Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation ...in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.
•Identification of SRP54 mutations in congenital neutropenia.•SRP54 mutations induce ER stress and autophagy associated with apoptosis.
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Allogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of ...the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning busulfan, cyclophosphamide and rabbit antithymocyte globulin (ATG). Since the first report of the series (1988-2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, non-engraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft-
-host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37;
=0.002) and lower (5-15
20 mg/kg) ATG dose (hazard ratio=4.55;
=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.
Neurodegenerative (ND) complications in Langerhans cell histiocytosis (LCH) are a late‐onset but dramatic sequelae for which incidence and risk factors are not well defined. Based on a national ...prospective registry of paediatric LCH patients, we determined the incidence rate of clinical ND LCH (cND‐LCH) and analysed risk factors, taking into account disease extent and molecular characteristics. Among 1897 LCH patients, 36 (1·9%) were diagnosed with a cND‐LCH. The 10‐year cumulative incidence of cND‐LCH was 4·1%. cND‐LCH typically affected patients previously treated for a multisystem, risk organ–negative LCH, represented in 69·4% of cND‐LCH cases. Pituitary gland, skin and base skull/orbit bone lesions were more frequent (P < 0·001) in cND‐LCH patients compared to those without cND‐LCH (respectively 86·1% vs. 12·2%, 75·0% vs. 34·2%, and 63·9% vs. 28·4%). The ‘cND susceptible patients’ (n = 671) i.e., children who had experienced LCH disease with pituitary or skull base or orbit bone involvement, had a 10‐year cND risk of 7·8% vs. 0% for patients who did not meet these criteria. Finally, BRAFV600E status added important information among these cND susceptible patients, with the 10‐year cND risk of 33·1% if a BRAFV600E mutation was present compared to 2·9% if it was absent (P = 0·002).
ELANE neutropenia is associated with myelodysplasia and acute leukemia (MDS-AL), and severe infections. Because the MDS-AL risk has also been shown to be associated with exposure to GCSF, since 2005, ...in France, patients receiving high daily GCSF doses (>15 μg/kg/day) are eligible for HSCT, in addition to classic indications (MDS-AL or GCSF refractoriness). We analyzed the effect of this policy. Among 144 prospectively followed ELANE-neutropenia patients enrolled in the French Severe Congenital Neutropenia Registry, we defined two groups according to period: "before 2005" for those born before 2005 and followed until 31/12/2004 (1588 person-years); and "after 2005" comprised of those born after 2005 or born before 2005 but followed after 2005 until 31/03/2019 (1327 person-years). Sixteen of our cohort patients underwent HSCT (14 long-term survivors) and six developed MDS-ALs. Six leukemic transformations occurred in the before-2005 group and none after 2005 (respective frequencies 3.8 × 10
vs. 0; P < 0.01), while four HSCTs were done before 2005 and 12 since 2005 (respective HSCT rates increased 2.5 × 10
vs. 9 × 10
; P < 0.01). Our results support early HSCT for patients with ELANE mutations who received high GCSF doses, as it might lower the risk of leukemic transformation.
In this retrospective study, we evaluate long-term complications in nearly all β-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. ...Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5
8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient's age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia.
to evaluate the safety and efficacy of a physical activity program (PAP) in children and adolescents with cancer.
children and adolescents with cancer were randomly assigned in a 1:1 ratio to the ...six-month PAP (intervention group) or to the control group. The first evaluation was performed at the end of the PAP (T0 + 6 mo). At T0 + 6 mo, both groups received the six-month PAP with a second evaluation at T0 + 12 mo. The primary outcome was the evolution of exercise capacity measured using the six-minute walk test (6 MWT) at T0 + 6 mo. Secondary outcomes included PAP safety and changes in other physical functions, self-esteem, and quality-of-life parameters.
The trial involved 80 children and adolescents (age range 5.0-18.4 years), of whom 41 were assigned to the interventional group and 39 to the control group. Underlying malignancies were leukemia (39%) and a broad range of solid tumors (61%). No adverse events occurred. At T0 + 6 mo, the evolution of the 6 MWT distance (±SEM) was improved in the intervention group vs. the control group (86 ± 12 m vs. 32 ± 6 m,
< 0.001). Several other physical parameters were significantly improved in the intervention group. Global self-esteem and parent-reported quality-of-life were significantly increased in the intervention group. Analysis at T0 + 12 mo showed persistence of the benefits in the intervention group on exercise capacity evolution (115 ± 18 m vs. 49 ± 11 m,
= 0.004) and on most physical and QoL parameters.
In children and adolescents with cancer, a physical activity program is safe, improves exercise capacity, and may have physical and psychological benefits.
Abstract
Background
Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed.
Methods
Among ...1482 children (< 15 years) registered in the French LCH registry (1994–2018), 111 (7.4%) had lung involvement. This retrospective study included data for 17 (1.1%) patients that required one or more intensive care unit (ICU) admissions for respiratory failure.
Results
The median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease.
First-line vinblastine–corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine:
n
= 7; etoposide-aracytine:
n
= 3; targeted therapy
n
= 2). A total of 6 children (35%) died (repeated pneumothorax:
n
= 3; diffuse micronodular lung infiltration in the context of multisystem disease:
n
= 2; following lung transplantation:
n
= 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging.
Conclusions
Severe lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.
Summary
This study aimed to describe kinetics of complete donor chimerism occurrence (cDC, >99·9% donor) after unrelated cord blood transplantation (UCBT), to identify its predictive factors and its ...impact on post‐transplant outcome. Ninety‐four children who received single UCBT after a myeloablative conditioning regimen had blood chimerism evaluation at predefined post‐transplant dates, using a real‐time polymerase chain reaction method with 0·1% sensitivity. Cumulative incidence of cDC at 1 year post‐transplantation was 61·8%. Three predictive factors were identified in multivariate analysis: history of malignant disease (P = 0·03), older age (above 2·16 years, the first quartile of age, P = 0·0055) and higher level of cord/recipient human leucocyte antigen mismatch (4/6 vs. 5‐6/6, P < 0·001) increased the probability of post‐transplant cDC. Although graft cell dose had a strong impact on haematological recovery, it did not apparently influence cDC occurrence. Early cDC (i.e. more than 99·9% donor chimerism on days 15–30 post‐transplant) appeared useful to predict engraftment (P = 0·003) as well as acute and chronic graft‐versus‐host disease (GvHD). Severe acute or chronic GvHD never occurred in patients with DC ≤99·9%, suggesting than even minimal residual host haematopoiesis is associated with a very low risk of GvHD after UCBT.
Summary
We report the post‐transplant lymphocyte subset recovery of 226 children treated with Unrelated Cord Blood transplant (UCBT) (n = 112) or Unrelated Bone Marrow Transplant (UBMT) (n = 114) for ...malignant or non‐malignant diseases. Absolute numbers of natural killer (NK), B and T cells were monitored by flow cytometry up to 5 years post‐transplant. Immunological endpoints were: time to achieve a CD3+ cell count >0·5 and 1·5 × 109/l, CD4+ > 0·2 and 0·5 × 109/l, CD8+ > 0·25 × 109/l, CD19+ > 0·2 × 109/l, NK > 0·1 × 109/l. These endpoints were analysed through the use of cumulative incidence curves in the context of competing risks. CD8+ T cell recovery was delayed after UCBT with a median time to reach CD8+ T cells > 0·25 × 109/l of 7·7 months whereas it was 2·8 months in UBMT (P < 0·001). B cell recovery was better in UCBT, with a median time to reach CD19+ cells > 0·2 × 109/l of 3·2 months in UCBT and 6·4 months in UBMT (P = 0·03). Median time for CD4+ T cell and NK cell recovery was similar in UCBT and UBMT. CD4+ T cells recovery was negatively correlated to age (better reconstitution in younger patients, P = 0·002). CD8+ T cells recovery was shorter in recipients with a positive cytomegalovirus serology (P = 0·001).
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