Spectrum of ELANE mutations in congenital neutropenia: a single-centre study in patients of Indian origin

AimsCongenital and cyclical neutropenia are rare inherited diseases that result in recurrent life-threatening bacterial infections due to a deficiency of mature neutrophils. Cyclical neutropenia is usually caused by heterozygous ELANE mutations while congenital neutropenia is genetically heterogeneous with mutations in genes like ELANE, HAX-1, G6PC3 and GFI1. The presence of ELANE mutation aids in the establishment of diagnosis and rules out other secondary causes of neutropenia such as autoimmune cytopenia and evolving aplasia. Further, patients with ELANE mutations are also at a high risk of developing myelodysplasia or acute myeloid leukaemia. Hence it is important to screen for these mutations in patients presenting with neutropenia early in life.MethodsThe study included 52 patients who were evaluated for inherited neutropenia. Genomic DNA was extracted from peripheral blood leucocytes and mutation analysis was done by bidirectional Sanger sequencing.ResultsTen different missense, frameshift or splice site variants in ELANE gene were identified in 11 patients: c.125C>T (p.Pro42Leu), c.164G>A (p.Cys55Tyr), c.169G>A (p.Ala57Thr), c.179T>C (p.Ile60Thr), c.770C>T (p.Pro257Leu), c.367–8C>A, c.597+1G>A along with three novel mutations c.302T>A (p.Val101Glu), c.468G>T (p.Try156Cys) and c.596delT (Phe199Ser fs*13). Family studies were available for three patients and, in all three instances, the mutation had a de novo origin.ConclusionThe widespread distribution of mutations suggests the need to screen all the exons in ELANE gene for proper characterisation of the genotype.

Clostridium septicum: An Unusual Link to a Lower Gastrointestinal Bleed

Clostridium septicum is a highly virulent pathogen which is associated with colorectal malignancy, hematological malignancy, immunosuppression, diabetes mellitus and cyclical neutropenia. Presentation may include disseminated clostridial infection in the form of septicemia, gas gangrene, and mycotic aortic aneurysms. We report the case of a 62-year-old female presenting with necrotizing fasciitis of her left thigh and subsequently developing rectal bleeding. While she was being treated with empiric antibiotics, her blood culture was found to be positive for C. septicum. We would like to highlight the importance of early colorectal cancer screening in minimizing the occurrence of undetected tumors which provide an optimal growth environment for C. septicum, leading to localized and/or remote infection.

Bistability and State Transition of a Delay Differential Equation Model of Neutrophil Dynamics

This paper studies the existence of bistable states and control strategies to induce state transitions of a delay differential equation model of neutrophil dynamics. We seek the conditions that a stable steady state and an oscillatory state coexist in the neutrophil dynamical system. Physiologically, stable steady state represents the healthy state, while oscillatory state is usually associated with diseases such as cyclical neutropenia. We study the control strategies to induce the transitions from the disease state to the healthy state by introducing temporal perturbations to system parameters. This study is valuable in designing clinical protocols for the treatment of cyclical neutropenia.

Hematopoiesis and its disorders: a systems biology approach

Scientists have traditionally studied complex biologic systems by reducing them to simple building blocks. Genome sequencing, high-throughput screening, and proteomics have, however, generated large datasets, revealing a high level of complexity in components and interactions. Systems biology embraces this complexity with a combination of mathematical, engineering, and computational tools for constructing and validating models of biologic phenomena. The validity of mathematical modeling in hematopoiesis was established early by the pioneering work of Till and McCulloch. In reviewing more recent papers, we highlight deterministic, stochastic, statistical, and network-based models that have been used to better understand a range of topics in hematopoiesis, including blood cell production, the periodicity of cyclical neutropenia, stem cell production in response to cytokine administration, and the emergence of imatinib resistance in chronic myeloid leukemia. Future advances require technologic improvements in computing power, imaging, and proteomics as well as greater collaboration between experimentalists and modelers. Altogether, systems biology will improve our understanding of normal and abnormal hematopoiesis, better define stem cells and their daughter cells, and potentially lead to more effective therapies.

Unusual cause of acute abdomen – omental infarction occurring in a child with cyclical neutropenia

Omental infarction is a rare cause of acute abdomen in childhood. We describe a case of omental infarction mimicking acute appendicitis occurring in a child with cyclical neutropenia. Neutropenic enterocolitis, a serious cause of the acute abdomen, has been linked with cyclical neutropenia. In neutropenic patients, omental infarction when diagnosed pre-operatively can be managed conservatively with the focus on improving the neutrophil count. If after imaging the diagnosis is in doubt, there should be a low threshold for laparoscopy. The low incidence of omental infarction will continue to mean that it is a diagnosis made at operation for suspected appendicitis. In these cases, the infarcted tissue may be removed by the laparoscopic or open technique.