Inherited bone marrow failure syndromes (IBMFSs) are genetically heterogeneous with an expanding spectrum of causative genes. Recent molecular advances are thought to have contributed to genetic identification, yet the true gain in diagnostic yield remains unclear. Accordingly, this study aims to investigate the evolving genetic landscape of IBMFSs using data from the Canadian Inherited Marrow Failure Registry by analysing patients enrolled from the 2001-2010 cohort to the 2011-2023 cohort. Among 407 genetically tested patients, 308 (75.7%) underwent molecular diagnosis, with variants identified in 62 distinct genes. These genes encompass diverse cellular pathways, including DNA repair, telomere maintenance, transcription, RNA splicing, ribosome biogenesis, nuclear envelope, Golgi, endoplasmic reticulum and mitochondrial integrity, cell signalling, cytokine receptor activity and cytoskeletal regulation. A total of 453 variants were identified, including pathogenic copy number variants in 12.7% (39/308) of cases, representing 10.4% (47/453) of all variants. Diagnostic yield increased from 51.6% in 2001-2010 to 75.7% in 2001-2023, and genetic testing enabled classification of 17.5% (54/308) of previously unclassified cases. These findings underscore the rapid growth of IBMFS genetic knowledge and the crucial value of comprehensive testing, although 24.3% of cases remain unresolved, likely due to novel syndromes and unrecognised IBMFS-related genes.

Pediatric autoimmune hemolytic anemia (AIHA) is a heterogeneous disease with significant morbidity due to the underlying condition and its treatment. Evidence-based guidelines for evaluation and management are lacking. Data from 399 patients with AIHA followed at 15 pediatric centers were collected to identify factors associated with secondary diagnoses, recurrent/chronic course, therapeutic efficacy, and mortality. Most had AIHA associated with secondary diagnoses including Evans syndrome (37%, 142/385), other autoimmunity (22%, 86/392), and inborn errors of immunity (IEI, 18%, 68/379). Of 305 patients tested, 82% had abnormal functional immune results. Genetic testing for an IEI was sent in 31% (109/348) with pathogenic findings identified in 32% of those tested. Patients with IEI or other autoimmunity more frequently had abnormal immunoglobulin and complement testing. Prevalence of IEI was not different between those presenting with or without infection. The median number of treatments for the first AIHA episode was 2 (range: 0-17). Of those with warm AIHA, 31% received steroid-sparing therapy during the first episode. Patients with recurrent AIHA (42%) had a higher rate of abnormal immune tests (OR=2.29, p=0.012), Evans syndrome (OR= 4.85; p<0.001), IEI (OR=3.88, p<0.001), and other autoimmune disorders (OR=3.29; p<0.001). With median follow up of 4.9 years (range: 0-19.4 years), 72/257 (28%) with warm AIHA continued to have active disease on treatment. Of the 399 patients, 10 died, all of whom had secondary diagnoses. Expansive immune evaluation, monitoring, and targeted treatments directed at immune diagnoses are needed for pediatric AIHA, highlighting the need for evidence-based pediatric AIHA guidelines.

Diamond-Blackfan anemia (DBA) is a rare inherited bone marrow failure syndrome characterized by erythroid aplasia, congenital anomalies, and cancer predisposition. Although corticosteroids are the standard first-line therapy for transfusion-dependent patients, treatment response varies, and reliable predictors remain undefined. We retrospectively analyzed data from the Canadian Inherited Marrow Failure Registry to identify clinical and genetic factors associated with steroid responsiveness. Among 80 patients with evaluable steroid response, 30 were classified as the responder group and 50 as the non-responder group (non-response or loss of response after initial improvement). The median age at diagnosis was significantly higher in the responder group than in the non-responder group (20 months vs. 3 months, p = 0.004). ROC curve analysis showed that age at diagnosis had predictive value for steroid responsiveness, with an optimal cutoff of 9.5 months. DBA-associated genetic mutations were identified in 58 patients. Notably, RPL5 mutations were significantly more frequent in the non-responder group than in the responder group (22.0% vs. 0%, p = 0.004). No significant difference in overall survival was observed between the responder and non-responder groups. Differences in corticosteroid response were associated with diagnostic age and specific genetic variants, offering potential guidance for individualized treatment decisions.

INTRODUCTION:The clinical course, outcome, risk of malignancy, and causes of mortality in the pediatric dyskeratosis congenita (DC) population have been described in a few studies. METHODS:Data of patients with DC enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) between January 2001 and December 2021 were analyzed. RESULTS:Forty-three patients with DC were diagnosed at a median age of 9 years. The underlying mutated genes included DKC1, PARN, RTEL1, TERC, TERT , and TINF2 . Nine patients developed severe bone marrow failure (BMF). Presence of severe BMF was associated with a higher risk of mortality (HR: 7.5). Patients with DC who were diagnosed at a younger age had lower overall survival. No pediatric patients developed malignancy. Eleven patients received a hematopoietic stem cell transplant. Ten patients died due to organ dysfunction, mostly related to DC. All 5 TINF2 patients died, but no patients died in the TERT, TERC , or RTEL1 groups. CONCLUSIONS:Pediatric patients with DC have a high mortality rate related to BMF and organ dysfunction, but malignancy is uncommon in this age group. Earlier age at diagnosis and presence of severe BMF could be risk factors for mortality. Patients with the TINF2 genotype tend to have a worse outcome than patients with RTEL1, TERC , and TERT .

Background: Constitutive inflammation and hemostatic activation have been identified as key contributors to the pathophysiology of sickle cell disease (SCD), leading to clinical consequences such as vaso-occlusive crises and stroke. Patients with hemoglobin SS (HbSS) and hemoglobin SC (HbSC) genotypes are reported to have different symptoms, as do patients in steady-state and crisis situations. Differences among these groups remain unclear in pediatric patients. Objectives: To compare hemostatic activity in HbSS and HbSC pediatric patients during steady state, in crisis, and in clinical follow-up and compare HbSS and HbSC patients with normal healthy children. Methods: Whole-blood coagulation assay thromboelastography (TEG) was used to assess hemostatic activity. In parallel, flow cytometry was used to assess procoagulant surface expression of platelets and red blood cells. Results: TEG results indicated no significant differences in clotting onset (R time), clot maximum amplitude, or maximum rate of thrombus generation among steady-state, crisis, and follow-up subgroups of HbSS and HbSC patients. TEG parameters did not differ significantly between HbSC patients and healthy children, while HbSS patients showed significantly shorter R time and greater maximum amplitude and maximum rate of thrombus generation, all indicative of a constitutive hypercoagulable state. Flow cytometry results did not detect increased platelet integrin alpha IIb beta 3 activation or red blood cell procoagulant surface expression in SCD patients compared with unaffected children. Conclusion: Our results indicate that pediatric SCD patients with the HbSS genotype have constitutively activated hemostasis relative to HbSC patients and healthy children. It remains to be determined how treatments that improve clinical outcomes in SCD patients affect this constitutively hypercoagulable state.

Introduction: The safety and efficacy of the extended half-life factor VIII (FVIII) product damoctocog alfa pegol (BAY 94-9027, Jivi (R)) has been demonstrated in the PROTECT VIII Kids study (NCT01775618), where male previously-treated patients (PTPs) aged <12 years old with severe haemophilia A and >= 50 exposure days (EDs) were treated prophylactically. The PROTECT VIII Kids extension study assessed the long-term safety and efficacy of damoctocog alfa pegol in the same population.Aim: To evaluate the long-term impact of damoctocog alfa pegol in a post hoc subgroup analysis of adolescent patients in the PROTECT VIII Kids study and its extension from 12th birthday onwards.Methods: The current analysis included PTPs aged >= 12 years old, who remained in the extension for >= 6 months following their 12th birthday. The observation period was defined as the time from 12th birthday to the end of the extension period; all data from this birthday were included whether in the main study or extension phase. The main efficacy variable was annualised bleeding rate (ABR) and the main safety variable was the frequency of inhibitor development.Results: This subgroup analysis comprised 25 patients. Median observation time after 12th birthday was 3.2 years. Median total/joint/spontaneous ABRs in the observation period were 1.7/0.7/0.3, respectively. Safety findings were consistent with those reported for the overall study population; no confirmed FVIII inhibitors or anti-drug antibodies were reported.Conclusions: Damoctocog alfa pegol is efficacious with a favourable safety profile in adolescents with haemophilia A, supporting its long-term use in children and adolescents.

Background: Autoimmune hemolytic anemia (AIHA) is a rare pediatric autoimmune disease in which there is limited guidance for evaluation and treatment and a poor understanding of the characteristics that influence prognosis and clinical course. Aim: To characterize the clinical features, laboratory findings, and treatment outcomes of children with AIHA over a 10-year period. Methods: An IRB-approved multicenter observational cohort study included patients (pts) from 15 institutions from the ITP Consortium of North America (ICON) who were 3 mo to 21 y and had hematology consultation between Jan 2011 and Dec 2020 with a diagnosis of AIHA. Post-stem cell transplant AIHA was excluded. Demographic, medical history, laboratory, and treatment data were collected. Continuous variables are summarized as mean (SD) or median (range) and compared with a two-sided t-test. Categorical variables are summarized as counts or percentages and compared with a two-sided chi-squared test. Results: A total of 402 pts were included: median age at diagnosis 7 y (n=397, range: 0-22) with median length of follow up 2.7 years (n=390, range: 0.1-19.2). 45% (180/398) were female. Warm AIHA (wAIHA) was the predominant subtype in 64% (252/395). Most pts (58%, 217/374) had a single AIHA episode that remitted; others had two episodes that remitted (8%, 29/374), multiple relapsing episodes (7%, 26/374), chronic course that remitted (13%, 48/374), or chronic ongoing course (14%, 54/374). Cold agglutinin disease (CA) was present in 12% (47/395), paroxysmal cold hemoglobinuria (PCH) in 6% (24/395), and mixed/unspecified AIHA in 18% (72/395). Secondary AIHA was common with 15% (57/389) with an underlying primary immunodeficiency, most commonly CVID (49%, 28/57), ALPS (33%, 19/57), and 22q11.2DS (16%, 9/57); and 16% (61/391) with another autoimmune disorder, most commonly SLE (49%, 30/61), neurologic disease (36%, 22/61), or APLA (16%, 10/61). Immune testing was sent in 100% (402/402) and abnormal in 60% (240/402). An immunologist was consulted in 136/342 (40%). Infectious testing was sent in 71% (260/366). Family history (1st or 2nd degree) was positive for immune cytopenias, immunodeficiency, or autoimmunity in 19% (78/402). Genetic testing (sent in 30%, 106/349), was most often a gene panel (67%, 71/106) or WES (28%, 30/106) with pathogenic findings identified in 30% (30/100). Evans syndrome (ES) was common (37%, 142/385) including ITP (92%, 131/142) and/or immune neutropenia (43%, 57/133) and most likely in those with wAIHA (47%, 113/241) compared with PCH (0%, 0/23) or CA (4%, 2/45). Compared with pts without ES (n=243), those with ES (n=142) were more likely to be older at first episode (9 y vs 5 y, p=0.010), have genetic testing (54% vs 18%, p<0.001), pathogenic gene findings (13% vs 5%, p=0.002), and treatment with steroid-sparing agents at first episode (35% vs 19%, p<0.001). There was no difference in response to steroids at first episode (77% vs 75%, p=0.748) or incidence of another autoimmune disorder (18% vs 14%, p=0.306). Similarly, those with secondary AIHA were more likely to be older at first episode (8 y vs 6 y, p=0.007) and have wAIHA (77% vs 62%, p=0.035). Secondary AIHA did not impact steroid response (77% vs 74%, p=0.653) or treatment with steroid-sparing agents at first episode (26% vs 24%, p=0.756). Pts with multiple episodes of AIHA were also more likely to have wAIHA (82% vs 52%, p<0.001), genetic testing (50% vs 19%, p<0.001), and treatment with steroid-sparing agents at first episode (34% vs 18%, p<0.001) but did not have a different age at presentation of 1st episode [8 y vs 5 y, p=0.203] or proportion with pathogenic gene findings (10% vs 6%, p=0.268). Of those with ongoing follow up, 68/249 (27%) of pts with wAIHA had active disease on treatment, 7/249 (3%) had active disease and were being observed, and 174/249 (70%) were in remission. Overall, mortality was 9.4%. Mortality was not associated with a diagnosis of ES, immunodeficiency or autoimmunity, number of AIHA episodes, or type of AIHA. Conclusion: AIHA is associated with significant morbidity in children with a high rate of secondary AIHA (~30%), 37% with ES, and 34% with a chronic or relapsing course. In this recently diagnosed cohort, there was a 9.4% mortality rate. These high morbidity and mortality rates require expanded testing, monitoring, and additional treatment approaches in this pediatric population.

Introduction Autoimmune hemolytic anemia (AIHA) is a disorder characterized by excessive premature red blood cell breakdown due to the presence of autoantibodies. It is rare in children, with an estimated incidence of 0.2 per one million individuals younger than 20 years. There are no guidelines on the investigation and management of pediatric AIHA, and contemporary approaches are derived from adult guidelines. AIHA is an important cause of morbidity in pediatric hematology patients, and a review of pediatric AIHA investigation, diagnosis, and treatment is warranted. This scoping review will summarize the current landscape of diagnosis and management of pediatric AIHA to inform future studies aimed at formulating a pediatric specific approach to the investigation and management of this small but complex patient population. Methods This review searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to July 27, 2021. All screening and data extraction was done in parallel by two reviewers. Experimental and observational studies reporting on diagnostic criteria, laboratory work up, or treatment/management of AIHA in populations with at least 20% of patients ≤18 years were included. Study characteristics, population characteristics, and study outcomes were extracted and synthesized narratively and descriptively using counts (percentages). Results After removing duplicates, the titles and abstracts of 1742 studies were screened and 109 studies were selected for full-text review. Forty three studies, published between 2003 and 2021, met inclusion criteria and proceeded to data extraction. Forty cohort studies (35 retrospective, 5 prospective) and 3 case-control studies were included. No randomized controlled trials were identified. Diagnostic criteria for AIHA was provided in 29 (67%) studies, with 4 (9%) studies classifying the severity of AIHA. All but one study defined AIHA with at least one of: positive direct antibody test, evidence of anemia, and evidence of hemolysis (including increased lactate dehydrogenase or bilirubin, or decreased haptoglobin). Patients with Evan's syndrome were included in 31 (72%) studies, and 30 (70%) studies included special populations such as transplant recipients or patients with underlying autoimmune conditions. AIHA treatments in pediatric patients were reported in 41 (95%) studies, with 26 (60%) studies dividing the treatments into first- and second-line therapies. Common first-line therapies included steroids (unspecified) in 18 (42%) studies, prednisone in 9 (21%) studies, methylprednisolone in 9 (21%) studies, intravenous immunoglobulin (IVIG) in 17 (40%) studies, and/or combinations of these therapies. Common second-line therapies included rituximab in 16 (37%) studies, cyclosporine in 16 (37%) studies, IVIG in 13 (30%) studies and/or combinations of these therapies. Discussion Compared to pediatric immune thrombocytopenia, there is substantially less information available describing pediatric AIHA. Most studies are retrospective and include both patients with isolated AIHA and Evan's syndrome. Data on diagnosis, investigation, and management are inconsistently reported. Only two studies reported their diagnostic approach for identifying secondary causes of AIHA. Although most studies described diagnostic criteria for AIHA, the specific criteria were variable, and only 4 studies classified AIHA according to severity. Specific treatments were variable. First-line treatments were most commonly a combination of corticosteroids and IVIG in keeping with guidelines for the management of AIHA in adults. Second-line treatments typically consisted of an immunosuppressive or immunomodulatory agent, with the specific medication or combination of medications varying depending on past therapies attempted and the patient's underlying disease. Conclusion Our review identified a deficit of high quality, prospective studies into pediatric AIHA. Prospective studies evaluating the treatment of pediatric AIHA are needed. A standardized definition and classification of pediatric AIHA will help guide much needed future studies of the appropriate investigation and management of pediatric AIHA.

APML, a subtype of acute myeloid leukemia, is highly curable, with cure rates over 90%. Despite its therapeutic success, APML poses elevated bleeding risks due to frequent prior disseminated intravascular coagulation. Less commonly recognized but critical is the thrombotic risk. We document a unique pediatric case: a 13-year-old with trisomy 21 diagnosed with APML had an asymptomatic aortic valve thrombus leading to thromboembolic arterial ischemic stroke. Through endovascular thrombectomy, cerebral circulation was re-established, extracting a fibrin thrombus with APML cells. Neurological recovery was swift. This report underscores the importance of vigilance for thrombotic complications in APML, highlighting the potential severity of overlooked risks.

Background :Hereditary thrombotic thrombocytopenia purpura (hTTP) is an ultra-rare disorder resulting from an inherited deficiency of ADAMTS13, a von Willebrand factor (VWF)-cleaving metalloprotease. The plasma-derived factor VIII/VWF Koate (FVIII/VWFKoate) has been shown to contain ADAMTS13, allowing for its use to treat hTTP at home by the patient/caregiver.Aim: Based on prior demonstration of safe and effective use of FVIII/VWFKoate in eight patients with hTTP, we conducted a retrospective study to gather additional data regarding the use of FVIII/VWF(Koate )for hTTP.Methods:This was a multicentre, retrospective, noninterventional chart review of patients who had received FVIII/VWFKoate for the management of hTTP. Data collected included demographics, medical history, relevant family history, past use and tolerability of fresh frozen plasma, and details regarding FVIII/VWFKoate therapy.Results:The cohort included 11 patients (seven males, four females) with hTTP, ranging in age at study entry from 2 to 28 years. The average duration of FVIII/VWFKoate therapy was 4.8 years (range, 0.5-6.5 years). Among nine patients using FVIII/VWF(Koat)e as prophylaxis, the normalized annual rate of breakthrough TTP episodes ranged from 0.2 to 1.1 episodes/year. All nine patients who received FVIII/VWFKoate prophylaxis had thrombocytopenia recorded at baseline, while eight (88.9%) did not have thrombocytopenia after using FVIII/VWFKoate. There was one AE (unspecified) attributed to FVIII/VWFKoate.Conclusion:These data suggest that FVIII/VWF(Koate )is a safe and well-tolerated source of the missing ADAMTS13 enzyme in patients with hTTP, producing a marked reduction in thrombocytopenia prevalence, low frequency of TTP episodes, and with the added benefit of self- or caregiver-administration.

Hereditary thrombotic thrombocytopenia purpura (hTTP) is an ultra-rare disorder resulting from an inherited deficiency of ADAMTS13, a von Willebrand factor (VWF)-cleaving metalloprotease. The plasma-derived factor VIII/VWF Koate (FVIII/VWF Koate ) has been shown to contain ADAMTS13, allowing for its use to treat hTTP at home by the patient/caregiver. Based on prior demonstration of safe and effective use of FVIII/VWF Koate in eight patients with hTTP, we conducted a retrospective study to gather additional data regarding the use of FVIII/VWF Koate for hTTP. This was a multicentre, retrospective, noninterventional chart review of patients who had received FVIII/VWF Koate for the management of hTTP. Data collected included demographics, medical history, relevant family history, past use and tolerability of fresh frozen plasma, and details regarding FVIII/VWF Koate therapy. The cohort included 11 patients (seven males, four females) with hTTP, ranging in age at study entry from 2 to 28 years. The average duration of FVIII/VWF Koate therapy was 4.8 years (range, 0.5–6.5 years). Among nine patients using FVIII/VWF Koate as prophylaxis, the normalized annual rate of breakthrough TTP episodes ranged from 0.2 to 1.1 episodes/year. All nine patients who received FVIII/VWF Koate prophylaxis had thrombocytopenia recorded at baseline, while eight (88.9%) did not have thrombocytopenia after using FVIII/VWF Koate . There was one AE (unspecified) attributed to FVIII/VWF Koate . These data suggest that FVIII/VWF Koate is a safe and well-tolerated source of the missing ADAMTS13 enzyme in patients with hTTP, producing a marked reduction in thrombocytopenia prevalence, low frequency of TTP episodes, and with the added benefit of self- or caregiver-administration.

Objectives:Sickle cell disease (SCD) is an inherited multisystem disorder with complications starting in the first year of life. Newborn screening (NBS) can identify infants with SCD and is associated with decreased morbidity and mortality. Variation in availability of NBS in Canada, and lack of standardized screening for immigrant children, may lead to delayed diagnosis.Methods:This was a retrospective cohort study of 126 children aged 0-18 years with SCD registered with the SCD clinic at the Alberta Children's Hospital between January 2003 and January 2018, prior to province-wide universal NBS for SCD. Patient demographic information, circumstances of diagnosis, and other contextual information were collected from patient health records. Descriptive statistics were used to summarize data, with Mood's median test used to compare medians between groups.Results:Forty-three (35%) patients were born in Alberta. Patients were mostly (95.3%) of African descent. Of patients born in Alberta, 63% (26/43) were diagnosed at >12 months of age, with a median age at diagnosis of 18 months (IQR = 4-39). This was significantly older (P < 0.001) than children born in the USA or in Canadian provinces with SCD NBS programs, where the median age at diagnosis was zero months (N = 36). Of the 42% of patients born outside North America, 64% were diagnosed following an acute complication.Conclusions:This study highlights the importance of NBS for early detection and management of SCD, and the importance of screening at-risk immigrants who may not have received NBS for SCD.

Pediatric benign neutropenia is a self-limited condition with a benign clinical course. An approach to this condition is not well-defined in the literature. Our objective was to use a case-based survey to elucidate trends in the diagnosis and management of benign neutropenia among pediatric hematology/oncology practitioners in Canada. We received 46 completed surveys (response rate 66%). At initial presentation with fever and neutropenia, 67% of respondents recommended partial septic workup but 11% recommended no investigations. Nearly 70% recommended admission for empiric intravenous antibiotics, while 24% would discharge home without antibiotics. In a patient with fever and known neutropenia, respondents were more likely to pursue outpatient antibiotic therapy. For investigation of chronic neutropenia, most respondents (60%) do not use antineutrophil antibody testing. Common indications for bone marrow biopsy were severe infection, prolonged neutropenia, or before initiating granulocyte colony stimulating factor. Indications for granulocyte colony stimulating factor were based on severity and frequency of infection. Most respondents (84%) would not recommend antibiotic prophylaxis. Results demonstrate the considerable variability in management of benign neutropenia among pediatric hematology/oncology practitioners in Canada and highlight the need for prospective studies to establish diagnostic criteria for benign neutropenia and evaluate management of fever in this population.

Classification of inherited bone marrow failure syndromes (IBMFSs) according to clinical and genetic diagnoses enables proper adjustment of treatment. Unfortunately, 30% of patients enrolled in the Canadian Inherited Marrow Failure Registry (CIMFR) with features suggesting hereditability could not be classified with a specific syndromic diagnosis. We analyzed the outcome of hematopoietic stem cell transplantation (HSCT) in unclassified IBMFSs (uIBMFSs) and the factors associated with outcome. Twenty-two patients with uIBMFSs and 70 patients with classified IBMFSs underwent HSCT. Five-year overall survival of uIBMFS patients after HSCT was inferior to that of patients with classified IBMFSs (56% vs 76.5%). The outcome of patients with uIBMFS who received cord blood was significantly lower than that of patients who received other stem cell sources (14.8% vs 90.9%). Engraftment failure was higher among patients with uIBMFS who received cord blood than those who received bone marrow. None of the following factors were significantly associated with poor survival: transfusion load, transplant indication, the intensity of conditioning regimen, human leukocyte antigen-identical sibling/alternative donor. We suggest that identifying the genetic diagnosis is essential to modulate the transplant procedure including conditioning agents and stem cell sources for better outcome and the standard cord blood transplantation (CBT) should be avoided in uIBMFS.