Clinical dose effect and functional consequences of R92Q in two families presenting with a TRAPS/PFAPA-like phenotype.

BACKGROUND: TNF receptor-associated syndrome (TRAPS) is a dominantly inherited autoinflammatory condition caused by mutations in the TNFRSF1A gene. The mechanism underlying the variable expressivity of the common variant R92Q (rs4149584; c.362G>A; p.Arg121Gln) is unclear and is of critical importance for patient care and genetic counseling. This study evaluated the impact of the number of R92Q mutations in two unique unrelated families. METHODS: Two patients with undefined but clear autoinflammatory symptoms were referred for genetic diagnosis. Blood samples were collected from the available family members to screen autoinflammatory genes and assess key steps of the TNFR1-mediated signaling pathway using flow cytometry and ex vivo culture. RESULTS: R92Q homozygosity was demonstrated for the two probands. In family 1, the segregation analysis revealed TRAPS-like symptoms in all carriers, with a more severe presentation in the proband, whereas in family 2, the heterozygous parents were totally asymptomatic, suggesting recessive transmission. Functional studies revealed a nonclassical pathogenesis of TRAPS in the two probands and suggested a compensatory mechanism without clear dose effect. CONCLUSION: We observed for the first time a possible clinical dose effect of R92Q. This work highlights the importance of familial studies to reconcile the contradictory reports published on the pathogenicity of this variant.

Invasive pneumococcal disease in children can reveal a primary immunodeficiency.

BACKGROUND: About 10% of pediatric patients with invasive pneumococcal disease (IPD) die from the disease. Some primary immunodeficiencies (PIDs) are known to confer predisposition to IPD. However, a systematic search for these PIDs has never been carried out in children presenting with IPD. METHODS: We prospectively identified pediatric cases of IPD requiring hospitalization between 2005 and 2011 in 28 pediatric wards throughout France. IPD was defined as a positive pneumococcal culture, polymerase chain reaction result, and/or soluble antigen detection at a normally sterile site. The immunological assessment included abdominal ultrasound, whole-blood counts and smears, determinations of plasma immunoglobulin and complement levels, and the evaluation of proinflammatory cytokines. RESULTS: We included 163 children with IPD (male-to-female ratio, 1.3; median age, 13 months). Seventeen children had recurrent IPD. Meningitis was the most frequent type of infection (87%); other infections included pleuropneumonitis, isolated bloodstream infection, osteomyelitis, endocarditis, and mastoiditis. One patient with recurrent meningitis had a congenital cerebrospinal fluid fistula. The results of immunological explorations were abnormal in 26 children (16%), and a PID was identified in 17 patients (10%), including 1 case of MyD88 deficiency, 3 of complement fraction C2 or C3 deficiencies, 1 of isolated congenital asplenia, and 2 of Bruton disease (X-linked agammaglobulinemia). The proportion of PIDs was much higher in children aged >2 years than in younger children (26% vs 3%; P < .001). CONCLUSIONS: Children with IPD should undergo immunological investigations, particularly those aged >2 years, as PIDs may be discovered in up to 26% of cases.

Human bocavirus infection in children with respiratory tract disease.

BACKGROUND: Human bocavirus (HBoV) is a ubiquitous, newly described member of the Parvoviridae family frequently detected in the respiratory tract of children, but only few reports provide data proving the link between HBoV and respiratory tract disease (RTD). OBJECTIVES: To evaluate the incidence of HBoV infection in children with RTD; to analyze the clinical features of HBoV infection; and to clinically compare HBoV, respiratory syncytial virus (RSV), and human metapneumovirus (HMPV) infections. STUDY DESIGN: A prospective 1-year study was conducted in children <5 years of age hospitalized with RTD and in asymptomatic control children. RESULTS: Human bocavirus was detected in 55 (10.8%) of the 507 children tested and in none of the 68 asymptomatic control children (P = 0.01). About 80% of these infections occurred between November and March. Coinfection with another virus was observed in 22 (40%) of the HBoV-positive children. HBoV viral load was significantly higher in samples from children with HBoV monoinfection than in those with coinfection. Subsequent detection of HBoV more than 2 months after the initial detection could be documented in 3 children. Clinical features associated with HBoV infection were similar to those observed with either RSV or HMPV infections, but HBoV infections were less severe than RSV infections. CONCLUSIONS: The difference observed in HBoV prevalence between children with RTD and controls provides support for a role of this virus in RTD. The frequent associations of HBoV with other respiratory viruses might be explained by the persistence of HBoV in the respiratory tract. The significance of HBoV viral load in nasopharyngeal secretions as a marker of pathogenicity merits further investigation.

Human metapneumovirus infection in young children hospitalized with respiratory tract disease.

BACKGROUND: Human metapneumovirus (hMPV) is a newly recognized pathogen associated with respiratory tract disease (RTD). OBJECTIVES: To evaluate the incidence of hMPV infection in children hospitalized with RTD and to analyze the virologic and clinical features of hMPV infection. STUDY DESIGN: All children younger than 5 years of age hospitalized for RTD were included in this 1-year prospective study. hMPV was detected in nasopharyngeal secretions by reverse transcription polymerase chain reaction. The hMPV F gene amplification products were sequenced, and a phylogenetic tree was constructed. Samples were also tested for other respiratory viruses by both direct immunofluorescence assay and virus culture. RESULTS: hMPV, detected in 50 of 589 (8.5%) children, represented the second leading cause of RTD after respiratory syncytial virus (RSV). Infections with hMPV occurred mainly between December and April. hMPV isolates clustered into the 4 subgroups (A1, A2, B1 and B2) currently recognized; the majority (72%) of hMPV isolates belonged to subgroup A1. Among the 35 children infected with hMPV alone, 23 (65.7%) had bronchiolitis, 5 (14.3%) had pneumonia, 2 (5.7%) had asthma exacerbation and 5 (14.3%) had a limited upper RTD. Fifteen (30%) of the hMPV-infected children were coinfected with RSV. As compared with children infected with hMPV or RSV alone, duration of hospitalization and requirement for supplemental oxygen were increased in the hMPV/RSV-coinfected children. CONCLUSIONS: hMPV is a frequent cause of RTD in young children. hMPV/RSV coinfection is frequent and could be more severe than a single hMPV or RSV infection.