonella, Shigella, Yersinia, and Cryptosporidium species.
Specific frequencies are not available.
X-linked agammaglobulinemia occurs at a rate of 5-10 cases per million population, and CVID occurs at approximately 10 cases per million population. In general clinical practice, CVID is the most common symptomatic primary antibody deficiency syndrome. It is much more common than X-linked agammaglobulinemia.
Prior to availability of parenteral immunoglobulin infusions, morbidity and mortality rates were high. Most patients experienced early death due to recurrent pulmonary infections. Currently, earlier diagnosis, broad-spectrum antibiotics, and intravenous gammaglobulin infusions have decreased morbidity and mortality rates.
For patients with X-linked agammaglobulinemia, chronic pulmonary disease due to bacterial pathogens and chronic enteroviral infections are still sources of significant morbidity. Arthritis (inflammatory with sterile effusions or with unusual organisms such as enteroviruses and Ureaplasma urealyticum) is relatively common. Up to 6% of patients may develop a lymphoreticular malignancy.
Patients with CVID have the same susceptibility to chronic pulmonary disease as those with X-linked agammaglobulinemia. They also have a dramatic increase in susceptibility to autoimmunity, gastrointestinal pathology, and malignancy. Autoimmunity paradoxically occurs in approximately 20% of patients. The most frequent syndromes are hemolytic anemia, thrombocytopenia, pernicious anemia, and hypothyroidism. Almost any other autoimmune process can occur. Chronic gastroenteritis is more common in patients with CVID and is variably associated with a spruelike syndrome, nodular lymphoid hyperplasia, and nonspecific colitis. The incidence of gastrointestinal and lymphoid malignancies is 11-13% in the fifth to sixth decades of life. Distinguishing lymphoid malignancies from atypical reactive lymphoid hyperplasia, which is common in these patients, is important. Patients with granulomatous-lymphocytic lung disease have a shortened median survival (14 years v. 29 years).
Race-based incidence data are not available.
As an X-linked disease, patients with Bruton agammaglobulinemia are all male.
CVID affects males and females in equal numbers.
X-linked agammaglobulinemia presents in infancy (ie, as early as 6 mo) once maternal IgG, which is placentally transferred, is catabolized. The half-life of IgG is approximately 21 days. Clinical diagnosis depends upon the presence of a significant infection, which may not occur immediately. Furthermore, with the use of antibiotics, appreciation of the immunologic defect may be delayed for several years.
CVID does not usually present until the second or third decade of life. In a recent study, the mean age at onset of symptoms was 23 years for males and 28 years for females, although both younger (pediatric) and older (geriatric) patients can be affected. A substantial number of patients are sick as early as their first decade of life, even though they may finally be diagnosed as an adult. In the above-mentioned study, both males and females experienced an average 5- to 6-year delay between symptom onset and diagnosis.
In X-linked agammaglobulinemia, a family history of male children with recurrent infections or death in childhood due to infection may be present.
In CVID, family members may have similar suggestive histories, autoimmune diseases, or selective IgA deficiency.
A history of recurrent or unusual infection initiates evaluation. Most commonly, these are in the upper and lower respiratory tract, but infection can occur in other systems.
Almost all patients with untreated or undertreated hypogammaglobulinemia report malaise and fatigue. Low-grade fever and occasional chills are also common.
Occasionally, patients with X-linked agammaglobulinemia have a history of failure to thrive.
Head, ears, eyes, nose, and throat: Patients with panhypogammaglobulinemia typically have recurrent rhinosinusitis or bronchitis, which responds poorly to antibiotics. Patients seek treatment at short intervals and require frequent courses of antibiotics.
A chronic productive or nonproductive cough is common.
Recurrent pneumonia is common.
Gastrointestinal tract: Gastrointestinal symptoms suggestive of colitis occur in a significant subset of patients with CVID.
General: X-linked agammaglobulinemia can cause growth failure if accompanied by chronic recurrent infections.
Head, ears, eyes, nose, and throat (common symptoms)
Purulent nasal discharge
Sinus pressure and tenderness suggestive of chronic sinusitis
If the patient has recurrent lower respiratory infections, rales or persistent rhonchi may be present.
Digital clubbing is unusual.
An important distinction between X-linked agammaglobulinemia and CVID is the absence of lymphoid tissue or detectable tonsils in Bruton agammaglobulinemia and the presence of normal or hyperplastic lymphoid tissue in CVID.
Patients with congenital hypogammaglobulinemia have an absence of lymph nodes in spite of recurrent sinopulmonary and other infections.
A patient with panhypogammaglobulinemia due to CVID may have an absence of lymph nodes, normal adenopathy, tender nodes of variable size, or diffuse adenopathy with splenomegaly.
Musculoskeletal system: Arthralgias and frank arthritis can occur.
These problems are generally benign.
Occasionally, a patient with CVID presents with splenomegaly.
Congenital hypogammaglobulinemia is an X-linked condition due to a loss in function of the Bruton tyrosine kinase (BTK) gene, which is located on the mid portion of the X chromosome (Xp22). The product of this gene is a tyrosine kinase that is essential for B cell development and activation.
The cause of CVID is unknown. This is a variable disorder that may have multiple etiologies. Mechanisms proposed to explain CVID include intrinsic B-cell defects, excessive T suppressor cell activity, deficient T cell helper function, cytokine deficiencies, and suboptimal T-cell and B-cell interactions. Commonly, IgA deficiency and autoimmune disease is present in family members, suggesting a possible autoimmune basis.
In addition to Bruton agammaglobulinemia and CVID, other diseases are characterized, at least in part, by decreased immunoglobulin concentrations. Drugs can also cause hypogammaglobulinemia.
Genetic disorders - X-linked lymphoproliferative disease and hyper-IgM syndrome
Neoplastic disorders - Immunodeficiency with thymoma, chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma
Disorders of excess catabolism or increased loss of immunoglobulins - Myotonic dystrophy, severe burns, nephrosis, severe malnutrition, thyrotoxicosis, and protein-losing gastroenteropathy
Disorders of decreased synthesis of immunoglobulin - Uremia and the effects of multiple drugs and toxins