Thalassemia major and sickle cell disease are the two most widely disseminated hereditary hemoglobinopathies in the world. The outlook for affected individuals has improved in recent years due to ...advances in medical management in the prevention and treatment of complications. However, hematopoietic stem cell transplantation is still the only available curative option. The use of hematopoietic stem cell transplantation has been increasing, and outcomes today have substantially improved compared with the past three decades. Current experience world-wide is that more than 90% of patients now survive hematopoietic stem cell transplantation and disease-free survival is around 80%. However, only a few controlled trials have been reported, and decisions on patient selection for hematopoietic stem cell transplantation and transplant management remain principally dependent on data from retrospective analyses and on the clinical experience of the transplant centers. This consensus document from the European Blood and Marrow Transplantation Inborn Error Working Party and the Paediatric Diseases Working Party aims to report new data and provide consensus-based recommendations on indications for hematopoietic stem cell transplantation and transplant management.
Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known ...adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.
Adenosine Deaminase 2 Deficiency (DADA2) syndrome is a rare monogenic disorder prevalently linked to recessive inherited loss of function mutations in the ADA2/CECR1 gene. It consists of an immune ...systemic disease including autoinflammatory vasculopathies, with a frequent onset at infancy/early childhood age. DADA2 syndrome encompasses pleiotropic manifestations such as stroke, systemic vasculitis, hematologic alterations, and immunodeficiency. Although skeletal abnormalities have been reported in patients with this disease, clear information about skeletal health, with appropriate biochemical-clinical characterization/management, its evolution over time and any appropriate clinical management is still insufficient. In this paper, after a general introduction shortly reviewing the pathophysiology of Ada2 enzymatic protein, its potential role in bone health, we describe a case study of two 27 year-old DADA2 monozygotic female twins exhibiting bone mineral density and bone turnover rate abnormalities over the years of their clinical follow-up.
Aim: Pediatric isolated leukopenia (IL) includes multiple conditions but data to guide evaluation of children and adolescents are scarce. The aim of this study was to investigate the underlying ...diagnoses of IL in a cohort of children and adolescents referred to our Clinic. Methods: Retrospective analysis of 134 consecutive patients with IL, evaluated and followed-up in a Pediatric Hematology Outpatient Clinic. First-level investigations included complete blood count (CBC) with differential, mean corpuscular volume (MCV), and fetal hemoglobin. Results: IL resolved in 50 subjects (37.3%). Seventy-two children (53.7%) were classified as having idiopathic leukopenia. Resolution was less likely if patients presented with more than 1 abnormality at first-level hematological investigations at the time of referral. Molecular analyses identified potential disease-causing variants in 6.7% of the patients. Autoimmune disorders (AID) and clinical primary immunodeficiencies (cPID) were common (10.4% and 9.7%, respectively). Five patients (3.7%) ultimately developed a myelodysplastic syndrome (MDS). Patients with monocytopenia and increased MCV had higher risk of developing MDS (p = 0.0002 and p = 0.0001, respectively). Conclusions: In case of recent infection without monocytopenia, increased MCV or multiple CBC abnormalities, post-infectious IL is frequent and white blood cells (WBC) fully recover. A consistent number of patients had underlying AID or cPID. Whenever leukopenia persists beyond 12 months, molecular analyses should be performed and a clonal hematopoietic disorder should be excluded.
Acquired aplastic anemia (AA) is a rare heterogeneous disease characterized by pancytopenia and hypoplastic bone marrow. The incidence is 2–3/million inhabitants/year, in Europe, but higher in East ...Asia. Survival in severe aplastic anemia (SAA) has markedly improved in the past 2decades because of advances in hematopoietic stem cell transplantation, immunosuppressive and biologic drugs, and supportive care. In SAA hematopoietic stem cell transplant (HSCT) from a matched sibling donor (MSD) is the treatment of choice. If a MSD is not available, the options include immunosuppressive therapy (IST) or unrelated donor HSCT. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of pediatric patients with AA. A preliminary, evidence-based document issued by a group of pediatric hematologists was discussed, modified and approved during a series of “Consensus Conferences” according to procedures previously validated by the AIEOP Board. The guidelines highlight the importance of referring pediatric patients with AA to pediatric centers with long experience in diagnosis, differential diagnosis, management, supportive care and follow-up of AA.
Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, including vasculitis, immunodeficiency, and hematologic ...manifestations, potentially progressing over time. The present study describes the long-term evolution of the immuno-hematological features and therapeutic challenge of two identical adult twin sisters affected by DADA2. The absence of plasmatic adenosine deaminase 2 (ADA2) activity in both twins suggested the diagnosis of DADA2, then confirmed by genetic analysis. Exon sequencing revealed a missense (p.Leu188Pro) mutation on the paternal
ADA2
allele. While, whole genome sequencing identified an unreported deletion (IVS6_IVS7del*) on the maternal allele predicted to produce a transcript missing exon 7. The patients experienced the disease onset during childhood with early strokes (Patient 1 at two years, Patient 2 at eight years of age), subsequently followed by other shared DADA2-associated features, including neutropenia, hypogammaglobulinemia, reduced switched memory B cells, inverted CD4:CD8 ratio, increased naïve T cells, reduced follicular regulatory T cells, the almost complete absence of NK cells, T-large granular cell leukemia, and osteoporosis. Disease evolution differed: clinical manifestations presented several years earlier and were more pronounced in Patient 1 than in Patient 2. Due to G-CSF refractory life-threatening neutropenia, Patient 1 successfully underwent an urgent hematopoietic stem cell transplantation (HSCT) from a 9/10 matched unrelated donor. Patient 2 experienced a similar, although delayed, disease evolution and is currently on anti-TNF therapy and anti-infectious prophylaxis. The unique cases confirmed that heterozygous patients with null ADA2 activity deserve deep investigation for possible structural variants on a single allele. Moreover, this report emphasizes the importance of timely recognizing DADA2 at the onset to allow adequate follow-up and detection of disease progression. Finally, the therapeutic management in these identical twins raises significant concerns as they share a similar phenotype, with a delayed but almost predictable disease evolution in one of them, who could benefit from a prompt definitive treatment like elective allogeneic HSCT. Additional data are required to assess whether the absence of enzymatic activity at diagnosis is associated with hematological involvement and is also predictive of bone marrow dysfunction, encouraging early HSCT to improve functional outcomes.
Neutropenia and neutrophil dysfunction in GSD-Ib have been recently ascribed to the intracellular accumulation of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) that, by inhibiting the activity of ...hexokinases, limits the phosphorylation of glucose and derails the glycolytic pathway, essential for the immunometabolic activation and the patrolling activity function of these cells 3. ...it was speculated that empagliflozin, beyond the mere effect in increasing absolute neutrophil count (ANC), might promote the polarization toward specific neutrophil subtypes in patients affected by GSD-Ib 8. TABLE 1 Clinical characteristics of glycogen storage disease type Ib (GSD-Ib) patients at basal evaluation and under empagliflozin treatment P1, M, 10y P2, M, 9y P3, M, 11y P4, F, 16y Variants in SLC37A4 c.92_94delTCT homozygous c.902A > C, c.985-2A > G heterozygous c.1042_1043delCT homozygous c.1124_del2 homozygous Empagliflozin final dose, mg/kg/d 0.4 mg/kg/d 0.5 mg/Kg/d 0.6 mg/kg/d 0.5 mg/kg/d G-CSF, mcg/kg/wk BL: 13,3, stop d31 BL: 19,6 stop d15 BL: 18, UE: 7,5 BL/UE: 45 Median ANC, 109/L BL: 1.59 UE: 2.16 BL: 4.4 UE: 3.14 BL: 0.32 UE:13.0 BL: 1.16 UE: 0.9 Infections before empagliflozin treatment Recurrent otitis Not reported Sepsis, Clostridium difficile infection, pneumonia with right pleural effusion Not reported Skin and mucosal lesions BL/UE: absent BL: mucosal bleeding UE: absent BL: recurrent aphthous stomatitis. Recently, it has been reported that empagliflozin may reduce the burden of inflammatory conditions in GSD-Ib patients 4, 8 and we observed an improvement in IBD in two patients, it is tempting to speculate that the benefit on inflammation resulting from the treatment with empagliflozin n GSD-Ib patients could be related to the reduction of this specific neutrophil subset, known to increase during either chronic and acute immunoinflammatory stresses 11.
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