A 6-day-old neonate presented with hypernatremic dehydration and weight loss. Fluids were started for rehydration. He was subsequently found to have signs of reduced lower limb perfusion and investigations revealed an abdominal aortic thrombus and bilateral occlusion of renal arteries. Systemic thrombolysis led to complete resolution of renal artery thrombi with no major complications. A review of similar cases with hypernatremic dehydration and thrombosis is provided.
Background Nutritional iron deficiency anemia (IDA) peaks in prevalence at 6to 36 months of age. Children with severe IDA often present to emergency departments and may be hospitalized. Currently, little is known about the management and use of packed red blood cell transfusion in hospitalized children with severe IDA. The current Canadian Paediatric Society (CPS) Practice Point on iron requirements in the first 2 years of life (February 2021) provides guidance on prevention of iron deficiency and iron therapy; however, there is no guidance on the use of blood transfusion in children with severe IDA. Choosing Wisely Canada provides guidance on blood transfusions for adults; however, there are no recommendations on transfusion in children. In contrast, the joint American Society of Hematology and American Society of Pediatric Hematology/Oncology Choosing Wisely Task Force recently published (January 2022) recommendations, including avoiding packed red blood cell transfusion for asymptomatic children with IDA and no active bleeding. Objectives To describe the rate of blood transfusion and characteristics of young children hospitalized with IDA. Design/Methods Data from children, 6 to 36 months, hospitalized with IDA (2001-2020) was abstracted from health records using a standardized data collection form. Eligibility criteria were discharge diagnosis of IDA according to International Classification of Diseases codes, and laboratory evidence of IDA (hemoglobin < 110 g/L and at least two abnormal markers such as MCV, ferritin, transferrin, iron). Descriptive statistics were used. Results Of 79 children hospitalized with nutritional IDA (mean age 18.5 months), 34 (43%) received a blood transfusion. Of those receiving a transfusion, the initial mean hemoglobin was 32g/L (range 17-56g/L). Volume of blood given was: 5mL/kg (n=23, 68%), 10mL/kg (n=8, 23%), and >10mL/kg (n=3, 9%). Two children experienced adverse reactions: allergic reaction; non-hemolytic transfusion reaction. Characteristics of the entire cohort (n=79) were: female (n=51, 65%); previously healthy (n=69, 87%); received iron therapy prior to hospitalization (n=6, 8%); tachycardia on presentation (n=47, 59%); daily milk intake (mean 1638mL, range 236-9000mL). Initial laboratory results (mean) were: hemoglobin 40g/L (range 15-85g/L); MCV 51fL; platelet count 574x109/L; ferritin 3ug/L. Management included dietitian consultation with recommendation to reduce milk intake (n=69, 87%) and all patients received oral iron therapy on discharge (n=79, 100%). No child received intravenous iron therapy during their admission. Conclusion Our findings suggest high rates of blood transfusion among young children hospitalized with iron deficiency anemia. Future research includes examining factors associated with transfusion and practices at other Canadian centres. Our overall aim is to help inform future CPS and Choosing Wisely Canada recommendations.
Introduction: Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by mutations in one of 13 telomere-related genes, resulting in disruption of normal telomere maintenance; however, about 30% of patients do not have a molecular diagnosis. DC patients are at increased risk for severe bone marrow failure (SBMF), myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumours. Life expectancy is compromised by SBMF, malignancy, pulmonary and liver fibrosis, and GI bleeding. Objectives: Among patients with DC in Canada, aims were to: (1) characterize the genetic profile of DC in Canada, (2) define the spectrum of clinical features of DC, (3) determine the incidence and age when SBMF, MDS, AML or solid tumours develop, (4) identify factors that are associated with higher mortality risk, and (5) describe the causes of death. Methods: Data of patients enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) and meeting diagnostic criteria for DC between January 1, 2001 and March 1, 2018 were included. The CIMFR is a multicentre registry that captures data on patients with inherited marrow failure syndromes from pediatric tertiary referral centres across all Canadian provinces. We investigated several continuous (e.g. age at diagnosis of SBMF/MDS/AML) and categorical (e.g. mutated gene) variables that are associated with specific outcomes, namely overall survival and development of SBMF. Cox proportional hazard models were used to assess risk of death based on age at diagnosis and presence of SBMF. Kaplan-Meier curves were used to assess overall survival. Results: As of March 1st, 2018, 35 patients with DC were enrolled. The mean age of diagnosis was 10.94 years (0-39.9). The underlying genotypes were: DKC1 (7), TERT (6), TINF2 (5), RTEL1 (3), PARN (2), TERC (2) but remained undetermined in the others (10). Twenty-seven patients were classified as classical DC, 7 had Hoyeraal-Hreidarsson syndrome and 1 patient had Coats plus syndrome. Eight patients (23%) developed SBMF. The mean age of SBMF was 4.22 years (1-8.66). No statistical difference was found between genotypes and progression to SBMF (P=0.1). Modelling death as a function of time varying SBMF status using a cox proportional hazard regression model showed that the presence of SBMF in DC patients was predictive of higher mortality rate (P= 0.009, hazard ratio 5.7, CI 1.54-21.5). None of the patients developed malignancy during childhood (0-18 years). One adult patient developed skin cancer. Eleven patients (31%) received a hematopoietic stem cell transplant (HSCT). The mean age of HSCT was 9.5 years (0.5-37). Ten (29%) patients died, five of whom were recipients of HSCT. Mean age of death was 12.98 years (2-24.6). Extra-hematological complications included gastrointestinal bleeding (50%), pulmonary fibrosis (40%), overwhelming infection (40%), liver fibrosis (20%), cardiomyopathy (10%), hemolytic uremic syndrome (HUS) (10%) and thrombotic microangiopathy (TMA) (10%). Most patients had more than one organ dysfunction. Analysis of survival showed that all patients with TINF2 mutations have died (at median age of 10.8 years, range 2.5-23.25) whereas none died in the TERT group. Patients diagnosed at younger age had lower overall survival compared to patients diagnosed at older ages (P= 0.03, HR: 0.72, CI: 0.57-0.90). All deaths were due to organ dysfunction related to DC. Fifty percent of the patients had concurrent SBMF at the time of death. Conclusion: In this analysis, we characterised the genetic and phenotypic spectrum of DC patients registered in the CIMFR. We found a high mortality rate mainly related to organ dysfunction and SBMF, and described the impact of genotype, earlier age at diagnosis and presence of SBMF in predicting survival. We found that malignancy is an uncommon complication in the pediatric age group. Figure Disclosures Klaassen: Amgen Inc: Consultancy; TranQoL and KIT: Other: creater and owner of Kids ITP tool and TranQoL; Octapharma AG: Speakers Bureau; Baxalta: Speakers Bureau; Biogen Canada Limited: Speakers Bureau; Novo Nordisk Canada Inc: Consultancy; Hoffman-LaRoche Ltd: Consultancy; Agios Pharmaceuticals Inc: Consultancy; Shire Pharma Canada Inc: Consultancy. Pastore:Pfizer: Honoraria. Lipton:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding.
Background. Dyskeratosis congenita (DC) is a telomere biology disorder with a high risk of bone marrow failure, cancer, pulmonary and liver disease. Mutation in multiple telomere related genes including DKC1, TINF2, RTEL1, TERC, TERT, WRAP53, CTC1, NOP10, NHP2 and TPP1 have been reported. Patients with mutations in several DC genes (e.g. heterozygous TINF2, hemizygous DKC1 and biallelic RTEL1 mutations) typically tend to have a particularly serious disease with severe bone marrow failure (SBMF) at a young age, non-hematological manifestations and very short telomeres. Currently, allogeneic hematopoietic stem cell transplantation (HSCT) is the only available curative treatment for bone marrow failure and leukemia in DC patients. Relatively few case series of patients with DC undergoing HSCT have been reported, which generally suggested a poor outcome. The present study aimed to characterize the outcome of HSCT in a Canadian cohort of patients with DC and determine potential relationships between outcome and genotype. Methods. The Canadian Inherited Marrow Failure Registry (CIMFR) is a multicenter registry that includes tertiary centers that care for IBMFS patients across all Canadian provinces. Patients with DC who had been enrolled in CIMFR and underwent HSCT between January 2001 and December 2019 were included. Data were extracted from the CIMFR database. Results. Among 35 patients with DC enrolled in the CIMFR, 11 underwent HSCT. Seven patients were male. Median age at presentation, diagnosis and HSCT was 2.1 years (range: 0 to 9.13s), 5.5 years (range: 1.94 to 35.25), and 7.0 years (range; 0.5-37), respectively. The diagnosis of 3 patients was made after HSCT. Median follow up time from HSCT was 5.89 years (range; 0.2-14.0 years). Among transplanted patients, five had TINF2 mutations, two had RTEL1 mutations, and one patient had DKC1 mutation. Eight patients underwent HSCT for severe bone marrow failure, and three patients for single or multilneage cytopenia. All patients had normal bone marrow karyotype before HSCT. All patients had a full matched donor; two were related and nine were unrelated. Ten patients received reduced-intensity conditioning, and one received myeloablative conditioning. Two patients experienced engraftment failure and underwent a second HSCT. Five years and ten years overall survival after HSCT were 90.9% (95% CI 73.9-100%) and 80% (95% CI 27.2- 97.5%), respectively; however, complications and deaths started appearing thereafter, mainly in patients with TINF2 mutation. All five patients with TINF2 mutation died, and other patients were alive. The causes of death were: 1) pulmonary fibrosis (N=2), 2) gastrointestinal bleeding (N=2), and 3) EBV infection (N=1). Two patients were diagnosed with pulmonary fibrosis after 8 and 11 years from HSCT and died 13.7 and 14 years post-transplant. Two patients had gastrointestinal bleeding after 3.9 years and 4.8 years from HSCT and died 6.6 and 5.7 years post-transplant. Of the patients with GI bleeding, both had hepatic fibrosis and one had pulmonary fibrosis. Summary: In this series, most patients with DC had resolution of the bone marrow failure and relatively good quality of life in the first few years post HSCT. However, longer outcome in the patients with TINF2 mutation was dismal because of DC-related complications, especially pulmonary fibrosis and gastrointestinal bleeding. Effective therapies to prevent these complications are critically needed. Additional reports about HSCT outcome of patients with DC are necessary to characterize HSCT in patients with other genetic groups and to replicate the above results in TINF2 patients. Disclosures No relevant conflicts of interest to declare.
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