Neutrophil-specific granule deficiency

Neutrophil-specific granule deciciency
Classification and external resources
ICD-10 D71
ICD-9-CM 288.2
OMIM 245480
MeSH C562873

Neutrophil-specific granule deficiency[1] (SGD, previously known as lactoferrin deficiency) is a rare congenital immunodeficiency characterized by an increased risk for pyogenic infections due to defective production of specific granules and gelatinase granules in patient neutrophils.

Symptoms

Atypical infections are the key clinical manifestation of SGD.[1] Within the first few years of life, patients will experience repeated pyogenic infections by species such as Staphylococcus aureus, Pseudomonas aeruginosa or other Enterobacteriaceae, and Candida albicans. Cutaneous ulcers or abscesses and pneumonia and chronic lung disease are common. Patients may also develop sepsis, mastoiditis, otitis media, and lymphadenopathy. Infants may present with vomiting, diarrhea, and failure to thrive.[2]

Diagnosis can be made based upon CEBPE gene mutation or a pathognomonic finding of a blood smear showing lack of specific granules. Neutrophils and eosinophils will contain hyposegmented nuclei (a pseudo-Pelger–Huet anomaly).

Genetics

A majority of patients with SGD have been found to have mutations in the CEBPE (CCAAT/enhancer-binding protein epsilon) gene, a transcription factor primarily active in myeloid cells.[3] Almost all patients have been found to be homozygous for the mutation, suggesting the disease is autosomal recessive. One patient, heterozygous for the mutation, was found to be deficient in GFI1, a related gene.[4]

Pathophysiology

The defect in CEBPE appears to block the ability of neutrophils to mature past the promyelocyte stage in bone marrow.[3] Since specific (secondary) and gelatinase (tertiary) granules are only produced past the promyelocyte stage of development, these are deficient in SGD. Lactoferrin is the major enzyme found in specific granules, and will be largely absent in the granulocytes of these patients, along with defensins (despite these also being found in azurophilic (primary) granules).[5] The other major components of azurophilic granules, such as lysozyme, cathepsin, and elastase will be normal, however a lack of defensins and lactoferrin drastically weakens the neutrophil innate ability to fight infection. Neutrophils will also display abnormal chemotaxis, such as a decreased response to fMLP, due to a lack of chemotactic receptors typically found in the specific granules.[6]

Treatment

Treatment consists mainly of high dose antibiotics for active infections and prophylactic antibiotics for prevention of future infections. GM-CSF therapy or bone marrow transplant might be considered for severe cases.[2] Prognosis is difficult to predict, but patients receiving treatment are generally able to survive to adulthood.

Epidemiology

Estimation of the frequency of SGD is difficult, as it is an extremely rare disease with few cases reported in literature. The condition was first reported in 1980, and since only a handful more cases have been published.

References

  1. 1 2 Breton-Gorius J, Mason DY, Buriot D, Vilde JL, Griscelli C (1980). "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. 99 (2): 413–28. PMC 1903492 Freely accessible. PMID 6155073.
  2. 1 2 Wynn RF, Sood M, Theilgaard-Mönch K, Jones CJ, Gombart AF, Gharib M, Koeffler HP, Borregaard N, Arkwright PD (2006). "Intractable diarrhoea of infancy caused by neutrophil specific granule deficiency and cured by stem cell transplantation". Gut. 55 (2): 292–3. PMC 1856503 Freely accessible. PMID 16407388. doi:10.1136/gut.2005.081927.
  3. 1 2 Lekstrom-Himes JA, Dorman SE, Kopar P, Holland SM, Gallin JI (1999). "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. 189 (11): 1847–52. PMC 2193089 Freely accessible. PMID 10359588. doi:10.1084/jem.189.11.1847.
  4. ↑ Khanna-Gupta A, Sun H, Zibello T, Lee HM, Dahl R, Boxer LA, Berliner N (2007). "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. 109 (10): 4181–90. PMC 1885490 Freely accessible. PMID 17244686. doi:10.1182/blood-2005-05-022004.
  5. ↑ Ganz T, Metcalf JA, Gallin JI, Boxer LA, Lehrer RI (1988). "Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and "specific" granule deficiency". J. Clin. Invest. 82 (2): 552–6. PMC 303547 Freely accessible. PMID 2841356. doi:10.1172/JCI113631.
  6. ↑ Gallin JI, Fletcher MP, Seligmann BE, Hoffstein S, Cehrs K, Mounessa N (1982). "Human neutrophil-specific granule deficiency: a model to assess the role of neutrophil-specific granules in the evolution of the inflammatory response". Blood. 59 (6): 1317–29. PMID 7044447.
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