CD40 Ligand Deficiency

Excerpt

Clinical characteristics: CD40 ligand deficiency, a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of immunoglobulin (Ig) G, IgA, and IgE with normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells. Defective oxidative burst of both neutrophils and macrophages has been reported. The range of clinical findings varies, even within the same family. More than 50% of males with CD40 ligand deficiency develop symptoms by age one year, and more than 90% are symptomatic by age four years. CD40 ligand deficiency usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with faltering growth. Neutropenia is common; thrombocytopenia and anemia are less commonly seen. Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder. Significant neurologic complications, often the result of a central nervous system infection, are seen in 5%-15% of affected males. Liver disease, a serious complication of CD40 ligand deficiency once observed in more than 80% of affected males by age 20 years, may be decreasing with adequate screening and treatment of Cryptosporidium infection.

Diagnosis/testing: The diagnosis of CD40 ligand deficiency is established in a male proband with typical clinical and laboratory findings and a hemizygous pathogenic variant in CD40LG identified by molecular genetic testing.

Management: Targeted therapy: Hematopoietic stem cell transplantation (the only curative treatment currently available) is ideally performed before age ten years or prior to evidence of organ dysfunction.

Treatment of manifestations: Ig replacement therapy (either intravenous or subcutaneous); appropriate antimicrobial therapy for acute infections; antimicrobial prophylaxis for opportunistic infection against Pneumocysitis jirovecii pneumonia; recombinant granulocyte colony-stimulating factor for chronic neutropenia; immunosuppressants for autoimmune disorders.

Agents/circumstances to avoid: Areas that place the affected individual at risk of contracting Cryptosporidium including pools, lakes, ponds, or certain water sources; drinking unpurified or unfiltered water; live vaccines such as rotavirus, MMR, varicella, live attenuated polio, and BCG.

Surveillance: At least annually, complete blood count with differential to monitor for cytopenias, testing of IgG levels and lymphocyte subpopulations, and pulmonary function tests after age seven years. Regular assessment of liver function, with consideration of abdominal imaging, and polymerase chain reaction-based testing for the presence of enteric pathogens including Cryptosporidium. Monitor growth and general health with a low threshold for lymph node biopsy given elevated oncologic risk.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of newborn at-risk male relatives of an affected individual to allow early diagnosis and prompt initiation of treatment and prevention of infections.

Genetic counseling: CD40 ligand deficiency is inherited in an X-linked manner. The risk to sibs of a male proband depends on the genetic status of the mother. If the mother of the proband has a pathogenic variant in CD40LG, the chance of the mother transmitting it in each pregnancy is 50%: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes. Heterozygous females are typically asymptomatic but may have a range of clinical manifestations depending on X-chromosome inactivation. Once the CD40LG pathogenic variant has been identified in an affected family member, heterozygote testing for at-risk female relatives and prenatal/preimplantation genetic testing for CD40 ligand deficiency are possible.