Br J Haematol

Acquired haemophilia A (AHA) is a rare haemorrhagic disease characterised by new-onset haemorrhagic symptoms associated with a dramatic decrease in factor VIII levels and an anti-factor VIII neutralising autoantibody concentration >0.6 Bethesda units. Elderly people are often affected, whereas children are rarely affected; the paediatric incidence reported in the literature is about 0.045 case/million/year. For some time, the paediatric standard of care has been that for adults, but clinicians have often reported poor outcomes. Here, we describe the largest retrospective paediatric AHA cohort assembled to date, including eight patients diagnosed in France from 2000 to 2020

Type I interferon-mediated autoinflammation due to DNase II deficiency

Microbial nucleic acid recognition serves as the major stimulus to an antiviral response, implying a requirement to limit the misrepresentation of self nucleic acids as non-self and the induction of autoinflammation. By systematic screening using a panel of interferon-stimulated genes we identify two siblings and a singleton variably demonstrating severe neonatal anemia, membranoproliferative glomerulonephritis, liver fibrosis, deforming arthropathy and increased anti-DNA antibodies. In both families we identify biallelic mutations in DNASE2, associated with a loss of DNase II endonuclease activity. We record increased interferon alpha protein levels using digital ELISA, enhanced interferon signaling by RNA-Seq analysis and constitutive upregulation of phosphorylated STAT1 and STAT3 in patient lymphocytes and monocytes. A hematological disease transcriptomic signature and increased numbers of erythroblasts are recorded in patient peripheral blood, suggesting that interferon might have a particular effect on hematopoiesis. These data define a type I interferonopathy due to DNase II deficiency in humans

Ostéonécrose et drépanocytose, impact de différentes thérapeutiques (chirurgie, programme transfusionnel, greffe de moelle)

La drépanocytose est la plus fréquente des hémoglobinopathies au monde. Elle est responsable de complications multi-viscérales parfois sévères. L ostéonécrose est une atteinte fréquente et engageant le pronostic fonctionnel des patients atteints. Nous avons étudié 45 patients ayant une ostéonécrose au sein d une cohorte pédiatrique de 571 patients drépanocytaires. Il s agit d une étude rétrospective dont l objectif est d étudier l évolution de ces ostéonécroses de hanches, d épaules et du rachis. Cette évolution est retracée à partir des clichés de radiographies standard et d IRM réalisées chez ces patients. Au sein de cette cohorte pédiatrique, l ostéonécrose atteint 7,8% des patients. L âge moyen de survenue est de 12 ans. Le facteur de risque principal est le nombre de crises vaso-occlusives. La symptomatologie principale est la douleur. L évolution naturelle - notamment au niveau de la hanche - se fait vers l aggravation progressive, jusqu à l arthrose, qui atteint alors de jeunes patients. Cette étude aura pour but de décrire l évolution des différentes ostéonécroses après prise en charge thérapeutique : chirurgie orthopédique, programme transfusionnel et greffe de moelle. En effet, pour éviter l aggravation des ostéonécroses, il faut aussi réduire le phénomène vaso-occlusif ; le traitement doit être associé à la prise en charge globale de la maladie drépanocytaire.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Pituitary stalk interruption syndrome in 53 postpubertal patients: factors influencing the heterogeneity of its presentation.

BACKGROUND: Pituitary stalk interruption syndrome (PSIS) may induce an isolated growth hormone (GH) deficiency or multiple hypothalamic-pituitary (HP) deficiencies. Patients with multiple HP deficiencies, primarily those with adrenocorticotropin (ACTH) deficiency, are at increased risk of morbidity and mortality. Our objective was to identify the factors influencing each symptom and the MRI features of the syndrome to enhance its diagnosis and genetic analysis. METHODS: This study was a retrospective, single-center, case-cohort study of 53 patients with PSIS who had reached pubertal age. RESULTS: Patients were classified as having an isolated GH deficiency (n = 24, Group 1) or HP deficiencies (n = 29, Group 2); of these, 19 had complete HP deficiency, and 10 had GH deficiency associated with TSH (n = 4), TSH and ACTH (n = 3), TSH and gonadotropin (n = 1) deficiencies or amenorrhea (n = 2). The following features were less frequent in Group 1 than in Group 2: breech presentation (4% vs 35%, P = 0.008), hypoglycemia (0% vs 59%, P<0.00001), micropenis (13% vs 69%, P<0.003), hypothalamic origin (0% vs 52%, P<0.000001), ophthalmic malformation (8% vs 38%, P<0.02) and psychomotor delay (0% vs 31%, P<0.004). The frequencies of all other malformations were similar in both groups (37% vs 59%). A visible pituitary stalk was characteristic of patients belonging to Group 1 (P<0.0002). The GH peak was greater in Group 1 than in Group 2 (P<0.0003), as was the anterior pituitary height (P = 0.01). CONCLUSION: The factors that best discriminate patients with multiple HP deficiencies from those with an isolated GH deficiency are breech presentation, hypoglycemia, and micropenis. No patient with an isolated GH deficiency had psychomotor delay, but associated malformations and/or syndromes, with the exception of ophthalmic disorders, occurred with similar frequencies in both groups. We have also shown that each of the above characteristics is associated with a given HP deficiency and/or malformation/syndrome in the majority of cases

Characteristics of the patients with isolated GH deficiency.

<p>Breech delivery, low Apgar score and IUGR only in case 8.</p><p>Cesarean section in case 15 because his mother’s haemophilia.</p><p>Cryptorchidism in cases 8 and 17.</p

Characteristics of the patients with multiple HP deficiencies.

<p>Prematurity in cases 27,32,41.</p><p>Cesarean section in cases 25,29,48,49.</p><p>IUGR in case 40.</p><p>Amenorrhea primary in cases 29,35,42,43 and 52 and secondary in case 53.</p

Management of von Willebrand disease with a factor VIII‐poor von Willebrand factor concentrate: Results from a prospective observational post‐marketing study

International audienceBackground A triple-secured plasma-derived von Willebrand factor (pdVWF) almost devoid of factor VIII (FVIII):WILFACTIN(R), was approved in France in 2003, and then in other countries for the treatment of patients with von Willebrand disease (VWD). Objective To investigate long-term safety and efficacy of the product in real-life over the first 5 post-approval years. Patients/Methods This prospective, observational, national post-marketing study (PMS) enrolled patients of all ages and VWD types. Patients were observed for up to 3 years and treated for one or more occasions. Efficacy was assessed for each major event. Breakthrough bleeding rate 3 days post-infusion and annualized bleeding rate (ABR) were also evaluated for long-term prophylaxis. Results Overall, 155 of 174 patients enrolled from 31 centers were eligible for efficacy assessment. Most patients (76.8%) were severely affected (VWF:RCo = 12 months. Excellent tolerability was confirmed with no safety concerns. No thrombotic events were observed. Conclusions Results from this PMS increase the clinical experience of a FVIII-poor pdVWF in patients of all ages and VWD types including those with thrombotic risk factors and emphasize that giving FVIII is not always mandatory to effectively treat patients with severe VWD

Gynecological and obstetric outcome in the French cohort of women with factor XIII deficiency

International audienceIntroduction: Congenital factor XIII deficiency is a very rare bleeding disorder affecting 33 patients in France. Besides its role in fibrin clot stabilization, factor XIII is involved in placental attachment. Fetal miscarriages represent a frequent and concerning issue for these patients. The aim of the present study was to describe clinical characteristics of women presenting severe congenital FXIII deficiency in France, to focus on gynecological and obstetrical events, and to report the management of these rare situations. Methods: We conducted a retrospective study in the French Hemophilia Comprehensive Care and Clinical Hemostasis Centers. Women between 15 and 65 years with factor XIII activity < 10 IU dL(-1) were included. Biological, clinical and therapeutic events that occurred to these patients during their gynecological and obstetrical period were recorded.Results: Among 31 centers, eleven patients were included. The median age at diagnosis was 1.5 years (range: 0-35), and at inclusion it was 30 years (range: 15-63). Fetal miscarriage was the primary manifestations in 2 (18%) patients, the remaining were diagnosed during hemorrhage. Menorrhagias were reported by 2 women (27%), 13 pregnancies were reported by 9 women including one abortion. Every pregnancy was conducted under factor XIII substitution, no hemorrhagic episode was reported. Four patients (36%) experienced at least one fetal miscarriage with a total amount of 30 miscarriages with 6 occurring during substitution.Conclusion: Altogether, our data confirmed the high incidence of miscarriage in women with factor XIII deficiency. Good outcome of pregnancies required prophylaxis in accordance with international guidelines

Reinvestigation of unidentified causative variants in FXI-deficient patients: Focus on gene segment deletions

International audienceIntroduction: Data on failure to identify the molecular mechanism underlying FXI deficiency by Sanger analysis and the contribution of gene segment deletions are almost inexistent. Aims and methods: Prospective and retrospective analysis was conducted on FXI-deficient patients’ DNA via Next Generation Sequencing (NGS), or Sanger sequencing and Multiplex Probe Ligation-dependent Assay (MLPA) to detect cryptic causative gene variants or gene segment deletions. Results: Sanger analysis or NGS enabled us to identify six severe and one partial (median activity 41 IU/dl) FXI deficient index cases with deletions encompassing exons 11–15, the whole gene, or both. After Sanger sequencing, retrospective evaluation using MLPA detected seven additional deletion cases in apparently homozygous cases in non-consanguineous families, or in previously unsolved FXI-deficiency cases. Among the 504 index cases with a complete genetic investigation (Sanger/MLPA, or NGS), 23 remained unsolved (no abnormality found [n = 14] or rare intronic variants currently under investigation, [n = 9]). In the 481 solved cases (95% efficiency), we identified F11 gene-deleted patients (14 cases; 2.9%). Among these, whole gene deletion accounted for four heterozygous cases, exons 11–15 deletion for five heterozygous and three homozygous ones, while compound heterozygous deletion and isolated exon 12 deletion accounted for one case each. Conclusion: Given the high incidence of deletions in our population (2.9%), MLPA (or NGS with a reliable bioinformatic pipeline) should be systematically performed for unsolved FXI deficiencies or apparently homozygous cases in non-consanguineous families