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Neutrophil-specific granule deficiency

Neutrophil-specific granule deficiency
Literature review current through: Jan 2024.
This topic last updated: Aug 31, 2022.

INTRODUCTION — Neutrophil-specific granule deficiency (SGD; previously called lactoferrin deficiency) is a rare congenital disorder. The cardinal clinical feature is increased susceptibility to pyogenic infections. Patients often present with large, smoldering, cutaneous infections that have persisted for months (picture 1). They may also have lung abscesses and mastoiditis. The major pathogens include Staphylococcus aureus, Pseudomonas aeruginosa, other enteric gram-negative bacteria, and Candida albicans.

On peripheral blood smear, neutrophils lack their specific granules and have bilobed nuclei, resembling the Pelger-Huet anomaly (picture 2). Most have low or absent eosinophil counts since they lack the typical red staining granules. The diagnosis is confirmed by molecular testing. Early diagnosis of infections, antimicrobial prophylaxis, and aggressive management of infectious complications are critical. Allogeneic hematopoietic cell transplantation (HCT) is also a treatment option.

Other congenital defects in phagocytic function are discussed separately. (See "Primary disorders of phagocyte number and/or function: An overview" and "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Chronic granulomatous disease: Treatment and prognosis" and "Chediak-Higashi syndrome" and "Congenital neutropenia".)

EPIDEMIOLOGY — An accurate estimate of the incidence or prevalence of neutrophil-SGD is difficult to obtain because the disease is so rare. Only a few cases in a handful of families have been reported worldwide since 1980, when the disorder was first defined [1]. Four case reports in the 1970s of patients with recurrent pyogenic infections and neutrophil maturation defects, with absence of secondary granules and impaired neutrophil function, may also have been cases of SGD [2-5]. The first case was reported in 1979 and a second case in 1980 [1,2]. Since then, several other cases have been identified [3-7]. The disease occurs in males and females [6].

GENETICS — SGD has an autosomal-recessive inheritance. SGD type 1 (SGD1) is caused by a defect in a myeloid-specific transcription factor, CCAAT/enhancer-binding protein epsilon (CEBPE) [8]. A five-base pair frameshift deletion in the second exon of CEBPE identified in one patient resulted in a truncated protein that no longer had a deoxyribonucleic acid (DNA) binding region or transcriptional activity. Homozygous mutations in CEBPE were identified in several additional patients with SGD1 [9-13]. One patient had a novel deletion in the leucine zipper domain of CEBPE with a clinically less severe phenotype [12]. Another patient had a heterozygous mutation in CEBPE but had elevated levels of CEBPE [11]. Growth factor independence 1 (Gfi-1) was low in this patient, although a mutation in the gene for this transcription factor was not found. Gfi-1 represses transcription of CEBPE and may result in decreased levels of specific granule proteins.

SGD type 2 (SGD2), which is phenotypically similar to SGD1, is caused by homozygous mutations in a component of the chromatin remodeling complex involved in regulating transcription factors, SWI/SNF-related, matrix associated, actin-depend regulator of chromatin, subfamily D, member 2 (SMARCD2) [14,15]. Identification of SMARCD2 as an interaction partner of CEBPE and the loss-of-function mutations in SMARCD2 provide a molecular basis for the phenotypic similarity of the two known subtypes of SGD, SGD1 and SGD2. Given that only these two genetic subentities (CEBPE-mutant and SMARCD2-mutant SGD) are defined, genetic diagnosis can be made by capillary sequencing of the aforementioned genes or via next-generation sequencing-based methods including targeted panel, exome, or genome sequencing.

PATHOGENESIS — CCAAT/enhancer-binding protein epsilon (CEBPE) is expressed exclusively in myeloid and T cells. The defect in CEBPE appears to block the transition of neutrophils from the promyelocyte to myelocyte stage upon binding of DNA through its basic leucine zipper domain (figure 1) [16], resulting in release of cells in an abnormal state [8]. Similarly, another study demonstrated defective myelopoiesis in a patient with SMARCD2-mutant SGD using in vitro differentiation of bone marrow CD34+ hematopoietic stem and progenitor cells [17]. Primary or azurophilic granule proteins are produced in myeloblasts and promyelocytes, whereas secondary or specific granule proteins are synthesized in myelocytes and metamyelocytes and tertiary or gelatinase granule proteins are generated in bands and polymorphonuclear neutrophils (PMNs) (table 1). Thus, both specific and gelatinase granules are absent in patients with SGD, and abnormalities are seen in azurophilic granules as well. Another study has shown that aberrant granule content in the remaining granules in CEBPE-mutant SGD appears to underlie the characteristically abnormal nuclear shape in SGD neutrophils [18].

Neutrophils Lactoferrin deficiency and absence of specific granules were the first defects noted in patients with this disorder [1,2,19]. Lactoferrin is absent in neutrophils of patients with neutrophil-SGD, but normal levels of lactoferrin are secreted by nasal epithelial cells in these patients [7,20]. Lactoferrin, which is the primary enzyme in specific granules, has strong bacteriostatic properties. Specific granules play an important role in neutrophil locomotion and oxidative metabolism. These granules contain various receptors as well as enzymes. Chemotactic receptors in specific granules translocate to the cell membrane when activated [21]. Levels of ribonucleic acid (RNA) for neutrophil-specific granule products, including lactoferrin, transcobalamin F, neutrophil collagenase, neutrophil gelatinase, and defensins, are greatly reduced in SGD bone marrow compared with normal bone marrow [22]. Neutrophils from a patient with SGD showed a reduced chemotactic response to several stimuli and decreased neutrophil and monocyte mobilization in response to skin abrasion (Rebuck skin window technique) [19]. Neutrophils also had decreased oxidative responses.

Neutrophils from patients with SGD are also deficient in defensins, microbicidal/cytotoxic proteins present in azurophilic granules [23]. This defect also occurs in Chediak-Higashi neutrophils, and it contributes to the tendency to develop severe pyogenic infections in both diseases. The almost complete absence of defensins is due to a reduced level of defensins per granule rather than a decrease in the number of azurophilic or primary granules [24]. Thus, both specific and azurophilic granules are affected in SGD.

Eosinophils – Eosinophil granules are also affected in this disease. Eosinophils in patients with SGD cannot be distinguished from neutrophils by light microscopy, because both are granule deficient [25]. These eosinophils contain eosinophil peroxidase (EPO) and Charcot-Leyden crystal protein and proliferate when exposed to granulocyte-macrophage colony stimulating factor (GM-CSF), as do normal eosinophils. However, these cells lack eosinophil-specific granule proteins, including eosinophilic cationic protein, eosinophil-derived neurotoxin, and major basic protein, and thus are assumed to be functionally impaired.

Monocytes – Abnormalities in monocytes are also seen with this disease. Monocytes (CD14+ cells) from a patient with SGD were found to have decreased levels of the monocyte-specific enzyme, nonspecific esterase, and electron-microscopic examination revealed morphologic differences between SGD monocytes and normal controls [26]. Correspondingly, macrophages from CEBPE knockout mice show functional defects including impaired differentiation and phagocytosis, as well as aberrant transcriptional profiles. Interleukin (IL) 6 modulates acute phase reactants and enhances B cell antibody production, and IL-8 is a chemoattractant involved in cellular migration into tissues during an inflammatory response. IL-6 levels were lower and IL-8 levels were higher during sepsis in patients with SGD compared with normal controls [26]. Macrophages in CEBPE knockout mice had decreased chemotaxis and cytokine production, as well as reduced capacity to accumulate lipids [27].

Platelets Platelet disorders with associated bleeding diatheses are also reported. One patient who had increased bleeding following surgical procedures lacked intermediate- and high-molecular-weight von Willebrand factor (vWf) multimers and had no poststimulation increase of vWf surface expression on platelets due to decreased binding [28]. Platelet fibrinogen and fibronectin were also reduced in this patient.

CLINICAL MANIFESTATIONS — Patients with neutrophil-SGD present within the first few years of life. The cardinal clinical feature is increased susceptibility to both skin and deep-seated pyogenic infections [1,2,19,29], although there is one reported patient with a unique mutation who had only cutaneous infections [12].

Patients with SGD usually present with severe, chronic cutaneous infections, often with ulcers and abscesses (picture 1). Chronic and recurrent lung infections, including pneumonia and abscesses, are also common. Recurrent pulmonary infections can lead to chronic lung disease. The patient may be clinically stable if infections are controlled and there is no permanent damage to the lungs or another vital organ. Patients may also develop septicemia and recurrent mastoiditis, otitis media, and lymphadenitis with draining lymph nodes. One infant presented with vomiting, intractable watery diarrhea, and failure to thrive [30].

Patients with SGD type 2 (SGD2) appear to have a higher incidence of myelodysplastic syndrome than SGD type 1 (SGD1) patients [15], though the very low numbers of identified patients make more precise estimates impossible. Additional features noted in patients with SGD2 include developmental delay, facial dysmorphic features, and distal skeletal anomalies, although, again, the full phenotypic spectrum of the disease and the relative incidence of such additional syndromic features are impossible to evaluate due to the scarcity of the disease.

LABORATORY FINDINGS — The pathognomonic laboratory findings in neutrophils on a peripheral smear are paucity or absence of specific granules and predominantly bilobed nuclei (pseudo Pelger-Huet anomaly) (picture 2) [1]. Eosinophils may be mononuclear and are not easily distinguished from other "granulocytes" by light microscopy, because they also lack their characteristic granules [25].

Neutrophils have abnormal chemotaxis (locomotion), normal aggregation but impaired disaggregation, decreased bactericidal activity, and abnormal superoxide release [19]. (See "Laboratory evaluation of neutrophil disorders".)

The major pathogens are S. aureus, P. aeruginosa, and other enteric gram-negative bacteria [31]. Fungal infections with C. albicans may also occur. Lesions often show characteristic paucity of polymorphonuclear neutrophils (PMNs), which is explained by the neutrophil chemotaxis defect in this disease.

Bleeding time may be prolonged [28]. Thrombocytopenia may occur during infection [32].

DIAGNOSIS — The diagnosis should be suspected in patients with recurrent skin and deep-seated pyogenic infections and pathognomonic findings on a peripheral smear (picture 2) [1,7,31]. It is confirmed by electron microscopy and molecular testing.

All the "granulocytes" will lack specific granules, making it difficult to distinguish neutrophils and eosinophils. Most of the neutrophils will have bilobed nuclei. Histochemical analysis of the neutrophils will reveal deficiency of lactoferrin, B-12 binding protein, and defensins.

Most patients have mutations in the CCAAT/enhancer-binding protein epsilon (CEBPE) gene (SGD type 1 [SGD1]). However, patients with SGD type 2 (SGD2) have SMARCD2 mutations and additional clinical features that influence the management approach. Thus, prompt genetic evaluation in addition to light and electron microscopy documentation of characteristic morphologic aberrations of granulocytes is warranted in all patients exhibiting characteristic features of SGD to determine the appropriate management. (See 'Genetics' above.)

TREATMENT — Infections are often more severe than suggested by the clinical examination because of defective inflammatory responses owing to decreased chemotactic ability and release of mediators. Early diagnosis of infections, antimicrobial prophylaxis, and aggressive management of infectious complications are critical management components. The approach is similar to that used in patients with chronic granulomatous disease. (See "Chronic granulomatous disease: Treatment and prognosis", section on 'Acute infections'.)

Treatment consists mainly of intensive intravenous antibiotics for active infections. Prophylactic antibiotics, such as trimethoprim-sulfamethoxazole, are recommended to prevent infection, based upon data from other primary phagocytic disorders. Antifungal prophylaxis is recommended similar to regimens used for chronic granulomatous disease, in particular covering Aspergillus spp infections using itraconazole. Growth factors, such as granulocyte-macrophage colony stimulating factor (GM-CSF), are sometimes used, in particular during episodes of severe infection. Surgical excision and debridement of the larger cutaneous and soft tissue abscesses are often required.

One patient with SGD type 1 (SGD1) underwent allogeneic hematopoietic cell transplantation (HCT) at 18 months of age [30]. The patient received busulfan, cyclophosphamide, and alemtuzumab conditioning prior to HCT. Her course was complicated by Candida infection, graft-versus-host disease (GVHD), and mild venoocclusive disease. At 1.5 years after HCT, she was well and had full donor cell engraftment. Her gastrointestinal symptoms (vomiting and intractable diarrhea) and recurrent infections had disappeared. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity".)

Given the potentially higher incidence of myelodysplasia, several patients with SGD type 2 (SGD2) have undergone HCT with good results. The risk-benefit assessment for HCT may eventually differ in both subtypes of the disease should larger numbers of patients strengthen the notion of a higher incidence of myelodysplasia in SGD2 [17,33,34].

There are no data on the best management approaches for the distal skeletal anomalies and developmental delay seen in patients with SGD2.

PROGNOSIS — Prognosis is difficult to predict given the rarity of the disease. Some patients with neutrophil-SGD have survived into adulthood. A key to decreasing morbidity and mortality is use of prophylactic antibiotics and aggressive treatment of active infections since infections may become life threatening.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inborn errors of immunity (previously called primary immunodeficiencies)".)

SUMMARY AND RECOMMENDATIONS

Clinical presentation – Neutrophil-specific granule deficiency (SGD) is a rare congenital disorder characterized by increased susceptibility to pyogenic infections, especially of the skin (picture 1), lungs, ears, and lymph nodes. The major pathogens include Staphylococcus aureus, Pseudomonas aeruginosa, other enteric gram-negative bacteria, and Candida albicans. (See 'Introduction' above and 'Epidemiology' above and 'Clinical manifestations' above.)

Genetics and pathogenesis – SGD is an autosomal-recessive disorder. The two known underlying gene defects are mutations affecting the CCAAT/enhancer-binding protein epsilon (CEBPE) gene and mutations in the SWI/SNF-related, matrix associated, actin-depend regulator of chromatin, sub2y D, member 2 (SMARCD2) gene that encodes a component of the chromatin remodeling complex involved in regulating transcription factors. Specific granules are significantly decreased to absent in neutrophils and eosinophils, and the function of neutrophils, eosinophils, monocytes, and platelets is impaired. (See 'Genetics' above and 'Pathogenesis' above.)

Diagnosis – The diagnosis should be suspected in patients with recurrent skin and deep-seated pyogenic infections and pathognomonic findings of paucity or absence of specific granules and predominantly bilobed nuclei (pseudo Pelger-Huet anomaly) (picture 2) in neutrophils on a peripheral smear. It is confirmed by electron microscopy. Flow cytometry for granule proteins may also be useful in confirming diagnosis in SGD type 1 (SGD1). Molecular genetic testing for both subtypes of SGD is also warranted to confirm the diagnosis, as this knowledge will help determine appropriate management and possibly facilitate genetic counseling. (See 'Diagnosis' above.)

Management – Early diagnosis of infections, antimicrobial prophylaxis, and aggressive management of infectious complications are critical management components. We suggest an approach similar to that taken with chronic granulomatous disease, except for the use of interferon gamma. Allogeneic hematopoietic cell transplantation (HCT) is also a treatment option for both types of SGD. (See 'Treatment' above and "Chronic granulomatous disease: Treatment and prognosis", section on 'Acute infections'.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Robert L Roberts, MD, PhD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

  1. Breton-Gorius J, Mason DY, Buriot D, et al. Lactoferrin deficiency as a consequence of a lack of specific granules in neutrophils from a patient with recurrent infections. Detection by immunoperoxidase staining for lactoferrin and cytochemical electron microscopy. Am J Pathol 1980; 99:413.
  2. Komiyama A, Morosawa H, Nakahata T, et al. Abnormal neutrophil maturation in a neutrophil defect with morphologic abnormality and impaired function. J Pediatr 1979; 94:19.
  3. Spitznagel JK, Cooper MR, McCall AE, et al. Selective deficiency of granules associated with lysozyme and lactoferrin in human polymorphs with reduced microbicidal capacity. J Clin Invest 1972; 51:93a.
  4. Strauss RG, Bove KE, Jones JF, et al. An anomaly of neutrophil morphology with impaired function. N Engl J Med 1974; 290:478.
  5. Parmley RT, Ogawa M, Darby CP Jr, Spicer SS. Congenital neutropenia: neutrophil proliferation with abnormal maturation. Blood 1975; 46:723.
  6. McIlwaine L, Parker A, Sandilands G, et al. Neutrophil-specific granule deficiency. Br J Haematol 2013; 160:735.
  7. Lomax KJ, Gallin JI, Rotrosen D, et al. Selective defect in myeloid cell lactoferrin gene expression in neutrophil specific granule deficiency. J Clin Invest 1989; 83:514.
  8. Lekstrom-Himes JA, Dorman SE, Kopar P, et al. Neutrophil-specific granule deficiency results from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon. J Exp Med 1999; 189:1847.
  9. Gombart AF, Shiohara M, Kwok SH, et al. Neutrophil-specific granule deficiency: homozygous recessive inheritance of a frameshift mutation in the gene encoding transcription factor CCAAT/enhancer binding protein--epsilon. Blood 2001; 97:2561.
  10. Khanna-Gupta A, Zibello T, Sun H, et al. C/EBP epsilon mediates myeloid differentiation and is regulated by the CCAAT displacement protein (CDP/cut). Proc Natl Acad Sci U S A 2001; 98:8000.
  11. Khanna-Gupta A, Sun H, Zibello T, et al. Growth factor independence-1 (Gfi-1) plays a role in mediating specific granule deficiency (SGD) in a patient lacking a gene-inactivating mutation in the C/EBPepsilon gene. Blood 2007; 109:4181.
  12. Wada T, Akagi T, Muraoka M, et al. A Novel In-Frame Deletion in the Leucine Zipper Domain of C/EBPε Leads to Neutrophil-Specific Granule Deficiency. J Immunol 2015; 195:80.
  13. Banday AZ, Kaur A, Akagi T, et al. A Novel CEBPE Variant Causes Severe Infections and Profound Neutropenia. J Clin Immunol 2022; 42:1434.
  14. Priam P, Krasteva V, Rousseau P, et al. SMARCD2 subunit of SWI/SNF chromatin-remodeling complexes mediates granulopoiesis through a CEBPɛ dependent mechanism. Nat Genet 2017; 49:753.
  15. Witzel M, Petersheim D, Fan Y, et al. Chromatin-remodeling factor SMARCD2 regulates transcriptional networks controlling differentiation of neutrophil granulocytes. Nat Genet 2017; 49:742.
  16. Wada T, Akagi T. Role of the Leucine Zipper Domain of CCAAT/ Enhancer Binding Protein-Epsilon (C/EBPε) in Neutrophil-Specific Granule Deficiency. Crit Rev Immunol 2016; 36:349.
  17. Schim van der Loeff I, Sprenkeler EGG, Tool ATJ, et al. Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2. J Allergy Clin Immunol 2021; 147:2381.
  18. Serwas NK, Huemer J, Dieckmann R, et al. CEBPE-Mutant Specific Granule Deficiency Correlates With Aberrant Granule Organization and Substantial Proteome Alterations in Neutrophils. Front Immunol 2018; 9:588.
  19. Gallin JI, Fletcher MP, Seligmann BE, et al. Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response. Blood 1982; 59:1317.
  20. Raphael GD, Davis JL, Fox PC, et al. Glandular secretion of lactoferrin in a patient with neutrophil lactoferrin deficiency. J Allergy Clin Immunol 1989; 84:914.
  21. Gallin JI. Neutrophil specific granule deficiency. Annu Rev Med 1985; 36:263.
  22. Johnston JJ, Boxer LA, Berliner N. Correlation of messenger RNA levels with protein defects in specific granule deficiency. Blood 1992; 80:2088.
  23. Ganz T, Metcalf JA, Gallin JI, et al. Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and "specific" granule deficiency. J Clin Invest 1988; 82:552.
  24. Parmley RT, Gilbert CS, Boxer LA. Abnormal peroxidase-positive granules in "specific granule" deficiency. Blood 1989; 73:838.
  25. Rosenberg HF, Gallin JI. Neutrophil-specific granule deficiency includes eosinophils. Blood 1993; 82:268.
  26. Shiohara M, Gombart AF, Sekiguchi Y, et al. Phenotypic and functional alterations of peripheral blood monocytes in neutrophil-specific granule deficiency. J Leukoc Biol 2004; 75:190.
  27. Gombart AF, Krug U, O'Kelly J, et al. Aberrant expression of neutrophil and macrophage-related genes in a murine model for human neutrophil-specific granule deficiency. J Leukoc Biol 2005; 78:1153.
  28. Parker RI, McKeown LP, Gallin JI, Gralnick HR. Absence of the largest platelet-von Willebrand multimers in a patient with lactoferrin deficiency and a bleeding tendency. Thromb Haemost 1992; 67:320.
  29. Ambruso DR, Sasada M, Nishiyama H, et al. Defective bactericidal activity and absence of specific granules in neutrophils from a patient with recurrent bacterial infections. J Clin Immunol 1984; 4:23.
  30. Wynn RF, Sood M, Theilgaard-Mönch K, et al. Intractable diarrhoea of infancy caused by neutrophil specific granule deficiency and cured by stem cell transplantation. Gut 2006; 55:292.
  31. Dinauer MC, Newburger PE. The phagocyte system and disorders of granulopoiesis and granulocyte function. In: Hematology of Infancy and Childhood, 7th ed, Orkin S, Nathan D, Ginsburg D, et al (Eds), Saunders, London 2008. p.1109.
  32. Sakura T, Murakami H, Matsushima T, et al. Ultrastructure of neutrophilic phagosome of autologous platelet in vivo in specific granule deficiency. Am J Hematol 1993; 43:149.
  33. Yucel E, Karakus IS, Krolo A, et al. Novel Frameshift Autosomal Recessive Loss-of-Function Mutation in SMARCD2 Encoding a Chromatin Remodeling Factor Mediates Granulopoiesis. J Clin Immunol 2021; 41:59.
  34. Kihtir Z, Çelik K, Tayfun Küpesiz F, et al. Specific Granule Deficiency Due To Novel Homozygote SMARCD2 Variant. Pediatr Allergy Immunol Pulmonol 2022; 35:43.
Topic 3933 Version 14.0

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