Purpose of review Mutations in the gene for neutrophil elastase, ELANE, cause cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). This study summarized data from the Severe Chronic Neutropenia International Registry (SCNIR) on genotype–phenotype relationships of ELANE mutations to important clinical outcomes. We also summarize findings for ELANE mutations not observed in SCNIR patients. Recent findings There were 307 SCNIR patients with 104 distinctive ELANE mutations who were followed longitudinally for up to 27 years. The ELANE mutations were diverse; there were 65 single amino acid substitutions; 61 of these mutations (94%) were ‘probably’ or ‘possibly damaging’ by PolyPhen-2 analysis, and one of the ‘benign’ mutations was associated with two cases of acute myeloid leukemia (AML). All frame-shift mutations (19/19) were associated with the SCN. The pattern of mutations in the SCN versus CyN was significantly different (P <10−4), but some mutations were observed in both groups (overlapping mutations). The cumulative incidence of severe adverse events, that is, myelodysplasia, AML, stem cell transplantation, or deaths was significantly greater for patients with SCN versus those with CyN or overlapping mutations. Specific mutations (i.e. G214R or C151Y) had a high risk for evolution to AML. Summary Sequencing is useful for predicting outcomes of ELANE-associated neutropenia.

Corticotroph-derived glycoprotein hormone (CGH), also referred to as thyrostimulin, is a noncovalent heterodimer of glycoprotein hormone alpha 2 (GPHA2) and glycoprotein hormone beta 5 (GPHB5). Here, we demonstrate that both subunits of CGH are expressed in the corticotroph cells of the human anterior pituitary, as well as in skin, retina, and testis. CGH activates the TSH receptor (TSHR); (125)I-CGH binding to cells expressing TSHR is saturable, specific, and of high affinity. In competition studies, unlabeled CGH is a potent competitor for (125)I-TSH binding, whereas unlabeled TSH does not compete for (125)I-CGH binding. Binding and competition analyses are consistent with the presence of two binding sites on the TSHR transfected baby hamster kidney cells, one that can interact with either TSH or CGH, and another that binds CGH alone. Transgenic overexpression of GPHB5 in mice produces elevations in serum T(4) levels, reductions in body weight, and proptosis. However, neither transgenic overexpression of GPHA2 nor deletion of GPHB5 produces an overt phenotype in mice. In vivo administration of CGH to mice produces a dose-dependent hyperthyroid phenotype including elevation of T(4) and hypertrophy of cells within the inner adrenal cortex. However, the distinctive expression patterns and binding characteristics of CGH suggest that it has endogenous biological roles that are discrete from those of TSH.

Mutations in CXCR4 cause severe leuko-penia in myelokathexis or WHIM syndrome. Plerixafor inhibits binding of CXCR4 to its ligand CXCL12. We investigated the effects of plerixafor (0.04 to 0.24 mg/kg) administered at 2-4 day intervals in 6 patients. Outcome measures were the patients' complete blood cell counts, CD34 cell counts and lymphocyte sub-types compared with 5 normal subjects similarly treated with plerixafor. All patients showed prompt leukocytosis with maximum blood neutrophils and lymphocytes at 6-12 hours. Blood neutrophils peaked at 6-12 hours, increasing from a mean baseline of 0.4 0.1 10 9 /L, to mean peak of 4.5 0.78 10 9 /L. Lymphocytes also increased; the greatest increase was in B cells (CD19 cells), a > 40-fold increase over baseline at the 0.08 mg/kg dose. None of the patients experienced any significant adverse effects. Plerixafor is a promising therapy for this condition. (Blood. 2011;118(18):4963-4966) Introduction WHIM syndrome (warts, hypogammaglobulinemia, immunodefi-ciency, and myelokathexis) is a rare autosomal dominant immuno-deficiency disorder attributable to mutations in CXCR4. 1 The WBC is usually 1.0 10 9 /L with severe neutropenia and lym-phocytopenia. If warts are absent, the condition is usually called "myelokathexis." 2 Marrow examinations show abundant neutro-phils with hyper-segmented nuclei and remnants of neutrophils in marrow macrophages. 3 Mutations in CXCR4 prevent the normal release of mature neutrophils from the marrow into the blood. 4 The mechanism for lymphocytopenia is not known, but it may be attributable to interruption of the normal trafficking of lymphocytes and their retention in the marrow and other lymphoid tissues. 5 Plerixafor is a small molecule inhibitor of the binding of CXCR4 to its natural ligand, the chemokine SDF1, also called CXCL12. 6 Subcutaneous administration of plerixafor causes dose-dependent leukocytosis and increases circulating leukocytes, including CD34 cells, and plerixafor is indicated for mobilization of hematopoietic stem cells for autologous transplantation in combination with granulocyte colony-stimulating factor (G-CSF) for patients with non-Hodgkin lymphoma and multiple myeloma. 7,8 We and others have hypothesized that plerixafor might also be useful as a molecularly targeted therapy for myelokathexis or WHIM syndrome, increasing circulating leukocytes by overcoming the impaired internalization and receptor dysfunction attributable to mutant CXCR4. 9 Study design We enrolled 6 patients (4 female, 2 male, ages 28-73 years) in this study, with informed consent, in accordance with the Declaration of Helsinki, and investigational review board approval of the University of Washing-ton and Federal approval for investigational use of plerixafor. Five patients from 3 different families had the same mutation (R334ter); the other patient had a novel mutation (S324fs365ter). Single subcutaneous doses of plerixafor, increasing from 0.04-0.24 mg/kg, were administered at 2-4 day intervals. Complete blood counts were determined at 1, 3, 6, ...

Objective To report outcomes associated with the administration of granulocyte colony–stimulating factor (G-CSF) to women with chronic neutropenia during pregnancy. Methods We conducted an observational study of women of child-bearing potential with congenital, cyclic, idiopathic, or autoimmune neutropenia enrolled in the Severe Chronic Neutropenia International Registry to determine outcomes of pregnancies, without and with chronic G-CSF therapy, 1999–2014. Treatment decisions were made by the patients’ personal physicians. A research nurse conducted telephone interviews of all enrolled U.S. women of child-bearing potential using a standard questionnaire. Comparisons utilized Fisher’s exact test analysis and Student’s t-test. Results One-hundred seven women reported 224 pregnancies, 124 without G-CSF therapy and 100 on chronic G-CSF therapy (median dose: 1.0 mcg/kg/day, range 0.02–8.6 mcg/kg/day). There were no significant differences in adverse events between the groups considering all pregnancies or individual mothers, e.g., spontaneous terminations (all pregnancies: no G-CSF 27/124, G-CSF 13/100; P=0.11, Fisher’s exact test,), preterm labors (all pregnancies, no G-CSF 9/124, G-CSF 2/100, P=0.12,). A study with at least 300 per group would be needed to detect a difference in these events with 80% statistical power (alpha=0.05). Four newborns of mothers with idiopathic or autoimmune neutropenia not on G-CSF (4/101) had life-threatening infections, whereas there were no similar events (0/90) in the treated group, but this difference was also not statistically significant. (p=0.124). Adverse events in the neonates were similar for the two groups. Conclusions This observational study showed no significant adverse effects of administration of G-CSF to women with severe chronic neutropenia during pregnancy.