Biology of Stem Cells and Disorders of Hematopoiesis

Infantile Genetic Agranulocytosis (Kostmann's Neutropenia)

Initially described in Sweden by R. Kostmann in 1956, infantile genetic agranulocytosis is characterized by severe neutropenia at birth, frequent infections, increased risk of early death, and autosomal-recessive inheritance. This syndrome is one of the severe chronic neutropenic disorders and is mentioned separately only to highlight this well-described clinical entry. The comments regarding treatment and prognosis of severe chronic congenital and idiopathic neutropenias are applicable to Kostmann's neutropenia.

Shwachman's Syndrome

Shwachman's syndrome, described in 1964, is characterized by pancreatic insufficiency and neutropenia. It is transmitted by autosomal-recessive inheritance. In addition, patients affected may also exhibit metaphyseal chondrodysplasia and dwarfism. While diarrhea, weight loss, failure to thrive, growth failure, and infections are noted in young children with this syndrome, these patients do not manifest the chronic pulmonary disease characteristic of cystic fibrosis. The degree of neutropenia is variable, with absolute neutrophil counts falling generally in the range of 200 to 400 cells/mm3 ; the monocytosis that accompanies severe congenital neutropenia is not observed with Shwachman's syndrome. Anemia and thrombocytopenia may also develop with time. Myeloid hyperplasia is noted upon examination of the bone marrow. While the neutropenia has been refractory to therapy historically, this disorder is a good candidate for therapy with recombinant growth factors.

Neutropenia with Immune Deficits

Both humoral and cell-mediated immune defects are seen in association with neutropenia. In X-linked agammaglobulinemia, approximately one-third of affected males exhibit neutropenia. Similarly, dysgammaglobulinemia type I (absence of IgA and IgG with normal to elevated IgM levels) has been associated with neutropenia. These patients have associated findings, including failure to thrive, hepatosplenomegaly, and frequent infections. A maturation arrest at the myelocyte stage has been noted. The prognosis has been poor, with little efficacy for corticosteroids, splenectomy, or thymectomy. Intravenous administration of gamma globulin was effective in at least one patient, raising a question as to whether this entity is due to peripheral neutrophil destruction. Severe neutropenia has been noted in association with eczema, polyarthralgias, recurrent bacterial infection, eosinophilia, and decreased cellular immunity; patients so affected are at risk of severe viral infection, such as varicella, in addition to their predisposition to bacterial disease.


Intramedullary destruction of neutrophils appears to be the pathophysiologic basis of myelokathexis. Patients demonstrate moderate neutropenia with morphologic abnormality of the neutrophilic nuclei. The circulating neutrophils are notable for their cytoplasmic vacuoles and for very thin nuclear strands connecting the nuclear lobes, while the bone marrow is hyperplastic with many degenerating hypersegmented granulocytes.

Cartilage-Hair Hypoplasia Syndrome

Short-limbed dwarfism, fine hair, moderate neutropenia, and increased risk of infection characterize cartilage-hair hypoplasia syndrome. This autosomal-recessive disorder is noted most prevalently in the Amish population. Impaired cellular immunity has been noted in some patients. Bone marrow transplantation has been used successfully in at least two patients with this syndrome.

Dyskeratosis Congenita

Dykeratosis congenita is an X-linked condition in which patients exhibit nail dystrophy., leukoplakia, reticulated hyperpigmentation, marrow hypoplasia, and neutropenia. Affected patients may develop additional cytopenias and present with a clinical picture resembling aplastic anemia rather than one of simple neutropenia.

Nutritional Deficiencies

Vitamin B12, folic acid, or copper deficiency, can result in suppressed or ineffective granulopoiesis. Similarly, starvation may be associated with neutropenia. Replenishment of nutrients generally corrects the neutropenia.

Bone Marrow Infiltration

Replacement of normal marrow elements with leukemic or tumor cells results in peripheral blood cytopenias, including neutropenia. Leukoerythoblastic blood smears are often noted when neoplastic marrow infiltration occurs. Other conditions causing marrow cavity compromise, including granulomatous infections, metabolic storage diseases, and osteopetrosis, can result in neutropenia.

Toxic Marrow Exposures

Certain inborn errors of metabolism are associated with neutropenia. These include isovaleric acidemia, propionic acidemia, methymalonic acidemia and hyerglycinemia. In vitro growth of myeloid progenitors is impaired by isovaleric acid and propionic acid, suggesting that in vivo growth may be adversely affected by high levels of these metabolites.

Many drugs used in the clinical setting have been associated with the development of selective neutropenia. The degree of neutropenia induced by drugs can be very severe, with the absolute neutrophil count falling below 200 cells/mm3 . Often, the neutropenia is due to an idiosyncratic reaction to the drug and is distinct from that which occurs after the use of known marrow toxins, such as the antineoplastic drugs. Mortality historically has been appreciable, with mortality in one series as high as 32%. The list of responsible drugs, anticonvulsants, phenothiazines, aspirin, acetaminophen, gold, levamisole, penicillamine, barbiturates and bonzodiazepines. While it is possible that some of these drugs produce neutropenia as an expression of an aberrant immune response, many have direct suppressive effects on the bone marrow progenitor cells or the microenvironment and the accessory cells.

While the marrow picture in drug-induced neutropenia is variable, the terminally differentiated marrow neutrophils are usually markedly reduced. The relative paucity of mature marrow neutrophils may be due at least in part to an expansion of the immature myeloid compartment in response to the demand for more circulating neutrophils. Withdrawal of the offending drug fosters further expansion of the proliferating myeloid compartment, resulting in restoration of normal marrow granulopoiesis within 7 to 14 days. A rebound neutrophilia may occur as recovery proceeds. The duration of neutropenia is quite variable, lasting from a few days to months depending upon the nature of the idiosyncratic reaction and upon continued exposure to the causative drug. For certain drugs, such as carbamazepine or the phenothiazines, which are used chronically in therapeutic programs, initial close monitoring of blood counts and the neutrophil count may be helpful.