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Background: In Fanconi anemia bone marrow failure is the major cause of morbidity and mortality and hematopoietic stem cell transplantation represents the only curative treatment. Liver disease, in terms of elevated liver function tests, as well as benign and malignant liver tumors, occurs especially in case of androgen treatment. We report a unique case of a child with Fanconi anemia with FANCD2 mutation who developed neonatal cryptogenic liver cirrhosis and bone marrow failure. The child successfully underwent sequential liver transplantation and hematopoietic stem cell transplantation in the first 2 years of life. Nineteen months after hematopoietic stem cell transplantation and 30 months after liver transplantation, the patient is clinically well with normal hematopoietic function and excellent liver function. Conclusion: This is the first FA patient who successfully received sequential LT and HSCT highlighting that successful sequential transplantation is feasible in Fanconi anemia patients. [ABSTRACT FROM AUTHOR]

Treosulfan is an immuno-suppressive and myeloablative alkylating agent that has been introduced as a conditioning agent in stem cell transplantation (SCT). Most studies have been performed in adult patients with malignancy where a low incidence of regimen-related toxicity has been reported. We report the use of treosulfan in 32 consecutive children undergoing SCT for non-malignant disease. Patients received a total treosulfan dose of 36 or 42 g/m2/patient given in three daily, divided doses. A range of other conditioning agents and serotherapy was administered to patients who underwent family donor SCT ( n = 11), or unrelated donor SCT ( n = 21). One patient (3%) died early. Transplant morbidity was limited and mucositis was only mild. Dermatological toxicity was frequent but mild. Twenty-eight patients (87·5%) established donor cell engraftment. In 25 patients (78%) there was adequate, stable donor engraftment. Four patients have required additional transplant procedures to maintain adequate donor-derived haemopoiesis. Twenty-seven patients (84%) survive with a median follow up of 417 d. There were four late deaths due to progression of the underlying disease, graft-versus-host disease or infection. Treosulfan-based conditioning regimens achieve excellent engraftment with reduced regimen-related toxicity in children with non-malignant disease at high risk for both regimen-related toxicity and graft failure. [ABSTRACT FROM AUTHOR]

We report on six patients who developed diabetes mellitus after hematopoietic cell transplantation (HCT). The prevalence in our cohort of long-term survivors after HCT performed below 18 yr of age was 3%. The median age at onset of diabetes was 22.4 yr (range 11.3–34.4). The median period between HCT and diabetes was 10.1 yr (range 5.6–22.1). Five out of the six patients received total irradiation therapy and five had other endocrinological abnormalities. The onset of diabetes in all patients was insidious and none had diabetic ketoacidosis. Body mass indexes at diabetes onset were within normal levels. The clinical and laboratory features that characterized our patients with diabetes after HCT make it difficult to classify them as having type-1 or type-2 diabetes. The relatively high prevalence of diabetes and its insidious onset in this group of patients, advocate clinicians to evaluate carefully even slight variations in fasting blood glucose, usually included in the routine biochemistry follow-up. These data also suggest that HbA1c and oral glucose-tolerance test should be added to the follow-up program of late complications if fasting blood glucose levels are slightly increased. [ABSTRACT FROM AUTHOR]

GATA2 deficiency is a rare disorder encompassing a broadly variable phenotype and its clinical picture is continuously evolving. Since it was first described in 2011, up to 500 patients have been reported. Here, we describe a cohort of 31 Italian patients (26 families) with molecular diagnosis of GATA2 deficiency. Patients were recruited contacting all the Italian Association of Pediatric Hematology and Oncology (AIEOP) centers, the Hematology Department in their institution and Italian societies involved in the field of vascular anomalies, otorhinolaryngology, dermatology, infectious and respiratory diseases. Median age at the time of first manifestation, molecular diagnosis and last follow-up visit was 12.5 (age-range, 2–52 years), 18 (age-range, 7–64 years) and 22 years (age-range, 3–64), respectively. Infections (39%), hematological malignancies (23%) and undefined cytopenia (16%) were the most frequent symptoms at the onset of the disease. The majority of patients (55%) underwent hematopoietic stem cell transplantation. During the follow-up rarer manifestations emerged. The clinical penetrance was highly variable, with the coexistence of severely affected pediatric patients and asymptomatic adults in the same pedigree. Two individuals remained asymptomatic at the last follow-up visit. Our study highlights new (pilonidal cyst/sacrococcygeal fistula, cholangiocarcinoma and gastric adenocarcinoma) phenotypes and show that lymphedema may be associated with null/regulatory mutations. Countrywide studies providing long prospective follow-up are essential to unveil the exact burden of rarer manifestations and the natural history in GATA2 deficiency. [ABSTRACT FROM AUTHOR]

Intermittent granulocyte maturation arrest, hypocellular bone marrow, and episodic normal neutrophil count can be associated with SRP54 mutations causing Shwachman-Diamond-like syndrome Keywords: inborn error of immunity; severe congenital neutropenia; Shwachman-Diamond syndrome; SRP54 EN inborn error of immunity severe congenital neutropenia Shwachman-Diamond syndrome SRP54 e171 e174 4 05/19/20 20200515 NES 200515 Congenital neutropenias (CN) are rare heterogeneous inborn errors of immunity (Fig 1A).[[1]] Recently, I SRP54 i mutations have been described in patients with profound and chronic neutropenia associated with Shwachman-Diamond Syndrome (SDS) (OMIM #260400) phenotype (Fig 2A).[[3], [5]] SRP54 is an evolutionarily conserved signal recognition particle (SRP) involved in ribosomal protein translation. Finally, we think it should be emphasised that an I SRP54 i mutation should be considered in the differential diagnosis of patients with suspected congenital neutropenia, occasionally normal neutrophil count and absence of maturation block at the promyelocyte/myelocyte stage in the bone marrow. [Extracted from the article]

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 2 decades 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. [ABSTRACT FROM AUTHOR]

Eighty-two children and adolescents who underwent allogeneic transplantation for acute lymphoblastic leukaemia in remission (period 2001-2011, median follow-up 4·9 years) had been assessed for minimal residual disease ( MRD) by real-time quantitative polymerase chain reaction before and at 1, 3, 6, 9 and 12 months after transplantation. Five-year event-free survival ( EFS) and cumulative incidence of relapse were 77·7% [standard error ( SE) 5·7] and 11·4% ( SE 4·4), respectively, for patients with pre-transplant MRD <1 × 10−4 (68%), versus 30·8% ( SE 9·1; P < 0·001) and 61·5% ( SE 9·5; P < 0·001), respectively, for those with MRD ≥1 × 10−4 (32%). Pre-transplant MRD ≥1 × 10−4 was associated with a 9·2-fold risk of relapse [95% confidence interval ( CI) 3·54-23·88; P < 0·001] compared with patients with MRD <1 × 10−4. Patients who received additional chemotherapy pre-transplant to reduce MRD had a fivefold reduction of risk of failure (hazard ratio 0·19, CI 0·05-0·70, P = 0·01). Patients who experienced MRD positivity post-transplant did not necessarily relapse (5-year EFS 40·3%, SE 9·3), but had a 2·5-fold risk of failure ( CI 1·05-5·75; P = 0·04) if any MRD was detected in the first 100 d, which increased to 7·8-fold ( CI 2·2-27·78; P = 0·002) if detected after 6 months. Anticipated immunosuppression-tapering according to MRD may have improved outcome, nevertheless all patients with post-transplant MRD ≥1 × 10−3 ultimately relapsed, regardless of immunosuppression discontinuation or donor-lymphocyte-infusion. In conclusion, MRD before transplantation had the strongest impact on relapse and MRD positivity after transplantation, mostly if detected early and at low levels, did not necessarily imply relapse. Additional intensified chemotherapy and modulation of immunosuppression may reduce relapse risk and improve ultimate outcome. [ABSTRACT FROM AUTHOR]

Despite advances in graft-versus-host-disease (GVHD) treatment, it is estimated that overall survival (OS) at 2 years for hematopoietic cell transplantation (HCT) recipients who experience steroid-resistant GVHD is 10%. Among recent therapeutic approaches for GVHD treatment, mesenchymal stromal cells (MSCs) hold a key position. We describe a multicenter experience of 11 pediatric patients diagnosed with acute or chronic GVHD (aGVHD, cGVHD) treated for compassionate use with GMP-grade unrelated HLA-disparate donors'' bone marrow-derived MSCs, expanded in platelet-lysate (PL)-containing medium. Eleven patients (aged 4-15 years) received intravenous (i.v.) MSCs for aGVHD or cGVHD, which was resistant to multiple lines of immunosuppression. The median dose was 1.2 × 106/kg (range: 0.7-3.7 × 106/kg). No acute side effects were observed, and no late side effects were reported at a median follow-up of 8 months (range: 4-18 months). Overall response was obtained in 71.4% of patients, with complete response in 23.8% of cases. None of our patients presented GVHD progression upon MSC administration, but 4 patients presented GVHD recurrence 2 to 5 months after infusion. Two patients developed chronic limited GVHD. This study underlines the safety of PL-expanded MSC use in children. MSC efficacy seems to be greater in aGVHD than in cGVHD, even after failure of multiple lines of immunosuppression. [Copyright &y& Elsevier]

A letter to the editor is presented on off-label use of granulocyte colony-stimulating factor in noncongenital neutropenia.

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. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 4-year-old girl who was referred to a hospital due to leukoneutropenia and recurrent pneumonia. Hypogammaglobulinemia was indicated through immunological evaluation and bone marrow aspiration showed granulocytic hyperplasia. The condition is generally treated with granulocyte colony-stimulating factor (G-CSF) therapy.

Reports that prognosis of patients with acute lymphoblastic leukemia (ALL) relapsing after hematopoietic cell transplantation is poor. Controversy regarding the efficacy of donor lymphocyte infusions in patients with ALL; Detailed description of medical history of the three-month-old child suffering from ALL; Treatment regimen of the infant; Factors contributing to the poor prognosis of the child after hematopoietic cell transplantation.