Missing Cells: Pathophysiology, Diagnosis, and Management of (Pan)Cytopenia in Childhood

Abstract

Peripheral blood cytopenia in children can be due to a variety of acquired or inherited diseases. Genetic disorders affecting a single hematopoietic lineage are frequently characterized by typical bone marrow findings, such as lack of progenitors or maturation arrest in congenital neutropenia or a lack of megakaryocytes in congenital amegakaryocytic thrombocytopenia, whereas antibody-mediated diseases such as autoimmune neutropenia are associated with a rather unremarkable bone marrow morphology. By contrast, pancytopenia is frequently associated with a hypocellular bone marrow, and the differential diagnosis includes acquired aplastic anemia, myelodysplastic syndrome, inherited bone marrow failure syndromes such as Fanconi anemia and dyskeratosis congenita, and a variety of immunological disorders including hemophagocytic lymphohistiocytosis. Thorough bone marrow analysis is of special importance for the diagnostic work-up of most patients. Cellularity, cellular composition, and dysplastic signs are the cornerstones of the differential diagnosis. Pancytopenia in the presence of a normo- or hypercellular marrow with dysplastic changes may indicate myelodysplastic syndrome. More challenging for the hematologist is the evaluation of the hypocellular bone marrow. Although aplastic anemia and hypocellular refractory cytopenia of childhood (RCC) can reliably be differentiated on a morphological level, the overlapping pathophysiology remains a significant challenge for the choice of the therapeutic strategy. Furthermore, inherited bone marrow failure syndromes are usually associated with the morphological picture of RCC, and the recognition of these entities is essential as they often present a multisystem disease requiring different diagnostic and therapeutic approaches. This paper gives an overview over the different disease entities presenting with (pan)cytopenia, their pathophysiology, characteristic bone marrow findings, and therapeutic approaches.

Introduction

(Pan)cytopenia in childhood can be caused by a variety of underlying diseases, including hematological and non-hematological entities. Overlapping phenotypes and pathophysiologies pose a major diagnostic challenge. However, an accurate and rapid diagnosis is essential for adequate therapy planning, surveillance, and genetic counseling. Bone marrow (BM) analysis is of special importance for the diagnostic work-up of cytopenias affecting one or more lineages. In the following, we will describe the individual disorders, their underlying pathophysiology and clinical characteristics, as well as typical BM findings.

The Hierarchy of Hematopoiesis

All peripheral blood cells originate from hematopoietic stem cells (HSCs) that reside in fetal liver and fetal or adult BM. HSCs are able to self-renew, which is essential for maintenance of lifelong hematopoiesis. They do not commit directly to single lineages, but instead differentiate into multipotent progenitors, common lymphoid and (erythro-) myeloid progenitors, which in turn give rise to more differentiated precursor cells. Lineage commitment is determined by a delicate network of transcription factors and epigenetic mechanisms that establish differentiation into the corresponding lineage while suppressing maturation toward other lineages (1). The hierarchical tree of hematopoiesis is depicted in Figure 1, but there is evidence that such a linear and rigid model is oversimplified (2). Also, a specific HSC subset has been reported to directly evolve into megakaryocytes, at least in the murine system (3). Depending on the differentiation stage affected, disturbances can occur in single or multiple lineages (Figure 1).

Figure 1

Signs and Symptoms of Cytopenia

The condition caused by low erythrocyte numbers and hemoglobin concentration is called anemia and is clinically characterized by paleness, weakness, and general malaise. Severe anemia due to rapid hemoglobin drop (i.e., blood loss, hemolysis) may lead to cardiovascular symptoms such as tachycardia and arterial hypotension. Anemia due to bone marrow failure usually has insidious manifestation. Reticulocytosis points toward active red cell production while lack of reticulocytes is indicative for insufficient erythropoiesis. Other informative parameters are mean corpuscular volume (MCV) and HbF levels as signs of stress hematopoiesis or low haptoglobin with increased unconjugated bilirubin in the presence or absence of a positive antiglobulin test indicating hemolysis (4).

Platelets are fragments of membrane and cytoplasm derived from megakaryocytes and important for hemostasis. Thrombocytopenia is characterized by cutaneous and mucosal bleeding signs, such as epistaxis, petechia, and purpura. Platelet size and morphology can help classifying the underlying disease. Platelets are abnormally small in patients with Wiskott–Aldrich syndrome (WAS) and large in patients with Bernard–Soulier syndrome or May–Hegglin anomaly (5). Platelet size diminishes over time, and therefore higher platelet volume may indicate the presence of less mature platelets in cases of increased degradation (e.g., idiopathic thrombocytopenic purpura, ITP) (6).

Lack of neutrophils, neutropenia, is characterized by an increased susceptibility to bacterial infections. Risk of infections correlates with granulocyte counts, with severe neutropenia (<500/μl) being associated with a high risk of life-threatening infections (7). Depending on the extent of neutropenia and the frequency of severe infections, prophylactic antibiotic treatment and/or G-CSF application might be considered. Response to G-CSF is indicative for the myelopoietic capacity of the BM.

In line with the many different types and developmental stages of lymphocytes, lymphopenia can affect an entire lineage (i.e., B, T, and/or NK cells) or individual mature cell types (e.g., regulatory T cells). Type of lacking cells as well as abundance of other lymphocyte types determine the phenotype of the individual disease. Phenotypes can be highly variable and range from (severe) combined immunodeficiency to mildly increased susceptibility to specific infections. Primary immune diseases can also be associated with immune dysregulation (8).

Neonatal cytopenias are particularly challenging due to the extremely diverse spectrum of differential diagnoses. Impairment of fetal erythropoiesis or thrombopoiesis due to inherited defects or prenatal infections can result in hydrops fetalis or perinatal hemorrhagic complications, respectively. Ineffective fetal hematopoiesis within the BM can lead to persistent extramedullary hematopoiesis in liver, spleen, and occasionally in the skin (9). Affected newborns are characterized by hepatosplenomegaly and may have skin infiltrations (so called “blueberry muffin” babies). The latter condition is indicative for hemolytic diseases, malignant BM infiltrations, infantile malignant osteopetrosis, or congenital infections (10). Neonatal erythroderma might indicate the presence of severe immune dysregulation as seen in Omenn’s syndrome, a hyperinflammatory variant of leaky SCID (11).

A detailed medical history is essential in all cases of cytopenias and should include details of concomitant health problems, susceptibility to bleeding or infections, previous exposure to drugs or toxins, and recent foreign travel. Family history should focus on hematological and immune disorders, cancer susceptibility, or unexplained infant deaths. Thorough physical examination should include the assessment of signs of lymphoproliferation (i.e., hepatosplenomegaly and lymphadenopathy), as well as dysmorphic features, and stigmata, indicating the presence of a syndromic disease.

Cytopenia Affecting a Single Lineage

In principle, single lineage-cytopenias may be caused by insufficient production or premature depletion of mature cells of the respective hematopoietic lineage. In the majority of cases, the latter is mediated by autoreactive antibodies, resulting in ITP, autoimmune neutropenia (AIN), or autoimmune hemolytic anemia (AIHA), respectively (12). Frequently, autoantibodies are formed as a reaction to infections or vaccinations due to the so-called “molecular mimicry” between pathogen components and blood cell antigens (13). Similarly, heparin-induced thrombocytopenia (HIT) is caused by antibodies specific for heparin-binding platelets (14). Generally, these disorders show normal BM morphology or hyperactive hematopoiesis in the corresponding lineage. Most tests for autoantibodies have a low sensitivity and specificity, and are therefore not required for the confirmation of the diagnosis, except for AIHA (15). Since the BM is normal in ITP or AIN and thus has the capacity of increased cell production if stressed, signs and symptoms are frequently milder compared to patients with hypoproliferative deficiencies of these cell lineages. Even in the complete absence of peripheral granulocytes, patients rarely suffer from life-threatening infections. In contrast to these clinically mostly benign autoimmune disorders, AIHA, especially in childhood, can be life-threatening because of rapid hemoglobin decline (16).

Furthermore, a premature destruction of red blood cells may be caused by defective hemoglobin, metabolic enzymes, or membrane components. These syndromes can be diagnosed by hemoglobin electrophoresis, determination of enzymatic activity or osmotic fragility tests, respectively, and will not be discussed here in more detail. Increased destruction of platelets and the subsequent risk of bleeding are also characteristic features of inherited disorders, such as Wiskott–Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT). While platelet generation has been shown to be unaffected in this syndrome, cytoskeletal changes occurring in circulating platelets lead to their premature degradation (17).

Similar to the single lineage-cytopenias caused by premature cell loss, disorders with inadequate cell generation can affect all individual lineages, i.e., megakaryopoiesis, erythropoiesis, and myelopoiesis. These disorders, their pathophysiologies, diagnostic characteristics, and symptoms are summarized in Table 1. Disorders with insufficient generation of lymphocytes result in (severe) combined or milder immunodeficiencies. Since they require distinct diagnostic approaches and therapies, these syndromes are beyond the scope of this review and were discussed elsewhere (18).

When More Lineages are Affected

Cytopenias affecting two or three blood lineages, the latter called pancytopenia (greek , pan = involving all), can also be caused by deregulation of either cell generation or degradation. As an additional layer of classification, the disorders can be divided into inherited or acquired BM failures. It is important to emphasize that inherited BM failure syndromes (IBMFS) as well as acquired BM failure can present in all age groups, and that in some cases an isolated cytopenia preceeds the development of pancytopenia. This requires particular attention and repeated reevaluation by the attending physician or hematologist. Isolated thrombocytopenia can initially be diagnosed as ITP, but additional anemia or neutropenia over time might indicate the presence of systemic autoimmune disorders such as systemic lupus erythematosus (SLE). Similarly, isolated neutropenia can be considered to be secondary to an infection, but the subsequent decrease of other blood cells should rapidly lead to BM analysis. In the following, we will describe the different forms of pancytopenia in more detail.

Pancytopenia as Consequence of Autoimmunity and Immune Dysregulation

While single-line immune-mediated degradation of platelets, erythrocytes, or neutrophils is frequent, combinations thereof are rare and often serious (35, 36). The combination of AIHA and thrombocytopenia, occurring either simultaneously or sequentially, is called Evans syndrome and is often a manifestation of the autoimmune lymphoproliferative syndrome (ALPS) (37). ALPS is caused by germline or somatic mutations in FAS, FASL, or CASP10, resulting in insufficient apoptosis of activated autoreactive lymphocytes via the extrinsic pathway (38, 39). Rarely, ALPS can be caused by RAS mutations resulting in defective intrinsic apoptosis of lymphocytes (40). Concomitant lymphoproliferation is characteristic for ALPS. Similarly, cytopenias can occur in acquired, multifactorial autoimmune syndromes such as SLE or the primary antiphospholipid syndrome (36). Germline syndromes characterized by autoimmunity are the IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked) syndrome caused by lack of regulatory T cells and the APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy) syndrome caused by insufficient induction of central (thymic) tolerance (41, 42). Other primary immunodeficiencies frequently leading to autoimmune cytopenia are leaky SCID, WAS, hyper-IgM syndrome, and common variable immunodeficiency (CVID) (36). Indicative of the presence of such syndromes are lymphoproliferation, autoantibodies, oligoclonal T cells, increased complement consumption, and signs of autoimmunity or autoinflammation affecting other organs (i.e., dermatitis, glomerulonephritis, and inflammatory bowel disease). Bone marrow findings are usually not characteristic and merely indicate increased cellular turnover.

Immune dysregulation is also the cause of pancytopenia in patients with hemophagocytic lymphohistiocytosis (HLH). This life-threatening syndrome is characterized by impaired pathogen elimination, hyperinflammation, and hystiocytic and lymphoid tissue infiltration. It can occur as familial disease (FHL with PRF1, UNC13D, STX11, or STXBP2 mutations), in syndromes characterized by additional albinism (i.e., Griscelli syndrome type II, Hermansky-Pudlak syndrome type II, and Chediak-Higashi syndrome) and secondary to infection, rheumatic, or neoplastic disorders. Secondary HLH is also known as macrophage activation syndrome (MAS). Deregulation of T and NK cell cytotoxicity and/or lysosomal trafficking are underlying mechanisms of HLH (43). Pancytopenia is not mediated by autoantibodies but instead by macrophage hyperactivation, resulting in hemophagocytosis and cytokine-mediated marrow suppression. Accordingly, hemophagocytosis in BM is one of the diagnostic criteria, next to hypertriglyceridemia, hypofibrinogenemia, and increased levels of ferritin and soluble IL2 receptor. Degranulation and cytotoxicity assays as well as genetic analysis confirm the diagnosis (44).

Extrinsic Conditions Associated with Impaired Hematopoiesis

Certain extrinsic, environmental conditions can interfere significantly with blood formation, either pre- or postnatally. The most frequent causes of impaired hematopoiesis are infections. Congenital TORCH infections (i.e., toxoplasmosis, rubella, cytomegalovirus, herpes simplex, and others) often result in decreased maturation of megakaryocytes and platelet formation, in combination with increased immune-mediated platelet destruction (45, 46). Parvovirus B19 infections lead to apoptosis and cell cycle arrest in infected fetal erythroblasts, thereby resulting in fetal anemia and hydrops (47). Also postnatally, parvovirus B19 can transiently affect erythroid progenitors. While healthy children are only mildly affected, children with hemolytic anemia and immunocompromised patients might develop aplastic crisis and persistent anemia, respectively (48). Many other viral infections are associated with transient hematopoietic depression of one or more lineages. Important infections to be considered in the differential diagnosis of peripheral cytopenias are hepatitis C, HIV (in children nowadays mostly due to vertical transmission), and Helicobacter pylori, all causing thrombocytopenia and some of them anemia. Visceral leishmaniasis, in contrast, results in an HLH-like disorder with massive phagocytosis of blood components (49, 50).

Other causes of suppressed hematopoiesis are nutritional deficiencies observed in anorexia nervosa or B12, folate, and iron deficiency. While mild deficiencies frequently cause anemia, severe lack of essential food components can result in complete BM failure and immunodeficiency (51–53).

Finally, hematopoiesis can be restricted by pathological microenvironmental conditions. In Gaucher disease, BM dysfunction is caused by accumulation of glucocerebrosides in macrophages and results in (pan)cytopenia (54). By contrast, osteopetrosis is caused by reduced bone resorption leading to bone sclerosis and, among other symptoms, restriction of the medullar cavity. This results in BM failure and compensatory extramedullary hematopoiesis. Different disease subtypes have been reported, with infantile malignant osteopetrosis being the most severe form (55).

Inherited Intrinsic Defects of Hematopoiesis

Various inborn genetic defects result in hematopoietic failure, and most of them are not restricted to hematopoiesis but also affect different organ systems. Traditionally, Fanconi anemia (FA), dyskeratosis congenita (DC), congenital amegakaryocytic thrombocytopenia (CAMT), thrombocytopenia with absent radii (TAR), Diamond Blackfan anemia (DBA), Shwachman Diamond syndrome (SDS), and severe congenital neutropenia (SCN) have been subsumed as inherited BM failure syndromes (IBMFS). BM failure can occur at different ages and has highly variable presentations. Disease kinetics and degree of severity depend on the underlying gene mutation and presumably on concomitant polymorphisms and environmental influences, such as life style, infections, and exposition to toxins (56). Underlying pathogenetic mechanisms are heterogeneous and comprise metabolic dysfunction, inhibition of differentiation, ribosomal dysfunction, DNA repair deficiency, and telomere maintenance.

In DBA, SDS, SCN, CAMT, and TAR, primarily one hematopoietic lineage is affected. These syndromes, their underlying pathogenesis, and phenotype, as well as characteristic BM findings are summarized in Table 1. However, it has to be kept in mind that patients with CAMT or SDS frequently show a progress from isolated thrombocytopenia or neutropenia, respectively, to complete BM failure (31). In DBA, erythropoiesis is primarily affected but full BM failure also occurs at low frequency (26, 56). Ribosomal dysfunction has been shown to induce excessive TP53 activation leading to apoptosis and being most harmful to highly proliferating erythroid progenitor cells (24, 26).

In the following, we will focus on syndromes affecting more than one hematopoietic lineage and frequently resulting in severe BM failure and pancytopenia. One of the most severe forms of hematopoietic failure is reticular dysgenesis, a rare, autosomal-recessive syndrome. Erythro- and megakaryopoiesis have been described to be unaffected in some patients, but newborns present with complete absence of neutrophils and early onset SCID. Due to the lack of both innate and adaptive immune functions, reticular dysgenesis is rapidly fatal unless hematopoietic stem cell transplantation (HSCT) is performed. Mutations in the AK2 gene have been identified to be causative for some cases, but most remain unsolved (57, 58).

The most frequent syndromes characterized by severe BM failure are FA and DC. In FA, mutations are found in 15 different genes (FANCA, FANCC, FANCG, FANCD2, and others), all involved in DNA damage repair, particularly in resolution of DNA interstrand cross-links during replication. Patients may present with congenital abnormalities, such as short stature, microphthalmia, thumb and radius deformities, café-au-lait spots and heart, renal and genitourinary malformations. Hematopoietic failure often emerges in childhood or adolescence, and most patients are only diagnosed with FA at the onset of pancytopenia (59). When treated with mitomycin C, FA cells accumulate chromosomal breaks and undergo G2 arrest, which is used as a diagnostic test (60). DC is a disease caused by mutations in genes affecting telomere elongation and maintenance (DKC1, TERC, TERT, TINF2, and others). Although the disease was first characterized by its mucocutaneous symptoms (i.e., skin pigmentation, nail dystrophy, and mucosal leukoplakia), it is now known that the development of BM failure may preceed the mucocutaneous manifestations. Age of onset and disease phenotype are highly variable and at least partially depend on characteristic mutations (61). By contrast, the diagnostic work-up invariably reveals very short telomeres at time of presentation. Unresolved DNA damage and critically short telomeres induce DNA damage checkpoint activation in FA and DC cells, respectively, with TP53 being a critical mediator (62). As a consequence, cells stop proliferation, and senescence or apoptosis are induced. Together, these pathways confer protection from malignant transformation but at the same time they contribute to BM failure and pancytopenia. As a consequence, FA and DC cells have a high selective pressure to inactivate the DNA damage checkpoint, as reflected by their high propensity to develop secondary MDS and AML (Tables 2 and 3) (63). The highest risk is observed in FA patients where accumulation of DNA damage and unresolved chromosomal aberrations rapidly lead to malignant transformation (64).

Other genetic diseases associated with pancytopenia are Seckel and Pearson syndromes. Seckel syndrome represents a DNA damage repair deficiency characterized by BM failure, dwarfism, microcephaly, mental retardation, and skeletal malformations. Among others, ATR mutations have been identified to be responsible for this rare syndrome (107). Pearson syndrome is caused by loss of mitochondrial DNA and thus one of the so called mitochondriopathies. Next to failure to thrive, exocrine pancreatic dysfunction, and susceptibility to metabolic imbalance, patients frequently suffer from anemia, thrombocytopenia, and/or neutropenia. BM analysis typically shows sideroblastic anemia and vacuolization of hematopoietic precursor cells (108).

It is hardly surprising that DNA damage deficiencies, telomeropathies, ribosomopathies, or mitochondriopathies do not only disturb hematopoiesis but also affect developmental programs and adult tissues. Many of the syndromes described here are additionally characterized by an increased susceptibility to malignancies, including hematological malignancies and solid tumors (Table 2) (65–71). It is obvious that both, the multisystemic nature of disease and the tumor susceptibility, have to be taken into account during patient care and therapy planning. It is therefore of great importance to recognize the underlying cause of BM failure even in patients with mild or no extrahematological symptoms (56, 109). Pitfalls and diagnostic approaches especially in disorders with hypocellular BM are discussed below.

Acquired Disorders of Hematopoiesis

Myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a clonal disorder originating from a hematopoietic stem/progenitor cell that supposedly has acquired driver mutations. Due to deregulation of differentiation and increased susceptibility to apoptosis, MDS is characterized by ineffective hematopoiesis in one or more lineages. BM analysis shows characteristic dysplastic cells, such as micromegakaryocytes, binucleated erythroid precursors, and hypo- or hypersegmented neutrophils. MDS has a high propensity to further progress to more advanced disease, including MDS-related acute myeloid leukemia (MDR-AML). This evolution is caused by additional subclonal driver mutations that have been acquired in a stepwise manner and result in further increase in proliferation and impairment of differentiation (110).

In general, MDS is a disease of old age, with an incidence of 50 cases per 100,000 persons aged over 70 years. As shown recently, even healthy, aged individuals frequently have clonal expansion of hematopoietic cells harboring driver mutations (i.e., DNMT3A, JAK2, TET2, and others), although they do not (yet) suffer from overt MDS or leukemia (77). Risk of MDS is further increased in people exposed to chemo- or radiotherapy earlier in life with a life-time risk of 2–10% after treatment with alkylating agents, topoisomerase II inhibitors, or ionizing irradiation (111).

By contrast, childhood MDS is rare, and differs from adult MDS in several aspects. For this reason, the WHO 2008 classification incorporated a classification specific for childhood MDS allowing unambiguous classification of most patients (112). Depending on the number of blasts in peripheral blood (PB) and BM, childhood MDS is classified as refractory cytopenia of childhood (RCC; PB blasts <2%, BM blasts <5%), refractory anemia with excess blasts (RAEB; PB blasts 2–10%, and/or BM blasts 5–19%), RAEB in transformation (RAEB-T; PB and/or BM blasts 20–29%), and MDR-AML (>30% BM blasts) (113). The most common subtype is RCC (50%). While adult MDS patients usually present with isolated anemia (“refractory anemia”), affected children frequently present with thrombocytopenia (<150,000/μl; 75%), neutropenia (<1,000/μl; 50%), and/or anemia (Hb <10 g/dl; 50%). HbF and MCV are frequently elevated (114). In >80% of all RCC cases, BM analysis reveals a marked decrease of cellularity. The remaining 20% of patients with RCC have a normo- or hypercellular BM (114).

Common cytogenetic abnormalities of childhood MDS are monosomy 7 (approximately 30%) and trisomy 8. Loss of chromosome 5q, frequently seen in adults, is only rarely found in children. A structurally complex karyotype (≥3 chromosomal aberrations including at least one structural aberration) is rare but invariably associated with poor prognosis (115–117). Chromosomal aberrations do not represent initiating events but indicate disease progression. Along this line, karyotypic evolution is usually accompanied by progression to more advanced MDS forms. The incidence of cytogenetic abnormalities is lowest in RCC with hypocellular BM. Patients with RCC and monosomy 7 are at high risk of progression with a cumulative incidence of 80% at 6 years from diagnosis and a median time to progression of 1.9 years (118). By contrast, RCC patients with a normal karyotype or trisomy 8 may have stable disease for many years. Patients with advanced MDS are at risk for further disease progression and have an indication for early HSCT (114). In infants, monosomy 7 or del(7q) has also been reported to disappear spontaneously, however, only in rare cases (119).

Next to sporadic cases, MDS can arise secondary to inherited or acquired BM disorders or in the context of chemo/radiotherapy. Importantly, all IBMFS described above have a risk to transform into secondary MDS, as described above in more detail for FA and DC (Table 2) (64). Lifetime risk of IBMFS patients is highly variable and ranges from very high in patients with FA (40–50% by the age of 40 years) to very low in DBA patients (65). Patients with other inherited syndromes might develop MDS directly without hypocellular prophase (120). GATA2 haploinsufficiency is the most frequent reason for such familiar MDS. Patients show variable disease complexes with extrahematological symptoms, such as lymphedema and deafness, and 40% develop MDS during adolescence and early adulthood. Preceding hematological and immunological symptoms are heterogeneous and include monocytopenia, mild neutropenia, and DC, B and/or NK cell deficiency. Depending on the predominant symptoms, the syndrome was named DCML (dendritic cell, monocyte, B and NK lymphoid) deficiency, Emberger syndrome, or MonoMAC (121). Similarly, patients with heterozygous germline RUNX1 mutation have a high propensity to develop MDS (20–50%). Since precedent hematological symptoms are limited to qualitative and quantitative platelet defects, the syndrome is called familial platelet disorder (FPD) (33). It is not yet fully understood, why patients with RUNX1 and GATA2 mutations are at such high risk for MDS (120).

Severe aplastic anemia

While MDS is an intrinsic disorder of hematopoiesis, severe aplastic anemia (SAA) is an autoimmune process. In contrast to autoimmune cytopenias affecting mature blood cells, immature and multipotent cells are targeted in SAA resulting in the severe phenotype characterized by pancytopenia and BM aplasia (88, 94). Evidence for the immune pathophysiology of the disease was first derived from clinical observations such as the response to immunosuppressive therapy (IST) or successful autologous recovery after failed allogeneic HSCT (122, 123). Since then, much effort has been invested in characterization of the immune phenotype, and certain HLA alleles have been associated with an increased risk (90, 91). Autoantibodies against different antigens (e.g., antimoesin or kinectin) have been detected in SAA patients but their significance remains unknown (92, 93). Detailed analysis of the T cell compartment revealed a recruitment of activated T cells to the BM (124) and oligoclonality in some cases (125–128). CD8+ cells isolated from SAA patients were able to suppress colony formation in vitro (129). Th1-shifted cytokine secretion with elevated IFNγ, TNFα, and IL-2 levels is thought to contribute to disease pathogenesis by suppressing hematopoiesis (89, 99–101).

Although SAA is primarily immune-mediated, acquisition of somatic mutations and clonal hematopoiesis seem to be relevant phenomena. Clonal evolution is thought to be driven mainly by two mechanisms: (i) proliferative pressure to compensate for hematopoietic failure, and (ii) immune escape.

Best described is the presence of a so-called paroxysmal nocturnal hemoglobinuria (PNH) clone in patients with SAA. In PNH, the clonal cell population harbors a mutation in the PIGA gene and thus lacks cell surface proteins linked to a glycosylphosphatidylinositol anchor. In clinically manifest PNH, this leads to complement-mediated hemolysis and the risk of thrombosis (80). It is possible that PIGA mutations occur to escape autoimmunity directed against glycosylphosphatidylinositol-bound antigens. Alternatively, the clone might exist a priori and be positively selected when other hematopoietic cells are hit by autoreactive T cells in SAA. Also, copy number-neutral loss of heterozygosity of chromosome 6p is observed disproportionately frequent in SAA patients (81). This is thought to be a mechanism of immune-escape by deletion of antigenic HLA alleles. Finally, SAA patients have been shown to carry somatic mutations similar to those mutated in MDS (i.e., ASXL1, DNMT3A, TET2, and others), indicating transformation into secondary MDS (82, 130).

B-cell precursor acute lymphoblastic leukemia

About 2% of patients with B-cell precursor acute lymphoblastic leukemia (ALL) present with pancytopenia and hypocellular BM. Usually, this prophase is transient and goes into spontaneous remission before ALL emerges with a latency of up to 9 months. Hematopoietic cells in the aplastic phase have been shown to carry the same gene mutations as the leukemic blasts (131, 132).

Inherited Bone Marrow Failure, MDS, and SAA: The Diagnostic Challenge of a Hypocellular Marrow

One of the major challenges in pediatric hematology is the correct diagnosis of patients with pancytopenia and hypocellular BM. Once infections and other more frequent conditions resulting in a transient suppression of hematopoieisis have been excluded, the main differential diagnosis includes SAA, hypoplastic MDS, and IBMFS, such as FA and DC. Careful diagnostic work-up and accurate distinction of these entities are mandatory because they require different strategies for therapy, surveillance, and counseling. In particular, IBMFS have to be excluded since they often present as multisystem and tumor-susceptibility syndromes with limited tolerance to various therapies (56, 64, 109). The diagnostic challenge is not only due to similar clinical presentation but also caused by a relevant overlap in the underlying pathophysiology. Table 3 shows different pathophysiological mechanisms contributing to IBMFS, MDS-RCC, and SAA to variable degrees. Further problems for the diagnostic work-up are scarce cell numbers isolated from hypocellular BM and lack of discriminating functional tests.

Since disorders of hypocellular BM are rare, diagnostic work-up should be performed by experienced hematologists and hematopathologists, and patients should be treated after consultation with reference centers. This ensures best care for affected patients and their families and prevents underdiagnosis of RCC and telomeropathies in SAA cohorts (109, 134–136).

It is also important to repeatedly reevaluate patients with IBMFS and SAA, since both disorders are at risk to progress into secondary MDS. Secondary MDS can be diagnosed by an increase in blast cells or BM cellularity, despite persistent pancytopenia, and by acquisition of chromosomal aberrations.

Therapeutic Approaches and Limitations

Treatment of (pan)cytopenia is based on a few symptomatic or curative therapeutic options. Symptomatic treatment includes the transfusion of blood products, such as red blood cells and platelets, and prevention or treatment of infections with antimicrobial drugs, and if indicated immunoglobulin substitutions. Granulocyte or T cell transfusions are technically feasible but restricted to very few life-threatening situations. Hematopoietic growth factors may be used to stimulate hematopoiesis and overcome reduced blood cell production. G-CSF is the therapy of choice for patients with SCN and has changed the fate of majority of children with this serious condition (19, 137). Today, allogeneic HSCT is limited to patients who do not respond to G-CSF or develop MDS (138). Although the situation is less clear, selected patients with SDS might benefit from G-CSF in case of severe neutropenia (66). The thrombopoietin analog eltrombopag has been successfully used in chronic ITP (139) and surprisingly induced multilineage responses in an early study in patients with refractory SAA (140). Other, less specific stimulants of hematopoiesis are the steroid prednisolone or the androgens, danazol and oxymetholone, used for DBA or DC, FA, and SAA patients, respectively (26, 141–144).

Some of the disorders described in this review require immune-modulatory or suppressive therapies. These include high dose-immunoglobulins, anti-thymocyte globulin (ATG), steroids, cyclosporine, mycophenolic acid, and others. Detailed treatment schedules for ITP, AIHA, ALPS, SLE, HLH, and others are beyond the scope of this review and described elsewhere.

Immunosuppressive therapy traditionally has been the therapy of choice for patients with SAA with no matched related donor (94, 145). The best established regimen consists of ATG in combination with cyclosporine A (95). In 2011, a randomized trial demonstrated that the source of ATG (horse vs rabbit) is relevant and the treatment with ATG derived from horses is more effective compared to products derived from rabbits (146). These results have subsequently been confirmed in multiple observational studies (147, 148). Using the combination of horse ATG and cyclosporine, the response rate is approximately 60–70% with a risk of relapse or clonal evolution of 10–30 or 10–20%, respectively (145). Attempts to improve efficacy were based on additional treatment with sirolimus, mycophenoalte mofetil, or danazol, and did not result in significant improvements. Also, the addition of G-CSF did not result in better response rates or improved survival, and therefore is not generally recommended. Based on the observation that autoimmunity contributes to the pathophysiology of MDS (Table 3) and that adult patients with hypoplastic MDS have successfully been treated with IST (149), selected pediatric patients with hypocellular RCC have successfully been treated with IST (87, 150, 151).

Hematopoietic stem cell transplantation is a curative treatment for patients with SAA and MDS, and the hematological manifestation of IBMFS. Patients with SAA traditionally were transplanted following a conditioning regimen consisting of cyclophosphamide/ATG in the presence of a matched sibling donor with excellent results (152). Based on less favorable results, HSCT from an unrelated donor was only performed in patients with non-response to IST, relapse, or clonal evolution. Lately, the results of HSCT from unrelated donors have improved considerably and upfront primary HSCT from a well-matched unrelated donor might be considered in selected cases if the donor is available in an acceptable timeframe (153–155).

In RCC, the indication for HSCT is based on the severity of pancytopenia (ANC <1000/μl and/or transfusion dependency) and the presence of cytogenetic aberrations (monosomy 7, 7q-, complex karyotype). Patients with hypocellular RCC with normal karyotype are successfully treated with a reduced intensity regimen, whereas patients with cytogenetic aberrations or a normo-/hypercellular marrow require a more intensive regimen. Patients with advanced MDS should be transplanted as soon as possible following an intensive conditioning regimen (118, 156, 157).

In IBMFS, allogeneic HSCT is able to treat the hematological, and immunological manifestations of the disease. However, extrahematological manifestations, such as pulmonary fibrosis in DC, are not only not treated by this therapeutic approach but may also be an insurmountable obstacle for HSCT. In addition, the majority IBMFS are multisystem disorders with a complex pathophysiology that result in an increased sensitivity to chemotherapeutic drugs requiring a specific adaption of conditioning regimens (158). The careful evaluation of possible related stem cell donors is of special importance in familial disease.

Finally, it has to be mentioned that HSCT is also the only curative treatment for all forms of primary immunodeficiencies and familial HLH. Experimental approaches such as targeted gene correction are under evaluation with regard to efficacy and safety, but not yet suitable for broad application.

In summary, it is still a great challenge to find the correct diagnosis for patients with (pan)cytopenia, especially in the presence of a hypocellular BM. Better definition and differentiation between the individual inherited and acquired disorders are required to ensure adequate medical care, surveillance, and genetic counseling for affected children and their families. To this end, the underlying pathophysiological mechanisms have to be investigated in more detail. Furthermore, functional tests and biomarkers with higher specificity for individual diseases have to be developed. Finally, we recommend that all affected children should be registered in registries and/or clinical trials and treated according to general guidelines.

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