OVERVIEW

What is Hyper IgM Syndrome?

Hyper IgM Syndrome, also known as Hyperimmunoglobulin M Syndrome, refers to a group of disorders characterized by elevated (or normal) serum IgM levels and reduced levels of other immunoglobulins (IgA, IgG, IgE) due to various causes. Patients may exhibit weakened immunity and increased susceptibility to infections.

What conditions can cause elevated serum IgM in Hyper IgM Syndrome?

A range of genetic disorders, congenital rubella syndrome, T-cell leukemia or lymphoma, and even oral phenytoin sodium can lead to increased blood IgM levels.

What are the most common types of Hyper IgM Syndrome?

• CD40L deficiency (Hyper IgM Syndrome Type 1)
• CD40 deficiency (Hyper IgM Syndrome Type 3)
• AID deficiency (Hyper IgM Syndrome Type 2)
• UNG deficiency (Hyper IgM Syndrome Type 5)
• Hyper IgM Syndrome Type 4.

Is Hyper IgM Syndrome common?

Hyper IgM Syndrome is a rare disease. The incidence of CD40L deficiency is 2 in 1,000,000; the exact prevalence of AID deficiency is unknown but estimated at 1 in 1,000,000; CD40 deficiency and UNG deficiency have only been reported in isolated cases.

SYMPTOMS

What are the manifestations of Hyper IgM Syndrome Type 1 or Hyper IgM Syndrome Type 3?

Patients with Hyper IgM Syndrome Type 1 or Hyper IgM Syndrome Type 3 share similar characteristics, leading to both humoral and cellular immune deficiencies, known as "combined immunodeficiency." The manifestations include:

• Recurrent sinopulmonary infections, such as frequent pneumonia, sinusitis, and otitis media.
• About one-third of patients experience chronic diarrhea starting in infancy (persistent or recurrent long-term diarrhea).
• Increased susceptibility to sclerosing cholangitis, liver cirrhosis, and cholangiocarcinoma, which may occur in childhood and could be related to Cryptosporidium parvum or cytomegalovirus infection.
• Higher risk of infections like Cryptococcus, Toxoplasma, and JC virus, leading to neurological disorders such as meningoencephalitis or progressive multifocal leukoencephalopathy.
• Common occurrences of cellulitis, sepsis, osteomyelitis, and aphthous stomatitis.
• Increased likelihood of gastrointestinal and pancreatic neuroectodermal tumors, as well as liver cancer and cholangiocarcinoma as mentioned earlier.
• Possible childhood osteoporosis, resulting in a higher risk of fractures.
• Greater susceptibility to autoimmune diseases, leading to inflammatory bowel disease or cytopenia.
• Lack of antibody response to protein antigens (tetanus, diphtheria, and Haemophilus influenzae type B) and polysaccharide antigens (Streptococcus pneumoniae), meaning vaccination fails to provide immunity against these diseases.

What are the manifestations of Hyper IgM Syndrome Type 2?

Hyper IgM Syndrome Type 2 primarily causes humoral immune deficiency.

Since it does not affect cellular immunity, it does not lead to lymph tissue deficiencies such as absent tonsils seen in CD40L deficiency. The manifestations of Hyper IgM Syndrome Type 2 include:

• Recurrent sinopulmonary infections, such as frequent pneumonia, sinusitis, and otitis media.
• Increased risk of bronchiectasis due to repeated infections.
• Common occurrences of meningitis, cellulitis, lymphadenitis, and gastrointestinal infections.
• Possible lymphoid hyperplasia, such as abnormally enlarged tonsils.
• About 20% of patients develop autoimmune diseases, leading to cytopenia, hepatitis, inflammatory bowel disease, or arthritis.
• Lack of antibody response to protein antigens (tetanus, diphtheria, and Haemophilus influenzae type B) and polysaccharide antigens (Streptococcus pneumoniae), meaning vaccination fails to provide immunity against these diseases.

What are the manifestations of Hyper IgM Syndrome Type 4 and Hyper IgM Syndrome Type 5?

Hyper IgM Syndrome Type 5 exhibits similar manifestations to Hyper IgM Syndrome Type 2. Hyper IgM Syndrome Type 4 also resembles Type 2 but is slightly milder in severity.

CAUSES

What are the causes of Hyper IgM Syndrome?

A range of genetic disorders, congenital rubella syndrome, T-cell leukemia or lymphoma, and even oral phenytoin sodium can lead to elevated IgM levels.

Which genetic diseases can cause Hyper IgM Syndrome?

• Activated phosphoinositide 3-kinase syndrome (Activated PI3K-δ syndrome);
• PMS2 deficiency;
• MutS homolog 6 (MSH6) deficiency;
• Ataxia-telangiectasia;
• Nijmegen breakage syndrome;
• Common variable immunodeficiency;
• CD40L deficiency, also known as Hyper IgM Syndrome type 1;
• CD40 deficiency, also known as Hyper IgM Syndrome type 3;
• Activation-induced cytidine deaminase (AID) deficiency, also known as Hyper IgM Syndrome type 2;
• Uracil N-glycosylase (UNG) deficiency, also known as Hyper IgM Syndrome type 5;
• Downstream class switch recombination defects in the switch (S) region DNA cleavage;
• Hyper IgM Syndrome type 4 with an unknown molecular basis.

How is Hyper IgM Syndrome inherited?

The most common form of Hyper IgM Syndrome, CD40L deficiency, follows an X-linked recessive inheritance pattern, meaning female carriers typically do not develop the disease, while affected males with the pathogenic gene will manifest symptoms.

The second most common form, AID deficiency, generally follows an autosomal recessive inheritance pattern.

UNG deficiency and CD40 deficiency also exhibit autosomal recessive inheritance, meaning only individuals with two pathogenic genes will develop the disease.

DIAGNOSIS

What abnormal results would be observed in laboratory tests for Hyper IgM Syndrome Type 1 or Hyper IgM Syndrome Type 3?

• Significantly reduced serum IgG and IgE levels (though in children under 4 months, IgG may not show a significant decline due to maternal IgG transfer).
• Normal or elevated serum IgM levels (approximately 50% of CD40L-deficient patients may have normal or even decreased serum IgM levels).
• Markedly reduced serum IgA levels (occasionally, CD40L-deficient patients may have normal serum IgA levels).
• Total B lymphocyte count is normal, but memory (CD27+) B lymphocytes are significantly reduced, and switched memory (IgD-CD27+) B lymphocytes are absent.
• Two-thirds of CD40L-deficient patients develop neutropenia, 15–32% have anemia, and 4% exhibit thrombocytopenia.
• CD40-deficient patients also display dendritic cell/monocyte defects.

What abnormal results would be observed in laboratory tests for Hyper IgM Syndrome Type 2 or Hyper IgM Syndrome Type 5?

• Significantly reduced serum IgG, IgA, and IgE levels (though in children under 4 months, IgG may not show a significant decline due to maternal IgG transfer).
• Normal or elevated serum IgM levels.
• Total B lymphocyte count is normal, but memory (CD27+) B lymphocytes are significantly reduced, and switched memory (IgD-CD27+) B lymphocytes are absent.

What abnormal results would be observed in laboratory tests for Hyper IgM Syndrome Type 4?

Similar to AID deficiency or UNG deficiency, but residual IgG production capacity may result in less noticeable IgG decline.

How is Hyper IgM Syndrome Type 1 diagnosed?

A preliminary diagnosis of CD40L-deficient Hyper IgM Syndrome can be made in males presenting with reduced serum IgG levels, normal or elevated serum IgM levels, and opportunistic infections.

Further confirmation requires:

• For infants under 6 months, genetic testing is necessary for diagnosis, as CD40L expression in CD4+ lymphocytes may be variably reduced in this age group.
• For older children, immunological analysis can confirm impaired CD40L expression on CD4+ T cells upon in vitro activation.
• For cases with high clinical suspicion of CD40L deficiency but normal anti-CD40L monoclonal antibody staining, genetic testing is also required.

Due to the inheritance pattern of CD40L deficiency, females typically do not exhibit CD40L defects. If a female presents with reduced serum IgG, normal or elevated IgM levels, and opportunistic infections, CD40 deficiency should be considered.

How is Hyper IgM Syndrome Type 3 diagnosed?

When a patient shows reduced serum IgG, normal or elevated IgM levels, and opportunistic infections, suggesting possible CD40L/CD40 deficiency, further confirmation requires:

• For females (who generally do not have CD40L deficiency), flow cytometry to assess CD40 expression.
• For males, after confirming normal CD40L (as described in the previous question), flow cytometry to assess CD40 expression.
• In rare cases where flow cytometry shows CD40 expression but clinical suspicion remains high, genetic testing is necessary.

How are Hyper IgM Syndrome Type 2 and Hyper IgM Syndrome Type 5 diagnosed?

Diagnosis relies on genetic testing.

How is Hyper IgM Syndrome Type 4 diagnosed?

There is no definitive diagnostic test; diagnosis is primarily made by excluding other genetic defects.

TREATMENT

Which department should be consulted for Hyper IgM Syndrome?

Rheumatology and Immunology, Infectious Diseases.

How is Hyper IgM Syndrome treated?

First, be vigilant against complications such as infections and treat them early if detected. Therefore, it is recommended:

• Check liver function every 4–6 months and perform a liver ultrasound at least once a year to detect liver complications early.
• Test for Cryptosporidium and Microsporidium in stool using PCR every 6 months to detect infections early. If detected, promptly use azithromycin or nitazoxanide to prevent progression.

Since patients generally have humoral immune deficiency, it is recommended:

• Administer intravenous immunoglobulin (IVIG) every 3–4 weeks at a dose of 400–600 mg/kg body weight. The interval should not exceed 4 weeks but also not be shorter than 2 weeks.
• Long-term oral co-trimoxazole for infection prevention. For AID deficiency, UNG deficiency, and Hyper IgM Syndrome type 4 patients without cellular immune defects, prophylactic antibiotics are necessary to treat chronic complications (including bronchiectasis, recurrent sinusitis, etc.).
• Subcutaneous recombinant human granulocyte colony-stimulating factor (G-CSF) for chronic severe neutropenia or severe infections.
• Recombinant CD40L therapy for those with biliary Cryptosporidium infection.

CD40L or CD40-deficient patients may also undergo hematopoietic stem cell transplantation (HSCT) for a cure, particularly suitable for younger patients without liver disease and those who have received myeloablative conditioning.

Early HSCT can prevent chronic liver disease.

What is the treatment efficacy for Hyper IgM Syndrome?

CD40L or CD40-deficient patients have both humoral and cellular immune defects. IVIG therapy alone can only improve humoral immunity but does not address existing cellular immune deficiencies.

Thus, the current best strategy is early HSCT before chronic liver disease develops, which offers a relatively better prognosis.

For AID deficiency and UNG deficiency patients, who only have humoral immune defects, IVIG therapy combined with active anti-infection treatment provides good prevention.

DIET & LIFESTYLE

What should patients with Hyper IgM Syndrome pay attention to in daily life?

Primarily, follow medical advice for regular check-ups and minimize exposure to infections. For example, maintain personal hygiene; avoid bathing in rivers, lakes, or unchlorinated pools to reduce the risk of Cryptosporidium infection as much as possible.

PREVENTION

Can Hyper IgM Syndrome Be Prevented?

Individuals with a family history of Hyper IgM Syndrome are advised to seek genetic counseling before planning a pregnancy. This helps predict the likelihood of their offspring developing the condition and aims to prevent the birth of children with Hyper IgM Syndrome.