Updated: 1/6/2018

Hyper IgM Syndrome

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Snapshot
  • A 6-month-old boy presents with a past medical history of skin infections presents with difficulty breathing, high fever, and nonproductive cough. He is immediately started on broad-spectrum antibiotics. On further questioning, his family history includes a maternal uncle dying at age 20 from overwhelming pneumonia. Sputum is induced with hypertonic saline inhalation, and eventual staining shows Pneumocystis. He is immediately started on IVIG.
Introduction
 

  • Inherited primary combined B- and T-cell immunodeficiency characterized by increased levels of IgM
  • Genetics
    • X-linked recessive
    • mutation in gene that codes for CD40 ligand (CD40L)
  • Pathogenesis
    • CD40L is expressed on activated T-helper cells
    • defect in humoral immunity
      • CD40L is necessary to induce B-cells to undergo Ig class-switching 
        • from IgM to IgG, IgA, and IgE
        • see illustration above
    • defect cell-mediated immunity
      • CD40L also required for maturation of T-cells, dendritic cells, and macrophages
  • Symptoms onset by 1 year, often with Pneumocystis infections
    • most diagnosed before 4 years
Presentation
  • Symptoms
    • severe pyogenic infections early in life
    • chronic diarrhea
    • opportunistic infections
      • pneumonia
      • Pneumocystis
      • Cryptosporidium
      • CMV
      • echovirus encephalitis
    • pancytopenia common
      • fatigue
      • infection
      • pallor
      • bleeding
Evaluation
  • Ig levels
    • ↑ IgM
    • ↓ IgA, IgG, and IgE
    • due to defect in class-switching
  • Diagnosis confirmed with flow cytometry
    • deficient expression of CD40L on activated T-helper cells
    • normal T- and B-cells
  • CBC
    • neutropenia
    • thrombocytopenia possible
Differential Diagnosis
  • Bruton agammaglobulinemia
  • CVID
  • SCID
Treatment
  • Prophylaxis of Pneumocystis
  • Regular IVIG replacement
Prognosis, Prevention, and Complications
  • Prognosis
    • 20% survival rate past young adulthood
    • leading cause of death
      • pneumonia
      • encephalitis
      • malignancy
  • Complications
    • increased risk of autoimmunity
    • increased risk of malignancies
      • HCC
      • carcinoid tumor
    • infection
    • bronchiectasis
 

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Questions (4)
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(M1.IM.15.74) A 15-month-old is referred to a pediatric immunologist by his pediatrician for further workup of recurrent sinopulmonary infections which have not abated despite adequate treatment. During the workup flow cytometry demonstrates a decrease in normal CD40L cells. Based on these findings, the immunologist decides to pursue a further workup and obtains immunoglobulin levels. Which of the following immunoglobulin profiles is most likely to be observed in this patient? Tested Concept

QID: 106685
1

Increased IgE; Decreased IgG, IgM

4%

(8/192)

2

Decreased IgE, IgM, IgA, IgG

10%

(19/192)

3

Increased IgE, IgA; Decreased IgM

6%

(11/192)

4

Increased IgE

2%

(4/192)

5

Increased IgM; Decreased IgG, IgA, IgE

76%

(146/192)

M 2 E

Select Answer to see Preferred Response

(M1.IM.14.126) A 3-year-old boy presents to the pediatrics clinic for follow-up. He has a history of severe pyogenic infections since birth. Further workup revealed a condition caused by a defect in CD40 ligand expressed on helper T cells. This congenital immunodeficiency has resulted in an inability to class switch and a poor specific antibody response to immunizations. Which of the following best characterizes this patient's immunoglobulin profile? Tested Concept

QID: 105524
1

Increased IgE

0%

(0/54)

2

Decreased IgA

2%

(1/54)

3

Decreased Interferon gamma

2%

(1/54)

4

Increased IgE and IgA; and decreased IgM

2%

(1/54)

5

Increased IgM; decreased IgG, IgA, and IgE

91%

(49/54)

M 2 D

Select Answer to see Preferred Response

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Evidence (3)
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