Anemia Due to Diminished Red Blood Cell Production
Zora R. Rogers
Anemia may be the first recognized hematologic finding in a child whose bone marrow is not functioning normally. It may be the sole problem (single cytopenia) or occur in conjunction with deficits in other cell lineages (pancytopenia). The cause may be a deficiency of a required nutrient (iron, folic acid, vitamin B12), the inability of the marrow to use nutrients because of concomitant medical conditions (inflammation, hypothyroidism), or intrinsic bone marrow failure. Bone marrow failure may be either inherited or acquired (aplastic anemia). These anemias are due to diminished RBC production.
BONE MARROW FAILURE
Patients with bone marrow failure usually have a macrocytic anemia, elevated fetal hemoglobin concentration, and evidence of progressive cytopenias. Many of the inherited bone marrow failure syndromes (IBMFSs) are also associated with recognizable patterns of congenital anomalies (principally short stature or thumb/radius defects) and increased risk of malignancy (usually myelodysplastic syndrome [MDS], acute myeloid leukemia [AML], solid tumors, and squamous cell carcinomas involving the head, neck, and genital tract). Overall, about one fourth of aplastic anemias during childhood are inherited.
ACQUIRED IDIOPATHIC APLASTIC ANEMIA
Aplastic anemia (AA) is usually insidious in onset. The patient typically presents with fatigue, pallor, and symptomatic thrombocytopenia (epistaxis or bruising). Organomegaly and adenopathy are rarely present. Systemic infection is rare at the outset. The reported incidence is estimated to be 2 per million children per year, one twenty-fifth the incidence of leukemia. Although AA is classically associated with exposure to radiation or toxic agents such as benzene, pesticides, and medications such as chloramphenicol, it actually results from a combination of exposures, a diversity of host genetic susceptibility factors, and individual differences in the immune response.
A careful personal history of recent illnesses, medications, exposures, and family history is useful in guiding evaluation. Although the majority of cases are idiopathic, evaluation requires ruling out infectious causes as well as the most common inherited bone marrow failure syndrome (IBMFS)—Fanconi anemia (FA; Table 432-1). The bone marrow biopsy, required for diagnosis, shows hypocellularity with empty spicules. The disease is categorized by the degree of cytopenia and bone marrow cellularity.
There is strong evidence for immune-mediated marrow suppression in many cases of AA. Current studies suggest that viruses, drugs, or toxins induce an immunologic reaction that in turn leads to apoptosis within the bone marrow. Marrow progenitors, and hence blood counts, would recover if the suppression could be removed and the proliferative capacity of the progenitors restored.
Treatment initially consists of meticulous supportive care. Medications and exposures potentially toxic to the marrow are avoided, and the patient carefully observed pending the results of the diagnostic evaluation. Anemia is corrected with red blood cells (RBCs) that are irradiated. Platelet transfusions are given only for bleeding. Growth factors such as granulocyte colony-stimulating factor (G-CSF) are used to attempt to increase the absolute neutrophil count (ANC) to more than 500 to 1000/μL. After obtaining blood cultures, fever (usually higher than 101.5°F) is managed aggressively by hospitalization and treatment with broad-spectrum antibiotics directed against gram-negative enteric organisms.
Personal and Family History of
Cytopenias (anemia, thrombocytopenia, neutropenia)
Malignancies prior to age 50 years (particularly acute myeloid leukemia [AML], myelodysplastic syndrome [MDS], squamous cell carcinoma)
Medications (particularly anticonvulsants, antibiotics such as sulfonamide containing compounds and chloramphenicol)
Recent illnesses or exposures (radiation, solvents, insecticides, heavy metals)
Birth weight and growth
Short stature and microcephaly
Size and location of café-au-lait spots, cutaneous hyper- and hypopigmentation
Abnormalities of thumbs or radius
Other congenital anomalies—renal, cardiac, gastrointestinal
Absence of lymph adenopathy, hepatosplenomegaly
Complete blood count with differential and reticulocyte counts
Examination of peripheral blood smear
Liver function—alanine aminotransferase (ALT), bilirubin
Bone marrow biopsy, aspirate and cytogenetics
Peripheral blood diepoxybutane (DEB) testing (see text)—chromosome breakage
Flow cytometry for glycosyl phosphatylinositol (GPI)-linked proteins (see text)
Infectious Disease Testing (once diagnosis of aplastic anemia is confirmed)
Hepatitis A IgG
Hepatitis B surface antigen and antibody
Ebstein-Barr virus (EBV) serology
Cytomegalovirus (CMV) serology
Parvovirus serology and polymerase chain reaction (PCR)
Consider human herpesvirus 6 by PCR
Human Leucocyte Antigen Typing of Patient, Siblings, and Parents (once diagnosis of aplastic anemia confirmed)
Once the diagnosis of idiopathic aplastic anemia (AA) is confirmed by exclusion of Fanconi anemia (FA) and other causes, a decision has to be made between treatment options. For most children with an human leucocyte antigen (HLA)-identical sibling donor, immediate stem cell transplantation (SCT) offers the best chances of cure, with 5-year survival rates of 80% to 90%. Chronic graft-versus-host disease is encountered less often in children than adults. Alternatively, immunosuppressive therapy using a combination of antithymocyte globulin (ATG) or antilymphocyte globulin (ALG), cyclosporine, and supportive care with transfusion and G-CSF may result in transfusion independence, but not normal blood counts, in 80% to 85% of patients. If immunosuppression does not result in transfusion independence within 3 months, an unrelated stem cell donor source should be sought for a transplant.
Relapse after immunosuppression is not uncommon and may be managed with either repeated immunosuppressive therapy, with second response rates of 50% to 60%, or stem cell transplantation. Both therapies are associated with a 10% to 15% risk in survivors of clinically symptomatic paroxysmal nocturnal hemoglobinuria (PNH), myelodysplastic syndrome, and acute leukemia. Overall survival in aplastic anemia, regardless of treatment, has continuously improved over the past decade, probably related to improvements in supportive care.6-8
INHERITED BONE MARROW FAILURE SYNDROMES
Although many inherited bone marrow failure syndromes (IBMFSs) are classically associated with only one cell lineage, many patients progress to pancytopenia and general bone marrow failure. IBMFSs generally present with macrocytic anemia, progressive pancytopenia, and congenital anomalies, particularly of kidneys and the radial side of the forearm. Short stature, intellectual limitation, and risk of malignancy are also characteristic. During the past decade, the inherited mutations responsible for many of these syndromes have been identified, increasing the precision of diagnosis and detection of less severely involved patients, as well as furthering our understanding of the mechanism of marrow failure.9-13
Fanconi anemia is a syndrome of defective double-strand DNA repair that is caused by a variety of inherited mutations. Inheritance is nearly always autosomal recessive. The disease occurs in all ethnic groups. Congenital anomalies are present in more than half of the patients. Most common are abnormalities of the thumb and radius ranging from hypoplasia of the thenar eminence to absence of thumbs or radii, short stature, microcephaly, and decreased or increased pigmentation, including multiple and large café-au-lait spots. Other organ systems may also be involved: renal—including horseshoe kidney, agenesis, or duplicated collecting system; gastrointestinal—imperforate anus or interrupted esophagus; genital—males with undescended or atrophic testes, hypospadias, or phimosis and females with malformations of the vagina, uterus, and ovary; and head and neck—microphthalmia, strabismus, and ear anomalies. Adults may have hypogonadism and infertility, and women usually have late menarche and early menopause. Growth failure may be constitutional or due to abnormal growth hormone secretion or hypothyroidism. Abnormal glucose tolerance and hyperinsulinemia may also affect growth. However, up to 25% of patients with FA, particularly those detected through the screening of siblings of diagnosed patients, have no physical abnormalities.
Symptoms are determined by the degree of cytopenia. Thrombocytopenia is usually observed first, generally prior to 4 years of age, and macrocytosis is generally present at the time of diagnosis. Marrow failure usually starts in the first decade of life. Patients are diagnosed at a median age of 6 years and by 16 years of age in more than 90% of cases.
The diagnosis is based on a hypocellular bone marrow biopsy and aspirate, without pathologic or cytogenetic evidence of myelodysplastic syndrome (MDS). A specific diagnosis of Fanconi anemia (FA) is made by confirmation of increased chromosomal fragility (chromatid breaks, rearrangements, gaps, endoreduplications, and chromatid exchanges) in peripheral blood lymphocytes cultured with diepoxybutane (DEB) or mitomycin C (MMC). Similar abnormalities can be seen in cultured skin fibroblasts. Once a patient is diagnosed, all siblings should be tested for FA.
Need for treatment is dictated by the degree of pancytopenia. If there is no transfusion requirement, quarterly blood counts and periodic bone marrow examinations to evaluate for the development of clonal hematopoiesis under the supervision of a pediatric hematologist may be all that is required.
Treatment of bone marrow failure should begin when the hemoglobin level is less than 8 g/dL, platelet count less than 30,000/μL, and absolute neutrophil count less than 500/μL. At that time, treatment with an oral androgen such as oxymetholone, to support blood counts or stem cell transplantation (SCT), should be discussed with the patient and family. Androgen therapy produces an RBC response in about half of the patients within 2 months, but it may take up to a year for platelets and white blood cells (WBCs) to rise. Potential side effects of androgen therapy include masculinization, cholestasis, peliosis hepatis (blood lakes in the liver), and growth acceleration. In addition to monthly monitoring of blood counts, patients should be monitored serially with hepatic ultrasound and physical examinations. Most patients lose the response to androgens as the bone marrow failure progresses.
SCT is the only curative modality for bone marrow failure, but FA patients are abnormally sensitive to pretransplant conditioning regimens (both radiation and chemotherapy) and experience excessive toxicity. Reduced intensity conditioning has resulted in survival for sibling donor transplants approaching 80%. However, SCT increases the chances of “secondary” bone marrow malignancy and solid tumors by more than fourfold.
PROGNOSIS AND OUTCOME
The projected median survival of patients is 23 years of age. The cumulative probability of cancer by 50 years of age is 85%, with the mean age of reported cases being 15 years. In addition to myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), patients with Fanconi anemia (FA) also have an increased risk of squamous cell carcinoma of the head, neck, esophagus, anus, and vulva. In some patients, squamous cell carcinoma, otherwise very rare during childhood, may be the first sign of FA.
Pearson marrow-pancreas syndrome is a disorder caused by large deletions in mitochondrial DNA (mtDNA). Patients present in the first years of life with a refractory sideroblastic anemia often requiring RBC transfusion, metabolic acidosis, and exocrine pancreatic insufficiency. The bone marrow has a decreased number of cells, and erythroid and myeloid precursors have prominent cytoplasmic vacuoles. Ringed sideroblasts (mitochondria-containing iron) are also present. Mitochondrial gene deletions of varying size result in impairment of multiple respiratory enzymes involved in oxidative phosphorylation. Patients fail to thrive and have repeated metabolic crises with exacerbations of acidosis due to depletion of respiratory enzymes. Treatment with enzymes such as coenzyme Q, thiamine, riboflavin, and L-carnitine may reduce the frequency and severity of these episodes. Median survival is 4 years with death, usually due to acidosis and renal or liver failure rather than aplastic anemia.
DIAMOND BLACKFAN ANEMIA
Diamond Blackfan anemia (DBA) is clinically heterogeneous disorder, the hallmark of which is RBC aplasia. The incidence is 6 to 7 per million with no ethnic or gender predilection. Although DBA usually presents in the first year of life, genetic testing has allowed definitive diagnosis of new cases in adults as well. Patients often have low birth weight, growth retardation, learning difficulties, and congenital abnormalities involving the head (microcephaly, hypertelorism, cleft palate), thumbs (hypoplastic or duplex/bifid), heart (atrial septal defect [ASD], ventricular septal defect [VSD], coarctation of the aorta), or genitourinary system (hypospadias, horseshoe or absent kidney). The disorder results from a cellular defect in ribosome biosynthesis in which erythroid cells are highly sensitive to death by apoptosis, leading to failure of RBC production.
Classical Diamond Blackfan anemia (DBA) presents with macrocystic anemia and reticulocytopenia in the first year of life but near-normal absolute neutrophil and platelet counts. The bone marrow shows normal cellularity with a virtual absence of RBC precursors. Erythrocyte adenosine deaminase (eADA) concentration is elevated by 3 or more standard deviations in 80% to 85% of patients.
About 40% to 45% of DBA cases are familial with autosomal-dominant inheritance, and the others are sporadic or occasionally autosomal recessive.
Although their mechanism of action is unknown, corticosteroid therapy results in rising hemoglobin in 80% of patients. The dose is then tapered to the lowest dose, preferably on an alternate day schedule, that will maintain hemoglobin of 8 to 10 g/dL. Steroid nonresponders and patients with unacceptable steroid toxicity, or those who lose their response to steroids over time, require chronic RBC transfusions with the need for chelation to avoid transfusion iron overload.
Eventually, 20% of patients will have a spontaneous remission and maintain adequate hemoglobin values without steroid treatment, whereas 40% will continue on corticosteroids and 40% will require transfusions. The projected median survival of patients in the literature is 39 years of age, but survival in the North American Diamond Blackfan Anemia Registry (DBAR) is 75% at 40 years. Crude estimates suggest that there is a 2% to 6% risk of malignancy compared to the population average of less than 1% by age 15 years. However, the cumulative probability of cancer is 52% by 50 years of age. Acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), sarcoma (primarily osteogenic), Hodgkin disease, and hepatocellular carcinoma are the most common malignancies observed in patients with Diamond Blackfan anemia (DBA).
TRANSIENT ERYTHROBLASTOPENIA OF CHILDHOOD
Transient erythroblastopenia of childhood (TEC) is the most common disorder that must be distinguished from Diamond Blackfan anemia (DBA).
Transient erythroblastopenia of childhood (TEC) is the spontaneous cessation of erythropoiesis in otherwise healthy children without congenital abnormalities. It usually presents in children between 6 months and 3 years of age and persists for weeks to several months. Although the RBC lineage is always involved, rarely neutropenia and sometimes thrombocytopenia may also occur.
Transient erythroblastopenia of childhood (TEC) is a diagnosis of exclusion and is confirmed only after the fact, when normal erythropoiesis is spontaneously restored. The RBC size or mean cell volume (MCV) is normal, fetal hemoglobin is not elevated, and the erythrocyte adenosine deaminase (eADA) concentration is normal in 90% of cases. The cause of TEC is not known.
Management is supportive with RBC transfusion as needed. Hemoglobin and reticulocyte counts should be monitored until normal.
PROGNOSIS AND OUTCOME
Once normal hematopoiesis is restored, the disorder does not usually recur.20
Shwachman-Diamond syndrome (SDS), sometimes called Shwachman-Bodian-Diamond syndrome (SBDS), is characterized by neutropenia and pancreatic insufficiency (also discussed in Chapter 417). Neutropenia commonly presents in infancy. It is chronic in one third of patients and intermittent in others. Anemia, either normocytic or macrocytic but with inappropriately normal reticulocyte counts, has been reported in 42% to 66% of patients, with the typical elevated fetal hemoglobin levels seen in inherited bone marrow failure syndromes (IBMFSs). Thrombocytopenia occurs in 24% to 60% of patients, and bleeding problems may occur. Pancytopenia develops in 10% to 44% of patients.
Pancreatic insufficiency with steatorrhea and failure to thrive begins in infancy. There may be hepatomegaly with elevated serum transaminase levels. Many SDS patients have short stature with half being below the third percentile for age, despite the prompt administration of pancreatic enzyme supplementation. Skeletal abnormalities are common, particularly short ribs with flared anterior ends, leading to a bell-shaped chest and metaphyseal dysostosis, particularly involving the femoral head.
Fecal fat excretion is increased in the absence of intestinal pathology, and pancreatic enzyme secretion is decreased in response to formal testing. Pathologically, the pancreas is replaced with fat with few acini and sparing of ducts and islets, a finding that can be demonstrated by ultrasound and computed tomographic imaging. Sweat chloride testing is normal. Serum trypsinogen and isoamylase levels are low in young children with SDS, but the trypsinogen level may normalize by age 3 years.
More than 90% of patients will have a variety of mutations in the Shwachman-Bodian-Diamond syndrome (SBDS) gene at 7q11 that results in decreased SBDS protein expression. About 60% of patients carry two mutations.
Blood counts should be monitored every 3 to 4 months and families educated to seek medical attention for every febrile illness. Consideration should be given to treatment with granulocyte colony-stimulating factor (G-CSF) for invasive infections, persistent severe neutropenia, severe gingivitis, or recurrent febrile illnesses. G-CSF therapy does not appear to further increase the risk of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) over its already high risk in SDS. Treatment of the pancreatic insufficiency is discussed in Chapters 417 and 514.
PROGNOSIS AND OUTCOME
The projected median survival is 35 years, with 22% of patients in the literature dead by 16 years of age. The cumulative probability of cancer by 40 to 50 years of age is estimated to be 71% with the median age of the patients diagnosed with cancer being 18 years. No solid tumors have been associated with Shwachman-Diamond syndrome (SDS).
The diagnostic triad of dyskeratosis congenita (DC) is lacy reticulated pigmentation, dysplastic nails, and oral leukoplakia. None of these finding are usually present in childhood. Other features of the disease are sparse, early graying hair, hypogonadism, urethral strictures, pulmonary fibrosis, and esophageal strictures. Hoyeraal-Hreidarsson syndrome (intrauterine growth retardation [IUGR] and developmental delay with microcephaly, immunodeficiency, bone marrow failure, and cerebellar hypoplasia) and Revesz syndrome (similar features plus exudative retinopathy) are two more severe pediatric variants.23 The median age at diagnosis is 15 years with a 4:1 male predominance.
The features of the classical triad of dyskeratosis congenita (DC) and cytopenias suggest the diagnosis, yet it can be confirmed in only 40% of cases by genetic testing. Very short telomeres are associated with DC, so the bone marrow failure may be related to the decreased proliferative potential of the stem cells. Short telomeres, seen in DC and other inherited bone marrow failure syndromes (IBMFSs), may promote the genomic instability and malignant progression that is observed in these disorders.
Hematologic parameters govern the frequency of peripheral blood count monitoring required, and routine marrow assessment may not be necessary. Although treatment with oral androgens may stabilize declining blood counts, stem cell transplantation (SCT) should be pursued when there is aplasia.
PROGNOSIS AND OUTCOME
The cumulative incidence of marrow failure is more than 90% by age 40 years, with a 35% cumulative incidence for malignancies by age 50 years. The majority of the cancers are carcinomas, particularly of the head, neck, and esophagus, but myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) have been reported. The median survival is predicted to be 45 years.24,25
Patients with amegakaryocytic thrombocytopenia (AMT) usually present as neonates with bruises and petechiae due to thrombocytopenia, which then may progress to aplastic anemia or myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). There are no specific physical abnormalities. The usual platelet count is around 20,000/uL, with normal size and appearance on peripheral blood smear.
Bone marrow aspirate shows normal cellularity and reduced to absent megakaryocytes. All cases of AMT exhibit recessive mutations in cMPL, the gene for the TPO receptor.
Historically, AMT patients with pancytopenia were believed to have an increase in their blood counts in response to oral androgens. However, today patients are encouraged to consider stem cell transplantation (SCT) as soon as the diagnosis is made because of the transitory duration of androgen response.
PROGNOSIS AND OUTCOME
The cumulative estimated incidence of aplastic anemia is 50% by 5 years of age and 91% by 13 years. Malignancy may rapidly occur with the incidence of AML being 55% by 17 years of age.26
THROMBOCYTOPENIA ABSENT RADII
Thrombocytopenia absent radii (TAR) syndrome is usually recognized at birth in a child with bilaterally absent radii but present, albeit hypoplastic or misplaced thumbs. This is in contrast to Fanconi anemia where thumbs may be absent. Children with TAR may also have short or absent ulnae or humeri, dislocated hips, abnormal knees, short stature, macrocephaly, capillary hemangiomas, and cardiac defects. Platelets appear normal in size on blood smear. Eosinophilia and a leukemoid reaction (often attributed to a milk protein allergy) are common.
The genetics of TAR are unclear. Most cases are autosomal recessive, but autosomal-dominant inheritance has also been reported.
Most patients require only supportive care. In infancy, gastrointestinal bleeding is the major challenge. Patients should be transfused with platelets only for severe bleeding.
PROGNOSIS AND OUTCOME
In most patients, the platelet counts begin to increase by the second year of life, facilitating any required orthopedic intervention for the upper limb anomalies. Platelet counts do not usually become completely normal. Among the first 300 patients in the literature, there were four cases of leukemia and three cases with multiple solid tumors. This disorder should therefore be reclassified as one of the inherited bone marrow failure syndromes (IBMFSs). Survival is reported to plateau at 78% at 5 years of age. Aplastic anemia has not been reported.
See references on DVD.