Hereditary Neutrophil Hypersegmentation

Hereditary neutrophil hypersegmentation designates a group of at least two disorders. The first is a benign autosomal dominant condition characterized by hypersegmented neutrophils (Figure 28-2) with no clinical signs or symptoms. The major concern is to distinguish this condition from the neutrophilic hypersegmentation found in megaloblastic anemia. In the hereditary form, a large majority of neutrophils are hypersegmented and there is no macrocytic anemia. In megaloblastic anemia, fewer than 50% of neutrophils are usually hypersegmented.

The second disorder is myelokathexis, an inherited form of neutropenia characterized by hypersegmented neutrophils and bone marrow hyperplasia of myeloid cells. There is increased programmed cell death (apoptosis) of granulocyte precursors.⁷ In this case the neutrophil nuclei, in addition to being hypersegmented, are pyknotic (to be described later), and the intrasegmental filaments are longer than normal.

Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome (CHS) is a rare and fatal autosomal recessive disease characterized by cells with enlarged lysosomal vesicles. All cells with lysosomal organelles are affected, including the melanosomes of melanocytes in the skin, the dense granules of platelets, and leukocyte granules. Patients usually have a tendency to bleed, frequent bacterial infections, symptoms of immunodeficiency, variable albinism, and progressive neurologic dysfunction.⁹ CHS is associated with a mutation in the LYST gene that encodes for a type of vesicle trafficking regulatory protein.¹⁰ Patients who do not die of bacterial infection develop a lymphohistiocytic infiltration into the major organs of the body, resulting in organ failure.⁹

Hematologic findings in CHS include giant lysosomal granules in granulocytes, monocytes, and lymphocytes (Figure 28-4). The platelet abnormality usually results in a prolonged bleeding time, and granule release by thrombin is impaired.¹¹

May-Hegglin Anomaly

May-Hegglin anomaly is one of a group of at least four overlapping autosomal dominant platelet disorders: May-Hegglin anomaly (MHA), Sebastian syndrome (SBS), Fechtner syndrome (FS), and Epstein syndrome (EPS). All are caused by mutations of the nonmuscle myosin heavy-chain type IIA gene referred to as MYH9.¹² MHA, SBS, and FS are characterized by large basophilic inclusions in leukocytes, thrombocytopenia, and giant platelets (Figure 28-5). FS and EPS are also associated with nephritis and deafness. Patients with MHA and SBS generally do not have renal disease or deafness; however, there have been a few reports of renal disease in individuals with MHA.¹³

The leukocyte inclusions in MHA have been described as “Döhle body–like” (Döhle bodies are discussed later in this chapter); however, there are striking ultrastructural differences. Döhle bodies are made up of lamellar rows of rough endoplasmic reticulum, whereas the MHA inclusions consist of randomly placed rods in an amorphous background. In addition, Döhle bodies are found only in neutrophils, whereas MHA inclusions are seen in neutrophils, eosinophils, basophils, and monocytes.¹⁴ MHA inclusions may stain a very pale color with Wright stain and may be missed in monocytes whose cytoplasm is also blue-grey.

Clinically, the majority of individuals with MHA are asymptomatic; however, a few have had bleeding episodes, possibly related to the thrombocytopenia.

Chronic Granulomatous Disease

Chronic granulomatous disease (CGD) is a disorder caused by the inability of phagocytes to produce superoxide and reactive oxygen species. The basic defect is one or more mutations in any of four genes responsible for proteins that make up a complex known as NADPH oxidase (NADPH is the reduced form of nicotinamide adenine dinucleotide phosphate). The majority of cases (approximately 60% to 65%) are X-linked recessive and 35% to 40% are autosomal recessive, depending on which gene has been mutated. The X-linked forms tend to carry a higher mortality rate.¹⁵

CGD results in a predisposition to bacterial and fungal infections and the formation of granulomas that can obstruct hollow organs such as the stomach, intestines, and urinary tract. Catalase-negative bacteria are rarely involved in CGD infections due to the fact that they generate their own hydrogen peroxide within the lysosome and can thus be killed by the neutrophil phagocytes.

In the nitroblue tetrazolium reduction test, normal neutrophils, when stimulated, reduce the yellow water-soluble nitroblue tetrazolium to a dark blue insoluble formazan. CGD neutrophils cannot perform this reduction (Figure 28-6). Flow cytometry uses a fluorescent probe, such as dihydrorhodamine-123, to measure intracellular production of reactive oxygen species.¹⁵

Leukocyte Adhesion Disorders

Leukocyte adhesion disorders (LADs) result in the inability of neutrophils and monocytes to adhere to endothelial cells and to transmigrate from the blood to the tissues. The consequence of this inability is increased and potentially lethal bacterial infections. The basic defect is a mutation in the genes responsible for the formation of cell adhesion molecules, including integrins and selectins (see Chapter 12). LADs have been subdivided into three subcategories. LAD-I is caused by a mutation in the gene(s) responsible for β₂ integrin subunits (CD11/CD18), resulting in either decreased or defective β₂ integrins, which are necessary for adhesion to endothelial cells, recognition of bacteria, and outside-in signaling.¹⁶ In addition to experiencing recurrent infections, patients with LAD-I frequently have neutrophilia.

LAD-II is considerably rarer than LAD-I and presents in a similar manner (recurrent infection, neutrophilia, and impaired pus formation); however, the leukocytes have normal β₂ integrins. In addition, patients with LAD-II may have mental retardation, growth defects, and/or deficiency in H blood group antigen.¹⁷ In this case, the basic defect is faulty ligands for selectin adhesive molecules.

Patients with LAD-III present with Glanzmann thrombasthenia–like bleeding problems (see Chapter 44) as well as LAD-I symptoms despite normal integrin expression. A recent report indicates that the basic defect is a mutation in KINDLIN3, a gene responsible for a protein that binds to the β₂ integrin subunit.¹⁸

Miscellaneous Granulocyte Disorders

Miscellaneous granulocyte disorders include several relatively rare diseases.

Hyperimmunoglobulinemia E, also known as Job syndrome, is characterized by elevated levels of immunoglobulin E, skeletal abnormalities, and recurrent severe bacterial infections.¹⁹ Neutrophils in these patients have poor directional motility. Evidence points to dysregulation in cytokine production by T cells, resulting in imbalances between interferon-γ and transforming growth factor β in relation to interleukin-4 (IL-4).²⁰

Lazy leukocyte syndrome is extremely rare and is characterized by neutropenia and poor neutrophil response to chemotactic agents.²¹ Abnormalities in neutrophil cytoplasmic actin and myosin microfilaments are responsible for the dsyfunction.²²

Myeloperoxidase (MPO) deficiency is probably the most common neutrophil abnormality; however, symptoms are relatively mild in most patients. The discovery of MPO deficiency is credited to the automated hematology analyzers that use MPO to identify cells. The MPO gene is located on chromosome 17, and up to 10 mutations have been described.²³

Diabetes mellitus can be either inherited or acquired. It has been associated with poor neutrophil function, especially when glucose levels are very high.²⁴ The most consistent abnormality is abnormal oxidative burst activity.²⁵

Monocyte/Macrophage Lysosomal Storage Diseases

Monocyte/macrophage lysosomal storage diseases can be subdivided into mucopolysaccharide (or glycosaminoglycan [GAG]) storage diseases and lipid storage diseases (Table 28-1). As a group, they represent inherited enzyme deficiencies or defects that result in flawed degradation of phagocytized material and buildup of the partially digested material within the phagocyte. All cells containing lysosomes can be affected, including T lymphocytes.²⁶

The mucopolysaccharidoses (MPSs) are a family of inherited disorders of GAG degradation. Each MPS is caused by deficient activity of an enzyme necessary for the degradation of dermatan sulfate, heparan sulfate, keratan sulfate, and/or chondroitin sulfate. The partially degraded GAG builds up in the lysosomes and eventually results in physical abnormality and sometimes mental retardation. The MPSs have been subdivided according to which enzyme is defective, which GAG is being stored, and whether the symptoms are severe or attenuated (see Table 28-1).²⁷

The peripheral blood of a patient with MPS may appear relatively normal; however, metachromatic Reilly bodies may be seen in neutrophils, monocytes, and lymphocytes (Figure 28-7). Bone marrow may reveal macrophages with large amounts of metachromatic material. Diagnosis relies on assays for the specific enzymes involved. Treatment has consisted of enzyme replacement therapy or hematopoietic stem cell transplantation.²⁷

Lipid storage diseases include a variety of disorders in which lipid catabolism is defective (Figure 28-8). Two of these disorders are characterized by macrophages with distinctive morphology and are discussed here.

Gaucher disease is the most common of the lysosomal lipid storage diseases. It is an autosomal recessive disorder caused by a defect in the catabolic enzyme β-glucocerebrosidase. This results in accumulation of glucocerebroside in macrophages throughout the body, including osteoclasts in bone and microglia in the brain. Gaucher disease has been subdivided into three types based on clinical signs and symptoms (Table 28-2).²⁸ Hematologic features may include anemia and thrombocytopenia reflecting the hypersplenism that is common in these patients. Bone marrow contains distinctive macrophages called Gaucher cells, occurring individually or in clusters, that have abundant fibrillar blue-grey cytoplasm with a striated or wrinkled appearance (sometimes described as onion skin–like) (Figure 28-9).

Treatment of Gaucher disease includes the use of recombinant glucocerebrosidase, which is quite expensive.²⁹