Congenital and Acquired Pediatric Bone Marrow Failure

The broad differential diagnosis of pediatric pancytopenia challenges pediatricians to efficiently evaluate, diagnose, and ensure rapid triage or treatment of rare, potentially life-threatening disorders of congenital and acquired bone marrow failure. An organized approach to patient evaluation is necessary, and a baseline knowledge of the systemic phenotypic presentation of severe aplastic anemia and inherited bone marrow failure syndromes is critical to accurately recognize these rare blood disorders and appropriately refer them to subspecialty care.After completing this article, readers should be able to: Initiate an organized clinical evaluation of pediatric pancytopenia.Differentiate congenital vs acquired causes of bone marrow failure.Recognize when to appropriately refer children with congenital or acquired causes of bone marrow failure to a pediatric hematologist/oncologist subspecialist.The bone marrow is a large, semisolid organ contained within axial and long cortical bone that produces peripheral blood cells. The bone marrow contains a small number of self-propagating hematopoietic stem cells responsible for delivering upwards of 2.5 billion red blood cells (RBCs), 1 billion granulocytes, and 2.5 billion platelets daily per kilogram of a child’s body weight.1 Although able to increase production 5- to 10-fold in response to peripheral demands, marrow hematopoiesis can be suppressed, transiently or persistently, by congenital and acquired causes. Prolonged bone marrow failure (BMF) results in dependence on transfused blood products and risks severe, life-threatening immunodeficiency. Prompt recognition and evaluation of pancytopenia (a decrease in all 3 blood cell lines below normal values for age and sex) can expedite the diagnosis of BMF, enabling timely collaboration with pediatric hematology/oncology subspecialists and thus improving patient survival.The identification of rare congenital or acquired BMF disorders among the many children with pancytopenia whom a pediatrician will evaluate can be challenging. Using a standardized approach to pediatric pancytopenia can help narrow a broad differential diagnosis and better identify those patients who require a more aggressive BMF evaluation (Figure 1). An initial evaluation requires assessment of a complete blood count with differential, reticulocyte count, peripheral smear review, and a complete history and physical examination, which, together, are used to characterize the pancytopenia as (1) one that is caused by abnormalities of production vs destruction of blood cells and (2) congenital vs acquired in presentation.2An initial evaluation of pediatric pancytopenia should investigate whether low peripheral blood counts are caused by inadequate or abnormal bone marrow production or caused by increased mechanisms of peripheral cellular destruction and/or consumption (Figure 1). Laboratory results that suggest abnormalities of bone marrow production include a markedly decreased reticulocyte count and immature platelet fraction (a measurement of newly released immature platelets in blood and an indicator of platelet production). Peripheral smear review may demonstrate evidence of abnormal/dysplastic blood cell morphology, including macrocytic or teardrop-shaped (dacrocytes) RBCs or dysplastic leukocytes. Direct communication and collaboration with a pediatric hematopathologist or pediatric hematologist/oncologist are often necessary for detailed interpretation of a peripheral blood smear. Alternatively, results suggestive of peripheral RBC destruction may include: decreased haptoglobin; elevation of unconjugated/indirect bilirubin, lactate dehydrogenase, or reticulocyte count; and/or positive direct Coombs, antiplatelet antibody, or antineutrophil antibody screen results. Peripheral smear review may demonstrate evidence of RBC hemolysis, including increased presence of microspherocytes or schistocytes (evidence of schistocytes in a peripheral smear is always an abnormal finding). Evidence of peripheral platelet consumption may include organomegaly (hepatomegaly and/or splenomegaly) and elevated immature platelet fraction.The second important question in the approach to pediatric pancytopenia is to determine whether the development of low blood counts was predisposed and present from birth (congenitally) vs induced as a secondary disorder (acquired). Younger age at presentation, additional clinical or physical signs and symptoms suggestive of a more systemic germline disorder, and a family history of blood or immune disorders may hint toward a genetic predisposition to pancytopenia. Older age, acuity of symptom onset, and association with a known source of systemic infection or inflammation may suggest a possible acquired cause of pancytopenia. Acquired systemic disorders that can infiltrate the marrow include liquid and solid malignant tumors, fibrosis, and autoimmune, granulomatous, and hyperinflammatory diseases. Of note, inherited bone marrow failure syndromes (IBMFSs), although congenital in nature, may not manifest symptoms until later in childhood, some even into adulthood, and many lack classically described clinical phenotypic abnormalities.This review will focus on the most common congenital and acquired causes of BMF that present as symptomatic, transfusion-dependent pancytopenia and risk myelodysplastic or malignant transformation (Table 1).Acquired pediatric severe aplastic anemia (SAA) is a rare blood disorder characterized by immune-mediated destruction of hematopoietic stem cell precursors in the bone marrow resulting in peripheral blood pancytopenia. Nationally, more than 100 children less than 18 years of age will be diagnosed with SAA annually, with no predilection for race, sex, or geographical location. Children with SAA will present with (1) symptoms of severe leukopenia (neutropenia and lymphopenia), representing a child’s greatest risk of morbidity and mortality from SAA, as they are challenged to clear an increased frequency of common infections and the possibility of invasive uncommon bacterial, viral, and fungal pathogens; (2) signs and symptoms of severe anemia, including fatigue/lethargy, pallor, tachycardia, headaches, and, in infants, the failure to wake appropriately for feeds; and/or (3) signs and symptoms of severe thrombocytopenia, including petechiae, epistaxis, heavy menstrual bleeding, and increased bruising often noted in atypical locations like the trunk and mouth. Children with SAA become dependent on peripheral blood transfusions, which may be complicated by transfusion reactions, blood alloimmunization, and eventual iron overload.Diagnostic criteria for pediatric SAA have been refined from the original criteria proposed by Camitta et al in 1975.3 Modern criteria for SAA include a hypocellular bone marrow (total marrow cellularity reported as <25% or between 25% and 50% with <30% residual hematopoietic precursor cells) and at least 2 of 3 peripheral blood cytopenias defined as (1) an absolute neutrophil count (ANC) less than 0.5 × 109/L, (2) an absolute reticulocyte count less than 60 × 109/L, and/or (3) a platelet count less than 20 × 109/L.4 Children with an ANC less than 0.2 × 109/L are often referred to as having very severe aplastic anemia, while those with cytopenias who fail to meet full SAA criteria are often referred to as having moderate or nonsevere aplastic anemia. Because the differential diagnosis of a child who meets the diagnostic criteria for SAA additionally includes leukemias, myelodysplastic syndrome (MDS), IBMFSs, and other systemic disorders, referral to a pediatric hematologist/oncologist with experience treating these disorders for a comprehensive evaluation to determine the underlying etiology of SAA is necessary. Both acquired and congenital forms of BMF risk transformation to pediatric MDS (the clonal proliferation of preleukemic, dysplastic stem cell precursors in the bone marrow) or leukemia—primarily, acute myeloid leukemia (AML).SAA can be caused by a variety of factors, including (1) infectious (viral infections such as hepatitis, Epstein-Barr virus [EBV], cytomegalovirus [CMV], parvovirus B19, and HIV); (2) medications (including certain antibiotics, arthritis drugs, and chemotherapeutic agents); (3) radiation exposure; (4) toxins (eg, benzene, pesticides, and insecticides); (5) autoimmune diseases (in which the immune system mistakenly attacks the bone marrow); and (6) idiopathic cases. The North American Pediatric Aplastic Anemia Consortium (NAPAAC) surveyed pediatric hematologists/oncologists in both 2014 and 2019 regarding the subspecialist’s standard approach to the clinical evaluation of children meeting diagnostic criteria for SAA.5,6 Consensus supports obtaining a unilateral bone marrow biopsy specimen and aspirate for morphologic and histologic review; documentation of marrow cellularity; and cytogenetic evaluation, including karyotype analysis and fluorescence in situ hybridization (FISH) for MDS. Standard upfront laboratory evaluation includes a complete blood cell count with differential, an absolute reticulocyte count, and a peripheral blood smear review; organ function evaluation comprises a complete metabolic panel including liver function tests and uric acid and lactate dehydrogenase serum levels to rule out evidence of increased cellular turnover (more commonly seen in malignant tumors); immunologic evaluation includes quantitative assessment of immunoglobulins (IgA, IgG, IgM) and lymphocyte subset immunophenotyping; rheumatologic/autoimmune evaluation includes antinuclear antibody, C3, C4, and direct Coombs tests; infectious evaluation includes EBV, CMV, hepatitis A/B/C/E, HIV, parvovirus, human herpes virus 6, and other viruses based on signs and symptoms; and further screening evaluation for paroxysmal nocturnal hemoglobinuria (PNH), Fanconi anemia (FA) with chromosome fragility testing, and telomere biology disorders (TBDs), such as dyskeratosis congenita (DC), with telomere length testing.Few children will self-resolve severe marrow hypoplasia that meets diagnostic criteria for SAA. Most require medical intervention in the form of either aggressive immunosuppressive therapy (IST) or an allogenic hematopoietic stem cell transplant (HSCT). Controversy remains regarding a standardized approach to initial treatment, the definition of treatment response and failure, and the concurrent use of hematopoietic growth factors.Several studies have demonstrated superior overall survival (OS) and failure-free survival (FFS) in children with SAA who received HSCT with a human leukocyte antigen matched sibling donor (MSD).7 If available, HSCT with an MSD remains the preferred therapy for children newly diagnosed with SAA. For children without an MSD, standard clinical practice has been to pursue IST, citing historical data that demonstrate superior OS compared with HSCT from an alternative donor. In 2023, Shimano et al surveyed subspecialist providers regarding how to standardize the treatment approach to pediatric SAA. Standard-of-care IST consists of a regimen of antithymocyte globulin (ATG) in combination with a calcineurin inhibitor, most often cyclosporine. The combination of equine ATG and cyclosporine IST is well tolerated when monitored closely and side effects are addressed proactively. Infusion of ATG risks the induction of serum sickness, and their use requires prophylactic corticosteroid administration as well as supportive-care antipyretics and antihistamines. Cyclosporine, often administered for 12 months, may cause complications of hypertension, hypertrichosis, gum hypertrophy, and nephrotoxicity.Active studies are ongoing to evaluate the use of alternative donors for HSCT, including matched unrelated donors, mismatched unrelated or related donors, and haploidentical/“half matched” donors. With improved conditioning regimens that reduced overall toxicity, and with improved supportive care for infections, blood cytopenias, acute organ injury, and acute and chronic graft-vs-host disease, the field is now demonstrating improved OS and FFS for these alternative donors.8,9IBMFSs represent an important and likely underrecognized cause of aplastic anemia, MDS, and AML. The timely diagnosis of an IBMFS can have immediate implications on clinical care, monitoring, and treatment. Regarding HSCT, identification of a germline IBMFS may impact donor selection and the preparative regimen required to successfully achieve transplantation in a patient. The diagnosis further influences family planning decisions, requiring close collaboration with a genetic counselor. In the following section, we provide an overview of the most common pediatric IBMFS (Table 1).FA is an IBMFS caused by defects in genes responsible for DNA repair, resulting in the easy breakage of chromosomes and a strong predisposition to BMF and malignant tumors.10 FA is rare (heterozygote frequency of 1:300) and has a slight male predominance of 1.2:1.10 Abnormal congenital anomalies are present in approximately 75% of patients with FA and can include café-au-lait spots, short stature, microcephaly, skeletal malformations (including radial ray anomalies [eg, absent thumbs]), endocrinopathies, cardiac defects, hearing loss, genitourinary tract malformation, and developmental delay in a subset of patients.10 These physical anomalies may be subtle or absent, yet most will present in the first decade of with including of RBC and bone marrow is caused by in one of genes in the DNA the most common in FA is most often inherited in an can be or of FA is an increased risk of both liquid and solid malignant with FA are at increased risk for MDS, and cell of the and and genitourinary with in have the risk for malignant tumors, with having at least 1 malignant by years of to defects in the DNA patients with FA are to radiation and and often experience severe side effects with of FA can be by either assessment of increased breakage of with either or or identification of a or likely in one of the known FA patients with FA require a comprehensive approach to including laboratory and physical as well as of their bone marrow for the development of SAA, MDS, or with FA who SAA, MDS, or require HSCT for hematopoietic and may require to malignant Because patients with FA have a in the DNA and are to they require to side Although HSCT to the of acquired BMF, not the ongoing risk for development of tumors, including and may or increase the of at the of chromosomes that the chromosomes from with cell until they a critical or represent a of caused by telomere to telomere with may experience the of these the including hematopoiesis that to BMF and complications such as fibrosis, liver and (eg, malformations and with require not for hematopoietic malignant for malignant tumors, including and cell of the and presentation of are with a of and organ system The most diagnosed is which is classically characterized by the combination of dysplastic and/or a on the or These peripheral of may or may not be present in all with most will demonstrate some of hematopoietic syndrome is a more severe form of with syndrome and syndrome are both with and can be with either or hematopoietic telomere are in at least genes inherited in either an (eg, (eg, and or (eg, that to length can be with which telomere length in a panel of blood cell with often demonstrate very short telomere below the first for comprehensive approach is required to patients with which includes and who severe cytopenias or SAA may require HSCT for hematopoietic and to the risk for development of as for HSCT for not the risk for development of or other organ with who HSCT for MDS or may require which be reduced to side with and/or liver can life-threatening syndrome and to liver and may require evaluation for and/or liver syndrome is a rare IBMFS to germline that (the The systemic of include bone marrow and abnormal skeletal has an of approximately 1 in and can a Children present in with and symptoms (eg, and to may in to 50% of patients by years of age and may not be present at diagnosis in some or peripheral blood is the in Anemia and can be seen to and patients a risk of to SAA, MDS, or and karyotype cytogenetic including and can be in the bone marrow of patients with and their presence may and have not been with malignant clinical may include skeletal (eg, with elevated liver function immune and and clinical diagnosis of includes evidence of and peripheral blood often diagnosis can clinical a in in the in more than of patients with or The reported that 50% of patients with a diagnosis of not present with the of and are patients who demonstrate the clinical of without genetic with with an ANC less than 0.5 × 109/L who experience infections may require treatment with If patients with have evidence of they may require with to help with as well as with and who BMF should be for for patients who HSCT they have MDS or are to those who and HSCT for supports the that patients should have of their blood counts and bone marrow to for evidence of transformation to SAA, MDS, or anemia syndrome is IBMFS caused by (the which, in this results in a more in the proliferation and of has an of approximately to per with an Children present at less than 1 of age with symptomatic, transfusion-dependent anemia with a of precursors in the bone Peripheral blood severe and macrocytic with have elevated levels of and 50% of patients with demonstrate at least 1 congenital such as or genitourinary and cardiac defects, in to short and an increased predisposition to malignant (eg, MDS, and The differential diagnosis for includes of is an acquired and red cell that often in children between 1 and years of age in response to a common Although is often for children with have normal and and a lack of congenital genetic in commonly or commonly genes can be in approximately to of patients with has been with in or in Children with are dependent on RBC to development and corticosteroid is often in to more of RBC Although to may to a corticosteroid many fail to an response The chronic to blood risks the development of systemic iron and the development of RBC use of iron can help the of systemic and RBC can help risk of acquired RBC who have chronic transfusions, experience organ from iron or demonstrate evidence of BMF may be for HSCT a donor is congenital is a congenital disorder of characterized by and a predisposition to myeloid malignant precursors demonstrate at the or of neutrophil development with of resulting in infections of the and in in the known as that for neutrophil are most commonly in in and as well as have been Most patients require supportive treatment with to increase neutrophil counts and life-threatening with require of their bone marrow to for development of SAA, MDS, or AML. who fail to to or of or evidence of should be for HSCT a donor is is to in the to patients demonstrate a and to their In at the demonstrating an ANC less than 0.2 × 109/L for 3 to Children may in the or the which are often less severe than those seen in patients with can be used in patients with to the and of often at and at than for patients with infections, and syndrome is a rare, characterized by the of and increased risk of infection to and to the of increased of myeloid cells in the bone often demonstrated by by and in are as the cause for syndrome to an for to out of the bone marrow to peripheral In to patients with syndrome have and with to human virus has been used successfully in some patients to increase peripheral blood neutrophil more the and has a for the treatment of is an of the that causes a of in the bone marrow and results in severe transfusion-dependent at with are predisposed to rapid to SAA, MDS, or and require evaluation for with is an additional severe congenital with strong predisposition and rapid to can be caused by either in or absent syndrome is an congenital caused by 2 genetic defects in chromosome 1 and an of characterized by severe in and the of most children with will demonstrate of peripheral platelet counts by 1 of age and to syndrome is a disorder characterized by severe and in that the common presentation of known inherited DNA results in peripheral liver and disease, and hematopoietic marrow cellular precursors and that in peripheral pancytopenia. in often as a of and organ is an disorder caused by in with predisposition to BMF, with increased risk for infections (eg, and increased risk for transformation to MDS, or chronic with can have a presentation from cytopenias to MDS in to infections can have additional organ including and such as congenital hearing loss, developmental and may present or as with a age of of myeloid malignant of 20 are the most common cause of MDS with in HSCT is the known for and is in patients with BMF, MDS, severe infections, or or syndromes are caused by a germline in either or which are to other on chromosome can present with a of organ system including and symptoms may from to SAA or MDS with in are the most common cause of MDS with in with a age of of for syndromes on the of with require close monitoring, those with MDS with often require The treatment approach for those with symptoms on the between and MDS with is yet to be less common that have a predisposition to malignant growth include germline in and These syndromes present with of as their clinical germline in and have an increased risk of myeloid malignant tumors, in increase the risk for precursor acute leukemia These syndromes all require and chronic as HSCT may be with congenital and acquired causes of BMF life-threatening complications of transfusion and an ongoing risk for malignant these in supportive improved of transfused blood for iron bone and, most improved preparative regimens and supportive care to decrease overall morbidity and mortality diagnosis and clinical in the treatment of cytogenetic and dysplastic within the bone marrow and peripheral malignant for a congenital or acquired BMF disorder remains in the of pediatricians who are to recognize hematopoietic and solid malignant in a family history and the of anomalies on their physical Children with severe, or of pancytopenia should referral to a practice with SAA and collaboration between care providers and a care of subspecialty providers can in improved of and risk of life-threatening pancytopenia is defined as a decrease in all 3 cell anemia, and below the for age and and requires recognition and evaluation with history and physical based on strong evidence and consists of a hypocellular bone marrow and at least 2 of 3 peripheral blood cytopenias, which may be either acquired or congenital in and requires a comprehensive evaluation to determine the underlying based on strong evidence and aplastic anemia is most commonly to immune-mediated destruction of the bone marrow be secondary to certain or to radiation of certain based on strong evidence and can present with anemia, and/or thrombocytopenia, and their recognition as the cause of aplastic anemia is recognition can have immediate implications on clinical care, monitoring, and based on strong evidence and may present later in childhood, or adulthood, and patients may not the seen with these disorders, requiring a of for based on strong evidence and