The clinical phenotype of interleukin 12 receptor β1 chain (IL-12Rβ1) deficiency and the function of human IL-12 in host defense remain largely unknown, due to the small number of patients reported. We now report 41 patients with complete IL-12Rβ1 deficiency from 17 countries. The only opportunistic infections observed, in 34 patients, were of childhood onset and caused by weakly virulent Salmonella or Mycobacteria (Bacille Calmette-Guérin -BCG- and environmental Mycobacteria). Three patients had clinical tuberculosis, one of whom also had salmonellosis. Unlike salmonellosis, mycobacterial infections did not recur. BCG inoculation and BCG disease were both effective against subsequent environmental mycobacteriosis, but not against salmonellosis. Excluding the probands, seven of the 12 affected siblings have remained free of case-definition opportunistic infection. Finally, only five deaths occurred in childhood, and the remaining 36 patients are alive and well. Thus, a diagnosis of IL-12Rβ1 deficiency should be considered in children with opportunistic mycobacteriosis or salmonellosis; healthy siblings of probands and selected cases of tuberculosis should also be investigated. The overall prognosis is good due to broad resistance to infection and the low penetrance and favorable outcome of infections. Unexpectedly, human IL-12 is redundant in protective immunity against most microorganisms other than Mycobacteria and Salmonella. Moreover, IL-12 is redundant for primary immunity to Mycobacteria and Salmonella in many individuals and for secondary immunity to Mycobacteria but not to Salmonella in most.
Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures.
Mutations in doublecortin ( DCX) affect the migration of neuronal precursor cells and cause subcortical band heterotopia and lissencephaly. DCX is known to bind and bundle microtubules; however, the impact of mutation on DCX function and its relation to the manifestation of DCX-associated disorders is still unclear. We analyzed the impact of DCX mutants on COS7 cell microtubule networks. We found that both mutant and wild type DCX are able to bind and bundle microtubules; however, mutants possess a decreased ability to perturb the mitotic machinery, to cause abnormal spindle orientation, and to impair mitotic progression. The magnitude of this decrease is proportional to the severity of the mutation-associated clinical symptoms, thereby providing a cell-based assay for the prognosis of DCX-associated neuronal migration disorders.
Nemaline myopathy belongs to the group of congenital non-progressive myopathies; however, in rare cases death occurs in early infancy. We report two cases of rapidly fatal nemaline myopathy. The first patient, who died at the age of 26 months, showed atrophy of type 1 fibers containing numerous rods in biopsy sections. Biopsy of the second patient, who had died at the age of 5 months, revealed severe maturational arrest and myopathy, but rods were so rare that diagnosis could only be made at the ultrastructural level. Autopsy of both patients showed that atrophy of type 1 fibers and maturational arrest had disappeared in the very same muscles; rods had moved to a central position in the first and significantly increased in number in the second case. Diaphragma muscles contained abundant amounts of rods in both cases. The cardiac musculature showed a few rods only in the first patient, who had developed heart insufficiency 11 months prior to death. Immunohistochemical analysis showed that rods did not contain desmin or ubiquitin.
Group A streptococcal (GAS) disease shows increasing incidence worldwide. We characterised children admitted with GAS infection to European hospitals and studied risk factors for severity and disability. This is a prospective, multicentre, cohort study (embedded in EUCLIDS and the Swiss Pediatric Sepsis Study) including 320 children, aged 1 month to 18 years, admitted with GAS infection to 41 hospitals in 6 European countries from 2012 to 2016. Demographic, clinical, microbiological and outcome data were collected. A total of 195 (61%) patients had sepsis. Two hundred thirty-six (74%) patients had GAS detected from a normally sterile site. The most common infection sites were the lower respiratory tract (LRTI) (22%), skin and soft tissue (SSTI) (23%) and bone and joint (19%). Compared to patients not admitted to PICU, patients admitted to PICU more commonly had LRTI (39 vs 8%), infection without a focus (22 vs 8%) and intracranial infection (9 vs 3%); less commonly had SSTI and bone and joint infections ( p < 0.001); and were younger (median 40 (IQR 21–83) vs 56 (IQR 36–85) months, p = 0.01). Six PICU patients (2%) died. Sequelae at discharge from hospital were largely limited to patients admitted to PICU (29 vs 3%, p < 0.001; 12% overall) and included neurodisability, amputation, skin grafts, hearing loss and need for surgery. More patients were recruited in winter and spring ( p < 0.001). Conclusion : In an era of observed marked reduction in vaccine-preventable infections, GAS infection requiring hospital admission is still associated with significant severe disease in younger children, and short- and long-term morbidity. Further advances are required in the prevention and early recognition of GAS disease. What is Known: • Despite temporal and geographical variability, there is an increase of incidence of infection with group A streptococci. However, data on the epidemiology of group A streptococcal infections in European children is limited. What is New: • In a large, prospective cohort of children with community-acquired bacterial infection requiring hospitalisation in Europe, GAS was the most frequent pathogen, with 12% disability at discharge, and 2% mortality in patients with GAS infection. • In children with GAS sepsis, IVIG was used in only 4.6% of patients and clindamycin in 29% of patients. Supplementary Information The online version contains supplementary material available at 10.1007/s00431-022-04718-y.
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