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Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

Autoimmune hemolytic anemia (AIHA) is a rare hematologic disorder in the pediatric population and most cases are associated with microbiological infection. The pathological process is not completely clear, but some evidence suggests immunological dysregulation triggered by bacterial or viral infections. Based on the thermal range of the pathogenic antibody, AIHA can be divided into warm (WAIHA) and cold (CAIHA) groups. Cytomegalovirus (CMV) is one of the most common viruses reported as a trigger of AIHA. We present an unusual case of AIHA in a 2-month-old infant positive for both the direct antiglobulin test (C3 complement fraction) and CMV–Polymerase chain reaction in blood samples. In this case, the dating of the infection was uncertain, making it impossible to discriminate between congenital flare-up or a primary acute episode, emphasizing the importance of CMV prenatal testing as a screening measure. We adopted multiple therapeutic strategies including steroids (methylprednisolone and prednisone), Intravenous Immunoglobulin, antivirals (ganciclovir and valganciclovir), and red blood cell transfusion.

Background: Asparaginase (ASPase) plays an important role in the therapy of acute lymphoblastic leukemia (ALL). Serum ASPase activity (SAA) can be modified and even abolished by host immune responses; therefore, current treatment guidelines recommend to monitor SAA during treatment administration. The SAA monitoring schedule needs to be carefully planned to reduce the number of samples without hampering the possibility of measuring pharmacokinetics (PK) parameters in individual patients. Complex modelling approaches, not easily applicable in common practice, have been applied in previous studies to estimate ASPase PK parameters. This study aimed to estimate PK parameters by using a simplified approach suitable for real-world settings with limited sampling. Methods: Our study was based on 434 patients treated in Italy within the AIEOP-BFM ALL 2009 trial. During the induction phase, patients received two doses of pegylated ASPase and were monitored with blood sampling at five time points, including time 0. PK parameters were estimated by using the individually available SAA measurements with simple modifications of the classical non-compartmental PK analysis. We also took the opportunity to develop and validate a series of limited sampling models to predict ASPase exposure. Results: During the induction phase, average ASPase activity at day 7 was 1380 IU/L after the first dose and 1948 IU/L after the second dose; therapeutic SAA levels (>100 IU/L) were maintained until day 33 in 90.1% of patients. The average AUC and clearance were 46,937 IU/L × day and 0.114 L/day/m2, respectively. The database was analyzed for possible associations of PK parameters with biological characteristics of the patients, finding only a limited dependence on sex, age and risk score; however, these differences were not sufficient to allow any dose or schedule adjustments. Thereafter the possibility of further sampling reduction by using simple linear models to estimate the AUC was also explored. The most simple model required only two samplings 7 days after each ASPase dose, with the AUC being proportional to the sum of the two measured activities A(7) and A(21), calculated by the formula AUC = 14.1 × [A(7) + A(21)]. This model predicts the AUC with 6% average error and 35% maximum error compared to the AUC estimated with all available measures. Conclusions: Our study demonstrates the feasibility of a direct estimation of PK parameters in a real-life situation with limited and variable blood sampling schedules and also offers a simplified method and formulae easily applicable in clinical practice while maintaining a reliable pharmacokinetic monitoring.

Background. Few data are available on quarterly 11.25 mg GnRH analog treatment in central precocious puberty (CPP). Aim. To assess the efficacy of triptorelin 11.25 mg in children with CPP. Patients. 17 patients (16 females) with CPP (7.9±0.9 years) were treated with triptorelin 11.25 mg/90 days. Methods. Gonadotropins, basal-, and GnRH-stimulated peak, gonadal steroids, and pubertal signs were assessed at preinclusion and at inclusion visit, 3 months, 6 months, and 12 months of treatment. Results. At 3, 6, and 12 months, all patients had suppressed LH peak (<3 IU/L after GnRH stimulation), as well as prepubertal oestradiol levels. Mean LH peak values after GnRH test significantly decreased from 25.7±16.5 IU/L at baseline to 0.9±0.5 IU/L at M3 (P<0.0001); they did not significantly changed at M6 and M12. Conclusions. Triptorelin 11.25 mg/90 days efficiently suppressed the pituitary-gonadal axis in children with CPP from first administration.

Pediatric T-cell acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of childhood ALL. It is associated with a high risk of relapse, with ~25% of patients failing conventional therapy. Resistance is driven by pro-survival signaling, impaired apoptosis, and metabolic adaptations that sustain leukemic proliferation under stress. Herein, we investigate the role of β3-adrenergic receptor (β3-AR) antagonist SR59230A signaling in the metabolic reprogramming and therapeutic vulnerability of pediatric T-ALL. β3-AR expression and transcriptomic profiling following SR59230A exposure were assessed in T-ALL cell lines by RNA sequencing, followed by gene set enrichment analysis of Gene Ontology and Hallmark pathways. Metabolic alterations were validated by Seahorse analyses of mitochondrial respiration, glycolysis, fatty acid oxidation (FAO), and fuel dependency. Systemic iron metabolism was evaluated by ferritin and free iron quantification using COBAS8000. β3-AR was markedly upregulated in T-ALL cells compared with normal hematopoietic counterparts, identifying a selective metabolic vulnerability. Pharmacologic inhibition of β3-AR with SR59230A affected mitochondrial oxidative phosphorylation, predominantly complex I, and suppressed FAO. The metabolic collapse disrupted bioenergetic flexibility and triggered ferroptotic cell death. This was accompanied by modulation of ferritin and transferrin levels, suggesting their potential role as biomarkers of metabolic response. Importantly, β3-AR blockade sensitized T-ALL cells to oxidative phosphorylation inhibition, resulting in synergistic cytotoxicity in refractory models. Collectively, these findings identify β3-AR as a central regulator of metabolic plasticity in pediatric T-ALL highlighting metabolic and iron-dependent vulnerabilities as potential combined targets for high-risk disease.

Autoimmune hemolytic anemia (AIHA) is a rare hematologic disorder in the pediatric population and most cases are associated with microbiological infection. The pathological process is not completely clear, but some evidence suggests immunological dysregulation triggered by bacterial or viral infections. Based on the thermal range of the pathogenic antibody, AIHA can be divided into warm (WAIHA) and cold (CAIHA) groups. Cytomegalovirus (CMV) is one of the most common viruses reported as a trigger of AIHA. We present an unusual case of AIHA in a 2-month-old infant positive for both the direct antiglobulin test (C3 complement fraction) and CMV–Polymerase chain reaction in blood samples. In this case, the dating of the infection was uncertain, making it impossible to discriminate between congenital flare-up or a primary acute episode, emphasizing the importance of CMV prenatal testing as a screening measure. We adopted multiple therapeutic strategies including steroids (methylprednisolone and prednisone), Intravenous Immunoglobulin, antivirals (ganciclovir and valganciclovir), and red blood cell transfusion.

Objective: The association between celiac disease (CD) and immune thrombocytopenia (ITP) is still uncertain. The aim of this study was to characterize the coexistence of these two diseases in Italian children. Materials and Methods: This is a retrospective multicenter study investigating the occurrence of CD in 28 children with ITP diagnosed from January 1, 2000, to December 31, 2019. Results: The first diagnosis was ITP in 57.1% and CD in 32.1% of patients. In 3 patients (10.7%), the two diagnoses were simultaneous. All the potential and silent cases of CD in our cohort were diagnosed in the groups of \"ITP first\" and \"simultaneous diagnosis\". In all children ITP was mild, and in 2 out of 8 not recovered from ITP at the time of CD diagnosis a normalization of platelet counts (>100,000/[micro]L) occurred 3 and 5 months after starting a gluten-free diet, respectively. Conclusion: We think that screening for CD should be considered in children with ITP regardless of the presence of gastrointestinal symptoms. Furthermore, some patients may recover from ITP after starting a gluten-free diet. Keywords: Celiac, Children, Immune, Thrombocytopenia, Pediatric Amac: Immun trombositopeni (ITP) ve colyak hastaligi (CH) arasindaki iliski hala belirsizligini korumaktadir. Bu calismanin amaci Italyan cocuklarinda bu iki hastalik arasindaki iliskiyi ortaya koymaktir. Gerec ve Yontemler: Bu calisma, 1 Ocak 2000'den 31 Aralik 2019'a kadar ITP tanisina ek olarak CH tanisi alan 28 cocugun arastirildigi geriye donuk cok merkezli bir calismadir. Bulgular: Hastalarin %57,1'inde ilk tani ITP ve %32,1'inde CH idi. Uc hastada (%10,7) iki tani ayni anda konulmustu. Kohortumuzdaki tum potansiyel ve sessiz CH olgulari \"once ITP\" ve \"eszamanli tani\" gruplarinda teshis edildi. Tum cocuklarda ITP hafifti ve CH tanisi sirasinda trombositopenisi devam eden 8 cocuktan 2'sinde, glutensiz diyete basladiktan sonra sirasiyla 3 ve 5 ayda trombosit sayilarinda normallesme (>100.000/[micro]L) goruldu. Sonuc: Bu calisma ITP'li cocuklarda gastrointestinal semptomlarin varligina bakilmaksizin CH taramasinin yapilmasi gerektigini dusundurmektedir. Bazi hastalarda trombosit sayilarinin glutensiz bir diyete basladiktan sonra duzelebilecegi akilda bulundurulmalidir. Anahtar Sozcukler: Colyak, Cocuklar, Immun, Trombositopeni, Pediatrik

Background: The association between inflammatory bowel disease (IBD) and immune thrombocytopenia (ITP) is still uncertain. In this multicenter retrospective study, the coexistence of both diseases was investigated in children diagnosed from 1 January 2000 to 31 December 2019. Methods: Clinical characteristics of both IBD and ITP, onset of disorders, and patient’s response to treatment were collected through a structured form sent to 55 Italian pediatric referring centers for hematological disorders. Result: Centers responded to the survey and reported the coexistence of IBD and ITP in 14 children. The first diagnosis was ITP in 57.1% and IBD in 35.7% of patients: it was simultaneous in 7.1%. IBD was classified as ulcerative colitis (57.1%), Crohn disease (35.7%), and unclassified (7.1%). No therapy for IBD other than steroids had any effect on ITP course. Colectomy resulted in recovery from ITP in 1 of the 2 patients surgically treated. ITP was always mild but turned to be chronic in half of patients. Conclusions: In all patients, ITP was mild without any evident impact on IBD severity, but the incidence of chronic ITP seems to be higher than what is usually observed in the pediatric age group. Colectomy had unpredictable effects on ITP.

Abstract Background/Aim: In children with central precocious puberty (CPP), gonadotropin-releasing hormone (GnRH) analogue treatment has been associated with an increase in body mass index (BMI). We evaluated BMI and body composition in adolescents treated with GnRH analogue at their near final height to assess the long-term effects of therapy on these parameters. Patients and Methods: We studied 20 patients (14.8 ± 1.6 years; 17 females) previously treated with triptorelin depot for CPP (3.75 mg/28 days) from 8.1 ± 0.8 to 11.5 ± 0.8 years. 23 healthy adolescents with normal onset of puberty (14.7 ± 2.1 years, 19 females) were the controls. BMI and body composition (dual-energy x-ray absorptiometry) were assessed. Results: Patients reached their near adult height (–0.5 ± 1.1 standard deviation score (SDS)); the girls were menstruating and the majority (15/17) had regular cycles, the boys showed normal testicular function. BMI was unchanged from the start of GnRH analogue therapy (0.4 ± 1.0 SDS) to near adult height (0.2 ± 1.0 SDS, p = NS vs. 0). Total fat mass (TFM) was significantly increased (16,144 ± 8,065 g; controls 10,712.1 ± 4,120.4 g, p < 0.02); glucose homeostasis and lipid profile corresponded to reference ranges. Conclusions: GnRH analogue therapy did not show long-term detrimental effects on BMI, but it may increase TFM, suggesting that body composition should be monitored till adulthood.