Hyper-IgM Syndrome

The hyperimmunoglobulin M (hyper-IgM) syndrome, is a group of rare inherited immunodeficiency disorders characterized by low or absent serum levels of IgA, IgG, and IgE and normal or elevated levels of IgM. Hyper-IgM syndrome is most commonly caused by X-linked mutations in the CD40 ligand gene, which results in abnormal signaling between B and T lymphocytes. Because of the pattern of inheritance, male individuals are most commonly affected. Typically, CD40 is involved in the generation of B cells with high-affinity immunoglobulin. CD40 is also involved in the maturation of T cells. The disease has a wide range of severity, ranging from opportunistic infections in early infancy to autoimmune conditions and malignancies. Management includes immunoglobulin replacement and administration of prophylactic antimicrobial agents. The only curative approach is hematopoietic cell transplantation.

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Overview

Epidemiology

  • Very rare group of diseases
  • Prevalence: approximately 2 in every 1 million newborn boys

Pathophysiology

  • CD40 ligand is found on the surface of T cells and attaches to its receptor on the membrane of B cells, which produce antibodies. 
  • Defective CD40 leads to a defective interaction between T cells and B cells and a humoral immune response.
  • B cells are incapable of class switching, resulting in an overproduction of IgM antibodies and an underproduction of IgA, IgG, and IgE.
  • Leads to vulnerability to encapsulated bacteria and toxins

Classification

There are various conditions that belong to hyper-IgM syndrome. Because of the rareness of the syndrome, only the most common causes are mentioned below.

CD40 ligand (CD40L) deficiency

  • Combined immunodeficiency
  • Most common form of hyper-IgM syndrome
  • X-linked inheritance
  • Impaired interaction between activated CD4+ T cells expressing CD40L and cells expressing CD40

Activation-induced cytidine deaminase (AID) deficiency

  • Humoral immunodeficiency
  • 2nd most common form of hyper-IgM syndrome 
  • Autosomal recessive inheritance

CD40 deficiency

  • Combined immunodeficiency
  • Much less common than CD40L and AID deficiency
  • Autosomal recessive inheritance
  • Impaired interaction between activated CD4+ T cells expressing CD40L and cells expressing CD40

Clinical Presentation

The median age at onset for hyper-IgM syndrome is approximately 2 years. It often takes a few more years for patients to be diagnosed with the condition. Possible signs and symptoms include:

  • Recurrent sinopulmonary infections in infancy
  • Opportunistic infections, especially:
    • Pneumocystis jirovecii pneumonia (PCP)
    • Histoplasma lung infection
    • Cryptosporidium gastroenteritis
    • GI infection with Giardia lamblia
    • Hepatitis C
  • Malignancies
  • Neutropenia
  • Autoimmune disorders
  • Hypothyroidism
  • Arthritis
  • Encephalopathy (degenerative)

Diagnosis

Laboratory abnormalities

  • Low levels of IgG, IgA, and IgE in serum
  • Normal or elevated levels of IgM in serum
  • Insufficient or missing antibody response to certain protein (tetanus, diphtheria, and Haemophilus influenzae) and polysaccharide (Streptococcus pneumoniae) antigens

Confirmatory tests

  • DNA analysis to confirm mutation of CD40
  • Flow cytometry showing absent or decreased expression of CD40 ligand protein on the surface of T cells

Management and Prognosis

Management

  • CD40L and CD40 deficiency: 
    • Immunoglobulin replacement therapy → reduces risk of bronchiectasis and infections
    • Allogeneic hematopoietic cell transplantation (HCT): curative approach
    • Monitoring: regular assessment of liver parameters plus ultrasound
  • AID deficiency: 
    • Immunoglobulin replacement therapy → reduces risk of bronchiectasis and infections
    • HCT: curative approach
    • Monitoring: regular checkups to monitor for bronchiectasis and lymphoproliferative diseases

Prognosis

  • CD40L and CD40 deficiency: 
    • Most common causes of death are infections, liver disease, and malignancies.
    • Life expectation is most impacted by the presence and severity of liver disease.
    • About 60% of patients live until 20 years of age.
    • Hematopoietic cell transplantation increases survival to 90% at 20 years of age.
  • AID deficiency: 
    • Better prognosis than CD40L and CD40 deficiency
    • Regular immunoglobulin replacement therapy and early treatment of infections improve outcome significantly.

Differential Diagnosis

  • Agammaglobulinemia or hypogammaglobulinemia: condition with absent or extremely low levels of immunoglobulins. The 3 major types that have been described are X-linked, early-onset, and late-onset. Patients present with recurrent infections and have no tonsils and adenoids. Diagnosis is made by measuring reduced serum immunoglobulins and by genetic testing. Management includes replacement of immunoglobulins.
  • Common variable immunodeficiency (CVID): One of the most common primary immunodeficiency diseases caused by defective B-cell maturation and immunoglobulin production. The cause of CVID remains unknown in most cases. Patients may present with recurrent infections, lymphoid hyperplasia, splenomegaly, and malignancies. Diagnosis includes measurement of serum immunoglobulins and poor response to vaccines. 

References

  1. Qamar N, Fuleihan RL. (2014). The hyper IgM syndromes. Retrieved March 22, 2021, from https://pubmed.ncbi.nlm.nih.gov/23797640/
  2. Karaca NE, Durandy A, Gulez N, Aksu G, Kutukculer N. (2011). Study of patients with hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature. European Journal of Pediatrics 170:1039–1047. https://doi.org/10.1007/s00431-011-1400-2
  3. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ. (2009). Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunological Reviews 229:152–172. https://doi.org/10.1111/j.1600-065X.2009.00782.x 
  4. Levy J, et al. (1997). Clinical spectrum of X-linked hyper-IgM syndrome. Journal of Pediatrics 131(1 Pt 1):47–54. https://doi.org/10.1016/s0022-3476(97)70123-9

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