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Classic Neutropenic Syndromes
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.
Myelokathexis
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.
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