Transient Hypogammaglobulinemia of Infancy

Updated: Aug 06, 2019
  • Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Transient hypogammaglobulinemia of infancy (THI) is a relatively common primary immunodeficiency disease that affects infants and young children. [1] Following birth, maternal immunoglobulin G (IgG) is catabolized, and IgG synthesized by the infant gradually accumulates. Serum levels typically reach their physiologic nadir in infants aged 3–6 months.

THI is characterized by decreased serum IgG with or without decreased immunoglobulin A (IgA) and immunoglobulin M (IgM) levels less than 2 standard deviations (SDs) from age-adjusted reference range levels in infants older than 6 months of age in the first years of life but with normal to near-normal antibody responses to protein immunizations. [2] In addition, other primary immunodeficiency disorders need to be excluded. These levels usually increase to the reference range by age 2–6 years in children with THI. Abnormalities of T-cell help have been identified as a cause of THI, but recent studies suggest that THI may be an intrinsic B-cell defect with abnormal antibody responses, especially to Streptococcus pneumoniae, respiratory viruses, and Haemophilus influenzae type B. [3]



Pathophysiology of THI is unknown. Siegal et al. [4] reported that decreased T-helper function in THI accounted for decreased synthesis of IgG and IgA and that no intrinsic B-cell defect was present. Subsequent studies have reported normal percentages and numbers of CD4+ T cells. [5, 3] Dorsey et al reported that the percentage and number of CD19+ B cells are increased. [3]

Antibody responses in THI vary; the responses to protein immunizations are typically normal, but the responses to polysaccharide and conjugated polysaccharide antigens are typically decreased. Antibody responses to protein immunizations are readily detected in THI, although responses may be lower than healthy controls. In the author's studies, antibody responses to bacterial polysaccharide antigens (S pneumoniae immunizations) were decreased.

Numerous subsequent studies have confirmed that antibody responses to both conjugated and unconjugated S pneumoniae and conjugated Haemophilus influenzae type B immunizations are decreased. [3, 5] Furthermore, antibody titers to viral respiratory infections (eg, influenza virus A and B; adenovirus; mycoplasma; respiratory syncytial virus; parainfluenza virus 1, 2, and 3) were decreased. [6] These decreased antibody responses probably account for the increased susceptibility to infections in children with THI.

In 1997, Kowalczyk et al. [7] reported increased synthesis of tumor necrosis factor (TNF)-α, TNF-β, and interleukin (IL)-10 (but not IL-1, IL-4, and IL-6) in patients with THI. When peripheral blood mononuclear cells were stimulated with pokeweed mitogen (PWM), TNF-α and TNF-β inhibited IgG and IgA synthesis. These studies were subsequently confirmed by examination of intracellular cytokine synthesis by Th1/Th2 cells. In CD4+ T cells, increased intracellular expression of TNF-α, TNF-β, and IL-10 was observed in patients with THI.

In addition, interferon-gamma (IFN-γ) Th1 T cells were increased in these patients. Furthermore, after normalization of the patients' IgG levels, TNF-α and TNF-β synthesis was decreased, but IL-10 synthesis was unchanged. The authors concluded that an imbalance of increased TNF-α that suppressed IgG and IgA synthesis and IL-10–induced IgG switching may be responsible for THI.

Artac et al. [8] reported reduced CD19 expression on B cells of patients with THI. The B-cell antigen receptor (BCR) is associated with co-receptors CD19, CD21, CD81, and CD225, which play a critical role in B-cell response. Though CD19 expression was reduced, CD21 and CD81 expressions were normal. IgM+ memory and class-switched B cells were decreased. They hypothesized that since CD19+ complex regulates B-cell activation following BCR-antigen stimulation, that this may lead to hypogammaglobulinemia.

Dalal et al. [5, 9] have identified 3 patterns of antibody responses in patients with low IgG and IgA levels in early infancy. In group 1, IgG and IgA levels and antibody responses normalize; this is classified as THI. In group 2, patients continue to have low IgG levels and abnormal protective antibody responses; this is classified as common variable immunodeficiency. In group 3, IgG levels normalize, but protective antibody responses are transient; this is classified as dysgammaglobulinemia.




The exact frequency of THI is unknown, although it has been estimated to be 0.061-1.1 cases per 1,000 live births. [10, 11, 12] In a nationwide survey in Japan, THI comprised 18.5% of primary immunodeficiency disorders. [13] In this author's experience, THI is a relatively common diagnosis in children referred for evaluation of recurrent infections. [14]


People with THI have increased frequency of upper respiratory tract infections, especially otitis media and sinusitis, and, occasionally, pneumonia. Life-threatening bacterial infections may occur but are infrequent.


THI is a congenital immunodeficiency disorder that manifests after the infant catabolizes maternal-derived IgG, typically by age 6 months. Most children outgrow this condition by age 2 years, when serum IgG, IgA, and immunoglobulin M (IgM) concentrations normalize, as do antibody responses to both protein and polysaccharide antigens; however, some children take up to age 6 years to outgrow THI.

THI occurs in people of all races.

Whelan et al. [15] and Ji-hong et al. [16] reported a male preponderance with a male-to-female ratio of approximately 2:1. McGeady reported in a review of 19 published series of 10 or more THI patients, the mean percentage of males was 65% with a range of 52–78%. [17]  Patients frequently have a family history of THI and may have a family history of other primary immunodeficiency diseases, such as selective IgA deficiency and common variable immunodeficiency. Tiller and Buckley [10]  reported increased family history of severe combined immunodeficiency (SCID).



Long-term prognosis for patients with THI is excellent; the immune system becomes normal in patients by age 2–6 years.

Serious life-threatening infections in patients with THI are rare.


Patient Education

Inform parents that THI is an immunodeficiency that eventually self-corrects because it is a maturational immunodeficiency.

Also inform parents that patients are unlikely to have serious life-threatening infections.

In addition, many infants with THI have or develop concomitant allergic diseases.