ABSTRACT
BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
Subject(s)
Immune System Diseases , Immunologic Deficiency Syndromes , Child , Humans , Autoimmunity/genetics , Cohort Studies , Gain of Function Mutation , Immunologic Deficiency Syndromes/genetics , Mutation , STAT3 Transcription Factor/genetics , Cell Proliferation , LymphocytesABSTRACT
The hypermobile Ehlers-Danlos syndrome (hEDS) GENE study is a multicenter, cohort study with the goal to identify genes associated with hypermobile EDS. Of the 148 people enrolled in the hEDS GENE study, 98 meet the 2017 hEDS criteria, 27 have a hypermobility spectrum disorder (HSD) and 23 are asymptomatic family members. More than 80% of participants are female with an average age of 41 years. Each participant has completed seven questionnaires to quantify disease-related symptomatology. People with hypermobility experience a variety of physical and somatic symptoms, especially in the areas of fatigue, kinesiophobia, gastrointestinal, and autonomic function. These cause a significant decrease in health-related quality of life. The frequency and severity of most symptoms were indistinguishable between participants with hEDS and HSD; however, there were significant differences in autonomic symptoms. Less than 20% of participants had autoantibodies known to be associated with dysautonomia. Subtle symptomatic differences in people meeting the 2017 diagnostic criteria suggest focusing further etiologic studies on autonomic pathways.
Subject(s)
Ehlers-Danlos Syndrome/genetics , Fatigue/genetics , Joint Instability/genetics , Primary Dysautonomias/genetics , Adolescent , Adult , Cohort Studies , Ehlers-Danlos Syndrome/diagnosis , Ehlers-Danlos Syndrome/epidemiology , Ehlers-Danlos Syndrome/pathology , Fatigue/diagnosis , Fatigue/epidemiology , Fatigue/pathology , Female , Humans , Joint Instability/diagnosis , Joint Instability/epidemiology , Joint Instability/pathology , Male , Primary Dysautonomias/diagnosis , Primary Dysautonomias/epidemiology , Primary Dysautonomias/pathology , Quality of Life , Surveys and Questionnaires , Young AdultABSTRACT
It has long been hypothesized that bleeding symptoms in people with hypermobility occur as a result of abnormalities in the collagen of the vessel wall or the connective tissues. The bleeding symptoms, particularly in the skin, have been attributed to the fragility of skin and blood vessels caused by "defective collagen wickerwork" of the reticular layer of the skin. Collagen, which forms the framework of vessel walls, is altered in many patients with Ehlers-Danlos syndrome (EDS) leading to weakening of the vessel wall or the supporting tissues. Another important function of subendothelial collagen is its interaction with platelets and von Willebrand factor, which results in the propagation of a platelet plug. Thus, abnormalities in subendothelial collagen may alter its interaction with platelets and VWF. More recently, hypermobile-EDS (hEDS) has been associated with mast cell disorders, a condition independently associated with bleeding symptoms. It has also been observed that patients with mild bleeding disorders have a more severe bleeding phenotype when they have co-existing joint hypermobility.
Subject(s)
Ehlers-Danlos Syndrome/classification , Ehlers-Danlos Syndrome/complications , Hemorrhage/etiology , Contusions/etiology , Ehlers-Danlos Syndrome/metabolism , Ehlers-Danlos Syndrome/pathology , HumansABSTRACT
Syncytial variant of nodular sclerosis (SV-NS) classical Hodgkin lymphoma (cHL) with its histologic features and clinical presentation is uncommon in adults and extremely rare in children. Here, we report a female teenager presenting with long-standing B symptoms, prominent soft tissue and bone involvement mimicking sarcoma and significant nodal disease who is diagnosed with advanced SV-NS cHL. Rare Reed-Sternberg-like cells displaying neutrophil and erythrocyte emperipolesis were seen on bone marrow aspiration slides. Despite initial complete response to chemotherapy and radiotherapy, the patient experienced early relapse suggestive of high-risk biology. This variant may constitute a unique entity.
Subject(s)
Hodgkin Disease/pathology , Adolescent , Bone Marrow Examination , Emperipolesis , Erythrocytes/pathology , Female , Humans , Neutrophils/pathology , RecurrenceSubject(s)
COVID-19 Drug Treatment , COVID-19 , Infections , Thrombotic Microangiopathies , Antibodies, Monoclonal, Humanized , COVID-19/complications , Child , Complement Inactivating Agents/therapeutic use , Humans , RNA, Viral , SARS-CoV-2 , Systemic Inflammatory Response Syndrome , Thrombotic Microangiopathies/diagnosis , Thrombotic Microangiopathies/drug therapy , Thrombotic Microangiopathies/etiologyABSTRACT
Neonates form a unique cohort with distinct features associated with the hemostatic system compared with older children and adults. The development of the human hemostatic system begins around 10 weeks in utero and continues to evolve during childhood. This dynamic period termed developmental hemostasis should be taken into consideration when diagnosing a neonate with disorders of bleeding or thrombosis.
Subject(s)
Hemorrhage , Hemostatic Disorders , Infant, Newborn, Diseases , Thrombosis , Adult , Female , Hemorrhage/blood , Hemorrhage/diagnosis , Hemorrhage/etiology , Hemorrhage/therapy , Hemostatic Disorders/blood , Hemostatic Disorders/complications , Hemostatic Disorders/diagnosis , Hemostatic Disorders/therapy , Humans , Infant, Newborn , Infant, Newborn, Diseases/blood , Infant, Newborn, Diseases/diagnosis , Infant, Newborn, Diseases/therapy , Male , Thrombosis/blood , Thrombosis/diagnosis , Thrombosis/etiology , Thrombosis/therapySubject(s)
Central Venous Catheters , Device Removal , Equipment Failure , Hemophilia A/therapy , Mechanical Phenomena , Child , Child, Preschool , Female , Humans , MaleABSTRACT
Thrombocytopenia in ill children is common; accurately diagnosing the underlying etiology is challenging and essential for appropriate management. Triggers for accelerated consumption of platelets are numerous; common downstream mechanisms of clearance include platelet trapping in microvascular thrombi, phagocytosis, and platelet activation. Thrombocytopenia with microangiopathic hemolytic anemia (MAHA) is frequently due to disseminated intravascular coagulation. Thrombotic microangiopathy (TMA) is a subgroup of MAHA. Specific TMA syndromes include thrombotic thrombocytopenic purpura, complement-mediated TMA (CM-TMA), and Shiga toxin-mediated hemolytic uremic syndrome. Isolated thrombocytopenia is characteristic of immune thrombocytopenia; however, concomitant cytopenias are frequent in critically ill patients, making the diagnosis difficult. Immune thrombocytopenia with large vessel thrombosis is a feature of heparin-induced thrombocytopenia and antiphospholipid antibody syndrome. In addition, thrombocytopenia is common with macrophage activation, which is characteristic of hemophagocytic lymphohistiocytosis. While thrombocytopenia in ill patients can be driven by hypoproliferative processes such as myelosuppression and/or bone marrow failure, this review will focus on consumptive thrombocytopenia due to immune and nonimmune causes.
Subject(s)
Anemia, Hemolytic , Hemolytic-Uremic Syndrome , Purpura, Thrombocytopenic, Idiopathic , Purpura, Thrombotic Thrombocytopenic , Thrombosis , Thrombotic Microangiopathies , Child , Humans , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/therapy , Purpura, Thrombotic Thrombocytopenic/diagnosis , Hemolytic-Uremic Syndrome/diagnosis , Thrombotic Microangiopathies/diagnosis , Anemia, Hemolytic/diagnosis , Thrombosis/complicationsSubject(s)
Leukemia, Myeloid, Acute/pathology , Neoplasm Regression, Spontaneous , Skin Neoplasms/pathology , Female , Histone-Lysine N-Methyltransferase/genetics , Humans , Infant , Leukemia, Myeloid, Acute/congenital , Leukemia, Myeloid, Acute/genetics , Myeloid-Lymphoid Leukemia Protein/genetics , Skin Neoplasms/genetics , Translocation, Genetic/geneticsABSTRACT
PURPOSE OF REVIEW: The approach to treating patients with hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) has shifted in recent years with the aim to limit exposure to genotoxic agents, such as etoposide, yet dampen hyperinflammation by targeting the activity of specific HLH/MAS-associated cytokines. In this review, we discuss recent efforts to reduce the dose of etoposide and/or incorporate cytokine-targeted therapies for the treatment of HLH/MAS. RECENT FINDINGS: There is emerging evidence that reduced-dose etoposide and/or cytokine-targeted therapies, including agents that neutralize or inhibit signaling induced by interferon gamma, interleukin (IL)-1, IL-18, and IL-6, can effectively ameliorate the clinical and laboratory manifestations of HLH/MAS and improve overall outcomes. SUMMARY: The application of novel regimens containing lower doses of etoposide and/or cytokine-directed agents to treat HLH/MAS holds potential to dampen inflammation while minimizing therapy-associated toxicities. Nevertheless, further research is needed to better understand, which patients represent the most appropriate candidates to receive cytokine-targeted therapies, elucidate the optimal timing and dose of these therapies, and decipher whether they should be administered alone or in combination with conventional HLH-directed therapies, such as dexamethasone and standard-dose or reduced-dose etoposide.
Subject(s)
Lymphohistiocytosis, Hemophagocytic , Macrophage Activation Syndrome , Humans , Macrophage Activation Syndrome/drug therapy , Lymphohistiocytosis, Hemophagocytic/drug therapy , Etoposide/therapeutic use , Cytokines , Interferon-gamma , Interleukin-1ABSTRACT
A 15-year-old-boy with Noonan syndrome and status post orthoptic heart transplant developed mixed mitral valve disease and underwent mechanical mitral valve replacement 6 months before presentation with acute respiratory distress. He developed massive pulmonary hemorrhage that required veno-venous extracorporeal membrane oxygenation (ECMO) support. He had a prolonged anticoagulation free ECMO course of 4 weeks, with ongoing recurrent pulmonary hemorrhage and underwent several rounds of coil embolization of aortopulmonary collaterals. ECMO course was complicated by significant nasopharyngeal bleeding that required embolization of the sphenopalatine artery. Shortly after decannulation, he developed massive gastrointestinal and peritoneal hemorrhage that was treated by embolization of the left gastric artery and a branch of the internal iliac artery. His bleeding was attributed to neo-angiogenesis. Initial treatment with propranolol was unsuccessful. Subsequent treatment with interferon α 2b demonstrated efficacy, but severe neutropenia required cessation of therapy. Because functional alterations of the rat sarcoma virus-mitogen activated protein kinase signaling pathway and protein tyrosine phosphatase nonreceptor type (PTPN11) mutations in Noonan syndrome are known to be associated with neo-angiogenesis, we used the mitogen-activated protein kinase inhibitor selumetinib as a gene-targeted therapy with the hope of controlling bleeding and inhibiting neo-angiogenesis. After initiation of selumetinib, bleeding stopped and allowed the patient to be discharged from the hospital on dipyridamole as antiplatelet prophylaxis for his mechanical mitral valve. He had no further bleeding episodes through 1 year after hospital discharge.
Subject(s)
Noonan Syndrome , Benzimidazoles , Dipyridamole , Gastrointestinal Hemorrhage/drug therapy , Gastrointestinal Hemorrhage/etiology , Humans , Interferon-alpha , Male , Mitogen-Activated Protein Kinases , Noonan Syndrome/complications , Noonan Syndrome/drug therapy , Propranolol , Protein Tyrosine Phosphatases , Proto-Oncogene Proteins p21(ras)ABSTRACT
The association between bleeding and joint hypermobility may not be as diagnostically obvious in patients with milder connective tissue disorders. We surveyed members of the Hemostasis and Thrombosis Research Society regarding their knowledge, evaluation, and management practices in patients with generalized hypermobility spectrum disorder/hypermobile Ehlers-Danlos syndrome (hEDS) and bleeding symptoms. The objectives of this study were to (1) evaluate hematologists' diagnosis and management practices for patients with bleeding symptoms and generalized hypermobility spectrum disorder/hEDS and (2) determine future education and research priorities regarding bleeding symptoms within this population. Evaluate hematologists' diagnosis and management practices for patients with bleeding symptoms and generalized hypermobility spectrum disorder/hEDS. Determine future education and research priorities regarding bleeding symptoms within this population. A web-based survey was sent to Hemostasis and Thrombosis Research Society physician members. Physician demographics, preferred evaluation for hEDS, management of bleeding episodes, and referral patterns were collected and descriptive statistics were performed. Only two-thirds of respondents reported evaluating for hypermobility, despite all respondents being aware of the association with bleeding. There were significant variations in referral patterns for genetic counseling, diagnostic evaluation, and management of nonhematologic symptoms. There were also significant variations in reported medical homes for this patient population. Research prioritization included understanding the evolution of bleeding symptoms with age in this population as well as the development of functional tests to identify the molecular mechanism of bleeding and the development of novel hemostatic agents for this population. Results from 33 respondents show differing physician practices regarding the evaluation and management of bleeding in hypermobile patients. Many physicians suggested further research priorities to include studying the natural history of the disease and development of functional diagnostic testing as well as targeted therapeutic options in this patient population.
Subject(s)
Ehlers-Danlos Syndrome , Joint Instability , Physicians , Ehlers-Danlos Syndrome/complications , Ehlers-Danlos Syndrome/diagnosis , Hemorrhage/diagnosis , Hemorrhage/etiology , Hemorrhage/therapy , Humans , Joint Instability/diagnosis , Joint Instability/therapy , Surveys and QuestionnairesABSTRACT
: Development of neutralizing alloantibodies in hemophilia B is a less common, but clinically challenging phenomenon. Novel therapeutics for hemophilia B have recently been developed and reports of clinical experience with these agents outside of clinical trials are needed. We report development of an inhibitor in a child with severe hemophilia B, and subsequent immune tolerance induction using an extended desensitization protocol with the addition of immunosuppression. This case highlights successful management of a rare complication in a rare bleeding disorder and the need for additional investigation into this infrequent and clinically challenging occurrence.
Subject(s)
Hemophilia B/immunology , Isoantibodies/biosynthesis , Child , Clinical Protocols , Factor IX/immunology , Humans , Immune Tolerance , Immunosuppression Therapy/methodsSubject(s)
4-Hydroxycoumarins/adverse effects , Anticoagulants/adverse effects , Blood Coagulation Disorders/chemically induced , Marijuana Use/adverse effects , Synthetic Drugs/adverse effects , Adult , Blood Coagulation Disorders/diagnosis , Blood Coagulation Disorders/therapy , Humans , Illinois , MaleABSTRACT
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a treatment modality for many oncologic as well as non-oncologic disorders. Although the side effects of different chemotherapy regimens have been well studied by several oncology consortiums, limited data is available regarding the late adverse effects of HSCT. Furthermore, pediatric-focused post-HSCT follow-up guidelines for primary care pediatricians do not exist. OBJECTIVE: To provide a summary of the most common late adverse effects of HSCT and give the primary care pediatrician guidance and evidence-based information for the screening and management of this patient population. DESIGN: The literature was searched using PubMed using keywords, including pediatric bone marrow transplant, hematopoietic stem cell transplant guidelines, pediatric bone marrow transplant guidelines, and pediatric bone marrow transplant immunizations. The most relevant articles out of the hundreds of results were reviewed. RESULTS: Based on 9 review articles from the Pediatric Clinics of North America and 3 articles from the Biology of Blood and Marrow Transplant Journal as well as their original references, a summary of the most common late adverse effects after HSCT was constructed. Pediatric HSCT patients have a high incidence of late adverse effects, with 93% of survivors having at least 1 late adverse effect after 7 years of follow-up. CONCLUSION: Late adverse effects after pediatric HSCT are common and require close screening and monitoring, which can be done by the primary care provider along with the oncologist.