Glucose-6-phosphatase catalyzes the final steps of gluconeogenesis and glycogenolysis in the endoplasmic reticulum (ER). Three genes with this activity have been described, the most widely expressed of which is glucose-6-phosphatase catalytic unit 3 (G6PC3) [59,60]. Mutations in this gene were found to be a cause of severe congenital neutropenia in 2009 . The neutrophils of patients with this disease, now known as severe congenital neutropenia type 4 (SCN4) [1▪▪], have an increased sensitivity to apoptosis. Associated findings include structural heart defects, urogenital abnormalities, and venous angiectasia. In the past 2 years, extensive work has been done to delineate both the pathophysiology and the range of phenotypes of this syndrome.
Although not commented upon by the authors, the ANCs of the Palestinian patients reported by Banka et al. [61▪] appear to be higher than those of the Aramean patients with the same mutation reported by Boztug et al. . In the earlier paper, two out of five patients never had ANCs above 100 cells/μl, whereas the lowest ANC reported by the Israeli–British team was 200 cells/μl. The youngest patient was able to mount an ANC of 7700 cells/μl, although under what clinical circumstances is not clear. Banka et al. do not mention the extent to which their patients were treated with G-CSF, and if they do have higher neutrophil counts than the patients of Boztug et al. they may not be cytokine-dependent. This difference may be explained by other genomic factors, or it could represent the variability of the newly described disease.
A potential second immunodeficiency involving CXCR4 and CXCL12 was identified in 2011 [75▪]. The reported patients had neutropenia, hypogammaglobulinemia, and recalcitrant warts, but did not have myelokathexis. Both patients had B-cell and natural killer cell lymphopenia, which is not typically associated with WHIM syndrome. Furthermore, no mutations in the CXCR4 gene were identified. The patients’ lymphocytes had reduced internalization of CXCR4 when stimulated with CXCL12, a finding which the authors had previously demonstrated in patients with WHIM syndrome .
Two groups described a new molecular etiology of combined immunodeficiency in April of 2012 [35▪,36▪]. The patients studied by Abdollahpour et al. [35▪] were three members of a single Iranian family with stop mutations due to a single nucleotide substitution in exon 7 of STK4, also known as MST1, a gene whose product has antiapoptotic activity. In addition to deficiencies of B and T cell numbers, all three patients had neutropenia. Infections were both bacterial and viral. T cells and neutrophils showed increased apoptosis. Although these patients presented between ages 2 and 10, and were able to make specific antibodies against tetanus and diphtheria toxoids, two other members of the kindred died from sepsis in infancy.
For the primary neutropenic disorders, G-CSF is the treatment of choice in the absence of curative HCT [83▪▪]. This treatment has reduced infectious morbidity  and mortality . Although only 5% of patients with SCN have no response to G-CSF , the amount of cytokine needed varies greatly from less than 5 to 120 μg/kg/day. Those patients who do not respond to 120 μg/kg/day of G-CSF are unlikely to respond to higher doses  and are appropriate candidates for HCT. Included among this group are patients with a constitutive extracellular G-CSFR mutation [14,89,90], who are absolutely refractory to G-CSF. Patients who require more than 8 μg/kg/day of G-CSF have an increased risk for leukemic transformation .
The use of pegfilgrastim instead of filgrastim is theoretically attractive, and has been tried in isolated cases [91–94], but has not been routinely accepted, and may in fact lead to an increase in adverse events [95,96]. One obstacle to the use of this agent in the United States is the packaging of the commercially available product in a syringe prefilled with the adult dose of 6 mg. This would require either intentional overdosing or the cumbersome prospect of pharmacist re-packaging of the medicine if pegfilgrastim were used for children.
Finally, genetically modified autologous HCT has been used as an investigational modality in several PIDDs [101–107], with notable successes in SCID, chronic granulomatous disease, and Wiskott–Aldrich syndrome. Gene therapy remains a potentially useful modality for PIDDs with neutropenia, but is still at the preclinical stage for most of them. Even in those disorders in which gene therapy has been carried out, its application must be judicious, given the potential for life-threatening or fatal adverse events [108–110] (and, press release from Hannover Medical School, http://www.asgct.org/UserFiles/file/Genetherapy_WAS_final_english.pdf, accessed 1 August 2012).
Papers of particular interest, published within the annual period of review, have been highlighted as:
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 72–73).
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