Lymphocyte cytosolic protein 1 (L-plastin) I232F mutation impairs granulocytic proliferation and causes neutropenia.

Neutrophils migrate into inflamed tissue, engage in phagocytosis, and clear pathogens or apoptotic cells. These processes require well-coordinated events involving the actin cytoskeleton. We describe a child with severe neutropenia and episodes of soft tissue infections and pneumonia. Bone marrow examination showed granulocytic hypoplasia with dysplasia. Whole-exome sequencing revealed a de novo heterozygous missense mutation in LCP1, which encodes the F-actin-binding protein Lymphocyte Cytosolic Protein 1. To determine its pathophysiological significance, we stably transduced cells with doxycycline-inducible wild-type LCP1 and LCP1 I232F lentiviral constructs. We observed dysplastic granulocytic 32D cells expressing LCP1 I232F cells. These cells showed decreased proliferation without a block in differentiation. In addition, expression of LCP1 I232F resulted in a cell cycle arrest at the G2/M phase, but it did not lead to increased levels of genes involved in apoptosis or the unfolded protein response. Both 32D and HeLa cells expressing mutant LCP1 displayed impaired cell motility and invasiveness. Flow cytometry showed increased F-actin. However, mutant LCP1-expressing 32D cells exhibited normal oxidative burst upon stimulation. Confocal imaging and subcellular fractionation revealed diffuse intracellular localization of LCP1, but only the mutant form was found in the nucleus. We conclude that LCP1 is a new gene involved in granulopoiesis, and the missense variant LCP1 I232F leads to neutropenia and granulocytic dysplasia with aberrant actin dynamics. Our work supports a model of neutropenia due to aberrant actin regulation.

Heterozygous CTLA4 splice site mutation c.458-1G > C presenting with immunodeficiency and variable degree of immune dysregulation in three generation kindred of Caribbean descent.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is an immune checkpoint, which downregulates T cell activation and T regulatory cell function. CTLA4 haploinsufficiency (CTLA4 HI) leads to T cell hyperactivation, immunodeficiency and variable degree of immune dysregulation. Furthermore, CTLA4 HI predisposes affected individuals to development of various cancers. Less well understood is the penetrance and expressivity of CTLA4 mutations. We describe five members of a single family with heterozygous CTLA4 splice site mutation c.458-1G > C, previously shown to result in CTLA-4 HI, who presented with immunodeficiency and variable degree of immune dysregulation. The host, environmental and the epigenetic factors affecting the penetrance and expressivity of CTLA4 mutations merits further investigation.

CTLA4 haploinsufficiency as a predisposition to classical Hodgkin lymphoma.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) haploinsufficiency (HI) is an immune dysregulation disorder characterized by T lymphocyte hyperactivation, and generalized lymphoproliferative and autoimmune disorders. Patients with CTLA4 haploinsufficiency are also prone to developing various malignancies. Due to the rare nature of this condition, the longitudinal evolution of CTLA4 haploinsufficiency clinical manifestations remains to be described. We report on over a decade-long course of a young adult men patient with known CTLA4 haploinsufficiency, who sequentially developed multiple autoimmune conditions along with two distinct episodes of classical Hodgkin Lymphoma (cHL) of unique histologies. Notably, the patient had serological and molecular evidence of Epstein Barr virus (EBV) infection at the time of diagnosis of both cHL. The allogeneic stem cell transplantation consolidated durable remission of cHL and CTLA-4 haploinsufficiency-related clinical manifestations, but failed to enable the patient to permanently suppress EBV viremia, which raises concerns for the development of other EBV infection-related conditions in the future. This case report adds on the current understanding of the natural clinical history of patients with CTLA4 haploinsufficiency, and their unique susceptibility to developing cHL.

Use of Thrombopoietin Receptor Agonists in Prolonged Thrombocytopenia after Hematopoietic Stem Cell Transplantation.

Prolonged thrombocytopenia after hematopoietic stem cell transplantation (HSCT) is a strong risk factor for transplantation-related morbidity and mortality, and no standard treatment guideline exists. Thrombopoietin receptor agonists (TPO-RAs), eltrombopag and romiplostim, increases the platelet production, and are being increasingly used in various conditions with thrombocytopenia. In this review, we present an overview of these TPO-RAs and review their efficacy and safety in prolonged post-HSCT thrombocytopenia. Through a systematic literature search, we identified 25 reports describing their use for this indication. Thirteen reports (8 case series and 5 case reports) described the use of eltrombopag in 78 patients with prolonged isolated thrombocytopenia (PIT) and 43 patients with secondary failure of platelet recovery (SFPR). A consistent and durable response with a rise in platelet counts >50 × 10 9/L for 7 consecutive days without platelet transfusion was seen in 85 of 121 patients (overall response rate [ORR], 70%). The responders included 56 patients with PIT (ORR for PIT, 72%) and 29 patients with SFPR (ORR for SFPR, 67%). No serious grade 3 or 4 adverse effects were reported. Similarly, 12 reports (6 case series and 6 case reports) described the use of romiplostim in prolonged post-HSCT thrombocytopenia (in 17 patients with PIT and 32 patients with SFPR). Response with the increment of platelet count was described in 40 out of 49 patients (ORR, 82%). Among the responders, 10 patients had PIT (ORR for PIT, 59%) and 30 patients had SFPR (ORR for SFPR, 94%). Our data show that TPO-RAs have an overall favorable response rate for both PIT and SFPR with a reasonable safety profile. However, given the lack of control groups, study heterogeneity, and the potential publication bias, these results should be interpreted with caution.

Use of complement monoclonal antibody eculizumab in Shiga toxin producing Escherichia coli associated hemolytic uremic syndrome: A review of current evidence.

Complement activation plays an important role in the pathogenesis of atypical hemolytic uremic syndrome. Eculizumab is a monoclonal antibody that blocks complement activity and has been approved for use in the treatment of atypical hemolytic uremic syndrome (HUS). Less well appreciated is the role of complement in Shiga toxin-induced HUS (Shiga toxin producing Escherichia coli [STEC]-HUS). To a limited extent, eculizumab has been used off label in patients with severe STEC-HUS with neurological involvement. Through a systematic search of available databases, we identified 16 reports describing the use of eculizumab in STEC-HUS (eight case reports/series, seven retrospective studies, and one prospective cohort study). All studies described its use in severe STEC-HUS with neurological or multiorgan dysfunction; none were randomized or blinded. Four studies used the control groups. Although the overall quality of evidence is low, some published studies showed positive clinical improvement after treatment with eculizumab in severe STEC-HUS with progressive neurological involvement.

Ovarian Torsion in an Adolescent with Beckwith-Wiedemann Syndrome and Unilateral Tubo-ovarian Hyperplasia.

BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is the most common pediatric overgrowth syndrome. BWS has a broad phenotypic presentation along with an increased propensity to develop various embryonal tumors. There are very few reported cases of gonadal hyperplasia in BWS patients in the existing literature. CASE: We describe a 13-year-old girl with BWS who presented with an episode of abdominal pain and was found to have torsion and necrosis of a markedly hyperplastic right ovary and fallopian tube. We present a brief literature review on ovarian hyperplasia in BWS patients for which we used an online search of the databases PubMed, Embase, Ovid Medline, and Cochrane. RESULTS AND CONCLUSION: Through an extensive literature search, we only found 3 previous reports of ovarian hyperplasia in BWS patients, all in postmortem specimens. Our case highlights a potentially important aspect of visceral organ hyperplasia in patients with BWS that could remain indolent until adolescence and might present as an abrupt-onset abdominopelvic catastrophe.