ABSTRACT
Mahvash disease is an exceedingly rare genetic disorder of glucagon signaling characterized by hyperglucagonemia, hyperaminoacidemia, and pancreatic α-cell hyperplasia. Although there is no known definitive treatment, octreotide has been used to decrease systemic glucagon levels. We describe a woman who presented to our medical center after three episodes of small-volume hematemesis. She was found to have hyperglucagonemia and pancreatic hypertrophy with genetically confirmed Mahvash disease and also had evidence of portal hypertension (recurrent portosystemic encephalopathy and variceal hemorrhage) in the absence of cirrhosis. These findings established a diagnosis of portosinusoidal vascular disease, a presinusoidal type of portal hypertension previously known as noncirrhotic portal hypertension. Liver transplantation was followed by normalization of serum glucagon and ammonia levels, reversal of pancreatic hypertrophy, and resolution of recurrent encephalopathy and bleeding varices.
Subject(s)
Genetic Diseases, Inborn , Glucagon , Hypertension, Portal , Liver Transplantation , Female , Humans , Esophageal and Gastric Varices/etiology , Esophageal and Gastric Varices/surgery , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/surgery , Glucagon/blood , Glucagon/genetics , Hypertension, Portal/blood , Hypertension, Portal/etiology , Hypertension, Portal/genetics , Hypertension, Portal/surgery , Hypertrophy/genetics , Liver Cirrhosis , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/surgery , Pancreatic Diseases/genetics , Pancreatic Diseases/pathology , Pancreatic Diseases/surgery , Glucagon-Secreting Cells/pathologyABSTRACT
BACKGROUND: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients. OBJECTIVES: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI. METHODS: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination. RESULTS: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response. CONCLUSIONS: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.
Subject(s)
2019-nCoV Vaccine mRNA-1273 , Antibodies, Neutralizing , COVID-19 , Genetic Diseases, Inborn , Immunologic Deficiency Syndromes , 2019-nCoV Vaccine mRNA-1273/blood , 2019-nCoV Vaccine mRNA-1273/immunology , 2019-nCoV Vaccine mRNA-1273/therapeutic use , Adult , Agammaglobulinemia/genetics , Agammaglobulinemia/immunology , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/genetics , Antibodies, Viral/immunology , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Common Variable Immunodeficiency/genetics , Common Variable Immunodeficiency/immunology , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Humans , Immunologic Deficiency Syndromes/blood , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Primary Immunodeficiency Diseases/genetics , Primary Immunodeficiency Diseases/immunology , Prospective Studies , SARS-CoV-2 , Spike Glycoprotein, CoronavirusABSTRACT
BACKGROUND: Urea cycle disorders (UCDs) are among the most common inborn errors of liver metabolism. As therapies for hyperammonemia associated with urea cycle dysfunction have improved, chronic complications, such as liver disease, have become increasingly apparent in individuals with UCDs. Liver disease in UCDs may be associated with hepatic inflammation, hepatic fibrosis, portal hypertension, liver cancer and even liver failure. However, except for monitoring serum aminotransferases, there are no clear guidelines for screening and/or monitoring individuals with UCDs for liver disease. Thus, we systematically evaluated the potential utility of several non-invasive biomarkers for liver fibrosis in UCDs. METHODS: We evaluated grey-scale ultrasonography, liver stiffness obtained from shear wave elastography (SWE), and various serum biomarkers for hepatic fibrosis and necroinflammation, in a cohort of 28 children and adults with various UCDs. RESULTS: Overall, we demonstrate a high burden of liver disease in our participants with 46% of participants having abnormal grey-scale ultrasound pattern of the liver parenchyma, and 52% of individuals having increased liver stiffness. The analysis of serum biomarkers revealed that 32% of participants had elevated FibroTest™ score, a marker for hepatic fibrosis, and 25% of participants had increased ActiTest™ score, a marker for necroinflammation. Interestingly, liver stiffness did not correlate with ultrasound appearance or FibroTest™. CONCLUSION: Overall, our results demonstrate the high overall burden of liver disease in UCDs and highlights the need for further studies exploring new tools for identifying and monitoring individuals with UCDs who are at risk for this complication. TRIAL REGISTRATION: This study has been registered in ClinicalTrials.gov (NCT03721367).
Subject(s)
Argininosuccinate Lyase/blood , Genetic Diseases, Inborn/blood , Liver Cirrhosis/blood , Liver Diseases/blood , Urea Cycle Disorders, Inborn/blood , Adolescent , Adult , Biomarkers/blood , Child , Child, Preschool , Elasticity Imaging Techniques , Female , Genetic Diseases, Inborn/diagnostic imaging , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/pathology , Humans , Hyperammonemia/blood , Hyperammonemia/genetics , Hyperammonemia/metabolism , Hyperammonemia/pathology , Liver/diagnostic imaging , Liver/pathology , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/genetics , Liver Cirrhosis/pathology , Liver Diseases/genetics , Liver Diseases/metabolism , Liver Diseases/pathology , Male , Metabolism, Inborn Errors/genetics , Middle Aged , Ultrasonography , Urea Cycle Disorders, Inborn/genetics , Urea Cycle Disorders, Inborn/metabolism , Urea Cycle Disorders, Inborn/pathology , Young AdultABSTRACT
BACKGROUND: Hereditary alpha-tryptasemia (HαT) is characterized by elevated basal serum tryptase due to increased copies of the TPSAB1 gene. Individuals with HαT frequently present with multisystem complaints, including anaphylaxis and seemingly functional gastrointestinal (GI) symptoms. OBJECTIVE: We sought to determine the prevalence of HαT in an irritable bowel syndrome cohort and associated immunologic characteristics that may distinguish patients with HαT from patients without HαT. METHODS: Tryptase genotyping by droplet digital PCR, flow cytometry, cytometry by time-of-flight, immunohistochemistry, and other molecular biology techniques was used. RESULTS: HαT prevalence in a large irritable bowel syndrome cohort was 5% (N = 8/158). Immunophenotyping of HαT PBMCs (N ≥ 27) revealed increased total and class-switched memory B cells. In the small bowel, expansion of tissue mast cells with expression of CD203c, HLA-DR, and FcεRI, higher intestinal epithelial cell pyroptosis, and increased class-switched memory B cells were observed. IgG profiles in sera from individuals with HαT (N = 21) significantly differed from those in individuals with quiescent Crohn disease (N = 20) and non-HαT controls (N = 19), with increased antibodies directed against GI-associated proteins identified in individuals with HαT. CONCLUSIONS: Increased mast cell number and intestinal epithelial cell pyroptosis in the small intestine, and class-switched memory B cells in both the gut and peripheral blood associated with IgG reactive to GI-related proteins, distinguish HαT from functional GI disease. These innate and adaptive immunologic findings identified in association with HαT are suggestive of subclinical intestinal inflammation in symptomatic individuals.
Subject(s)
Gastrointestinal Diseases , Genetic Diseases, Inborn , Immunoglobulin G/immunology , Intestine, Small/immunology , Mastocytosis , Tryptases , Adult , Epithelial Cells/immunology , Female , Gastrointestinal Diseases/blood , Gastrointestinal Diseases/genetics , Gastrointestinal Diseases/immunology , Gastrointestinal Diseases/pathology , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/immunology , Genetic Diseases, Inborn/pathology , Genotype , Humans , Immunoglobulin G/blood , Intestine, Small/cytology , Intestine, Small/pathology , Male , Mast Cells/immunology , Mastocytosis/blood , Mastocytosis/genetics , Mastocytosis/immunology , Mastocytosis/pathology , Middle Aged , Pyroptosis , Tryptases/blood , Tryptases/genetics , Young AdultABSTRACT
Objective: Heterogeneous clinical characteristics are observed in acquired isolated adrenocorticotropic hormone (ACTH) deficiency (IAD); however, its classification remains to be established because of its largely unknown pathophysiology. In IAD, anti-pituitary antibodies have been detected in some patients, although their significance remains unclear. Therefore, this study aimed to classify patients with IAD and to clarify the significance of anti-pituitary antibodies. Design and Methods: We analyzed 46 consecutive patients with IAD. Serum anti-pituitary antibodies were analyzed via immunofluorescence staining using a mouse pituitary tissue. Principal component and cluster analyses were performed to classify IAD patients based on clinical characteristics and autoantibodies. Results: Immunofluorescence analysis using the sera revealed that 58% of patients showed anti-corticotroph antibodies and 6% of patients showed anti-follicular stellate cell (FSC) antibodies. Principal component analysis demonstrated that three parameters could explain 70% of the patients. Hierarchical cluster analysis showed three clusters: Groups A and B comprised patients who were positive for anti-corticotroph antibodies, and plasma ACTH levels were extremely low. Groups A and B comprised middle-aged or elderly men and middle-aged women, respectively. Group C comprised patients who were positive for the anti-FSC antibody and elderly men; plasma ACTH levels were relatively high. Conclusions: Patients with IAD were classified into three groups based on clinical characteristics and autoantibodies. The presence of anti-corticotroph antibody suggested severe injury to corticotrophs. This new classification clearly demonstrated the heterogeneity in the pathogenesis of IAD.
Subject(s)
Adrenal Insufficiency/blood , Adrenal Insufficiency/epidemiology , Autoantibodies/blood , Adrenal Insufficiency/diagnosis , Adrenocorticotropic Hormone/blood , Adrenocorticotropic Hormone/deficiency , Adult , Aged , Animals , Case-Control Studies , Cluster Analysis , Endocrine System Diseases/blood , Endocrine System Diseases/diagnosis , Endocrine System Diseases/epidemiology , Female , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/epidemiology , Humans , Hypoglycemia/blood , Hypoglycemia/diagnosis , Hypoglycemia/epidemiology , Japan/epidemiology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Principal Component Analysis , Retrospective StudiesABSTRACT
The great advances in the knowledge of inherited thrombocytopenias (ITs) made since the turn of the century have significantly changed our view of these conditions. To date, ITs encompass 45 disorders with different degrees of complexity of the clinical picture and very wide variability in the prognosis. They include forms characterized by thrombocytopenia alone, forms that present with other congenital defects, and conditions that predispose to acquire additional diseases over the course of life. In this review, we recapitulate the clinical features of ITs with emphasis on the forms predisposing to additional diseases. We then discuss the key issues for a rational approach to the diagnosis of ITs in clinical practice. Finally, we aim to provide an updated and comprehensive guide to the treatment of ITs, including the management of hemostatic challenges, the treatment of severe forms, and the approach to the manifestations that add to thrombocytopenia.
Subject(s)
Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/therapy , Thrombocytopenia/diagnosis , Thrombocytopenia/therapy , Alleles , Clinical Decision-Making , Disease Management , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/etiology , Genetic Predisposition to Disease , Genotype , Germ-Line Mutation , Humans , Phenotype , Practice Guidelines as Topic , Thrombocytopenia/blood , Thrombocytopenia/etiologyABSTRACT
PURPOSE OF REVIEW: To discuss the association between the common dominantly inherited genetic trait hereditary alpha-tryptasemia (HαT) and hymenoptera venom-induced anaphylaxis (HVA). RECENT FINDINGS: Elevated BST has been correlated with more severe systemic anaphylaxis in humans in a number of settings - most notably in HVA. Clonal mast cell disease, in particular, systemic mastocytosis, is frequently associated with elevated BST, and is a major risk factor for severe HVA. However, clonal mast cell diseases are believed to be rare, whereas HVA is relatively more common. HαT affects an estimated 3-5% of Western populations and is the common cause for elevated BST in these individuals. An association between HαT and severe HVA, as well as clonal mast cell disease has recently been demonstrated wherein this trait modifies reaction severity in venom allergic individuals. A mechanism underlying this association has been proposed through the identification of naturally occurring heterotetrameric tryptases and characterization of their unique physical attributes. SUMMARY: Here we discuss the long-standing association between elevated BST and HVA severity, how HαT fits into this landscape, and review the clinical and mechanistic evidence that supports HαT as a modifier of HVA.
Subject(s)
Anaphylaxis/etiology , Arthropod Venoms/adverse effects , Genetic Diseases, Inborn/blood , Insect Bites and Stings/blood , Insect Bites and Stings/immunology , Tryptases/blood , Anaphylaxis/blood , Anaphylaxis/genetics , Animals , Genetic Diseases, Inborn/immunology , Humans , Hymenoptera/immunology , Insect Bites and Stings/genetics , Mast Cells/immunology , Mastocytosis, Systemic/blood , Mastocytosis, Systemic/genetics , Severity of Illness Index , Tryptases/geneticsSubject(s)
Erythrocyte Transfusion/adverse effects , Genetic Diseases, Inborn , Pregnancy Complications , Transfusion Reaction , Adult , Female , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/therapy , Humans , Pregnancy , Pregnancy Complications/blood , Pregnancy Complications/diagnosis , Pregnancy Complications/therapy , Rh-Hr Blood-Group System/blood , Transfusion Reaction/blood , Transfusion Reaction/diagnosis , Transfusion Reaction/therapyABSTRACT
Risk for childhood asthma is conferred by alleles within the 17q21 locus affecting ORMDL sphingolipid biosynthesis regulator 3 (ORMDL3) expression. ORMDL3 inhibits sphingolipid de novo synthesis. Although the effects of 17q21 genotypes on sphingolipid synthesis in human asthma remain unclear, both decreased sphingolipid synthesis and ORMDL3 overexpression are linked to airway hyperreactivity. To characterize the relationship of genetic asthma susceptibility with sphingolipid synthesis, we analyzed asthma-associated 17q21 genotypes (rs7216389, rs8076131, rs4065275, rs12603332, and rs8067378) in both children with asthma and those without asthma, quantified plasma and whole-blood sphingolipids, and assessed sphingolipid de novo synthesis in peripheral blood cells by measuring the incorporation of stable isotope-labeled serine (substrate) into sphinganine and sphinganine-1-phosphate. Whole-blood dihydroceramides and ceramides were decreased in subjects with the 17q21 asthma-risk alleles rs7216389 and rs8076131. Children with nonallergic asthma had lower dihydroceramides, ceramides, and sphingomyelins than did controls. Children with allergic asthma had higher dihydroceramides, ceramides, and sphingomyelins compared with children with nonallergic asthma. Additionally, de novo sphingolipid synthesis was lower in children with asthma compared with controls. These findings connect genetic 17q21 variations that are associated with asthma risk and higher ORMDL3 expression to lower sphingolipid synthesis in humans. Altered sphingolipid synthesis may therefore be a critical factor in asthma pathogenesis and may guide the development of future therapeutics.
Subject(s)
Asthma , Chromosomes, Human, Pair 17 , Genetic Diseases, Inborn , Membrane Proteins , Sphingolipids/biosynthesis , Adolescent , Asthma/blood , Asthma/genetics , Asthma/pathology , Case-Control Studies , Child , Child, Preschool , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 17/metabolism , Female , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/pathology , Humans , Male , Membrane Proteins/blood , Membrane Proteins/genetics , Risk FactorsABSTRACT
Familial hypercholesterolaemia (FH) is caused by a major genetic defect in the low-density lipoprotein (LDL) clearance pathway. Characterised by LDL-cholesterol elevation from birth, FH confers a significant risk for premature coronary artery disease (CAD) if overlooked and untreated. With risk exposure beginning at birth, early detection and intervention is crucial for the prevention of CAD. Lowering LDL-cholesterol with lifestyle and statin therapy can reduce the risk of CAD. However, most individuals with FH will not reach guideline recommended LDL-cholesterol targets. FH has an estimated prevalence of approximately 1:250 in the community. Multiple strategies are required for screening, diagnosing and treating FH. Recent publications on FH provide new data for developing models of care, including new therapies. This review provides an overview of FH and outlines some recent advances in the care of FH for the prevention of CAD in affected families. The future care of FH in Australia should be developed within the context of the National Health Genomics Policy Framework.
Subject(s)
Coronary Artery Disease , Genetic Diseases, Inborn , Hypercholesterolemia , Models, Cardiovascular , Cholesterol, LDL/blood , Coronary Artery Disease/blood , Coronary Artery Disease/genetics , Coronary Artery Disease/therapy , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/therapy , Humans , Hypercholesterolemia/blood , Hypercholesterolemia/genetics , Hypercholesterolemia/therapy , Practice Guidelines as Topic , PrevalenceABSTRACT
PURPOSE OF REVIEW: To describe inherited and acquired genetic variants and clinical entities associated with increased basal serum tryptase (BST), distinguish these levels from those which acutely rise due to mast cell activation, and finally to characterize the association between chronically elevated basal serum tryptase and episodic mast cell activation. RECENT FINDINGS: Hereditary alpha-tryptasemia is a commonly inherited genetic cause for basally elevated serum tryptase and explains elevated BST in many individuals who do not have evidence of clonal myeloid or mast cell disease. When clonal myeloid disease is present, BST may be elevated and can be a biomarker of a number of disparate disorders of the myeloid compartment. Elevated BST is most commonly caused by hereditary alpha tryptasemia but may also be indicative of clonal myeloid disease. Clinical reports suggest that elevated BST is associated with increased risk for more severe systemic allergic reactions to a number of eliciting agents and exposures. Additional studies are needed to determine the role that inherited or acquired genetic variants associated with elevated BST and clonal or non-clonal myeloid diseases may play in these reactions.
Subject(s)
Genetic Diseases, Inborn/genetics , Mast Cells/physiology , Tryptases/blood , Genetic Diseases, Inborn/blood , Genetic Variation , HumansSubject(s)
Genetic Diseases, Inborn/immunology , Monocytes/immunology , Neutropenia/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Cell Separation , Female , Flow Cytometry , Genetic Diseases, Inborn/blood , Healthy Volunteers , Humans , Male , Middle Aged , Neutropenia/blood , Young AdultABSTRACT
Cancer immunotherapy has been used in several malignancies with clinical benefit. Despite the clinical success, immune-related adverse events are frequent and endocrinopathies can be particularly severe. We report a 55-year-old male patient with stage IV pulmonary carcinoma treated with nivolumab who presented with thyroid dysfunction after the sixth administration of the drug. One year after thyroid dysfunction, the patient complained of severe fatigue, asthenia and weight loss. Laboratory testing showed low morning cortisol with undetected adrenocorticotropic hormone; other pituitary hormones were normal and MRI showed homogeneous enhancement of the pituitary gland and no space-occupying lesions. The diagnosis of nivolumab-induced hypophysitis was made and replacement treatment with hydrocortisone was started with clinical improvement. This case demonstrates that patients under immunotherapy are at risk for a large spectrum of endocrine dysfunctions that may worsen their prognosis. Close monitoring of these patients is warranted.
Subject(s)
Adrenocorticotropic Hormone/deficiency , Antineoplastic Agents, Immunological/adverse effects , Endocrine System Diseases/etiology , Genetic Diseases, Inborn/etiology , Hypoglycemia/etiology , Hypothyroidism/chemically induced , Lung Neoplasms/drug therapy , Nivolumab/adverse effects , Adrenocorticotropic Hormone/blood , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Carcinoma , Endocrine System Diseases/blood , Endocrine System Diseases/diagnosis , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/diagnosis , Humans , Hydrocortisone/administration & dosage , Hydrocortisone/therapeutic use , Hypoglycemia/blood , Hypoglycemia/diagnosis , Hypophysitis/chemically induced , Hypophysitis/diagnostic imaging , Hypophysitis/drug therapy , Hypothyroidism/complications , Lung Neoplasms/pathology , Magnetic Resonance Imaging/methods , Male , Middle Aged , Nivolumab/therapeutic use , Treatment OutcomeSubject(s)
Cell-Free Nucleic Acids/blood , DNA, Neoplasm/blood , Genetic Diseases, Inborn/diagnosis , Noninvasive Prenatal Testing/standards , Pregnancy Complications, Neoplastic/blood , Pregnancy Complications, Neoplastic/therapy , Cell-Free Nucleic Acids/analysis , Chromosome Aberrations/embryology , Chromosome Aberrations/statistics & numerical data , Cohort Studies , DNA, Neoplasm/analysis , False Negative Reactions , False Positive Reactions , Female , Fetus/metabolism , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/epidemiology , Humans , Noninvasive Prenatal Testing/statistics & numerical data , Ploidies , Predictive Value of Tests , Pregnancy , Pregnancy Complications, Neoplastic/diagnosis , Pregnancy Complications, Neoplastic/epidemiology , Prenatal Diagnosis/methods , Prenatal Diagnosis/standards , Prenatal Diagnosis/statistics & numerical dataABSTRACT
The increased use of immune checkpoint inhibitors (ICIs) has led to the observation of a variety of immune-related adverse events (irAEs). These irAEs occur usually within the first months after ICIs onset and can involve theorically all organs. We describe two rare irAEs occurring in a 70-year-old caucasian man who was treated with nivolumab for an advanced urothelial cancer of the left kidney. He developed an isolated adrenocorticotropic hormone deficiency that was diagnosed at week 19 and a neurological complication that appeared at week 79 and initially confounded with a lumbar spinal stenosis. Diagnosis of Guillain-Barré syndrome was finally confirmed with the complete resolution of symptoms after 5 days of intravenous immunoglobulin and corticosteroids. We highlight the importance of quickly recognising these potential life-threatening irAEs such as cortisol insufficiency and neurologic adverse events whose initially presentation could be non-specific.
Subject(s)
Adrenocorticotropic Hormone/deficiency , Antineoplastic Agents, Immunological/adverse effects , Endocrine System Diseases/diagnosis , Genetic Diseases, Inborn/diagnosis , Guillain-Barre Syndrome/diagnosis , Hypoglycemia/diagnosis , Nivolumab/adverse effects , Adrenocorticotropic Hormone/blood , Aged , Diagnosis, Differential , Endocrine System Diseases/blood , Endocrine System Diseases/chemically induced , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/chemically induced , Guillain-Barre Syndrome/chemically induced , Guillain-Barre Syndrome/complications , Guillain-Barre Syndrome/physiopathology , Humans , Hypoglycemia/blood , Hypoglycemia/chemically induced , Male , Urethral Neoplasms/drug therapy , Urethral Neoplasms/surgeryABSTRACT
Growth factor-independent 1B (GFI1B) variants are a rare cause of thrombocytopenia. We report on a male child who was initially diagnosed with immune thrombocytopenia. However, subtle clinical signs led to suspicion of a genetic cause of thrombocytopenia. Gene panel sequencing revealed a rare variant in GFI1B (C168F), which has recently been reported in several families with thrombocytopenia. We demonstrate that this variant significantly alters platelet parameters in population studies. This case highlights how diagnoses of exclusion, such as immune thrombocytopenia, can be confounded by genetic variation. Our understanding of blood disorders will undoubtedly evolve from an increased knowledge of human genetic variation.
Subject(s)
Blood Platelets/metabolism , Genetic Diseases, Inborn , Mutation, Missense , Proto-Oncogene Proteins/genetics , Purpura, Thrombocytopenic, Idiopathic , Repressor Proteins/genetics , Child, Preschool , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Humans , Male , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/geneticsABSTRACT
Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi- or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi-allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.
Subject(s)
Genetic Diseases, Inborn , Genetic Predisposition to Disease , Germ-Line Mutation , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Neoplasm Proteins , Thrombocytopenia , Allografts , Genes, Dominant , Genetic Counseling , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/therapy , Hematologic Neoplasms/blood , Hematologic Neoplasms/diagnosis , Hematologic Neoplasms/genetics , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Mutation , Myelodysplastic Syndromes/blood , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , Thrombocytopenia/blood , Thrombocytopenia/diagnosis , Thrombocytopenia/genetics , Thrombocytopenia/therapyABSTRACT
BACKGROUND: Flow cytometric platelet activation has emerged as an alternative diagnostic test for inherited platelet disorders. It is, however, labor intensive and few studies have directly compared the performance of flow cytometric platelet activation (PACT) to light transmission aggregometry (LTA). The aims of this study were 1/ to develop a simplified flow cytometric platelet activation assay using microtiter plates and 2/ to correlate the outcome to gold standard method LTA, and to clinical bleeding assessment tool scores (BAT score). METHODS: The PACT method was developed in microtiter plates using adenosine diphosphate (ADP), collagen-derived peptide (CRP-XL) and thrombin receptor activator for peptide 6 (TRAP-6) as agonists. Antibodies against GPIIb-IIIa activation epitope (PAC1), P-selectin (CD62P) and lysosome-associated membrane glycoprotein 3 (LAMP3; CD63) were used as platelet activation markers. Sixty-six patients referred to the coagulation unit for bleeding symptoms were included in this single-center observational study. Platelet activation was determined by PACT and LTA. The results of both methods were correlated to BAT score. RESULTS: A two-by-two analysis using Cohen's kappa analysis gave moderate agreement between LTA and PACT (82%, kappa = 0.57), when PACT analysis with ADP and CRP-XL was compared to LTA. Using LTA as reference method, positive predictive value was 70% and negative predictive value was 87%. A substantial number of patients had high BAT score and normal LTA and PACT results. Patients with abnormal LTA or PACT results had higher BAT score than patients with normal results, but the difference was not significant. CONCLUSIONS: The performance in microtiter plates simplified the PACT method and enabled analysis of more patients at the same time. Our results indicate that with modification of the current PACT assay, a higher negative predictive value can be obtained. Furthermore, with comparable result to LTA the PACT could be used as a screening assay for inherited platelet disorders.
Subject(s)
Blood Platelet Disorders , Blood Platelets/metabolism , Flow Cytometry/methods , Genetic Diseases, Inborn , Platelet Activation , Blood Platelet Disorders/blood , Blood Platelet Disorders/diagnosis , Female , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/diagnosis , Humans , Male , Middle Aged , Platelet Function Tests/methodsABSTRACT
AIM: The aim of the present study was to characterize the molecular basis of complement factor I deficiency in Tunisian atypical haemolytic and uremic syndrome patients with low factor I levels. METHODS: Six adults and seven children were enrolled in this study. Complement factor I levels were assessed by a homemade sandwich ELISA and ranged between 12.5% and 60%. Genomic DNA was amplified by way of a polymerase chain reaction using intronic primers flanking the 13 coding exons. Sequencing of amplified products was carried out by the dye terminator sequencing method. Molecular study was performed on parental samples for three dead paediatric patients. The control group consisted of 100 healthy Tunisian donors. RESULTS: We identified a total of 13 substitutions and one insertion: seven in introns, four in exons and three in UTR. The new mutations were c.-132G > C, c.71 + 181 T > A in 5'UTR and intron 1, respectively. Three intronic polymorphisms were predicted to have impact on splicing events: c.482 + 6C > T, c.884-42_884-41insTTAAA (rs34422850) and c.1429 + 33 A > G (rs9998151). They were three missense mutations leading to a p.Ile 357Met, p.Ile416Leu and p.GLu548Gln. p.Ile 357Met was found in two patients and one relative. Half of the patients had associated mutation and/or polymorphisms. CONCLUSION: This is the first genetic study in Tunisian and Maghrebin atypical haemolytic and uraemic syndrome patients. The high occurrence of Ile357Met mutation may reflect a founding effect. Functional impact of the two new mutations c.-132G > C and c.71 + 181A > T have to be studied. Association of simultaneous genetic abnormalities may explain the variability of atypical haemolytic and uraemic syndrome, penetrance and disease phenotype.
Subject(s)
Atypical Hemolytic Uremic Syndrome , Complement C3/deficiency , Complement Factor I , Genetic Diseases, Inborn , Adult , Atypical Hemolytic Uremic Syndrome/diagnosis , Atypical Hemolytic Uremic Syndrome/epidemiology , Atypical Hemolytic Uremic Syndrome/genetics , Child , Child, Preschool , Cohort Studies , Complement C3/genetics , Complement Factor I/analysis , Complement Factor I/genetics , Female , Genetic Diseases, Inborn/blood , Genetic Diseases, Inborn/epidemiology , Genetic Diseases, Inborn/genetics , Hereditary Complement Deficiency Diseases , Humans , Infant , Male , Mutation , Polymorphism, Genetic , Tunisia/epidemiologyABSTRACT
INTRODUCTION: Isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) is a rare cause of adrenal insufficiency and T-box pituitary restricted transcription factor (TBX19) mutations are responsible for two-thirds of the neonatal onset form of the disease. IAD presents with hypoglycemia and prolonged jaundice in the neonatal period. TBX19 is important for both pro-opiomelanocortin (POMC) gene transcription and differentiation of POMC-expressing cells. We describe 2 patients, 1 with a reported and 1 with a novel TBX19 mutation, and present information about the long-term follow-up of these patients. CASE PRESENTATION: Both patients had critical illnesses, recurrent hypoglycemia, convulsions, and neonatal hyperbilirubinemia. They also had low cortisol and ACTH levels, while other pituitary hormones were within the normal range. Pituitary imaging was normal. After hydrocortisone treatment, there was resolution of the hypoglycemia and the convulsions were controlled. Genetic studies of the patients revealed both had inherited a homozygous mutation of the TBX19 gene. The first patient had an alteration of NM_005149.3:c.856C>T (p.R286*) and the second patient had a novel NM_005149.3:c.584C>T (p.T195I) mutation, analyzed by next-generation sequencing. The noteworthy findings of the patients at follow-up were: short stature, microcephaly, and decreased pubic hair in the first, and dysmorphic features, Chiari type 1 malformation, tall stature, and low bone mineral density (BMD) in the second. CONCLUSION: Congenital IAD can be life-threatening if it is not recognized and treated early. TBX19 mutations should be considered in the differential diagnosis of IAD. Further cases or functional analyses are needed for genotype-phenotype correlations. Low BMD, dysmorphic features, Chiari type 1 malformation, and sparse pubic hair are some of the important features in these patients.