ABSTRACT
BACKGROUND: Immune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune-related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity. PROCEDURE: We assessed family history in two ways: via patient report for ITP and ES and by population-based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB. RESULTS: Chart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19-2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63-1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy. CONCLUSIONS: The findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.
Subject(s)
Anemia, Hemolytic, Autoimmune , Autoimmunity , Purpura, Thrombocytopenic, Idiopathic , Thrombocytopenia , Humans , Anemia, Hemolytic, Autoimmune/immunology , Anemia, Hemolytic, Autoimmune/epidemiology , Anemia, Hemolytic, Autoimmune/genetics , Female , Male , Purpura, Thrombocytopenic, Idiopathic/immunology , Purpura, Thrombocytopenic, Idiopathic/genetics , Purpura, Thrombocytopenic, Idiopathic/epidemiology , Child , Child, Preschool , Thrombocytopenia/immunology , Thrombocytopenia/genetics , Adolescent , Infant , Adult , Young Adult , Risk Factors , Middle AgedABSTRACT
Polycythemia vera (PV) is a clonal disorder arising from the acquired somatic mutations of the JAK2 gene, including JAK2V617F or several others in exon 12. A 38-year-old female had a stroke at age 32 and found to have elevated hemoglobin, normal leukocytes, normal platelets, and tested negative for JAK2V617F and exon 12 mutations. Next generation sequencing revealed a novel mutation: JAK2R715T in the pseudokinase domain (JH2) at 47.5%. Its presence in her nail DNA confirmed a germline origin. Her mother and her son similarly had erythrocytosis and a JAK2R715T mutation. Computer modeling indicated gain-of-function JAK2 activity. The propositus and her mother had polyclonal myelopoiesis, ruling out another somatic mutation-derived clonal hematopoiesis. Some erythroid progenitors of all three generations grew without erythropoietin, a hallmark of PV. The in vitro reporter assay confirmed increased activity of the JAK2R715T kinase. Similar to PV, the JAK2R715T native cells have increased STAT5 phosphorylation, augmented transcripts of prothrombotic and inflammatory genes, and decreased KLF2 transcripts. The propositus was not controlled by hydroxyurea, and JAK2 inhibitors were not tolerated; however, Ropeginterferon-alfa-2b (Ropeg-IFN-α) induced a remission. Ropeg-IFN-α treatment also reduced JAK2 activity in the propositus, her mother and JAK2V617F PV subjects. We report dominantly inherited erythrocytosis secondary to a novel germline JAK2R715T gain-of-function mutation with many but not all comparable molecular features to JAK2V617F PV. We also document a previously unreported inhibitory mechanism of JAK2 signaling by Ropeg-IFN-α.
Subject(s)
Germ-Line Mutation , Janus Kinase 2 , Polycythemia , Adult , Female , Humans , Gain of Function Mutation , Interferon-alpha/therapeutic use , Janus Kinase 2/genetics , Pedigree , Polycythemia/genetics , Polycythemia/drug therapy , Polycythemia Vera/genetics , Polycythemia Vera/drug therapyABSTRACT
A transfusion-requiring "late anemia" can complicate the management of neonates convalescing from hemolytic disease of the fetus and newborn (HDFN). This anemia can occur in any neonate after HDFN but is particularly prominent in those who received intrauterine transfusions and/or double-volume exchange transfusions. Various reports describe this condition as occurring based on ongoing hemolysis, either due to passive transfer of alloantibody through breast milk or persistence of antibody not removed by exchange transfusion. However, other reports describe this condition as the result of inadequate erythrocyte production. Both hypotheses might have merit, because perhaps; (1) some cases are primarily due to continued hemolysis, (2) others are primarily hypoproductive, and (3) yet others result from a mixture of these two mechanisms. We propose prospective collaborative studies that will resolve this issue by serially quantifying end-tidal carbon monoxide. Doing this will better inform the assessment and treatment of neonates recovering from HDFN.
Subject(s)
Erythroblastosis, Fetal , Humans , Infant, Newborn , Erythroblastosis, Fetal/therapy , Female , Blood Transfusion, Intrauterine , Pregnancy , Hemolysis , Anemia, Neonatal/therapy , Exchange Transfusion, Whole Blood , Erythrocytes , ErythropoiesisABSTRACT
BACKGROUND: Patients with partial DiGeorge syndrome (pDGS) can present with immune dysregulation, the most common being autoimmune cytopenia (AIC). There is a lack of consensus on the approach to type, combination, and timing of therapies for AIC in pDGS. Recognition of immune dysregulation early in pDGS clinical course may help individualize treatment and prevent adverse outcomes from chronic immune dysregulation. OBJECTIVES: Objectives of this study were to characterize the natural history, immune phenotype, and biomarkers in pDGS with AIC. METHODS: Data on clinical presentation, disease severity, immunological phenotype, treatment selection, and response for patients with pDGS with AIC were collected via retrospective chart review. Flow cytometric analysis was done to assess T and B cell subsets, including biomarkers of immune dysregulation. RESULTS: Twenty-nine patients with the diagnosis of pDGS and AIC were identified from 5 international institutions. Nineteen (62%) patients developed Evan's syndrome (ES) during their clinical course and twenty (69%) had antibody deficiency syndrome. These patients demonstrated expansion in T follicular helper cells, CD19hiCD21lo B cells, and double negative cells and reduction in CD4 naïve T cells and regulatory T cells. First-line treatment for 17/29 (59%) included corticosteroids and/or high-dose immunoglobulin replacement therapy. Other overlapping therapies included eltrombopag, rituximab, and T cell immunomodulators. CONCLUSIONS: AIC in pDGS is often refractory to conventional AIC treatment paradigms. Biomarkers may have utility for correlation with disease state and potentially even response to therapy. Immunomodulating therapies could be initiated early based on early immune phenotyping and biomarkers before the disease develops or significantly worsens.
Subject(s)
Cytopenia , DiGeorge Syndrome , Humans , DiGeorge Syndrome/diagnosis , DiGeorge Syndrome/therapy , Retrospective Studies , Antigens, CD19 , Disease ProgressionABSTRACT
Severe congenital neutropenia (SCN) is a rare disorder, often due to pathogenic variants in genes such as ELANE, HAX1, and SBDS. SRP54 pathogenic variants are associated with SCN and Shwachman-Diamond-like syndrome. Thirty-eight patients with SRP54-related SCN are reported in the literature. We present an infant with SCN, without classic Shwachman-Diamond syndrome features, who presented with recurrent bacterial infections and an SRP54 (c.349_351del) pathogenic variant. Despite ongoing granulocyte colony-stimulating factor therapy, this patient has no evidence of malignant transformation. Here we establish a framework for the future development of universal guidelines to care for this patient population.
Subject(s)
Neutropenia , Infant , Humans , Virulence , Mutation , Neutropenia/genetics , Neutropenia/pathology , Congenital Bone Marrow Failure Syndromes/genetics , Shwachman-Diamond Syndrome , Signal Recognition Particle/genetics , Adaptor Proteins, Signal Transducing/geneticsABSTRACT
Hereditary fructose intolerance is a rare autosomal recessive metabolic disorder characterized by liver failure, renal tubulopathy, growth retardation, and occasionally death upon exposure to fructose. We present a 2-month-old male infant diagnosed with pyloric stenosis who developed disseminated intravascular coagulopathy following pyloromyotomy. Unexplained persistent coagulopathy, acute liver failure, and metabolic dysfunction led to whole-exome sequencing, which revealed compound heterozygous variants in ALDOB (p.Arg60Ter and p.Ala150Pro), diagnostic of hereditary fructose intolerance. Shortly after initiating a fructose-free diet, our patient had resolution of his coagulopathy, hepatic, and metabolic dysfunction.
Subject(s)
Fructose Intolerance , Pyloromyotomy , Diet , Fructose Intolerance/diagnosis , Humans , Infant , Liver , MaleSubject(s)
Anemia , Thrombocytopenia , Adolescent , Anemia/diagnosis , Anemia/etiology , Female , Humans , Thrombocytopenia/complications , Thrombocytopenia/diagnosisSubject(s)
Atypical Hemolytic Uremic Syndrome , Thrombotic Microangiopathies , Adolescent , Female , HumansABSTRACT
In North America, jaundiced neonates are not usually tested for G6PD deficiency if the family is of European ancestry. However, we describe such a family where ≥35 males have had severe (Class I) G6PD deficiency. Many of the jaundiced neonates did not have this diagnosis considered, at least three of whom developed bilirubin neurotoxicity. Over seven generations 35 affected males were identified. Three developed signs of kernicterus spectrum disorder; three had exchange transfusions for hyperbilirubinemia; and nine received one or more blood transfusions during childhood.
Subject(s)
Glucosephosphate Dehydrogenase Deficiency/genetics , Glucosephosphate Dehydrogenase/genetics , Polymorphism, Single Nucleotide , Female , Humans , Hyperbilirubinemia/genetics , Infant, Newborn , Kernicterus/genetics , Male , North America , Pedigree , White People/geneticsABSTRACT
Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations. They all presented with perinatal anemia and required transfusions during infancy. Anemia spontaneously improved during infancy in three patients; two became transfusion-independent rapidly after starting interferon-α2; and two remain transfusion-dependent at last follow-up at ages 5 and 30 y.o. One of the transfusion-dependent patients underwent splenectomy at 11 y.o due to misdiagnosis and returned to medical attention at 27 y.o with severe hemolytic anemia and pulmonary hypertension. All patients developed iron overload even without transfusions; four were treated with chelation. Genetic testing allowed for more rapid and accurate diagnosis; the median age of confirmed diagnosis in our cohort was 3 y.o compared to 17.3 y.o historically. In conclusion, CDAR provides an organized research network for multidisciplinary clinical and research collaboration to conduct natural history and biologic studies in CDA.
Subject(s)
Anemia, Dyserythropoietic, Congenital/diagnosis , Anemia, Dyserythropoietic, Congenital/therapy , Adolescent , Adult , Anemia, Dyserythropoietic, Congenital/epidemiology , Anemia, Dyserythropoietic, Congenital/genetics , Blood Transfusion , Bone Marrow/pathology , Child , Child, Preschool , Female , Genetic Testing , Glycoproteins/genetics , Humans , Male , Mutation , North America/epidemiology , Nuclear Proteins/genetics , Registries , Young AdultABSTRACT
The Congenital Dyserythropoietic Anemia (CDA) Registry was established with the goal to facilitate investigations of natural history, biology, and molecular pathogenetic mechanisms of CDA. Three unrelated individuals enrolled in the registry had a syndrome characterized by CDA and severe neurodevelopmental delay. They were found to have missense mutations in VPS4A, a gene coding for an ATPase that regulates the ESCRT-III machinery in a variety of cellular processes including cell division, endosomal vesicle trafficking, and viral budding. Bone marrow studies showed binucleated erythroblasts and erythroblasts with cytoplasmic bridges indicating abnormal cytokinesis and abscission. Circulating red blood cells were found to retain transferrin receptor (CD71) in their membrane, demonstrating that VPS4A is critical for normal reticulocyte maturation. Using proband-derived induced pluripotent stem cells (iPSCs), we have successfully modeled the hematologic aspects of this syndrome in vitro, recapitulating their dyserythropoietic phenotype. Our findings demonstrate that VPS4A mutations cause cytokinesis and trafficking defects leading to a human disease with detrimental effects to erythropoiesis and neurodevelopment.
Subject(s)
ATPases Associated with Diverse Cellular Activities/genetics , Anemia, Dyserythropoietic, Congenital/genetics , Endosomal Sorting Complexes Required for Transport/genetics , Vacuolar Proton-Translocating ATPases/genetics , Adenosine Triphosphatases/metabolism , Anemia, Dyserythropoietic, Congenital/pathology , Bone Marrow/pathology , Bone Marrow Cells/metabolism , Child , Child, Preschool , Cytokinesis , Endosomes/metabolism , Erythroblasts/metabolism , Erythrocytes/cytology , Erythropoiesis , Female , Humans , Induced Pluripotent Stem Cells/cytology , Male , Neurodevelopmental Disorders/metabolism , Phenotype , Protein Transport , Reticulocytes/cytologyABSTRACT
We report a novel glucose-6-phosphate dehydrogenase (G6PD) variant (c.1375C>G) discovered in a 3-day-old Hispanic male child from Salt Lake City, UT, USA. This newborn presented with severe hyperbilirubinemia (29.8 mg/dL or 510 µmol/L) and marked hemolysis evidenced by elevated end-tidal carbon monoxide concentration (5.9 ppm, normal <1.7 ppm). Despite a very low prevalence of G6PD deficiency in Hispanic populations, we pursued testing for this condition and found he had low erythrocyte G6PD enzyme activity (2.8 U/g Hb, normal 9.9-16.6 U/g Hb) and a novel G6PD variant. His mother was heterozygous for this same variant, and she had a moderate decrease in G6PD enzyme activity (7.1 U/g Hb). On the basis of these findings, we propose this variant as a novel pathogenic mutation.
Subject(s)
Glucosephosphate Dehydrogenase Deficiency , Glucosephosphate Dehydrogenase , Hyperbilirubinemia , Female , Glucosephosphate Dehydrogenase/genetics , Glucosephosphate Dehydrogenase Deficiency/genetics , Heterozygote , Hispanic or Latino/genetics , Humans , Hyperbilirubinemia/genetics , Infant, Newborn , MaleABSTRACT
Dizygotic twin males, born at 34 weeks gestation, had prolonged jaundice, microcytic, hypochromic anemia, FABarts hemoglobin, elevated end-tidal CO, and blood films consistent with hereditary pyropoikilocytosis. DNA sequencing revealed both had a heterozygous alpha spectrin (SPTA1) mutation (c.460_462dup) inherited from their asymptomatic mother, plus a 3-base pair duplication in alpha globin (HBA2) (c.364_366dupGTG) inherited from their asymptomatic father.
Subject(s)
Anemia, Hemolytic/complications , Anemia, Hypochromic/complications , Elliptocytosis, Hereditary/complications , Jaundice/complications , Anemia, Hemolytic/blood , Anemia, Hemolytic/genetics , Anemia, Hypochromic/blood , Anemia, Hypochromic/genetics , Elliptocytosis, Hereditary/blood , Elliptocytosis, Hereditary/genetics , Humans , Infant, Newborn , Jaundice/blood , Jaundice/genetics , Male , Point Mutation , Spectrin/genetics , Twins, Dizygotic/geneticsABSTRACT
Infantile pyknocytosis is a rare, self-limited, hemolytic condition of unknown pathogenesis. It is diagnosed when a neonate with Coombs-negative hemolytic anemia has abundant pyknocytes and a characteristic clinical course after other hemolytic disorders has been excluded. Previous reports suggest that transfusions might be avoidable in this condition by administering recombinant erythropoietin. We cared for a patient with this disorder where we employed novel diagnostics and therapeutics. Despite these, and a good outcome free of transfusions, we continue to consider the condition to be idiopathic.
ABSTRACT
The congenital dyserythropoietic anemias are a heterogeneous group of disorders characterized by anemia and ineffective erythropoiesis. Congenital dyserythropoietic anemia type I (CDA1) can present in utero with hydrops fetalis, but more often it presents in childhood or adulthood with moderate macrocytic anemia, jaundice, and progressive iron-overload. CDA1 is inherited in an autosomal recessive manner, with biallelic pathogenic variants in CDAN1 or C15orf41. This case report documents a severe fetal presentation of CDA1 where we identified two novel compound heterozygous mutations in CDAN1 and describes the associated pathologic findings and levels of iron-regulatory proteins hepcidin, erythroferrone, and GDF15.
Subject(s)
Anemia, Dyserythropoietic, Congenital/diagnosis , Anemia, Dyserythropoietic, Congenital/genetics , Genetic Association Studies , Genetic Predisposition to Disease , Glycoproteins/genetics , Heterozygote , Mutation , Adult , Anemia, Dyserythropoietic, Congenital/blood , Biomarkers , Biopsy , Bone Marrow , Female , Humans , Infant, Newborn , Male , Nuclear ProteinsABSTRACT
Proper hematopoietic cell fate decisions require co-ordinated functions of transcription factors, their associated co-regulators, and histone-modifying enzymes. Growth factor independence 1 (GFI1) is a zinc finger transcriptional repressor and master regulator of normal and malignant hematopoiesis. While several GFI1-interacting proteins have been described, how GFI1 leverages these relationships to carry out transcriptional repression remains unclear. Here, we describe a functional axis involving GFI1, SMYD2, and LSD1 that is a critical contributor to GFI1-mediated transcriptional repression. SMYD2 methylates lysine-8 (K8) within a -(8)KSKK(11)- motif embedded in the GFI1 SNAG domain. Methylation-defective GFI1 SNAG domain lacks repressor function due to failure of LSD1 recruitment and persistence of promoter H3K4 di-methyl marks. Methylation-defective GFI1 also fails to complement GFI1 depletion phenotypes in developing zebrafish and lacks pro-growth and survival functions in lymphoid leukemia cells. Our data show a discrete methylation event in the GFI1 SNAG domain that facilitates recruitment of LSD1 to enable transcriptional repression and co-ordinate control of hematopoietic cell fate in both normal and malignant settings.
Subject(s)
DNA-Binding Proteins/physiology , Histone Demethylases/metabolism , Transcription Factors/physiology , Transcription, Genetic/physiology , Amino Acid Sequence , Animals , Cell Line , Cell Lineage , DNA Methylation , DNA-Binding Proteins/chemistry , Humans , Sequence Homology, Amino Acid , Transcription Factors/chemistry , ZebrafishABSTRACT
Burkitt lymphoma (BL) and B-lymphoblastic lymphoma are subtypes of pediatric non-Hodgkin lymphoma with different presenting features, treatment, and outcomes. This case report documents a 5-year-old female who presented with B-cell lymphoma with lymphoblastic morphology, terminal deoxynucleotidyl transferase expression, MYC rearrangement, and features overlapping with BL. Genomic microarray analysis identified a gain on the long arm of chromosome 1 without other definitive changes. She was treated according to a BL protocol and remains in remission 16-months after initial diagnosis.