Immunodeficiency Without Anhidrotic Ectodermal Dysplasia

A number sign (#) is used with this entry because a form of X-linked pure immunodeficiency is caused by mutation in the NF-kappa-B essential modulator (NEMO) gene (IKBKG; 300248) on chromosome Xq28.

Clinical Features

Orange et al. (2004) described a 15-year-old boy with a specific pattern of infectious susceptibility and immunodeficiency. He did not have ectodermal dysplasia and had normal dentition, hair pattern, and perspiration. He had pneumonia 4 times between the ages of 3 and 7 years and Haemophilus influenzae type b sepsis at age 5 years. He had a normal total IgG level, but IgG3 levels that were never greater than 10 mg/dL and no specific antibody against tetanus toxoid (despite receiving immunization) or H influenzae polyribosyl phosphate, and thus he was treated with immunoglobulin replacement. Despite receiving this therapy, a lesion on his abdomen developed at age 13 years, which was composed of granulomatous tissue, contained acid-fast bacilli, and grew Mycobacterium bovis when cultured.

The patient described by Niehues et al. (2004) was the only child of healthy unrelated Polish parents living in Germany. From the age of 15 months, he suffered from multiple episodes of disseminated Mycobacterium avium disease (affecting mostly lymph nodes and bones). At the age of 7 years, he was diagnosed with bronchiectasis caused by Haemophilus influenzae and Streptococcus pneumoniae. At the age of 11 years, the patient presented extraintestinal disease caused by Salmonella enteritidis. At the age of 12, he developed severe autoimmune hemolytic anemia and died from herpes simplex virus 1 meningoencephalitis. Immunologic workup showed low IgA and IgG levels, with markedly high serum IgM levels. No serum antibodies against diphtheria toxoid and tetanus toxoid were detected, and titers of antibodies against H. influenzae were low despite complete routine vaccination. The patient also presented low serum titers of antibodies against S. pneumoniae and had no allohemagglutinin antibodies. Known molecular causes of hyper IgM syndrome (308230) were excluded. The numbers of T, B, and NK lymphocytes and the proportions of the CD4+ and CD8+ T lymphocyte subsets were within normal ranges at the ages of 2 and 4 years. However, the patient lacked memory B cells. The proliferative responses of T lymphocytes to mitogens were normal.

Molecular Genetics

Orange et al. (2004) found that the patient described by them had a splice mutation in the IKBKG gene that resulted in the skipping of exon 9, with a premature stop codon inserted at position 373 of the NEMO protein (300248.0018). Puel et al. (2006) found a 1-bp insertion in exon 2 of the NEMO gene (300248.0019) in the patient reported by Niehues et al. (2004).