Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

ObjectiveTo develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA).MethodsA multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA–associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference.ResultsExperts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best‐performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ = 0.76).ConclusionWe have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.

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The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily char- IntroductionThe study of human T-cell primary immunodeficiencies has enabled the molecular characterization of many diseases caused by Mendelian inheritance of mutated genes [1][2][3][4] and has revealed the function of key molecules in T-cell biology. SCIDs are characterized by complete lack of T-cell development and, in some conditions, developmental blocks on other lymphoid lineages. 1,2 Several mechanisms can leads to faulty T-cell differentiation, such as the premature death of progenitor cells and impaired ␥c-dependent cytokine signaling, VDJ recombination, or pre-TCR signaling. 1 In other forms of T-cell primary immunodeficiency, TCR-mediated T-cell activation is defective but T-cell differentiation is partially or fully preserved. The latter variously include deficiencies in DOCK8, ZAP-70, ITK, ORA1, and STIM-1, all of which are involved in the signaling cascade downstream of the TCR, and in molecules involved in the NFB pathway, such as NEMO and IKB␣. 2,5,6 These conditions are collectively referred to as combined immunodeficiencies (CIDs), because the functional consequences also include defective Ab production.The molecular signatures of many more T-cell immunodeficiency phenotypes have yet to be identified. In the present study, we describe a new form of human CID observed in 4 patients from 2 families that is primarily characterized by a dramatically reduced pool of circulating naive T cells and impaired in vitro survival of the T-lymphocyte population. These patients were shown to carry homozygous mutations in the serine-threonine protein kinase 4 (STK4) gene, coding for the ubiquitously expressed mammalian sterile 20-like protein MST1. Methods Case reportsPatient F1P1 was born to a consanguineous family of Turkish origin (see Figure 1A). Since the age of 2, he had suffered from recurrent skin and lower respiratory tract infections caused by Streptococcus pneumoniae and Haemophilus influenzae, leading to bronchiectasis, recurrent perioral herpes simplex infections with positive anti-HSV1-2 IgG titer, Varicella zoster virus (VZV) infections, and extensive molluscum contagiosum. In addition, the patient had chronic EBV infection with persistent EBV viremia (53 000 copies/mL at the age of 11 years) and positive anti-EBNA-1 and anti-VCA IgG Ab. At the age of 5, patient F1P1 was successfully treated for EBV ϩ Hodgkin B-cell lymphoma. The patient (now 17) is receiving Ig replacement therapy and anti-infective prophylaxis with antibiotics and antivirals. Apart from lymphocytopenia, his blood counts are consistently normal. A CT scan of the thymus performed at 11 years of age was normal in appearance, structure, and size compared with agematched controls. He has no dysmorphic syndrome and his growth was within the normal range.Family F2 is consanguineous and of Turkish origin, with 3 children affected ( Figu...

Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.

Objective Mevalonate kinase deficiency (MKD) is a rare metabolic disease characterized by recurrent inflammatory episodes. This study was undertaken to describe the genotype, phenotype, and response to treatment in an international cohort of MKD patients. Methods All MKD cases were extracted from the Eurofever registry (Executive Agency for Health and Consumers project no. 2007332), an international, multicenter registry that retrospectively collects data on children and adults with autoinflammatory diseases. Results The study included 114 MKD patients. The median age at onset was 0.5 years. Patients had on average 12 episodes per year. Most patients had gastrointestinal symptoms (n = 112), mucocutaneous involvement (n = 99), lymphadenopathy (n = 102), or musculoskeletal symptoms (n = 89). Neurologic symptoms included headache (n = 43), cerebellar syndrome (n = 2), and mental retardation (n = 4). AA amyloidosis was noted in 5 patients, almost twice as many as expected from findings in previous cohorts. Macrophage activation syndrome occurred in 1 patient. Patients were generally well between attacks, but 10–20% of the patients had constitutional symptoms, such as fatigue, between fever episodes. Patients with p.V377I/p.I268T compound heterozygosity had AA amyloidosis significantly more often. Patients without a p.V377I mutation more often had severe musculoskeletal involvement. Treatment with nonsteroidal antiinflammatory drugs relieved symptoms. Steroids given during attacks, anakinra, and etanercept appeared to improve symptoms and could induce complete remission in patients with MKD. Conclusion We describe the clinical and genetic characteristics of 114 MKD patients, which is the largest cohort studied so far. The clinical manifestations confirm earlier reports. However, the prevalence of AA amyloidosis is far higher than expected.

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