Early diagnosis of PI3Kδ syndrome in a 2 years old girl with recurrent otitis and enlarged spleen.

Heterozygous gain of function mutations in the gene encoding p110δ subunit of PI3K have been recently associated with activated PI3K-δ syndrome (APDS), a novel combined immune deficiency characterized by recurrent sinopulmonary infections, lymphopenia, reduced class-switched memory B cells, lymphadenopathy, CMV and/or EBV viremia and EBV-related lymphoma. Here we report a dominant gain of function PIK3CD mutation (E1021K) in a patient presenting with recurrent otitis media, massive splenomegaly, and persistent EBV-viraemia. The immunological studies showed low IgA level, but normal IgM, IgG, and normal antibody response to diphtheria and tetanus toxoid vaccination. Analysis of B lymphocyte subsets revealed abnormal expansion of transitional B cells, and low percentage of switched CD27+IgD- and CD27+IgD+ memory B cells. Analysis of T cell compartment unveiled prevalence of terminally differentiated cells. This study suggests that PIK3CD gain of function mutations should be suspected despite incomplete phenotype in patients with early onset splenomegaly, persistent EBV viremia and abnormal B and T cell subsets despite normal IgG levels. Currently the optimal treatment is still debated, but prompt management can hopefully diminish incidence of severe long-lasting sequelae (i.e. bronchiectasis, ear and sinus damage).

Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene.

OBJECTIVE: To analyze the long-term impact of the R92Q mutation of TNFRSF1A in children with periodic fever, in comparison with children with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with TNFRSF1A structural mutations and children with periodic fever of unknown origin fulfilling the criteria for periodic fever, aphthosis, pharyngitis, and adenitis syndrome (PFAPA). METHODS: The extracellular region of TNFRSF1A was analyzed in 720 consecutive children with periodic fever, using denaturing high-performance liquid chromatography and DNA sequencing. Followup data on 11 pediatric patients with TNFRSF1A structural mutations (cysteine or T50M), 23 pediatric patients with an R92Q substitution, and 64 pediatric patients with PFAPA were collected during routine clinic visits. The 50-item Child Health Questionnaire was used to assess health-related quality of life (HRQOL). RESULTS: The frequency of typical TRAPS-related clinical manifestations was significantly lower and the impact of the disease on HRQOL was significantly reduced in patients with the R92Q mutation compared with TRAPS patients carrying structural mutations of TNFRSF1A. Followup data on 11 TRAPS patients with TNFRSF1A structural mutations (mean followup 7.9 years), 16 patients with theR92Q substitution (mean followup 7.3 years), and 64 patients with PFAPA (mean followup 5.2 years) were available. Patients with R92Q mutations and patients with PFAPA displayed a higher rate of self-resolution or amelioration of the fever episodes than did TRAPS patients with structural mutations. CONCLUSION: Although some cases may progress to a more chronic disease course, the majority of children with an R92Q mutation of the TNFRSFA1 gene show a milder disease course than that in children with TNFRSFA1 structural mutations and have a high rate of spontaneous resolution and amelioration of the recurrent fever episodes.

A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children.

OBJECTIVE: To identify a set of clinical parameters that can predict the probability of carrying mutations in one of the genes associated with hereditary autoinflammatory syndromes. METHODS: A total of 228 consecutive patients with a clinical history of periodic fever were screened for mutations in the MVK, TNFRSF1A, and MEFV genes, and detailed clinical information was collected. A diagnostic score was formulated based on univariate and multivariate analyses in genetically positive and negative patients (training set). The diagnostic score was validated in an independent set of 77 patients (validation set). RESULTS: Young age at onset (odds ratio [OR] 0.94, P = 0.003), positive family history of periodic fever (OR 4.1, P = 0.039), thoracic pain (OR 4.6, P = 0.05), abdominal pain (OR 33.1, P < 0.001), diarrhea (OR 3.3, P = 0.028), and oral aphthosis (OR 0.2, P = 0.007) were found to be independently correlated with a positive genetic test result. These variables were combined in a linear score whose ability to predict a positive result on genetic testing was validated in an independent data set. In this latter set, the diagnostic score revealed high sensitivity (82%) and specificity (72%) for discriminating patients who were genetically positive from those who were negative. In patients with a high probability of having a positive result on genetic testing, a regression tree analysis provided the most reasonable order in which the genes should be screened. CONCLUSION: The proposed approach in patients with periodic fever will increase the probability of obtaining positive results on genetic testing, with good specificity and sensitivity. Our results further help to optimize the molecular analysis by suggesting the order in which the genes should be screened.

Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome.

OBJECTIVE: To evaluate the efficacy and safety of treatment with the interleukin-1 receptor antagonist anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS) requiring high cumulative doses of steroids. METHODS: Four children (mean age 9.1 years [range 4-13 years]) and 1 adult (age 33 years) with TRAPS were enrolled in the study. The 3 children with cysteine mutations (C52Y, C55Y, C43R) had prolonged and frequent attacks of fever. One child with the R92Q mutation and the adult patient with the C43R mutation displayed a more chronic disease course, with fluctuating, nearly continuous symptoms and persistent elevation of acute-phase reactant levels (including serum amyloid A [SAA]). All patients were treated with anakinra (1.5 mg/kg/day). RESULTS: All of the patients had a prompt response to anakinra, with disappearance of symptoms and normalization of acute-phase reactant levels, including SAA. In all pediatric patients, anakinra was withdrawn after 15 days of treatment. After a few days (mean 5.6 days [range 3-8]) a disease relapse occurred, which dramatically responded to reintroduction of anakinra. During the following period of observation (mean 11.4 months [range 4-20 months]), the patients did not experience episodes of fever or other disease-related clinical manifestations. Levels of acute-phase reactants remained in the normal range. No major adverse reactions or severe infections were observed. CONCLUSION: Continuous treatment with anakinra effectively controlled both the clinical and laboratory manifestations in patients with TRAPS and prevented disease relapses.