Hematology

Neutrophil specific granule deficiency

Neutrophil specific granule deficiency

What every physician needs to know:

Neutrophil specific granule deficiency (SGD) is most commonly caused by mutations in Ccaat-enhancer-binding proteins (C/EBP) epsilon, an early neutrophil transcription factor. It leads to defects in neutrophil secondary granule formation as well as deficiency of defensins, primary granule proteins that exert potent antibacterial activity.

Patients develop recurrent Gram positive and Gram negative bacterial infections but not fungal infections. The disease is usually recessive, but a dominant case has been published.

Are you sure your patient has neutrophil specific granule deficiency? What should you expect to find?

Patients typically have a peripheral smear that shows large pale neutrophils with abnormal nuclei. The cytoplasmic background is pale due to lack of eosinophilic granules. Evaluation of protein content will reveal absent defensins, lactoferrin, and vitamin B12 binding protein.

Beware of other conditions that can mimic neutrophil specific granule deficiency:

The blood picture in severe burns can mimic SGD.

Which individuals are most at risk for developing neutrophil specific granule deficiency:

Inheritance of SGD is typically recessive, so it is more likely to be found in consanguineous unions. However, a dominant form has been recognized, which appears to be sporadic.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Inspection of the blood smear by a hematologist or hematopathologist will reveal large, pale neutrophils with abnormal neutrophil nuclear segmentation. Absence of defensins and lactoferrin can be documented in neutrophil lysates. Sequence of C/EBP epsilon will show either recessive or dominant mutations in those cases in which the disease is linked to that gene. Not all cases of SGD have been associated with mutations in C/EBP epsilon, and the gene responsible for C/EBP epsilon-negative cases is unknown.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of neutrophil specific granule deficiency?

None

If you decide the patient has neutrophil specific granule deficiency, what therapies should you initiate immediately?

None

More definitive therapies?

Bone marrow transplantation is the only definitive therapy.

What other therapies are helpful for reducing complications?

Prophylactic antibiotics are prudent. Trimethoprim/sulfamethoxazole has been used extensively in antibiotic prophylaxis. An appropriate dose would be 2.5mg/kg of trimethoprim twice daily (one double strength twice a day for an adult). There is no indication for fungal prophylaxis and no clear indication for cytokine therapy, such as interferon gamma or G-CSF. However, the latter have not been tried.

What should you tell the patient and the family about prognosis?

Since both recessive and dominant cases have been identified, counseling will depend on molecular characterization. In general, if the patient is the product of a consanguineous union the chances of recessive inheritance are high, so the chances of vertical transmission are low. On the other hand, if the mutation is dominant, the risk of transmission is 50% for each birth.

The prognosis in the recessive forms has been poor due to infections. In the dominant form, in which neutrophils retain more activity, survival has been good.

What if scenarios.

As is true for many immune deficiencies, patients with SGD may have understated symptoms with infections more extensive and more difficult to treat than initially appreciated. Therefore, they should be examined and imaged thoroughly to assure complete appreciation of the extent of infection.

Pathophysiology

C/EBP epsilon is a transcription factor that regulates myeloid ontogeny, including the biogenesis of neutrophil specific granules and the synthesis of defensins and neutrophil lactoferrin. Hence, mutation in C/EBP epsilon leads to abnormal neutrophil granules, especially the secondary granules, and also loss of other proteins that are controlled by C/EBP epsilon, notably defensins. The absence of these factors contributes to infection susceptibility and also to poor wound healing.

What other clinical manifestations may help me to diagnose neutrophil specific granule deficiency?

One reported case had associated aortic root dilatation, but this has not been the case with all cases identified.

What other additional laboratory studies may be ordered?

Neutrophil nuclei are typically bilobed and may be confused with Pelger-Huet phenomenon. In vitro killing and chemotaxis are impaired. Gfi-1 levels are reduced in SGD neutrophils.

What’s the evidence?

Khanna-Gupta, A, Hong, S, Zibello, T, Lee, HM, Dahl, R, Boxer, LA, Berliner, N. " 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. vol. 109. 2007. pp. 4181-4190.

[First report of a dominant mutation in C/EBPe leading to impaired Gfi-1 activity and milder disease than the homozygous patients.]

Lekstrom-Himes, JA, Dorman, SE, Kopar, P, Holland, SM, Gallin, JI. "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. vol. 189. 1999. pp. 1847-1852.

[First report of a mutation in C/EBPe leading to SGD.]

Gombart, AF, Koeffler, HP. "Neutrophil specific granule deficiency and mutations in the gene encoding transcription factor C/EBPe". Current Opinion Hematol. vol. 9. 2002. pp. 36-42.

[Review of the role of C/EBPε in neutrophil specific granule deficiency.]
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