Distinctive phenotypes in two children with novel germline RUNX1 mutations - one with myeloid malignancy and increased fetal hemoglobin.

RUNX1 associated familial platelet disorder (FPD) is a rare autosomal dominant hematologic disorder characterized by thrombocytopenia and/or altered platelet function. There is an increased propensity to develop myeloid malignancy (MM) - acute myeloid leukemia, myeloproliferative neoplasms or myelodysplastic syndrome often in association with secondary somatic variants in other genes. To date, 23 FPD-MM pediatric cases have been reported worldwide. Here, we present two new kindreds with novel RUNX1 pathogenic variants in which children are probands. The first family is a daughter/mother diad, sharing a heterozygous frameshift variant in RUNX1 gene (c.501delT p.Ser167Argfs*9). The daughter, age 13 years, presented with features resembling juvenile myelomonocytic leukemia - severe anemia, thrombocytopenia, high white cell count with blast cells, monocytosis, increased nucleated red cells and had somatic mutations with high allele burden in CUX1, PHF6, and SH2B3 genes. She also had increased fetal hemoglobin and increased LIN28B expression. The mother, who had a long history of hypoplastic anemia, had different somatic mutations- a non-coding mutation in CUX1 but none in PHF6 or SH2B3. Her fetal hemoglobin and LIN28B expression were normal. In the second kindred, the proband, now 4 years old with thrombocytopenia alone, was investigated at 3 months of age for persistent neonatal thrombocytopenia with large platelets. Molecular testing identified a heterozygous intragenic deletion in RUNX1 encompassing exon 5. His father is known to have increased bruising for several years but is unavailable for testing. These two cases illustrate the significance of secondary mutations in the development and progression of RUNX1-FPD to MM.

Utility of thromboelastography for the diagnosis of von Willebrand disease.

Von Willebrand disease (VWD) is an inherited bleeding disorder that is caused by a quantitative or qualitative deficiency of von Willebrand factor (VWF). The National Heart, Lung, and Blood Institute (NHLBI) guidelines for the diagnosis of VWD state that a VWF activity (VWF:RCo) of <30 IU/dL or <50 IU/dL with symptoms of clinical bleeding are consistent with the diagnosis of VWD. However, current gold-standard diagnostic testing takes days to have complete results. Thromboelastography (TEG) is a testing method that provides a graphical trace that represents the viscoelastic changes seen with fibrin polymerization in whole blood, therefore providing information on all phases of the coagulation process. This study describes the TEG characteristics in 160 patients who presented for workup of a bleeding disorder and a subset of those were subsequently diagnosed with VWD. The TEG parameters, K-time (representing the dynamics of clot formation) and the maximal rate of thrombus generation (MRTG), were found to be sensitive in detecting patients with VWF:RCo <30 IU/dL. The TEG, unlike VWF:RCo, can be done in real time, and results are available to the clinician within an hour. This will definitely be beneficial in acute situations such as evaluation of and management of acute bleeding in patients with acquired deficiencies of VWF and may play an important role in the surgical management of patients with VWD.

The Coags Uncomplicated App: Fulfilling Educational Gaps Around Diagnosis and Laboratory Testing of Coagulation Disorders.

BACKGROUND: Patients with coagulation disorders may present to a variety of physician specialties; however, accurate and efficient diagnosis can be challenging for physicians not specialized in hematology, due to identified gaps in knowledge around appropriate laboratory assays and interpretation of test results. Coags Uncomplicated was developed to fill this unmet educational need by increasing practical knowledge of coagulation disorders among nonexpert physicians and other health care professionals (HCPs) in a point-of-care (POC) setting. OBJECTIVE: The aim of this study was to assess patterns of use of the mobile app Coags Uncomplicated, a tool designed to support education regarding accurate and efficient diagnosis of bleeding disorders. METHODS: App metrics were obtained by tracking registered user data. Additionally, a survey was distributed to registered users, to assess circumstances and frequency of use. RESULTS: The most common specialties of 7596 registered US users were hematology-oncology (n=1534, 20.19%), hematology (n=1014, 13.35%), and emergency medicine (n=1222, 16.09%); most identified as physicians (n=4082, 53.74%). Specialties accounting for the greatest numbers of screen views were hematology-oncology (99,390 views), hematology (47,808 views), emergency medicine (23,121 views), and internal medicine (22,586 views). The most common diagnostic endpoints reached were disseminated intravascular coagulation (DIC; 2713 times), liver disease effect (2108 times), and vitamin K deficiency (1584 times). Of 3424 users asked to take the survey, 262 responded (7.65%); most were physicians in direct clinical care (71%) and specialized in hematology-oncology (39%) or emergency medicine (21%). Most frequent use was reported by hematologists (69%, ≥6 times) and hematologists-oncologists (38%, ≥6 times). Most physicians (89.2%) reported using the app for patient-case-related education around appropriate use of laboratory tests in diagnostic evaluation. Physicians rated Lab Value Analyzer (mean 4.43) and Lab Test Algorithm (mean 4.46) tools highly on a 5-point "how helpful" scale and were likely to recommend the app to colleagues. CONCLUSIONS: App use among physicians and other HCPs is consistent with value as a POC educational tool, which may facilitate differential diagnoses and appropriate early consultation with hematologists.

Acute megakaryoblastic leukemia with t(17;22)(q21;q13) and liver dysfunction.

The t(1;22)(p13;q13) is associated with acute megakaryoblastic leukemia (AMKL) seen mostly in young infants and known to have a poor prognosis. A 5-year-old child had prolonged prothrombin and partial thromboplastin times, low albumin, and decreased vitamin K-dependent coagulation factors and factor V activities at the time of AMKL diagnosis. All of these factors normalized following chemotherapy when remission was achieved. Cytogenetic analysis revealed a female karyotype with a balanced t(17;22)(q21;q13). Here, we present an AMKL pediatric case with a novel translocation and significant hepatocellular dysfunction that resolved with chemotherapy. The t(17;22) (q21;q13) may represent a variant of t(1;22)(p13;q13).