Hurry up!
: : Get The Offer
Unlimited Access Step ( one, two and three ).
Priority Access To New Features.
Free Lifetime Updates Facility.
Dedicated Support.
1
Question:

A 6-year-old boy is being evaluated in the office due to a history of recurrent infections and failure to thrive.  He has been hospitalized for pneumococcal pneumonia twice and has had 5 episodes of otitis media.  The patient also has a history of prolonged diarrhea caused by Giardia intestinalis.  Physical examination shows a lack of tonsillar tissue, as well as minimally palpable cervical, axillary, and inguinal lymph nodes.  Further evaluation shows that the patient has defective signaling between activated CD4 T cells and B cells.  Which of the following laboratory findings are most likely to be found in this patient?

Hurry up!
: : Get The Offer
Unlimited Access Step ( one, two and three ).
Priority Access To New Features.
Free Lifetime Updates Facility.
Dedicated Support.


Explanation:

There are many explanatory sources, such as pictures, videos, and audio clips to explain these explanations and questions and explain the answers, but you must subscribe first so that you can enjoy all these advantages. We have many subscription plans at the lowest prices. Don't miss today's offer. Subscribe

Hyper-IgM syndrome

Genetics

  • Most commonly due to X-linked recessive CD40L deficiency

Pathophysiology

  • Impaired T-cell activation of B cells
    • Lack of immunoglobulin class switching
    • ↓ Memory B-cell production
  • Impaired T-cell interaction with APCs → lack of germinal centers

Clinical features

  • Sinopulmonary, gastrointestinal & opportunistic infections
  • Failure to thrive
  • Small lymphoid tissue

Diagnosis

  • ↑ IgM
  • ↓ IgG, IgA, IgE
  • Absent CD40L on CD4+ lymphocytes

APCs = antigen-presenting cells; CD40L = CD40 ligand.

This patient's recurrent infections, failure to thrive, and defective signaling between CD4 cells and B cells indicate hyper-IgM syndrome, a genetic disorder most often caused by mutations in CD40 ligand (CD40L).

CD40L is expressed on the surface of activated CD4 cells.  It binds to CD40 on activated B-cells, which is required for B-cells to undergo class-switch recombination, allowing them to produce IgE, IgA, or IgG instead of IgM and IgD.  Cytokines released by nearby CD4 T cells determine which isotype is produced by promoting specific splicing of the heavy-chain constant region.  The heavy-chain variable region, which binds antigenic epitopes, is unaffected.

Because patients with defects in CD40L are unable to generate significant immunoglobulins other than IgM, laboratory evaluation shows elevated IgM and absent or low IgE, IgA, and IgG.  Common manifestations of hyper-IgM syndrome include the following:

  • Sinopulmonary infections (eg, pneumonia, otitis media) due to insufficient opsonizing IgG to help clear encapsulated bacteria (eg, Streptococcus pneumoniae, Haemophilus influenzae)

  • Chronic diarrhea (eg, Giardia lamblia) due to an absence of significant IgA at the mucosal border

  • Opportunistic infections (eg, Pneumocystis, Cryptosporidium) due to impaired cell-mediated immunity from decreased antigen-presenting cell activity (CD40 is also expressed by antigen-presenting cells and helps to stimulate them)

  • Minimal lymphoid tissue (eg, lymph nodes, tonsils) due to the impaired formation of germinal centers.

Recurrent infections often result in failure to thrive.

(Choice B)  All 3 complement pathways (alternative, classical, lectin) converge on C3 convertase, which splices C3 into the anaphylatoxin C3a and the opsonizing protein C3b.  Although the alternative and lectin pathways are unaffected by hyper-IgM syndrome, the classical pathway may be mildly impaired because it relies primarily on IgG to serve as a foundation for the C1 complex.  However, complement levels tend to be normal, particularly when no acute infection present.

Educational objective:
Hyper-IgM syndrome is usually caused by a defect in CD40 ligand, which prevents B cells from undergoing class-switch recombination.  Clinical features include recurrent sinopulmonary, gastrointestinal (eg, Giardia), and opportunistic infections.  Laboratory findings include elevated IgM and low or absent IgG, IgA, and IgE.