The paradox of autoimmunity and autoinflammation in inherited neutrophil disorders - in search of common patterns.

Congenital defects of neutrophil number or function are associated with a severe infectious phenotype that may require intensive medical attention and interventions to be controlled. While the infectious complications in inherited neutrophil disorders are easily understood much less clear and explained are autoimmune and autoinflammatory phenomena. We survey the clinical burden of autoimmunity/autoinflammation in this setting, search for common patterns, discuss potential mechanisms and emerging treatments.

Venetoclax Use in Paediatric Haemato-Oncology Centres in Poland: A 2022 Survey.

Venetoclax, the best established BH3-mimetic, is a practice-changing proapoptotic drug in blood cancers in adults. In paediatrics the data are fewer but exciting results were recently presented in relapsed or refractory leukaemias demonstrating significant clinical activity. Importantly, the in-terventions could be potentially molecularly guided as vulnerabilities to BH3-mimetics were re-ported. Currently venetoclax is not incorporated into paediatric treatment schedules in Poland but it has been already used in patients that failed conventional therapy in Polish paediatric haemato-oncology departments. The aim of the study was to gather clinical data and correlates of all paediatric patients treated so far with venetoclax in Poland. We set out to gather this experience to help choose the right clinical context for the drug and stimulate further research. The questionnaire regarding the use of venetoclax was sent to all 18 Polish paediatric haemato-oncology centres. The data as available in November 2022 were gathered and analysed for the diagnoses, triggers for the intervention, treatment schedules, outcomes and molecular associations. We received response from 11 centres, 5 of which administered venetoclax to their patients. Clinical benefit, in most cases consistent with hematologic complete remission (CR), was reported in 5 patients out of ten, whereas 5 patient did not show clinical benefit from the intervention. Importantly, patients with CR included subtypes expected to show venetoclax vulnerability, such as poor-prognosis ALL with TCF::HLF fusion. We believe BH3-mimetics have clinical activity in children and should be available to pae-diatric haemato-oncology practitioners in well-selected applications.

Challenges in the interpretation of a germline TERT variant in a patient with juvenile myelomonocytic leukemia.

Dyskeratosis congenita (DC) is a bone marrow failure syndrome with extrahematopoietic abnormalities. DC is a paradigmatic telomere biology disorder (TBD) caused by germline mutations in genes responsible for telomere maintenance including TERT. Cryptic TBD is a bone marrow failure syndrome due to premature telomere shortening but without additional symptoms, frequently clinically indistinguishable from severe aplastic anemia (SAA) or hypoplastic myelodysplastic syndrome. We present the complex diagnostic pathway in a boy with a rare germline p.Thr726Met TERT variant with previous reports of SAA association and compromised enzymatic function who presented with juvenile myelomonocytic leukemia, which is a rare myelodysplastic/myeloproliferative neoplasm of childhood.

Germline 3p22.1 microdeletion encompassing RPSA gene is an ultra-rare cause of isolated asplenia.

BACKGROUND: Isolated Congenital Asplenia (ICA, OMIM #271400) is a rare, life-threatening abnormality causing immunodeficiency, which is characterized by the absence of a spleen. Diagnosis should be completed in early childhood and antibiotic prophylaxis applied with additional vaccinations. CASE PRESENTATION: We report the case of a six-month old girl with hematologic abnormalities and asplenia documented in imaging, with Howell-Jolly bodies in peripheral blood smear. Targeted Next Generation Sequencing screening did not reveal any pathogenic variant in genes associated with congenital asplenia. Since absence of the spleen was found by imaging, high-resolution copy number variations detection was also performed using genomic Single Nucleotide Polymorphism microarray: a heterozygous 337.2 kb deletion encompassing the RPSA gene was observed, together with SLC25A38, SNORA6, SNORA62 and MOBP genes. Despite haploinsufficiency of SLC25A38, SNORA6, SNORA62 and MOBP, no change in the clinical picture was observed. A search of available CNV databases found that a deletion of the RPSA locus seems to be unique and only duplications were found in this region with the frequency of less than 0.02%. CONCLUSIONS: Copy number variations in RPSA gene locus are ultrarare cause of isolated asplenia. Furthermore, since the patient does not present any concomitant clinical features, it would appear that haploinsufficiency of SLC25A38, SNORA6, SNORA62 and MOBP genes does not affect the phenotype of patients. However, to confirm this thesis a longer follow-up of the patient's development is needed.