Invasive Pneumococcal Disease, Recurrent Isolated, 1

A number sign (#) is used with this entry because recurrent isolated invasive pneumococcal disease (IPD1) can be caused by mutation in the IRAK4 gene (606883). Another form of this disorder (IPD2; 300640) is caused by mutation in the NEMO gene (300248). Protection against IPD has been associated with a coding single-nucleotide polymorphism (SNP) in the TIRAP gene (606252.0001).

Description

Recurrent invasive pneumococcal disease (IPD) is defined as 2 episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains (Ku et al., 2007). Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.

Clinical Features

Ku et al. (2007) described 2 otherwise healthy children with isolated recurrent IPD as the only clinical infectious manifestation of an inherited disorder in nuclear factor kappa-B (see 164011)-dependent immunity. One was found to carry a hemizygous mutation in the NEMO gene (see IPD2, 300640). The other was a 7-year-old boy born to unrelated Hungarian parents. He received immunizations with no complications. At age 3 years, he developed arthritis of the right hip caused by Streptococcus pneumoniae serotype 14. He was successfully treated with intravenous antibiotic for 12 days. At age 5.5 years, he developed meningitis caused by Streptococcus pneumoniae serotype 14, with moderate headache and a slightly high temperature. The patient recovered without sequelae after treatment for 12 days with intravenous antibiotic. He had no other bacterial, viral, or fungal disease. Poor clinical and biologic inflammatory responses during infectious episodes and antipolysaccharide antibody deficiency suggested genetic defects in Toll-like receptor (TLR) (see 603030)-NF-kappa-B-mediated immunity. Fibroblasts showed no response to interleukin-1-beta (147720), but normal responses to TNF-alpha (191160), stimulation; overall, responses suggested a defect in TLR and IL1R signaling pathways. He was immunized with the heptavalent pneumococcal conjugate vaccine and with a 23-valent pneumococcal vaccine, and prescribed monthly intravenous immunoglobulin infusions. He remained well with no further infections to the time of the report.

Molecular Genetics

In a 7-year-old boy born of unrelated Hungarian parents, Ku et al. (2007) found that recurrent invasive pneumococcal disease (IPD1; 610799) was related to compound heterozygosity for 2 mutations in the IRAK4 gene, located in the intron between exons 10 and 11: 1189-1G-T and 1188+520A-G (606883.0005). The authors noted that this patient was the first in whom noncoding mutation in the IRAK4 gene had been found.

Autosomal recessive IRAK4 deficiency (607676) and X-linked recessive NEMO deficiencies (e.g., 300291, 300584) are primary immunodeficiencies that affect NF-kappa-B-mediated immunity and cause a relatively broad susceptibility to infections. The patients described by Ku et al. (2007) displayed none of the other known infectious phenotypes associated with these disorders.

Khor et al. (2007) found that heterozygous carriage of a leucine substitution at ser180 of the TIRAP gene (606252.0001) associated independently with protection against 4 infectious diseases, including invasive pneumococcal disease, in several different study populations.