Transcobalamin deficiency - a rare genetic defect in transportation of cobalamin; case report.

BACKGROUND: Vitamin B12 is primarily transported from plasma to cells by Transcobalamin. Deficiency of Transcobalamin is a rare autosomal recessive disorder that results in unavailability of cobalamin in cells and accumulation of homocysteine and methylmalonic acid. CASE REPORT: We report a case of a 2-year-old male child with persistent pancytopenia, recurrent infections, and megaloblastic anemia. Next-generation sequencing identified a novel variant in exon 8 of TCN2 gene. Substantial improvement has been observed following administration of high doses of parenteral methylcobalamin. CONCLUSION: In patients with unresolved pancytopenia and megaloblastic anemia, Transcobalamin deficiency should be investigated and treated promptly to prevent any irreversible and harmful outcome.

Donor-derived stem cell infusion for sustained pancytopenia after CD19 CAR-T therapy for relapsed patients post allogeneic stem cell transplantation.

OBJECTIVES: To investigate the effectiveness of donor-derived chimeric antigen receptor T (CAR-T) cells in the treatment of relapsed cases after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and whether donor-derived peripheral blood stem cells (PBSCs) have a therapeutic effect on pancytopenia after CAR-T cell therapy. METHODS: We analyzed data from five adults with B-cell acute lymphoblastic leukemia (ALL) who had relapse after allo-HSCT and received donor-derived CAR-T cell therapy and donor-derived PBSCs to promote hematopoietic recovery. RESULTS: All patients had negative minimal residual disease after CAR-T therapy, grade 1-2 cytokine release syndrome, and developed grade 4 hematologic toxicity. During the pancytopenia stage after CAR-T cell therapy, donor-derived PBSCs were transfused without graft-versus-host disease (GVHD) prophylaxis. Four patients had grade I-II acute GVHD (aGVHD). After corticosteroid treatment, aGVHD resolved and hematopoiesis was restored. Although steroids in combination with etanercept and ruxolitinib relieved symptoms in one patient with grade IV aGVHD, complete hematopoietic recovery was not achieved, and the patient died due to severe infection. CONCLUSIONS: Donor-derived CAR-T cell therapy is safe and effective in patients with relapsed/refractory ALL after allo-HSCT. Donor-derived PBSCs infusion could achieve hematopoietic recovery with controllable aGVHD in patients with persistent pancytopenia.

Pancytopenia related to acquired sea-blue histiocytosis during chronic parenteral nutrition.

Bone marrow smear showing histiocytes (black arrow) containing sea blue granules stained with May-Grünwald Giemsa.

Management of granulomatosis with polyangiitis complicated by intestinal perforation and pancytopenia: a case report and literature review.

Granulomatosis with polyangiitis is a systemic vasculitis. While the classic triad typically comprises otorhinolaryngologic, pulmonary, and renal manifestations, it is essential to recognize that granulomatosis with polyangiitis can affect any organ. Furthermore, reports have documented less common sites of involvement, such as the gastrointestinal tract. In this case-based review, we focus on a case of granulomatosis with polyangiitis presenting with intestinal perforation and the added challenge of concurrent pancytopenia.A 25-year-old female was diagnosed with granulomatosis with polyangiitis, with her clinical course progressing from joint pain to severe multi-organ involvement, including gastrointestinal complications. Treatment challenges emerged with the development of pancytopenia. While this may not directly result from granulomatosis with polyangiitis, it introduced an additional layer of complexity and delayed the induction of remission with immunosuppressants. Despite initial stabilization, an unexpected jejunal perforation occurred, requiring surgical intervention and subsequent postoperative care. The case underscores the complex nature of granulomatosis with polyangiitis and its potential complications. A literature search yielded discrete relevant cases in the context of our patient's intricate presentation, which has been summarized.We highlight the complexities in diagnosing and managing granulomatosis with polyangiitis-related complications, especially in uncommon presentations, and emphasize the importance of a personalized approach to patient care in these circumstances.

Pancytopenia with aplastic anemia in systemic lupus erythematosus: case series and literature review.

Aplastic anemia (AA) is a rare, potentially catastrophic hematopoiesis failure manifested by pancytopenia and bone marrow aplasia. AA occurrence in Systemic Lupus Erythematosus (SLE) patients is extremely rare. The diagnosis may be delayed due to other possible pancytopenia etiologies. Confirmation of peripheral cytopenias diagnosis necessitates a bone marrow aspiration. The management of AA is challenging, and the literature reported using glucocorticoids, danazol, plasmapheresis, cyclophosphamide, intravenous immunoglobulin, and cyclosporine. We report two cases of SLE patients who presented with pancytopenia, with bone marrow biopsy confirmed AA. One case was treated with cyclophosphamide but unfortunately succumbed to Acute Respiratory Distress Syndrome (ARDS), while the other case was managed with rituximab with a good response. Interestingly, both patients were on azathioprine before the diagnosis of AA. A comprehensive search for reported cases of AA in PubMed, Scopus, and the Directory of Open Access Journals databases was performed to enhance the understanding of the diagnostic and management challenges associated with AA in SLE, facilitating ongoing exploration and research in this field. The decision to do a BM aspiration and biopsy is recommended for SLE patients with an abrupt decline in blood counts and previously stable blood counts.

Pancytopenia Due to Folate Deficiency.

We found the article on "The Digital Technology in Clinical Medicine: From Calculators to ChatGPT" interesting.1 According to Kulkarni et al., humanity has witnesses four important social system changes, starting with the primitive huntersgatherers and progressing to horticultural, agricultural, industrial, and the current fifth, which is based on digital information technology and has altered the way we present, recognize, and utilize different factors of production. In clinical medicine, digital technology has advanced significantly since the days of computations. According to Kulkarni et al., we have to benefit from these advancements as we all improve the lives of our patients while being cautious not to overturn the doctor-patient relationship. If technology, clinical expertise, and humanistic values are properly balanced, Kulkarni et al. concluded that the future is quite glorious.1 Regulatory organizations are pushing for improvements through clinical trials as a result of recognition of the expanding influence of digital technology in healthcare delivery. The "World Health Organizations Guidelines for Digital Interventions" and the "Food and Drug Administration's Digital Health Center of Excellence" are only two of the projects that are currently being highlighted in the study as efforts to analyze and implement digital health services.

A Curious Case of Autoimmunity, Pancytopenia, and Disseminated Intravascular Coagulation.

HISTORY AND EXAMINATION: A 21-year-old female patient presented to us with severe low back pain for 4 months. On examination, patient was afebrile, with severe pallor, and tenderness in both sacroiliac (SI) joints. Patient was being admitted and evaluated, and during the course of evaluation, developed severe headache, which was severe in intensity and associated with nausea and projectile vomiting. Initial investigations: An X-ray of the bilateral SI joints revealed inflammation, and the antinuclear antibody (ANA) turned out to be 4+ with pancytopenia and raised lactate dehydrogenase (LDH), but the liver function tests were normal. Rest of the rheumatological profile was unremarkable. During the course of the evaluation, she developed a severe headache, which, on imaging, showed presence of cerebral edema with chronic subdural hematoma, and a concomitant coagulopathy workup revealed evidence of disseminated intravascular coagulation (DIC). DISCUSSION: Taking the whole picture into consideration, a malignant process in the body was suspected, and serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA-125) were sent, all of which were raised. Validating the clinical clue was the bone marrow biopsy done for pancytopenia, which revealed malignant epithelial infiltration. A contrast-enhanced computed tomography (CECT) thorax and whole abdomen were done to find out the primary, which showed a neoplastic mass at the gastroesophageal junction along with bony metastases in the vertebrae and left adrenal. Tissue from the primary lesion was taken for histopathological examination (HPE) through upper gastrointestinal endoscopy. Although HPE revealed grade III poorly differentiated stomach adenocarcinoma, the patient had succumbed to the disease process by the time the diagnosis came to light. CONCLUSION: In short, this case perfectly illustrates how solid organ malignancies might be a mimicker of multisystem disorders, thereby delaying diagnosis and worsening the prognosis even further.

[Two cases of cytopenia associated with multiple malformations]. / 血细胞减少伴多发畸形2例.

The first patient, a 10-year-old girl, presented with pancytopenia and recurrent epistaxis, along with a history of repeated upper respiratory infections, café-au-lait spots, and microcephaly. Genetic testing revealed compound heterozygous mutations in the DNA ligase IV (LIG4) gene, leading to a diagnosis of LIG4 syndrome. The second patient, a 6-year-old girl, was seen for persistent thrombocytopenia lasting over two years and was noted to have short stature, hyperpigmented skin, and hand malformations. She had a positive result from chromosome breakage test. She was diagnosed with Fanconi anemia complementation group A. Despite similar clinical presentations, the two children were diagnosed with different disorders, suggesting that children with hemocytopenia and malformations should not only be evaluated for hematological diseases but also be screened for other potential underlying conditions such as immune system disorders.

A novel mutation in MECOM affects MPL regulation in vitro and results in thrombocytopenia and bone marrow failure.

MECOM-associated syndrome (MECOM-AS) is a rare disease characterized by amegakaryocytic thrombocytopenia, progressive bone marrow failure, pancytopenia and radioulnar synostosis with high penetrance. The clinical phenotype may also include finger malformations, cardiac and renal alterations, hearing loss, B-cell deficiency and predisposition to infections. The syndrome, usually diagnosed in the neonatal period because of severe thrombocytopenia, is caused by mutations in the MECOM gene, encoding for the transcription factor EVI1. The mechanism linking the alteration of EVI1 function and thrombocytopenia is poorly understood. In a paediatric patient affected by severe thrombocytopenia, we identified a novel variant of the MECOM gene (p.P634L), whose effect was tested on pAP-1 enhancer element and promoters of targeted genes showing that the mutation impairs the repressive activity of the transcription factor. Moreover, we demonstrated that EVI1 controls the transcriptional regulation of MPL, a gene whose mutations are responsible for congenital amegakaryocytic thrombocytopenia (CAMT), potentially explaining the partial overlap between MECOM-AS and CAMT.

Haploidentical transplant for paediatric patients with severe thalassaemia using post-transplant cyclophosphamide and methotrexate: A prospectively registered multicentre trial from the Bone Marrow Failure Working Group of Hunan Province, China.

Haploidentical transplantation strategies for patients with transfusion-dependent thalassaemia (TD-TM) remain to be investigated. In this study, 54 paediatric patients with TD-TM were treated with a novel approach using post-transplant cyclophosphamide (PTCy) and low-dose methotrexate (LD-MTX), following a myeloablative regimen. The incidence of neutrophil and platelet engraftment was 96.3% ± 2.6% and 94.4% ± 3.1% respectively. The cumulative incidence of grades II-III acute graft-versus-host disease (GVHD) was 13.8% ± 4.8% at 100 days. At three years, the cumulative incidence of chronic GVHD was 28.5% ± 8.5%. With a median follow-up of 520 days (132-1325 days), the overall survival (OS) and event-free survival (EFS) were 98.1% ± 1.8% and 90.7% ± 3.9% respectively. Compared with the low-dose cyclophosphamide (CTX) conditioning regimen (120 mg/kg), the high-CTX regimen (200 mg/kg) achieved a higher incidence of stable engraftment (100% vs 66.7% ± 15.7%, p = 0.003), a comparable incidence of grades II-III acute GVHD, a lower incidence of chronic GVHD (20.2% ± 8.3% vs 66.6% ± 19.2%, p = 0.011), and better overall survival (100% vs 88.9% ± 10.5%, p = 0.025) as well as EFS (95.6% ± 3.1% vs 66.7% ± 15.7%, p = 0.008). Our results using unmanipulated haploidentical grafts and PTCy with LD-MTX in TD-TM are encouraging. (chictr.org.cn ChiCTR1800017969).

Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function.

Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.

Genomic and computational analysis of four novel variants of MPL gene in Congenital Amegakaryocytic Thrombocytopenia.

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare, genetic, autosomal recessive disorder characterized by severe thrombocytopenia, due to inefficient bone marrow megakaryopoiesis eventually leading to aplasia. Majority of the cases are due to homozygous or compound heterozygous mutations in MPL gene encoding for thrombopoietin (THPO) receptor protein. CAMT can be diagnosed at early phase of life, with major complication of transfusion dependency and hematopoietic transplantation as only curative treatment. We have investigated the sequence variations in MPL gene of 7 bone marrow failure (BMF) subjects, who presented with clinically diverse phenotypes, through next generation sequencing (NGS). Plasma THPO levels were estimated using ELISA. Insilico sequence and structure-based analyses were performed to understand the structural and functional implications of mutations, identified through NGS. We studied 7 CAMT subjects suspected of BMF, who presented with severe thrombocytopenia followed by pancytopenia, bleeding manifestation and physical anomalies. The plasma THPO levels were significantly elevated (p<0.05) in all the cases. Molecular analysis by NGS identified 9 genomic mutations in MPL gene. These included 7 non-synonymous substitution, 1 nonsense substitution and 1 in-del mutations, of which 4 are novel mutations. Insilico analysis predicted damaging effects on THPO-R and its reduced affinity for THPO for all the identified mutations. CAMT is a rare disorder with diverse clinical phenotypes and diagnosis is challenging. The elevated plasma THPO levels should be considered for the primary diagnosis and prognosis of the disease. However, molecular analysis of MPL gene is important for the diagnosis and management of the disease through genetic counselling. Though the cytokines, THPO-R agonist are used for the treatment of CAMT, HSCT is the only curative therapy.

Complex considerations - Fever and pancytopenia after solid organ transplantation.

This case describes a 42-year-old man who underwent kidney transplantation and developed fevers, pancytopenia, and elevated liver function tests starting on post-operative day 9. An extensive microbiologic and molecular workup was performed, ultimately leading to a diagnosis of donor-derived toxoplasmosis with associated hemophagocytic lymphohistiocytosis in the recipient. This case highlights the potential for post-transplant toxoplasmosis in high-risk mismatch (D+/R-) recipients, as well as the role of Toxoplasma-targeted prophylaxis in such patients.

Lysinuric protein intolerance presenting as pancytopenia and splenomegaly mimicking acute leukaemia: a case report.

BACKGROUND: Lysinuric protein intolerance is a rare inherited metabolic disease due to autosomal recessive mutations of the SLC7A7 gene. The affected patients commonly present with protein-rich food intolerance, failure to thrive, hepatosplenomegaly, muscle hypotonia and lung involvement due to impaired intestinal absorption and excessive urinary excretion of dibasic amino acids. Presentation with splenomegaly and cytopenia without other features has not been reported. Here we report a Sri Lankan girl with lysinuric protein intolerance presenting with pancytopenia and splenomegaly mimicking acute leukaemia. CASE PRESENTATION: Two years and six months old Sri Lankan girl presented with persistent pancytopenia following a viral illness. She was asymptomatic without vomiting, diarrhoea, abdominal pain or irritability. Physical examination revealed pallor and isolated firm splenomegaly of 2 cm. Growth parameters and other system examinations were normal. Full blood count revealed anaemia, leukopenia and thrombocytopenia. The blood picture showed a mixture of hypochromic microcytic and normochromic normocytic red cells with occasional pencil cells and macrocytes. Bone marrow examination was normal except for occasional megaloblasts; however, serum vitamin B12 and red blood cell folate were normal. The metabolic screen showed a high anion gap compensated metabolic acidosis, high lactate and ketosis. Genetic mutation analysis using whole exome sequencing revealed compound heterozygous variants of the SLC7A7 gene, confirming the diagnosis of lysinuric protein intolerance. CONCLUSION: We report a child with lysinuric protein intolerance presenting with pancytopenia and splenomegaly without other disease features. This case report adds to the heterogenic presentations of lysinuric protein intolerance, which is considered a multifaceted disease.

The journey from viral hepatitis to hypocythemia: Two case reports.

Acute viral hepatitis, including hepatitis A, B, E, D, and G, can lead to severe bone marrow suppression due to cytotoxic lymphocytes. The bone marrow suppression causes aplastic anaemia which is mostly unresponsive to immunosuppressive therapy. Such patients require bone marrow transplant for a complete cure. The pancytopenia can evolve during recovery from transaminitis. We are presenting two case reports relating aplastic anaemia with acute viral hepatitis in two young patients-23 and 16 years of age. The 23-year-old female patient had hepatitis A associated with aplastic anaemia whereas the young 16-year-old male patient was diagnosed with Hepatitis E IgG associated aplastic anaemia. Unfortunately, the first patient could not cope with the complications relating to pancytopenia and was unable to reach the bone marrow transplant stage. The second patient did not have a bone marrow transplant but showed an excellent response to immunosuppressive therapy before the transplant and survived.

Persistent Pancytopenia as a Long-COVID Manifestation in a Patient with Adult-Onset Still's Disease: A Case Report.

Background: Adult-onset Still's disease (AOSD) is a rare rheumatic inflammatory condition with an extremely heterogeneous clinical presentation and systemic impairment. Uncommon manifestations may be challenging to manage, especially in patients with previous severe acute SARS-CoV-2 infection. For the first time, we report the case of a patient affected by refractory AOSD presenting with severe pancytopenia as a long-COVID manifestation. The purpose of this case report is to illustrate the clinical presentation, diagnostic and therapeutic management of this unusual manifestation. Moreover, we examine the mechanisms that are potentially responsible for the onset of the pancytopenia observed in our patient. Case presentation: We describe the case of a 40-year-old male who presented with a history of fever for 2 years, arthralgia, maculopapular salmon-pink rash and a previous SARS-CoV-2 infection which required admission to intensive care. The patient's laboratory results revealed elevated inflammatory markers levels (erythrocyte sedimentation rate and C-reactive protein), hyperferritinemia and severe pancytopenia that needed multiple transfusions. A diagnosis of AOSD was made based on clinical and laboratory presentation after excluding neoplastic, infectious and other rheumatic diseases. The previous empirical treatment was not adequate to control the condition; therefore, treatment with high-dose steroids, canakinumab and epoetin alfa was started and led to the resolution of the man's symptoms and a reduction in inflammatory marker levels, whereas blood cell count remained stable without a need for further blood transfusions. The patient is currently under rheumatologic and hematologic follow-up every month. Conclusions: Neither AOSD nor SARS-CoV-2 infection usually manifests with pancytopenia, except in hemophagocytic syndrome or immunodeficient patients, respectively. Identifying the underlying etiology of pancytopenia is mandatory to establish a prompt treatment that generally resolves the disorder. However, in our case, all common causes of pancytopenia were excluded, suggesting a potential manifestation of the long-COVID syndrome. Despite the resolution of the acute infection and the remarkable treatment of AOSD, pancytopenia persists. Herein, we propose for refractory AOSD patients with previous SARS-CoV-2 infection a novel approach to the diagnosis and treatment of pancytopenia.

Clonal hematopoiesis and risk for hematologic malignancy.

Clonal hematopoiesis (CH) is common in older persons and is associated with an increased risk of hematologic cancer. Here, we review studies establishing an association between CH and hematopoietic malignancy, discuss features of CH that are predictive of leukemic progression, and explore the role of hematopoietic stressors in the evolution of CH to acute myeloid leukemia or myelodysplastic syndrome. CH due to point mutations or structural variants such as copy-number alterations is associated with an ∼10-fold increased risk of hematopoietic malignancy. Although the absolute risk of hematopoietic malignancy is low, certain features of CH may confer a higher risk of transformation, including the presence of TP53 or spliceosome gene mutations, a variant allele fraction >10%, the presence of multiple mutations, and altered red blood indices. CH in the setting of peripheral blood cytopenias carries a very high risk of progression to a myeloid malignancy and merits close observation. There is emerging evidence suggesting that hematopoietic stressors contribute to both the development of CH and progression to hematopoietic malignancy. Specifically, there is evidence that genotoxic stress from chemotherapy or radiation therapy, ribosome biogenesis stress, and possibly inflammation may increase the risk of transformation from CH to a myeloid malignancy. Models that incorporate features of CH along with an assessment of hematopoietic stressors may eventually help predict and prevent the development of hematopoietic malignancies.