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A letter to the editor is presented which discusses the case of a patient with Epstein-Barr virus (EBV)+ hydroa vacciniforme (HV)-like T-cell lymphoma relative to allogeneic hematopoietic stem cell transplantation (allo-SCT) and the efficacy of EBV-specific cytotoxic T-lymphocyte (CTL) immunotherapy.

Cutaneous T-cell lymphoid neoplasms in childhood are exceedingly rare, presenting with a wide spectrum of clinical presentation and outcomes. Due to numerous clinical and pathological mimics, an integrated evaluation of clinical, histopathological, immunohistochemical, and molecular findings is critical for a diagnosis. Here, we review the clinical and pathological features, updated classifications, and critical differential diagnoses of cutaneous T-cell lymphoid neoplasms in children., (© 2024 Wiley Periodicals LLC.)

Here we describe a pediatric patient with febrile infection-related epilepsy syndrome with a good functional and neurologic outcome after treatment with early and aggressive cytokine-directed immunomodulatory therapy and a seizure management strategy that intentionally avoided a barbiturate coma. A 5-year-old previously healthy male presented with staring, behavioral arrest, and encephalopathy evolving to super-refractory status epilepticus. He had had onset of fever 5 days prior. He was treated with early and aggressive immunomodulatory therapy targeted to his evolving cytokine profile. He was also treated with the ketogenic diet, antiseizure medications, and continuous anesthetic infusions. Pentobarbital was purposely avoided. Now, 2½ years later, he attends mainstream school, has attention-deficit hyperactivity disorder (ADHD), mild neurocognitive impairment, and well-controlled epilepsy. By using cytokine-directed immunotherapy and avoiding a barbiturate coma, we were able to successfully treat a pediatric patient with febrile infection-related epilepsy syndrome and achieve a good outcome., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Context.—: Posttransplant lymphoproliferative disorder (PTLD) remains a significant complication in pediatric patients undergoing solid organ transplant (SOT). The majority involve Epstein-Barr virus (EBV)-driven CD20+ B-cell proliferations, which respond to reduction of immunosuppression and anti-CD20-directed immunotherapy. Owing to the low overall incidence, prospective studies of pediatric PTLD are scarce, leading to a lack of comprehensive understanding of this disorder in pediatric populations. This review aims to bridge this knowledge gap by providing a comprehensive analysis of the clinical, morphologic, and molecular genetic features of PTLD in children, adolescents, and young adults after SOT., Objective.—: To examine the clinical features, pathogenesis, and classification of pediatric PTLDs after SOT., Data Sources.—: Personal experiences and published works in PubMed., Conclusions.—: PTLD includes a broad and heterogeneous spectrum of disorders, ranging from nonmalignant lymphoproliferations to lymphomas. While most pediatric PTLDs are EBV+, an increasing number of EBV- PTLDs have been recognized. The pathologic classification of PTLDs has evolved in recent decades, reflecting advancements in understanding the underlying pathobiology. Nevertheless, there remains a great need for further research to elucidate the biology, identify patients at higher risk for aggressive disease, and establish optimal treatment strategies for relapsed/refractory disease., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Langerhans cell histiocytosis (LCH) is a myeloid neoplastic disorder characterized by lesions with CD1a-positive/Langerin (CD207)-positive histiocytes and inflammatory infiltrate that can cause local tissue damage and systemic inflammation. Clinical presentations range from single lesions with minimal impact to life-threatening disseminated disease. Therapy for systemic LCH has been established through serial trials empirically testing different chemotherapy agents and durations of therapy. However, fewer than 50% of patients who have disseminated disease are cured with the current standard-of-care vinblastine/prednisone/(mercaptopurine), and treatment failure is associated with long-term morbidity, including the risk of LCH-associated neurodegeneration. Historically, the nature of LCH-whether a reactive condition versus a neoplastic/malignant condition-was uncertain. Over the past 15 years, seminal discoveries have broadly defined LCH pathogenesis; specifically, activating mitogen-activated protein kinase pathway mutations (most frequently, BRAFV600E) in myeloid precursors drive lesion formation. LCH therefore is a clonal neoplastic disorder, although secondary inflammatory features contribute to the disease. These paradigm-changing insights offer a promise of rational cures for patients based on individual mutations, clonal reservoirs, and extent of disease. However, the pace of clinical trial development behind lags the kinetics of translational discovery. In this review, the authors discuss the current understanding of LCH biology, clinical characteristics, therapeutic strategies, and opportunities to improve outcomes for every patient through coordinated agent prioritization and clinical trial efforts., (© 2024 American Cancer Society.)

Background: Drug shortages are a common issue that healthcare systems face and can result in adverse health outcomes for patients requiring inferior alternate treatment. The United States recently experienced a national drug shortage of intravenous immunoglobulin (IVIG). Several reported strategies to address the IVIG and other drug shortages have been proposed; however, there is a lack of evidence-based methods for protocol development and implementation., Objective: To evaluate the efficacy of introducing a multidisciplinary task force and tier system of indications and to minimize adverse effects during a shortage of IVIG., Methods: Faculty members across disciplines with expertise in IVIG use were invited to participate in a task force to address the shortage and ensure adequate supply for emergent indications. A tier system of IVIG indications was established according to the severity of diagnosis, urgency of indication, and quality of supporting evidence. Based on inventory, indications in selected tiers were auto-approved. Orders that could not be automatically approved were escalated for task force review., Results: Overall, there were 342 distinct requests for IVIG during the study period (August 1, 2019 to December 31, 2019). All Tier 1 indications were approved. Of all requests, only 2.6% (9) of requests were denied, none of which resulted in adverse effects based on retrospective chart review. Seven patients who regularly receive IVIG had possible adverse effects due to dose reduction or spacing of treatment; however, each complication was multifactorial and not attributed to the shortage or tier system implementation alone., Conclusion: Implementation of a multidisciplinary task force and tier system to appropriately triage high-priority indications for limited pharmaceutical agents should be considered in health institutions faced with a drug shortage., (© 2024 Wiley Periodicals LLC.)

Abstract: Posttransplant lymphoproliferative disease (PTLD) in pediatric solid organ transplant (SOT) recipients is characterized by uncontrolled proliferation of Epstein-Barr virus-infected (EBV+) B cells due to decreased immune function. This study evaluated the feasibility, safety, clinical and immunobiological outcomes in pediatric SOT recipients with PTLD treated with rituximab and third-party latent membrane protein-specific T cells (LMP-TCs). Newly diagnosed (ND) patients without complete response to rituximab and all patients with relapsed/refractory (R/R) disease received LMP-TCs. Suitable LMP-TC products were available for all eligible subjects. Thirteen of 15 patients who received LMP-TCs were treated within the prescribed 14-day time frame. LMP-TC therapy was generally well tolerated. Notable adverse events included 3 episodes of rejection in cardiac transplant recipients during LMP-TC therapy attributed to subtherapeutic immunosuppression and 1 episode of grade 3 cytokine release syndrome. Clinical outcomes were associated with disease severity. Overall response rate (ORR) after LMP-TC cycle 1 was 70% (7/10) for the ND cohort and 20% (1/5) for the R/R cohort. For all cohorts combined, the best ORR for LMP-TC cycles 1 and 2 was 53% and the 2-year overall survival was 70.7%. vβT-cell receptor sequencing showed persistence of adoptively transferred third-party LMP-TCs for up to 8 months in the ND cohort. This study establishes the feasibility of administering novel T-cell therapies in a cooperative group clinical trial and demonstrates the potential for positive outcomes without chemotherapy for ND patients with PTLD. This trial was registered at www.clinicaltrials.gov as #NCT02900976 and at the Children's Oncology Group as ANHL1522., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Pediatric cutaneous T-cell lymphoma with γδ immunophenotype is extremely rare. Only a few cases of γδ T-cell neoplasm have been reported in the literature, and therefore little is known whether γδ T-cell neoplasms in children are distinct from their adult counterparts with respect to the clinicopathological presentation, behavior, and prognosis. In this study, we demonstrate three unique pediatric cutaneous T-cell neoplasm and mimics with increased γδ T cells. All cases showed an indolent clinical course., (© 2024 Wiley Periodicals LLC.)

The Children's Oncology Group (COG) Young Investigators (YI) Committee is an administrative committee in which liaisons represent 30 COG committees, and was created to facilitate the integration of YIs into the organization, and prepare them for future COG leadership roles. The mentorship program has mentored over 400 YIs since 2005 and currently has 175 active participants. The COG YI Master Roster is a database YIs can join, which allows them to post their interests and accomplishments to COG leadership, and 321 YIs have already joined this list. The YI Committee has held virtual symposia designed to describe how COG operates and provide guidance on how YIs can reach their goals; over 300 YIs have attended these since 2021 and have consistently rated them as helpful. Through these and other elements of the program, the YI Committee remains committed to developing a future pipeline of new investigators., (© 2023 Wiley Periodicals LLC.)

Pediatric non-Hodgkin lymphoma (NHL) includes over 30 histologies (many with subtypes), with approximately 800 cases per year in the United States. Improvements in survival in NHL over the past 5 decades align with the overall success of the cooperative trial model with dramatic improvements in outcomes. As an example, survival for advanced Burkitt lymphoma is now >95%. Major remaining challenges include survival for relapsed and refractory disease and long-term morbidity in NHL survivors. Langerhans cell histiocytosis (LCH) was added to the NHL Committee portfolio in recognition of LCH as a neoplastic disorder and the tremendous unmet need for improved outcomes. The goal of the Children' Oncology Group NHL Committee is to identify optimal cures for every child and young adult with NHL (and LCH). Further advances will require creative solutions, including engineering study groups to combine rare populations, biology-based eligibility, alternative endpoints, facilitating international collaborations, and coordinated correlative biology., (© 2023 Wiley Periodicals LLC.)

There are limited data pertaining to the prognostic features and optimal therapeutic approach for the 20%-25% of children with lymphoblastic lymphoma (LLy) who have the B-lymphoblastic subtype. Outcomes are favorable following treatment modeled after acute lymphoblastic leukemia (ALL) regimens, but prognosis is dismal after relapse, and there are no established features for predicting therapy response. Ongoing US and international trials will include the largest cohort of uniformly treated patients with B-LLy to date, providing an opportunity to define clinical and molecular predictors of relapse and to establish a standard of care for treatment to improve outcomes for this rare pediatric cancer., (© 2023 Wiley Periodicals LLC.)

Post-transplant Lymphoproliferative Disease (PTLD) remains a major complication of solid organ transplantation (SOT) in pediatric patients. The majority are Epstein-Barr Virus (EBV) driven CD20 + B-cell proliferations responsive to reduction to immunosuppression and anti-CD20 directed immunotherapy. This review focusses on the epidemiology, role of EBV, clinical presentation, current treatment strategies, adoptive immunotherapy and future research in EBV + PTLD in pediatric patients., Competing Interests: Declaration of competing interest None of the authors have any conflict of interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology., (© 2019 Wiley Periodicals, Inc.)

Background: Identification and development of young investigators (YI) is critical to the long-term success of research organizations. In 2004, the Children's Oncology Group (COG) created a mentorship program to foster the career development of YIs (faculty <10 years from initial appointment). This study sought to assess mentors' long-term assessment of this program., Procedure: In 2018, 101 past or current mentors in the COG YI mentorship program completed an online survey. Statistical comparisons were made with the Kruskal-Walis test., Results: The response rate was 74.2%. As some mentors had multiple mentees, we report on 138 total mentee-mentor pairs. Mentors were 57.4% male, and mentees were 39.1% male. Mentors rated being mentored as a YI as important with a median rating of 90 on a scale of 1-100, interquartile range (IQR) 80-100. Most mentors reported that being mentored themselves helped their own success within COG (78.2%) and with their overall career development (92.1%). Most mentors enjoyed serving in the program (72.3%) and the median success rating (on a scale of 1-100) across the mentor-mentee pairings was 75, IQR 39-90. Success ratings did not differ by mentor/mentee gender, but improved with increased frequency of mentor-mentee interactions (P < .001). Mentor-mentee pairs who set initial goals reported higher success ratings than those who did not (P < .001). Tangible successes included current mentee COG committee involvement (45.7%), ongoing mentor-mentee collaboration (53.6%), and co-authored manuscript publication (38.4%)., Conclusion: These data indicate that mentorship is important for successful professional development. Long-term mentoring success improves when mentors and mentees set goals upfront and meet frequently., (© 2019 Wiley Periodicals, Inc.)

Vitamin B12 (B12) deficiency in infancy can present with nonspecific symptoms. We report a 5-month old exclusively breastfed full-term infant with emesis, lethargy, progressive pancytopenia, hemolysis, hypofibrinogenemia, elevated lactate dehydrogenase and a hypercellular bone marrow with dyserythropoiesis. The B12 level in the serum was undetectable. The infant's lethargy resolved within 48 hours of intramuscular B12 injection, followed by rapid improvement of pancytopenia. The asymptomatic mother had a normal hemoglobin and mean corpuscular volume, but undetectable B12 level and positive antibodies to intrinsic factor, consistent with pernicious anemia masked by folate supplementation in the mother but causing symptoms in her infant.

Background: Recurrent genomic changes in B-lymphoblastic leukemia (B-ALL) identified by genome-wide single-nucleotide polymorphism (SNP) microarray analysis provide important prognostic information, but gene copy number analysis of its rare lymphoma counterpart, B-lymphoblastic lymphoma (B-LBL), is limited by the low incidence and lack of fresh tissue for genomic testing., Procedure: We used molecular inversion probe (MIP) technology to analyze and compare copy number alterations (CNAs) in archival formalin-fixed paraffin-embedded pediatric B-LBL (n = 23) and B-ALL (n = 55)., Results: Similar to B-ALL, CDKN2A/B deletions were the most common alteration identified in 6/23 (26%) B-LBL cases. Eleven of 23 (48%) B-LBL patients were hyperdiploid, but none showed triple trisomies (chromosomes 4, 10, and 17) characteristic of B-ALL. IKZF1 and PAX5 deletions were observed in 13 and 17% of B-LBL, respectively, which was similar to the reported frequency in B-ALL. Immunoglobulin light chain lambda (IGL) locus deletions consistent with normal light chain rearrangement were observed in 5/23 (22%) B-LBL cases, compared with only 1% in B-ALL samples. None of the B-LBL cases showed abnormal, isolated VPREB1 deletion adjacent to IGL locus, which we identified in 25% of B-ALL., Conclusions: Our study demonstrates that the copy number profile of B-LBL is distinct from B-ALL, suggesting possible differences in pathogenesis between these closely related diseases., (© 2016 Wiley Periodicals, Inc.)

Deferesirox (DFX), an oral chelating agent, is used to treat chronic iron overload in several hematological diseases such as β-thalassemia, sickle cell disease, and myelodysplastic anemia. DFX is generally well tolerated with the exception of gastrointestinal disturbances and rash, although cases of renal toxicity, as well as acute and chronic liver failure, have been reported in adults and children. Here we describe a 3-year-old girl with β-thalassemia undergoing treatment with DFX who presented with acute liver failure and Fanconi's syndrome. It is important for pediatric gastroenterologists, hepatologists, and hematologists to be aware that the commonly used drug DFX can lead to acute liver failure in children, and liver function should be monitored closely in all patients taking DFX.

Purpose of Review: Post-transplant lymphoproliferative disease (PTLD) is a major complication of hematopoietic stem cell and solid organ transplantation. The incidence of transplantation in childhood has been steadily rising, making PTLD the most common form of lymphoproliferation in childhood. The purpose of this review is to summarize the role of the Epstein-Barr virus (EBV) in the pathophysiology and discuss the management of PTLD., Recent Findings: More than 90% of pediatric PTLD is EBV-positive. In immunocompetent hosts, the virus is controlled by cytotoxic T-cells, the cells targeted by immunosuppression to avoid graft-versus-host disease and/or organ rejection in transplant patients. The majority of pediatric transplant candidates are EBV-negative prior to transplant increasing the risk of EBV-induced lymphoproliferation upon seroconversion after transplant. Treatment options include reduction of immunosuppression, anti-CD20 monoclonal antibodies, and/or chemotherapy. Advanced understanding of the importance of cellular immunity in controlling lymphoproliferation has led to the development of cellular therapies targeting virus-specific antigens., Summary: PTLD is the most common form of lymphoproliferation in childhood due to the rising incidence of transplantation. EBV plays a pivotal role in the pathophysiology. Cellular therapies targeting viral antigens may replace chemotherapy in the treatment of PTLD in the near future.

EBV-SMT are a rare entity following organ transplantation. Given the rarity of the tumor, there is no standard approach to diagnosis and treatment. A literature search identified 28 reported cases of EBV-SMT in addition to our own experience with one case. The aim of this review is to summarize the existing data regarding pathogenesis, diagnosis, and treatment., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Epstein-Barr virus (EBV) viremia (EV) in pediatric solid organ transplant (SOT) recipients is a significant risk factor for posttransplant lymphoproliferative disease (PTLD) but not all patients with EV develop PTLD. We identify predictive factors for PTLD in patients with EV. We conducted a retrospective chart review of all pediatric SOT recipients (0 to 21 y) at a single institution between 2001 and 2009. A total of 350 pediatric patients received a SOT and 90 (25.7%) developed EV. Of EV patients, 28 (31%) developed PTLD. The median age at transplant was 11.5 months in the PTLD group and 21.5 months in the EV-only group (P=0.003). Twenty-three (37%) EV-only patients had immunosuppression increased before EV, compared with 28 (100%) of PTLD patients (P<0.001). The median peak EBV level was 3212 EBV copies/10 lymphocytes for EV-only and 8392.5 EBV copies/10 lymphocytes for PTLD (P=0.005). All patients who developed PTLD had ≥1 clinical symptoms. Younger age at transplant, increased immunosuppression before EV, higher peak EBV level, and presence of clinical symptoms have predictive value in the development of PTLD in SOT patients with EV.

Post-transplant lymphoproliferative disease (PTLD) in solid organ transplant (SOT) recipients has become one of the most common forms of lymphoproliferation in childhood and is a serious complication of SOT. More than 90% of cases are of B-cell origin, Epstein Barr virus (EBV) positive and are mostly occurring in the early post-transplant period. Pathologically and clinically it is a heterogenous disease ranging from being responsive to reduced immunosuppression without further intervention to rapidly progressive fulminant PTLD requiring prompt initiation of therapy. Prognosis overall is favorable. Current treatment strategies as well new promising targeted immune-based therapies such as rituximab and EBV-specific cytotoxic T-lymphocytes are being discussed.

Treatment of primary EV and PTLD in pediatric LT recipients (pLT) involves IS reduction/cessation. Retrospective review of pLT at our institution from 2001-2009 was conducted to characterize risk factors for GR after EV/ PTLD. Of 184 pLT, EV occurred in 61 (33%) at mean 16.5 m (0-82) and PTLD in 18 (9.8%) at mean 17.7 m (3-78) post-LT. Median age at pLT was 11 m (1-245 m) and follow-up six yr. For EV, 86% underwent IS reduction and 51% received antivirals. GR occurred in 12 (27.9%) with EV and 15 (83.3%) after PTLD diagnosis (relative risk of GR for PTLD 2.98). GR treated with methylprednisolone bolus in half and/or oral IS in half. Following GR therapy, four had PTLD relapses, no graft loss and one EV patient required re-transplantation. GR history before EV was a risk factor for GR after EV (p = 0.024). GR at any point after pLT was a risk factor for PTLD (p = 0.001). Children with EV and GR prior to EV should be monitored closely for GR after IS reduction and GR is a significant risk factor for PTLD. Most children with PTLD eventually developed GR., (© 2012 John Wiley & Sons A/S.)

Cytopenias are common among pediatric SOT; however, autoimmune cytopenias are infrequently reported. We report five cases of autoimmune cytopenias in pediatric LT patients: two with isolated IgG-mediated AIHA, two with ITP, and one with Evans syndrome (ITP and AIHA). All patients were maintained on tacrolimus as immunosuppression. Viral illness commonly preceded the autoimmune cytopenias. All patients responded well to medical therapy (steroids, intravenous immunoglobulin, and rituximab) and lowering tacrolimus serum level. Prognosis appears to be worse when more than one cell line (e.g., Evans syndrome) is affected, and/or there is no preceding viral illness. A critical literature review of autoimmune cytopenias in children following SOT is conducted. Autoimmune cytopenias are a rarely reported complication of pediatric SOT, but clinicians taking care of pediatric transplant recipients need to be aware of this complication., (© 2011 John Wiley & Sons A/S.)

There are only a few published reports of tumor emboli from osteosarcoma. We are reporting a 17-year-old adolescent boy with a history of localized osteosarcoma who developed a symptomatic pulmonary artery tumor embolus. He was initially diagnosed with a pulmonary thromboembolism. This is the first reported case of a single tumor embolus developing after surgical resection of a tumor with 100% necrosis after chemotherapy and no evidence of metastatic disease at the time of surgery. Pulmonary tumor embolism should be considered in the differential diagnosis in patients with cancer who present with dyspnea. The differentiation of tumor embolus from other causes of dyspnea is important for treatment plan., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: This single center, retrospective study describes experience with a hybrid prevention strategy combining short-course antiviral prophylaxis and preemptive cytomegalovirus (CMV) polymerase chain reaction (PCR) monitoring., Methods: One hundred twenty-two pediatric liver transplantation recipients were followed up for a median of 2.3 years posttransplantation. Subjects received a minimum of 14 days of postoperative ganciclovir, followed by monthly CMV PCR monitoring., Results: Forty-three CMV seronegative recipients received seropositive grafts and were considered high risk for CMV; 79 subjects were routine risk. CMV was detected by PCR in the absence of symptoms in 34.4% of subjects and was more likely in high risk than in routine risk recipients (58.1% vs. 21.8%, P=0.0001). Twelve subjects (9.8%) developed CMV disease (8 high risk vs. 4 routine risk, P=0.03). Three subjects developed acute rejection in the 6 months after detection of CMV, but CMV was preceded by rejection in 13 subjects. There were no mortalities secondary to CMV. A total of 38.5% of subjects were spared antiviral medications beyond their initial postoperative prophylaxis., Conclusions: These results suggest that a hybrid preventative approach for CMV is a reasonable alternative to prolonged antiviral prophylaxis and may reduce unnecessary exposure to antiviral therapy. However, patients who receive intensified immunosuppression after acute rejection are at increased risk for CMV and may require extended prophylaxis and closer monitoring.

Background: Familial hemophagocytic lymphohistiocytosis (FHLH) is an autosomal recessively inherited multisystem disease characterized by fever, rash, splenomegaly, cytopenias, and variable central nervous system (CNS) manifestations., Case History: We report the case of a 3-year-old boy who presented with splenomegaly and normocytic anemia 4 months after returning to the US from a region endemic for Leishmania infection. The child later developed progressive neurological impairment and had radiologic evidence of widespread demyelinating disease. Gene studies showed homozygosity for a mutation at Munc13-4, confirming FHLH type 3., Discussion: The diagnostic uncertainty that accompanies FHLH was compounded by our patient's travel history and CNS disease mimicking acute disseminated encephalomyelitis (ADEM). Diagnostic criteria for hemophagocytic lymphohistiocytosis were not consistently met, despite aggressive disease., Conclusions: FHLH may present with fulminant demyelinating disease, mimicking ADEM, and without necessarily meeting previously defined clinical and laboratory criteria. We strongly recommend expeditious molecular testing and genetic counseling for FHLH mutations in cases of undiagnosed inflammatory CNS disease in the pediatric population.

STAT3 has been described as an essential component of G-CSF-driven cell proliferation and granulopoiesis. This notion was tested by conditional gene ablation in transgenic mice. Contrary to expectation, granulocytes developed from STAT3 null bone marrow progenitors, and STAT3 null neutrophils displayed mature effector functions. Rather than a deficit in granulopoiesis, mice lacking STAT3 in their hematopoietic progenitors developed neutrophilia, and bone marrow cells were hyperresponsive to G-CSF stimulation. These studies provide direct evidence for STAT3-independent granulopoiesis and suggest that STAT3 directs a negative feedback loop necessary for controlling neutrophil numbers, possibly through induced expression of the signaling inhibitor, SOCS3.

We investigated an 8-year-old Arab girl with severe factor XI deficiency; one sibling and her father also have severe factor XI deficiency. Her parents and her father's parents are first cousins. Restriction analysis and DNA sequencing excluded the type I, II, III and IV mutations. We demonstrated a previously undescribed C-->A mutation at nucleotide 1254 in exon 11 resulting in a threonine to asparagine (T-->N) substitution at amino acid 386. We postulate that this substitution interferes with folding and secretion of the molecule.