<p>Introduction: Congenital dyserythropoietic anemia type 1 (CDA-1) is a rare inherited erythroid disorder. The neonatal clinical presentation is non-specific, making diagnosis challenging and requiring a multidisciplinary approach. To date, no specific placental characteristics have been associated to this condition, highlighting the importance of placental examination and pathologic investigations. Case Presentation: We present the case of a term newborn affected by CDA-1. The patient displayed poor neonatal adaptation with severe anemia, persistent pulmonary arterial hypertension, right ventricular dysfunction, hypotensive shock, cholestasis, hepatitis, severe hyperferritinemia, disseminated intravascular coagulation, thrombocytopenia, acute renal failure, and transient hyperinsulinism. Placentomegaly was noted and histology demonstrated severe megaloblastic erythroblastosis. Genetic research confirmed the diagnosis. The patient required intensive care during the first weeks of life and blood cell transfusions every 5 weeks until 6 months. The outcome was favorable. Conclusion: CDA-1 is a rare, serious disorder requiring a complex diagnostic approach. Placental analysis provides additional clues for establishing a diagnosis. </p>.

The vast majority of childhood cytopenias are transient, mostly secondary, and not the consequence of primary bone marrow processes. Yet, every few months we see patients in the pediatric hematology centers of the Hungarian Pediatric Oncology Network in whom repeated bone marrow sampling and extensive laboratory hematological investigations do not lead to a diagnosis and the cytopenia persists chronically. In these cases, the identification or exclusion of genetically determined benign or premalignant hematological conditions – such as congenital neutropenia, hereditary hemolytic or dyserythropoietic anemia, inherited thrombocytopenia, congenital bone marrow failure syndrome – is essential for modern therapy planning. In correctly selected pediatric patients with chronic cytopenia, modern high-throughput molecular genetic testing by next-generation sequencing is the most cost-effective diagnostic option, and its early use avoids many invasive interventions and inappropriate therapeutic attempts. At the initiative of Semmelweis University, a national molecular genetic diagnostics program was launched to map the etiology, epidemiology and prognosis of hereditary chronic cytopenias in children in Hungary. In the present work, we summarize the technical details of the testing modality and the indications we propose to apply in clinical practice. As a proof of concept, we present a discovery cohort of 30 patients selected according to these indications: 67% of them were identified with a gene variation that at least partially explained the phenotype, 47% with a variation that revised the diagnosis initially assumed by the treating physician, and 43% with a variation that determined the next substantive therapeutic decision. Of these, 45% were likely pathogenic or pathogenic aberrations and 55% were variants of unknown clinical significance. We propose to consider and apply this high-throughput molecular genetic modality, which generates significant clinical benefit and has a high diagnostic success rate according to our own and international data presented, as a priority element of the hematological diagnostic workflow in our country, within a regulated, professional framework. Orv Hetil. 2025; 166(1): 3–19. A gyermekkori cytopeniák döntő többsége átmeneti, leginkább szekunder jelenség, és nem primer csontvelői folyamatok következménye. Mégis néhány havonta találkozunk olyan betegekkel a Magyar Gyermekonkológiai Hálózat kötelékébe tartozó gyermekhematológiai centrumokban, akiknél többszöri csontvelői mintavétel és széles körű laboratóriumi hematológiai kivizsgálás sem vezet diagnózishoz, a cytopenia pedig krónikusan fennáll. A korszerű terápiatervezéshez ezekben az esetekben elengedhetetlen a genetikailag determinált benignus vagy praemalignus hematológiai kórállapotok – mint például congenitalis neutropeniák, hereditaer haemolyticus vagy dyserythropoeticus anaemiák, örökletes thrombocytopeniák, örökletes csontvelő-elégtelenségi szindrómák – megállapítása vagy kizárása. A helyesen szelektált krónikus cytopeniás gyermekpopulációban a modern, újgenerációs szekvenálásra épülő, nagy áteresztőképességű molekuláris genetikai vizsgálat a leginkább költséghatékony diagnosztikus megoldás, amelynek korai alkalmazásával számos invazív beavatkozás és nem megfelelő terápiás próbálkozás elkerülhető. A Semmelweis Egyetem kezdeményezésére nemzeti szinten szervezett molekuláris géndiagnosztikai programot indítottunk a gyermekkori örökletes krónikus cytopeniák hazai etiológiai, epidemiológiai és prognosztikai feltérképezésére. Jelen közleményünkben a vizsgálati modalitás technikai részleteit és a klinikai gyakorlatban javaslatunk szerint alkalmazandó indikációs köreit összegezzük. Koncepciónk igazolásaként bemutatunk az indikációs körök szerint kiválasztott, 30 betegből álló mintapopulációt: közöttük 67%-ban a fenotípust legalább részben magyarázó, 47%-ban az eredetileg a kezelőorvos által feltételezett diagnózist revideáló, 43%-ban pedig a következő érdemi terápiás döntést meghatározó géneltérést azonosítottunk. Ezek 45%-a volt valószínűleg patogén vagy patogén aberráció, 55%-a pedig ismeretlen klinikai szignifikanciájú variáns. A jelentős klinikai hasznot generáló, közleményünkben bemutatott saját és nemzetközi adatok szerint is nagy találati aránnyal jellemezhető nagy áteresztőképességű molekuláris genetikai modalitást szabályozott szakmai keretek között a gyermekhematológiai kivizsgálás hazánkban is elérhető, kiemelt elemeként javasoljuk számba venni és alkalmazni a jövőben. Orv Hetil. 2025; 166(1): 3–19.

Cytopenia due to the abnormal regulation of GATA1 could manifest as varying degrees of thrombocytopenia and/or anemia and more severely in male children than in female children. Here, we describe the case of pancytopenic and transfusion-dependent twin brothers at our center whose bone marrow puncture revealed low bone marrow hyperplasia. Whole-exome sequencing revealed that the twins had a new germline GATA1 mutation (nm_002049: exon 3:c.515 T >C:p.F172S), which confirmed the diagnosis of GATA1 mutation-related pancytopenia. The mutation was inherited from their mother, who was heterozygous for the mutation. Sanger sequencing verified the pathogenicity of the mutation. Further family morbidity survey confirmed that GATA1 mutation-related pancytopenia is an X-linked recessive genetic disorder. We developed haploid hematopoietic stem cell transplantation programs for twins, with the father as the only donor, and finally, the hematopoietic reconstruction was successful. Although they experienced acute graft-versus-host disease, hemorrhagic cystitis, and a viral infection in the early stage, no abnormal manifestations or transplant-related complications were observed 3 months after transplantation. Through hematopoietic stem cell transplantation technology for one donor and two receptors, we eventually cured the twins. The p.F172S variant in the new germline GATA1 mutation may play an essential role in the pathogenesis of GATA1 mutation-related cytopenia.

The GATA1 transcription factor is essential for normal erythropoiesis and megakaryocytic differentiation. Germline GATA1 pathogenic variants in the N-terminal zinc finger (N-ZF) are typically associated with X-linked thrombocytopenia, platelet dysfunction, and dyserythropoietic anemia. A few variants in the C-terminal ZF (C-ZF) domain are described with normal platelet count but altered platelet function as the main characteristic. Independently performed molecular genetic analysis identified a novel hemizygous variant (c.865C>T, p.H289Y) in the C-ZF region of GATA1 in a German patient and in a Spanish patient. We characterized the bleeding and platelet phenotype of these patients and compared these findings with the parameters of two German siblings carrying the likely pathogenic variant p.D218N in the GATA1 N-ZF domain. The main difference was profound thrombocytopenia in the brothers carrying the p.D218N variant compared to a normal platelet count in patients carrying the p.H289Y variant; only the Spanish patient occasionally developed mild thrombocytopenia. A functional platelet defect affecting αIIbβ3 integrin activation and α-granule secretion was present in all patients. Additionally, mild anemia, anisocytosis, and poikilocytosis were observed in the patients with the C-ZF variant. Our data support the concept that GATA1 variants located in the different ZF regions can lead to clinically diverse manifestations.