Transient Hypogammaglobulinemia of Infancy Clinical Presentation

Updated: Aug 06, 2019
  • Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Presentation

History

Patients with THI may be symptomatic or asymptomatic. Approximately 5% of infants with THI are symptomatic when they are younger than 6 months, 50% become symptomatic at 6–12 months, and 25% become symptomatic when they are older than 12 months. [15] Infants with THI typically begin to experience increasingly frequent and recurrent otitis media, sinusitis, and bronchial infections. Life-threatening infections with polysaccharide-encapsulated bacteria may occur but are unusual. Dalal et al. [9] reported that upper respiratory tract infections occurred in most patients and pneumonia occurred in 23% of patients. [5] In a prospective study of 77 children with THI, Moschese et al. [18] reported infections in 91%, allergies in 47%, and autoimmune diseases of hemolytic anemia and neutropenia in 4% of patients. Infrequently, severe varicella, persistent oral candidiasis, sepsis, and meningitis were seen.

Because antigen-specific antibody responses are largely intact, this likely accounts for the lack of serious bacterial infections observed in THI. In children older than 3 years, the frequency of infections typically diminishes, even if serum immunoglobulin levels have not yet normalized. T cell immunity is intact, and infections with opportunistic microorganisms do not usually occur.

Although some investigators reported that atopic disease is not frequently associated with THI [9] , other investigators have reported increased incidence of atopic diseases, such as food allergy, asthma, and allergic rhinitis. [11, 14, 3] GI allergic-related symptoms may also occur.

Hematologic abnormalities have also been reported in THI; these included neutropenia and thrombocytopenia. [9] One patient developed acute lymphocytic leukemia (ALL).

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Physical

Physical examination findings are typically normal. Tonsils, adenoids, and lymph nodes are normal in patients with THI, which helps to differentiate THI from other congenital intrinsic B-cell immune defects. In X-linked infantile agammaglobulinemia (Bruton agammaglobulinemia) and common variable immunodeficiency, peripheral lymph nodes, tonsillar tissue, and adenoid tissue are hypotrophic. However, hypertrophic tonsillar tissue and splenomegaly may be present in as many as 25% of patients with common variable immunodeficiency. In hyper-IgM syndrome (HIGM), lymphoid hyperplasia and splenomegaly is uniformly present. Growth is typically normal in patients with THI, as it is in most primary B-cell immunodeficiencies.

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Causes

The cause(s) of THI is unknown. Investigators have identified abnormalities in T cells, B cells, and monocytes in THI. 

T-cell abnormalities

Siegal et al. [4] reported decreased CD4+ T-helper cell numbers and function and decreased T cell help of B-cell synthesis of IgG and IgA in THI; subsequent studies have been able to confirm this. Kowalczyk et al. [7]  reported that THI lymphocytes synthesize increased TNF-α, TGF-β, and IL-10 with PHA stimulation, proposing that this suppressed Ig synthesis. When the IgG levels normalized in THI so did the cytokine imbalance.   Subsequently, Kowalcyk et al. [19] proposed that there was increased TH1 bias in THI with increased TNF-α, TNF-β, IL-10, IL-12 in CD4+ T cells and increased IL-12 and IL-18 synthesis. Rutkowska et al. [20] reported that CD4+CD25high FoxP3+ T regulatory cells were increased in patients with THI; whereas they are decreased in patients with CVID.​ Furthermore, as THI resolved T regulatory cells decrease to normal. This may be useful then in differentiating THI from CVID and following THI patients as the IgG levels normalize. The mechanism of this is unknown. 

B-cell abnormalities

A number of defects in B cell numbers, memory and switch B cells have been identified, which are further discussed in the section on Laboratory Studies.

Monocyte abnormalities

Kowalcyk et al. [21] reported decreased CD40 expression on monocytes of patients with THI, possibly resulting in decreased colligation of Th CD40L and B cell CD40 stimulation necessary for class switching and memory B cell development. 

Antibody responses to protein antigens are normal or near normal; however, a selective antibody deficiency to bacterial polysaccharide antigens (eg, S pneumoniae immunizations, H influenzae type B) is present with IgA deficiency and IgG-2 subclass deficiency. Decreased total B cells and decreased memory and switched B cells have been observed. Because most children "outgrow" their immunodeficiency, it appears to be a maturational defect in infants and young children. Therefore, THI may represent a maturational defect affecting CD4+ T cells, B cells, and/or antigen-presenting cells.

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