Pancytopenia/Aplastic Anemia/Bone Marrow Failure

Fanconi Anemia

Fanconi anemia (FA) is an autosomal recessive genetic disorder associated with congenital anomalies, cancer predisposition, and pancytopenia due to bone marrow failure (see Fig. 50.1 ). The classic physical exam findings include short stature, skin hyperpigmentation, and upper limb anomalies (such as absent, hypoplasia, or bifid thumb). Because ∼50% of patients with FA have normal physical findings, they are often undiagnosed until they present with hematologic abnormalities. This is typically in the first decade of life.

The test of choice for FA detects chromosomal breakage in cells exposed to diepoxybutane (DEB) and mitomycin C (MMC), cross-linking agents. There are multiple genes in the FA pathway and their protein products are involved in the DNA damage recognition and repair pathways; these lead to the chromosome fragility seen in FA (see Tables 50.3 and 50.10 ).

Marrow failure classically begins with thrombocytopenia followed by granulocytopenia, macrocytosis, and then macrocytic anemia. The marrow will often show decreased or absent megakaryocytes, hypocellularity, and fatty replacement. About 10% of patients will present with acute myeloid leukemia (AML). Because of the fragility to alkylating agents, these patients cannot be treated with the typical intensive therapy used in AML.

The curative therapy for FA is hematopoietic stem cell transplantation (HSCT). The HSCT therapy must avoid the associated chromosome fragility seen in FA, and the timing of transplant is often delayed as long as safely possible. Long-term survival outcomes following a matched sibling transplant is ∼80%.

Dyskeratosis Congenita

Dyskeratosis congenita (DC) is an inherited (X-linked, autosomal recessive or dominant) bone marrow failure syndrome (see Tables 50.3 and 50.10 ). Patients first present with lacy skin pigmentation on the face, neck, chest, and arms and nail dystrophy followed by oral mucosal leukoplakia (see Fig. 50.2 ). Marrow failure will become apparent by their teen years.

Telomeres protect the ends of chromosomes; their length decreases with each cell cycle. Stem cells are able to activate telomerase, which allows for self-renewal. Gene variants seen in DC lead to inheritance of short telomeres and defects in the maintenance of telomeres, leading to stem cell exhaustion and eventually producing pancytopenia.

Patients will initially present with isolated thrombocytopenia, which will then evolve into pancytopenia. There is also macrocytosis and elevated fetal hemoglobin levels. In addition to hypocellularity of marrow, there can be signs of myelodysplasia or leukemia.

The anabolic steroid oxymetholone can improve marrow function. About 60% of patients will respond to this therapy, which can have a long-lasting effect. HSCT can be used in DC; however, the survival rate remains poor at 50%. There is significant morbidity and mortality following HSCT specific to DC including pulmonary fibrosis and gastrointestinal (GI) bleeding secondary to vascular anomalies.

Shwachman-Diamond Syndrome

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder. The typical clinical characteristics include exocrine pancreas insufficiency, which presents as fat malabsorption; skeletal changes including delayed bone maturation, metaphyseal dysostosis, short or flared ribs, and bifid thumbs; and bone marrow failure ( Table 50.11 ).

The pathologic gene SBDS seen in SDS is involved in ribosomal biogenesis, which is associated with pancytopenia, although the exact mechanism is not completely understood. Failure of pancreatic acinar development leads to fatty infiltration of the pancreas and associated exocrine dysfunction. Marrow failure is a result of dysfunctional stem cells, apoptosis of progenitor cells, and inability of the microenvironment to support hematopoiesis. Diagnosis is made based on clinical findings and genetic variant analysis for SBDS .

The most common hematologic finding in SDS is neutropenia, which predisposes to bacterial and fungal infections. About 10–65% of patients will present with pancytopenia; the majority of patients will have elevated fetal hemoglobin levels. Marrow cellularity can be variable; there is also a risk for myelodysplastic syndrome (MDS) and AML.

Management of SDS includes granulocyte colony-stimulating factor (G-CSF) for patients with severe neutropenia as well as transfusions for anemia and thrombocytopenia. The management of exocrine pancreatic insufficiency involves oral pancreatic enzyme replacement and fat-soluble vitamin supplements. HSCT is used in SDS with improved outcomes if performed prior to the development of leukemia, but data are limited and outcomes remain poor.

Congenital Amegakaryocytic Thrombocytopenia

Congenital amegakaryocytic thrombocytopenia (CAMT) is an autosomal recessive disorder that begins in infancy with isolated thrombocytopenia. Patients with CAMT present with signs of thrombocytopenia, cerebellar and cerebral atrophy, developmental delay, and various congenital heart defects. MPL is a gene for the receptor of thrombopoietin that impacts megakaryocytic proliferation as well as apoptotic regulation and survival of stem cells. Pathologic gene variants of MPL have different effects on thrombopoietin receptor function, which produces a wide spectrum of severity.

The marrow findings will initially demonstrate amegakaryocytosis with normal cellularity. Among patients who progress to pancytopenia, the marrow cellularity decreases, and fatty infiltration is noted. These patients are also at risk for development of MDS and AML. Androgens and corticosteroids have been used to treat pancytopenia with some improvement, but HSCT remains the only curative option.

Other Genetic Syndromes

There are several other genetic syndromes that can develop pancytopenia. These include Down syndrome, Noonan syndrome, Dubowitz syndrome, Seckel syndrome, reticular dysgenesis, Schimke immunoosseous dysplasia, cartilage-hair hypoplasia, and familial aplastic anemia ( Table 50.12 ). In addition, cytopenias including pancytopenia may occur in primary immunodeficiency diseases ( Fig. 50.4 ). These include common variable immunodeficiency (CVID), autoimmune lymphoproliferative syndrome (ALPS), and immune disregulation polyendocrinopathy enteropathy X-linked (IPEX) and IPEX-like syndromes.