Venous thromboembolism [TE] is a multifactorial disease and antithrombin deficiency [ATD] constitutes a major risk factor. In the present study the prevalence of ATD and the clinical presentation at TE onset in a cohort of paediatric index cases are reported. In 319 unselected paediatric patients (0.1-18 years) from 313 families, recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. 21 of 319 paediatric patients (6.6%), corresponding to 16 of 313 families (5.1%), were AT-deficient with confirmed underlying AT gene mutations. Mean age at first TE onset was 14 years (range 0.1 to 17). Thrombotic locations were renal veins (n=2), cerebral veins (n=5), deep veins (DVT) of the leg (n=9), DVT & pulmonary embolism (n=4) and pelvic veins (n=1). ATD co-occurred with the factor-V-Leiden mutation in one and the prothrombin G20210A mutation in two children. In 57.2% of patients a concomitant risk factor for TE was identified, whereas 42.8% of patients developed TE spontaneously. A second TE event within primarily healthy siblings occurred in three of 313 families and a third event among siblings was observed in one family. In an unselected cohort of paediatric patients with symptomatic TE, the prevalence of ATD adjusted for family status was 5.1%. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high risk population.

Congenital sideroblastic anaemia (CSA) is a rare disease caused by germline mutations of genes involved in haem and iron-sulphur cluster formation, and mitochondrial protein biosynthesis. We performed a retrospective multicentre European study of a cohort of childhood-onset CSA patients to explore genotype/phenotype correlations. We studied 23 females and 20 males with symptoms of CSA. Among the patients, the most frequently mutated genes were ALAS2 (n = 10; 23Á3%) and SLC25A38 (n = 8; 18Á6%), causing isolated forms of microcytic anaemia of varying severity. Five patients with SLC19A2 mutations suffered from thiamine-responsive megaloblastic anaemia and three exhibited the 'anaemia, deafness and diabetes' triad. Three patients with TRNT1 mutations exhibited severe early onset microcytic anaemia associated with thrombocytosis, and two exhibited Bcell immunodeficiency, inflammatory syndrome and psychomotor delay. The prognoses of patients with TRNT1 and SLC2A38 mutations were generally dismal because of comorbidities or severe iron overload. No molecular diagnosis could be established in 14/43 cases. This study emphasizes the frequency of ALAS2 and SLC25A38 mutations and provides the largest comprehensive analysis to date of genotype/phenotype correlations in CSA. Further studies of CSA patients with data recorded in an international registry would be helpful to improve patient management and establish standardized guidelines.

Keywords: inflammatory brain disease, cerebral vasculitis in children, pediatric acute ischemic stroke, primary angiitis of the CNS in children cPACNS, immunomodulative therapy, cerebral arteriopathies, vascular imaging

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Immune tolerance induction (ITI) in haemophilia B patients with inhibitor should be carefully considered because of the relatively poor (25%) overall success rate and the high risk of complications. ITI in combination with an immunosuppressive treatment was started in two children with haemophilia B with factor IX (FIX) inhibitor. To avoid anaphylactic reactions and inhibitor boost, the FIX replacement therapy was stopped and patients received a treatment with recombinant activated factor VII (rFVIIa). After disappearance of FIX inhibitor, a combination of mycophenolate-mofetil (MMF), dexamethasone (DEXA) and intravenous immunoglobulin (IVIG) and a high dose FIX replacement therapy was started. Immune tolerance could be induced in patient 2, whereas eradication of FIX inhibitor was incomplete in patient 1. Both patients benefited from the immune suppressive treatment and FIX replacement therapy was tolerated without any allergic complications. Neither development of a nephrotic syndrome nor a severe bleeding episode was observed. Strategies to induce tolerance in haemophilia B patients with inhibitors need to be explored in a systematic way. Given the low frequency of disease and even lower incidence of inhibitors, prospective randomized studies may not be possible. International registry-based retrospective and prospective data collection could play the key role in the study of the outcome variables in ITI for haemophilia B.