Transient Hypogammaglobulinemia of Infancy Workup

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

Laboratory Studies

In evaluating transient hypergammaglobulinemia of infancy (THI), serum IgG levels are decreased less than 2 SDs for age-adjusted reference range levels. Often, serum IgA levels are also decreased; however, IgM levels are typically within the reference range. Flow cytometry studies reveal that the percentages and numbers of CD3+ and especially CD4+ T cells may be slightly decreased but are typically normal. T-cell function assessed by delayed type hypersensitivity (DTH) and in vitro lymphoproliferative responses are normal. Percentages and numbers of CD19+ B cells may be increased; however, in the author's experience, CD27+ memory and CD27+IgD-IgM- switched B cells may be decreased.

Antibody titers to protein immunizations (eg, tetanus toxoid, diphtheria toxoid, polio) are at normal or near-normal concentrations. This distinguishes THI from more serious B- and T-cell immunodeficiency disorders. However, antibody responses to viral respiratory infections may also be decreased. Furthermore, Dalal and Roifman [9]  reported that antibody responses following immunization may be normal but may not persist on serial determinations.

In contrast to responses to protein antigens, antibody responses to polysaccharide antigens are often abnormal. In children with THI older than 2 years, Wolpert and Knutsen [14]  observed poor antibody responses to the unconjugated pneumococcal vaccine (Pneumovax); in children with THI younger than 2 years, poor antibody response to the conjugated-pneumococcal vaccine (Prevnar) was observed. [14] Dorsey et al. [3] (2006) reported that immunizations to conjugated polysaccharide antigens are often subnormal in children with THI. These authors observed decreased antibody responses to both conjugated H influenzae type B vaccine and S pneumoniae immunization in children with THI.

Memory and switched B cells should be analyzed. CD19+/CD27+ memory B cells and IgM-IgD-CD27+ switched B cells are decreased in many of the B-cell immunodeficiencies, such as CVID, HIGM syndrome, and selective antibody deficiency (SAD). Note the following:

  • Bukowska-Strakova et al. [22] analyzed memory and switched B cells in CVID, THI and selective IgA deficiency (SIgAD). Memory and switched B cells were typically decreased in 56 children with CVID but normal in 37 children with THI and in 39 children with SIgAD compared to age-matched control children age 0–7 years. However, they did observe in some children younger than 5 years with symptomatic THI, decreased memory, and switched B cells.

  • Moschese et al. [23, 18] reported decreased CD27+ memory B cells and decreased IgM-IgD-CD27+ switched B cells in children with THI older than 2 years. The investigators postulated that these children may have a permanent immunodeficiency later in life.

  • Karaca et al. [24] on the other hand found normal numbers of T cells, B cells including memory and switched B cells in 101 infants with THI. 
  • Recently, Rutkowska et al. [20] reported that CD4+CD25highFoxP3+ T-regulatory (Treg) cells were increased in patients with THI; whereas they are decreased in patients with CVID. Furthermore, as THI resolved, T-regulatory cells decreased to normal. This may be useful in differentiating THI from CVID and following THI patients as the IgG levels normalize. The mechanism of this is unknown.

  • Van Winkle et al. [25] reported that when the sum of IgG, IgA, and IgM levels is less than 81% of the sum of lower limit of age-adjusted IgG, IgA, and IgM levels, then resolution of THI is prolonged.

The phenotype of decreased IgG and decreased specific antibody deficiency has been associated with mutations of CD20, CD21, and CD81. [26, 27, 28] The serum immunoglobulin pattern of decreased IgG and IgA levels resembles X-linked hyper-IgM (XL-HIGM type 1) syndrome, autosomal recessive CD40 deficiency HIGM (type 2), and common variable immunodeficiency. In HIGM and common variable immunodeficiency, mature B cells are present. In addition, memory and switched B cells are decreased in these conditions, which may be seen in THI as well. [29]  However, a severe antibody deficiency distinguishes these conditions from THI. Deficiency of T-cell CD40 ligand (gp39, CD154) is the genetic defect in XL-HIGM, and deficiency of B-cell CD40 is the genetic defect in HIGM type 3. CD40L and CD40 can be analyzed using flow cytometry.

Deficiency of activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase (UNG) in B cells has been associated with autosomal recessive forms of HIGM that affect B cells (HIGM type 2). Gene analysis of these defects in HIGM can be analyzed by commercial laboratories that specialize in genetic defects.