The Inherited Pancytopenias

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Chapter 462 The Inherited Pancytopenias

Pancytopenia refers to a reduction below normal values of all 3 peripheral blood lineages: leukocytes, platelets, and erythrocytes. Pancytopenia requires microscopic examination of a bone marrow biopsy specimen and a marrow aspirate to assess overall cellularity and morphology. There are 3 general categories of pancytopenia depending on the marrow findings.

Hypocellular marrow on biopsy is seen with inherited (“constitutional”) marrow failure syndromes, acquired aplastic anemia of varied etiologies (Chapter 463), the hypoplastic variant of myelodysplastic syndrome (MDS; Chapter 124), and some cases of paroxysmal nocturnal hemoglobinuria with pancytopenia.
Cellular marrow is seen (1) with primary bone marrow disease, such as acute leukemia (Chapter 489), and MDS, and (2) secondary to systemic disease, such as autoimmune disorders (systemic lupus erythematosus; Chapter 152), vitamin B12 or folate deficiency (Chapters 46 and 448), storage disease (Gaucher and Niemann-Pick diseases; Chapter 80), overwhelming infection, sarcoidosis, and hypersplenism.
Bone marrow infiltration can cause pancytopenia in myelofibrosis, osteopetrosis (Chapter 698), hemophagocytic lymphohistiocytosis (Chapter 501), and metastatic solid tumors.

Inherited (“constitutional”) pancytopenia is defined as a decrease in marrow production of the 3 major hematopoietic lineages that occurs on an inherited basis, resulting in anemia, neutropenia, and thrombocytopenia. Any of these conditions (Table 462-1) can be transmitted as a simple mendelian disorder by mutant genes with inherited patterns of autosomal dominant, autosomal recessive, or X-linked types. Modifying genes and acquired factors may also be operative. Inherited pancytopenias account for approximately 30% of cases of pediatric marrow failure. Fanconi anemia is the most common of these disorders.

Fanconi Anemia


Patients have abnormal chromosome fragility, which is seen in metaphase preparations of peripheral blood lymphocytes cultured with phytohemagglutinin and enhanced by adding clastogenic agents such as diepoxybutane (DEB) and mitomycin C. Cell fusion of FA cells with normal cells or with cells from some unrelated patients with FA produces a corrective effect on chromosomal fragility, a process called complementation. This phenomenon allows subtyping of cases of FA into discrete complementation groups. Fourteen separate complementation groups have been identified, and 14 mutant FA (FANC) genes have been cloned so far (A, B, C, D1/BRCA2, D2, E, F, G, I, J, L, M, N, and O) all prefixed with FANC, e.g. FANCA, FANCB and so on); FANCD1 is identical to the breast cancer susceptibility protein BRCA2. The protein products of wild-type FANC genes are involved in the DNA damage recognition and repair biochemical pathways. Therefore, mutant gene proteins lead to genomic instability, chromosome fragility, and FA. An inability of FA cells to remove oxygen-free radicals, resulting in oxidative damage, is a contributing factor in the pathogenesis. Additional factors are also operative. Leukocyte telomere length is significantly shortened but telomerase activity is increased, suggesting a high proliferative rate of marrow progenitors that ultimately leads to their premature senescence. Increased marrow cell apoptosis occurs and is mediated by Fas, a membrane glycoprotein receptor containing an integral death domain. A consistent finding is diminished cellular interleukin-6 production along with markedly heightened tumor necrosis factor-α generation.

Clinical Manifestations

The most common anomaly in FA is hyperpigmentation of the trunk, neck, and intertriginous areas, as well as café-au-lait spots and vitiligo, alone or in combination (Fig. 462-1 and Table 462-2). Half the patients have short stature. Growth failure may be associated with abnormal growth hormone secretion or with hypothyroidism. Absence of radii and thumbs that are hypoplastic, supernumerary, bifid, or absent are common. Anomalies of the feet, congenital hip dislocation, and leg abnormalities are seen. A male patient with FA may have an underdeveloped penis; undescended, atrophic, or absence of the testes; and hypospadias or phimosis. Females can have malformations of the vagina, uterus, and ovary. Many patients have a FA “facies,” including microcephaly, small eyes, epicanthal folds, and abnormal shape, size, or positioning of the ears (see Fig. 462-1). Ectopic, pelvic, or horseshoe kidneys are detected by imaging and may show other organs as duplicated, hypoplastic, dysplastic, or absent kidneys. Cardiovascular and gastrointestinal malformations also occur. Approximately 10% of patients with FA are cognitively delayed.


Skin pigment changes ± café-au-lait spots 55
Short stature 51
Upper limb abnormalities (thumbs, hands, radii, ulnas) 43
Hypogonadal and genital changes (mostly male) 35
Other skeletal findings (head/face, neck, spine) 30
Eye/lid/epicanthal fold anomalies 23
Renal malformations 21
Gastrointestinal/cardiopulmonary malformations 11
Hip, leg, foot, toe abnormalities 10
Ear anomalies (external and internal), deafness 9


A hematologist and a multidisciplinary team should supervise patients with FA. If the hematologic findings are stable and there are no transfusion requirements, observation is indicated. Subspecialty consultations for anomalies and disabilities can be arranged during this interval. If growth velocity is below expectations, endocrine evaluation is needed to identify growth hormone deficiency or hypothyroidism. Screening for glucose intolerance and hyperinsulinemia should be performed annually or biannually, depending on the degree of hyperglycemia found on initial testing. Blood counts should be performed every 1-3 mo; bone marrow aspiration and biopsy are indicated annually for leukemia and MDS surveillance by means of morphology and cytogenetics. Patients should be assessed for solid tumors at least annually. Beginning at menarche, female patients should be screened annually for gynecologic cancer. Administration of human papilloma virus quadrivalent vaccine to prevent squamous cell carcinoma will likely become a standard intervention.

Hematopoietic stem cell transplantation (HSCT; Chapter 129) is the only curative therapy for the hematologic abnormalities. Patients with FA <10 yr old who undergo transplantation using an HLA–identical sibling donor have a survival rate >80%. Survival rates are lower for patients undergoing the procedure when >10 yr. Preparative regimens are continuously evaluated, refined, and improved worldwide. For patients who do not have a matched sibling donor, a search for a matched unrelated donor (including a search of umbilical cord blood banks) might be initiated. Because of the heightened graft vs host response in patients with FA, the survival and cure rates have not been as good as those for matched sibling donor HSCT (≈ 30% survival). Molecular technology has led to preimplantation genetic diagnosis on parent-derived blastomeres to find an HLA-matched sibling donor without FA.

The potential for recombinant growth factor (cytokine) therapy for FA has not been defined. Granulocyte colony-stimulating factor (G-CSF) can usually induce an increase in the absolute neutrophil count and occasionally may boost platelet counts and hemoglobin levels. However, there may be a heightened risk of marrow cell cytogenetic clonal expansion with monosomy 7. Combination therapy consisting of G-CSF given subcutaneously daily or every 2 days along with erythropoietin given subcutaneously or IV 3 times/wk results in improved neutrophil counts in almost all patients and a sustained rise in platelets and hemoglobin levels in approximately one third of patients, although most patients lose the response after 1 yr owing to progression of marrow failure.

Androgens produce a response in 50% of patients, heralded by reticulocytosis and a rise in hemoglobin within 1-2 mo. White blood cell counts may increase next, followed by platelet counts, but it may take many months to achieve the maximum response. When the response plateaus, androgen dosage can be slowly tapered but not stopped entirely. Oral oxymetholone is used most frequently once a day. Low-dose prednisone orally every 2nd day may be added to counter androgen-induced growth acceleration and prevent thrombocytopenic bleeding by promoting vascular stability. In many patients who are taking androgens, the disease becomes refractory as marrow failure progresses. Potential side effects include masculinization, elevated hepatic enzymes, cholestasis, peliosis hepatis, and liver tumors. Screening for these changes should be performed serially.

The premise for gene therapy in FA is based on the assumption that corrected hematopoietic cells offer a growth advantage. Attempts at gene therapy have been disappointing, possibly because of the type of vector but also because of the chromosomal fragility and impaired proliferative function of the hematopoietic progenitors. Encouraging preclinical data from studies using lentiviral vectors offer hope that gene therapy will be a safe and effective treatment for FA. Transposons are nonviral vectors that have been used successfully for gene delivery in murine models and may hold promise for use in humans.


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