OVERVIEW
X-linked hyperIgMemia (XHIM) is a relatively rare primary immunodeficiency disease. It is characterized by recurrent infections with decreased serum immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE) levels and normal or elevated IgM.
Etiology
It is a rare primary immunodeficiency disease.
Symptoms
1. Infection
With the attenuation of antibodies from the mother, children with XHIM develop recurrent upper respiratory tract infections, bacterial otitis media, and pneumonia from 6 months to 2 years of age, and some rarer opportunistic infections, such as Pneumocystis carinii pneumonia and Cryptosporidium infections, can be the earliest manifestation of the disease. Gastrointestinal complications and malabsorption are also common, and Giardia and Cryptosporidium infections can lead to prolonged diarrhea. Tonsil, skin, and soft tissue infections are common, and peritracheal soft tissue infections are often life-threatening. Persistent stomatitis and recurrent oral ulcers result from neutropenia.
2. Lymphoid tissue proliferation and autoimmune diseases
Hyperplasia and enlargement of lymphoid tissues such as tonsils, spleen and liver are common manifestations of XHIM. The presence of autoantibodies is associated with thrombocytopenia, hemolytic anemia, hypothyroidism and arthritis.
3.Tumors
Lymphoid tissue tumors are the most common, accounting for 56% of XHIM tumors; liver and biliary tract tumors may also occur, which are rarely seen in other primary immunodeficiency diseases.
The diagnosis can be confirmed by the clinical features of recurrent severe infections, together with the increase of serum IgM and the decrease of IgG and IgA, as well as the corresponding changes of peripheral blood picture.
Examination
1. Immunoglobulin
Serum IgG, IgA, IgE are lacking or significantly reduced, serum IgA and IgE can be elevated in very few patients, serum IgM level is normal or up to 1000mg/ml, showing IgM polyclonal amplification. The most common cause of this disease is related to mutations in CD40L, the ligand for CD40. The CD40L mutation leads to hyperIgMemia because CD40 and CD40L do not bind properly resulting in immunoglobulin not being secreted properly, B-lymphocyte antibody class conversion disorders causing reduced levels of IgG, IgA, and IgE, and IgM being secreted even in the absence of CD40L.
Antibody responses to T-cell-dependent antigens (e.g. phage φx174) show reduced IgM antibody responses with no IgG antibody formation. b-cells stimulated by antigens have a reduced rate of mutation in the V region of surface IgM, which affects its affinity and specificity.
2. Peripheral blood immunologic examination
T cells and B cells, peripheral blood B cell count and expression of membrane IgM and IgD are normal, occasionally expressing both IgM and IgG, not expressing other types of immunoglobulins. The total T-cell count and subpopulation percentage are in the normal range, but the T-cell proliferative response is reduced.
3. Other tests
50% of children present with persistent or periodic neutropenia, and 25% have anemia and thrombocytopenia due to autoantibodies.
Diagnosis
The diagnosis is based on the clinical features of recurrent severe infections, increased serum IgM and decreased IgG and IgA, and corresponding changes in the peripheral blood picture.
Treatment
Monthly infusions of intravenous immunoglobulin (IVIG) at 500 mg/kg are important to reduce the frequency and severity of infections. If the child does not respond well, the amount and frequency of IVIG infusion can be increased. To prevent complications such as bronchiectasis, serum IgG levels should be kept at the high end of the normal IgG range. Routine IVIG infusion may result in a reduction or normalization of serum IgM levels, a return to normal growth, and the disappearance of clinical symptoms; neutropenia is relieved in some children.
Sulfamethoxazole/metronidazole (cotrimoxazole) prophylaxis is used to prevent the development of Pneumocystis carinii pneumonia. Persistent neutropenia can be treated with fexofenadine (G-CSF). Hormonal therapy may be used in children with concomitant lymphocytosis, arthritis, or other autoimmune diseases that do not respond to IVIG.
Prognosis
Overall, X-HIM has a poor prognosis. The high incidence of autoimmune diseases, intestinal disorders, neutropenia, and malignant tumors adds to the additional morbidity and mortality of the disease. Therefore, early bone marrow transplantation should be performed.