Reduced AKT activation accompanied with high TP53 expression is implicated in the impaired hematogenesis in Ziegler-Huang syndrome and the Znt7 null mice partially recapitulates the human disease linked to pancytopenia

BackgroundInherited bone marrow failure (IBMF) is a life-threatening condition. Excessive expression of TP53 induces cell cycle arrest and apoptosis of hematopoietic cells in individuals with IBMF. We recently discovered two pathogenic variants, NM_001144884:c.21dup;p.(Asp8ArgfsTer3) and NM_001144884:c.842 + 15 T > C, in ZNT7 associated with IBMF (Ziegler-Huang Syndrome; BMF8). However, the pathophysiologic mechanism of IBMF caused by ZNT7 mutations remained unknown.MethodWe investigated TP53 expression and the activation of its upstream regulator, AKT, in cell lines from affected individuals. We rescued the wild-type phenotype of AKT activation via transduction of wild-type ZNT7 into patient's fibroblasts. We performed fluorescence microscopy to assess co-expression patterns of ZNT7 with hematopoietic cell markers in different human and mouse bone marrow cell types. Finally, we evaluated the hematological features of Znt7 deficient mice.ResultsThe growth of patient's EBV-transformed B (B-EBV) lymphoblasts was impaired. We observed excessive expression of TP53 in the patient's B-EBV lymphoblasts accompanied by a significant decrease in AKT activation. Importantly, overexpression of wild-type ZNT7 in patient's fibroblasts rescued the activation of the AKT pathway by insulin. Additionally, human ZNT7 was expressed in myeloid and lymphoid lineage cells, whereas mouse ZnT7 was mainly expressed in the nucleated hematopoietic cells in the respective bone marrow. Despite these differences, we observed progressive cytopenia in Znt7KO mice, partially recapitulating BMF8 in humans.ConclusionExcessive expression of TP53 and down-regulation of AKT activation induced by ZNT7 deficiency might impair cell survival, which may contribute to the pathophysiology of bone marrow failure in affected individuals with BMF8

Long-term kidney complications in childhood leukemia survivors: a study from the Childhood and Adolescent Leukaemia (LEA) project

Acute leukaemias represent the 1st cause of cancer in children. Their prognosis has improved significantly due to remarkable advances in therapeutic management, despite the risk of long-term consequences, especially for patients who underwent allogenic hematopoietic stem cell transplantation (aHSCT). Through the Leukaemia in Children and Adolescents (LEA) long-term follow-up cohort, we conducted a French national multicentre prospective study on the occurrence and risk factors of chronic kidney disease (CKD), differentiating glomerular and tubular dysfunctions, corresponding to the NephroLEA project. Among the 1676 patients included, the median [interquartile range] age at evaluation was 15.8 [11.3-20.5] years, with a median follow-up of 9.2 [5.8-13.9] years. aHSCT was performed on 343 (20.6%) patients, half of whom have undergone the procedure after achieving 2nd or greater remission. A higher percentage of children among transplanted patients had diastolic and systolic blood pressure above 95th, with 13.7% vs 5.2% (P =3x10-3) and 15% vs 6.5% (P = 9x10-2), respectively. A total of 187 patients (11.1%) had a mild CKD (i.e., eGFR between 75 and 90 mL/min/1.73 m2), while 3% (n=50) exhibited mild to severe CKD (eGFR < 75 mL/min/1.73 m2). Notably, no patient reached kidney failure. Twenty-one patients (1.3%) had decreased GFR associated with tubular impairment. The principal risk factors for developing CKD were aHSCT and leukaemia relapse. In conclusion, CKD represents a long-term risk for patients who relapsed and/or underwent aHSCT. These patients could benefit from nephroprotection advice to further improve their long-term outcomes, which is becoming a public health issue

Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity

Background: Activated phosphoinositide-3-kinase d syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain of-function (GOF) disease; and identify predictors of severity in APDS. Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs. Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS. Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients. (J Allergy Clin Immunol 2023;152:984-96.

Characterization of greater middle eastern genetic variation for enhanced disease gene discovery

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia1-3, has resulted in an elevated burden of recessive disease4. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics

Evaluation de la thymopoïèse des enfants et adultes traités pour un lymphome de Hodgkin à distance d'un traitement par radiothérapie médiastinale

ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Causes, devenir et thérapeutiques des malades avec hypogammaglobulinémie

L hypogammaglobulinémie est un déficit de l immunité humorale qui est caractérisée par une altération de la production d anticorps aussi appelés immunoglobulines. On classe les étiologies des hypogammaglobulinémies suivant la pathologie ou le trouble qui occasionne une diminution des Immunoglobulines de type G en particulier. Si le Déficit Immunitaire Commun Variable (DICV) est le plus fréquent des déficits primitifs, il faut savoir que de nombreux déficits secondaires ont une origine médicamenteuse. La problématique infectieuse est très importante chez ces patients, notamment au niveau pulmonaire, ORL et digestif. La prise en charge de ce type de déficit immunitaire passe par deux thérapeutiques phares, l antibioprophylaxie et la substitution en immunoglobulines injectables. Le diagnostic précoce d hypogammaglobulinémie permet d améliorer le pronostic des patients et de proposer une prise en charge adaptée. Notre étude porte sur les caractéristiques étiologiques des hypogammaglobulinémies, les devenirs et thérapeutiques des patients suivis au CHU d Angers entre 2005 et 2010, pour lesquels le dosage d IgG en 2005 était inférieur à la normale.ANGERS-BU Médecine-Pharmacie (490072105) / SudocSudocFranceF

Le syndrome de Wiskott-Aldrich

International audienceW iskott-Aldrich syndrome (WAS) is a primary immunode- ficiency disorder, characterized by a classic triad of microthrombocytopenia, eczema and infections. It is a monogenic X-linked recessive disorder. X-linked thrombocy- topenia (XLT) is now part of this syndrome with clinical forms initially described as less severe, but whose non-serious evolution is now questioned. WAS/XLT usually occurs during childhood, but a neonatal onset is possible. This pathology is associated with an increased risk of autoimmune manifesta- tions and onco-hematological complications which can occur regardless of the initial severity. The first manifestations are hemorrhagic (petechiae, bruising, purpura, epistaxis, oral or intracranial bleeding, bloody diarrhea). The second characte- ristic is acute or chronic eczema. Due to the immune deficiency, there are infectious manifestations (airways, digestive tract, skin) due to conventional or opportunistic bacteria. The severity of the disease, in addition to severe infectious complications, is linked to autoimmune manifestations in more than 40% of cases (hemolytic anemia and/or autoimmune neutropenia, vasculitis, inflammatory colitis, glomerulopathy, inflammatory joint pathologies). Patients with WAS also have an increased risk of developing tumors (especially lymphomas) at any age. Therapeutic progress in recent years are based on better management of complications, better results of bone marrow transplantation and development of gene therapy