Summary Hereditary spherocytosis (HS) is a common inherited haemolytic anaemia attributed to disturbances in five different red cell membrane proteins. We performed a retrospective study of 166 children with HS and describe the clinical phenotype according to the genotype. In 160/166 (97%) children with HS a disease‐causing mutation was identified. Pathogenic variants in ANK1, SPTB, SLC4A1 and SPTA1 were found in 49%, 33%, 13% and 5% of patients. Children with SLC4A1‐HS had the mildest phenotype, showing the highest haemoglobin (P < 0·001), lowest reticulocyte counts (P < 0·001) and lowest unconjugated bilirubin levels (P = 0·006), and none required splenectomy in childhood (P < 0·001). Conversely, children with autosomal recessive SPTA1‐HS had the most severe clinical phenotype, with almost all patients undergoing splenectomy in early childhood. Patients with ANK1 and SPTB variants showed a similar clinical phenotype. Within each gene, variant type or location did not predict disease severity or likelihood of splenectomy. Among patients with a genetic diagnosis, 47 (29%) underwent splenectomy (23 partial; 24 total) while 57 (36%) underwent cholecystectomy. Total splenectomy led to greater improvements in haemoglobin (P = 0·02). Select use of genetic testing (especially in patients without a family history) may help predict clinical phenotype in childhood and guide family counselling.

Hereditary spherocytosis (HS) is the most common congenital hemolytic anemia in Caucasians. Patients with HS show a high degree of phenotypic variability from asymptomatic to transfusion dependence. Much of this variability stems from HS not being a single uniform disorder but instead being a collection of disorders involving mutations in 5 different genes (ANK1, SPTB, SPTA1, SLC4A1, and EPB42 ) encoding for the 5 major cytoskeletal proteins in red blood cells (ankyrin, β and α spectrin, band 3, and protein 4.2 respectively). These proteins are responsible for maintaining the biconcave disk morphology of red blood cells. Traditionally the diagnosis of HS has been made without genetic testing. We believe that knowledge of the HS subtype may impact future clinical management decisions, e.g. what type of splenectomy to perform-partial vs total and impact on genetic counseling needs. As a result we are now pursuing genetic testing on all our patients with HS. Over the past 16 years at Sick Kids Hospital (Toronto, Canada), we have followed 257 children with HS. In the past year we have also been offering genetic testing (following informed consent) to all children (<18 years old) still being followed in our center. DNA is sent to Prevention Genetics (Wisconsin, USA) where Next Generation sequencing is performed. Mutations are verified by Sanger sequencing. In total, we have genetic test results on 103 children from 87 families to date. Mutations in ANK1 were most common (50 children/43 families); followed by mutations in SPTB (32 children/26 families); SLC4A1 (7 children/7 families) and finally SPTA1 (6 children/3 families) EPB42 mutations were not found to be causative for HS in our cohort. In 8 children (8 families) no causative mutation for HS was found. In 23% of children multiple mutations were found -particularly heterozygous mutations of SPTA1 in combination with ANK1 or SPTB mutations. The majority of mutations in our patients were nonsense, frameshift, or splice site mutations. Most were novel - not previously described mutations, and unique to families. There were 5 exceptions to this; 1) c.4339-99C>T in SPTA1 (referred to as the αLEPRA mutation) in 4 children/2 families with an α spectrin form of HS, and in another 2 children (1 family) with an ankyrin form of HS; 2) an ANK1 c.5097-33G>A (8 children/6 families); 3) an ANK1 c.1405-9G>A (4 children/3 families); 4) SPTB c.6037C>T (3 children/2 families); and 5) SPTB c.5266C>T (3 children/2 families). The ANK1 c.5097-33G>A mutation had not been previously identified and yet was the most frequently detected mutation in our HS population. Most children (68/103) were found to have autosomal dominant (AD) HS: 33 children with the ankyrin subtype, 26 with the β spectrin subtype, 4 with the band 3 subtype and 5 in whom no mutation could be found but where there was a clear history of AD inheritance. Autosomal recessive (AR) inheritance was confirmed in 7 children - all 6 with α spectrin form of HS and 1 with a β spectrin form of HS. Twenty-eight children were spontaneous new mutations for HS: ANK (n=17), β spectrin (n=5), band 3 (n=3) and 3 in whom no mutation could be found. In all AR forms of HS, the index case had initially been thought to be a spontaneous new mutation for an AD form of HS; genetic testing resolved the inheritance pattern. Patients were categorized according to disease severity, primarily on the basis of their need for transfusions (a reflection of baseline hemoglobin) and splenectomy. The proportion of children that have required transfusions and needed splenectomies was: 83%/83% (α spectrin); 48%/18% (ankyrin), 23%/10% (β spectrin) and 29%/0% (band 3). Most children in our center undergoing splenectomy have undergone partial splenectomy; few have required subsequent total splenectomy. However, of the 5/6 children with α spectrin form of HS that underwent partial splenectomy 3 have subsequently needed, or are being considered for, total splenectomy. This suggests that due to the extreme severity of the α spectrin subtype of HS, children with this form of HS may not do well long-term with partial splenectomy and are likely to eventually require a total splenectomy. Our study to date represents one of the largest and most comprehensive genetic analyses of a cohort of HS patients. Our findings will add to the growing understanding of the disease, and will be important to provide comprehensive genetic counseling and possibly in the future to guide management of selected cases. Disclosures Drury: Prevention Genetics: Employment.

Objectives To assess the safety and efficacy of rapamycin in treating children with vascular tumours and malformations. Study design We performed a retrospective review at a large tertiary care paediatric centre to assess the efficacy and safety of using rapamycin to treat vascular tumours and malformations. Response to therapy was defined by patient-reported symptom improvement, radiological reduction in size of lesions, and/or improvement of laboratory parameters. Results Forty-two patients (7 with vascular tumours and 35 with vascular malformations) have been treated with rapamycin. Despite 33 of 42 patients being diagnosed in the first year of life, the median age of initiating rapamycin was 11 years. Of the 38 children treated for a minimum of 4 months, 29 (76%) exhibited a clinical response. Twenty-one patients had follow-up imaging studies and of these, 16 (76%) had radiographic decrease in lesion size. Median time to demonstration of response was 49 days. All five children with vascular tumours and all three children with vascular malformations under the age of 4 years showed a clinical response. Response rate was lower for children ≥ 4 years of age (0/2, 0% for vascular tumours; 21/28, 75% for vascular malformations). No patient experienced an infection directly related to rapamycin or discontinued rapamycin due to toxicity. Conclusions Rapamycin is safe and efficacious in most children with select vascular tumours and malformations. Young children appear to respond better, suggesting that early initiation of rapamycin should be considered.

Purpose: Fibroadipose vascular anomaly (FAVA) is a complex vascular anomaly associated with postzygotic somatic PIK3CA mutations. FAVAs can cause significant pain, swelling, and musculoskeletal dysfunction. Treatment options are limited. Sirolimus is a well-tolerated and effective treatment for patients with FAVA. We report our experience of using sirolimus to treat 11 children with FAVAs. Methods: We conducted a retrospective review of all patients with FAVA treated with sirolimus in our institution. Results: Fourteen patients (10 females) were referred for sirolimus therapy for FAVA. Eleven patients were initiated on sirolimus at a mean age of 14 years (range: 9–17.9 years) and were then treated for a mean of 19 months (range: 1–46 months). Five had previously undergone sclerotherapy without benefit. Sirolimus was initiated at a dose of either 2.5 mg/m2 once daily or 0.8 mg/m2 twice daily. Doses were titrated to maintain sirolimus trough levels of 5–15 ng/L. Goals of treatment were improvement in pain and musculoskeletal dysfunction. All 11 patients reported reduced pain; 7 reporting this within 3 weeks of starting sirolimus. This allowed for discontinuation of analgesia. Function improved significantly in 9 of 11, leading to resumption of sports or work participation. Sirolimus side effects were similar to prior reports, most commonly mouth sores, mildly elevated lipids and acne. There was no grade III/IV toxicity. Conclusion: Sirolimus is a well-tolerated and effective treatment for patients with FAVA. Initial symptom improvement is rapid, with significantly reduced pain and improved function. We believe that sirolimus should be considered for all patients with FAVA as a first-line therapy before surgical/interventional approaches.

Primary Subject area Emergency Medicine - Paediatric Background While the management of febrile neutropenia in patients with cancer has clear, evidence-based guidelines, the management of previously healthy, immunocompetent children with a febrile illness and first episode of neutropenia is less understood. These patients are often similarly treated with empiric antibiotics and hospitalization despite studies demonstrating that this population, if they are well-appearing with a short history of neutropenia, is at low risk of serious bacterial infections. Therefore, less aggressive management should be considered in patients meeting low risk criteria. Objectives The aim of our quality improvement (QI) study was to decrease the number of unnecessary hospitalizations and empiric antibiotics prescribed by 50% over a 12-month period for otherwise healthy, well appearing patients presenting to the emergency department (ED) with a first episode of febrile neutropenia. Design/Methods A team of stakeholders from Hematology, Infectious Disease, Pediatrics and Emergency Medicine was assembled. A review of the literature, peer institutions and local practices of managing febrile neutropenia in healthy children was performed. Using the Model for Improvement, a guideline for the management of healthy children with first episode of febrile neutropenia was developed and refined using PDSA cycles. In January 2020, the guideline was launched for clinical use in the ED. Education, targeted audit and feedback, pathway modifications, and reminders were used to address knowledge gaps and staff turnover. A family of measures was analyzed using run charts and statistical process control (SPC) methods. Results Eighteen months of baseline data identified nineteen low risk patients with 84% either hospitalized and/or received antibiotics. It was also uncovered that many patients were misdiagnosed with neutropenia by excluding bands from the absolute neutrophil count (ANC). After the first twelve months of the intervention, sixteen patients met low risk criteria. Hospitalization and/or antibiotics use for this population decreased to 25% and all blood cultures were negative. Recognition of true severe febrile neutropenia also improved. Forty-one patients had a neutrophil count &lt; 0.5, but an ANC &gt; 0.5. Hospitalization and/or antibiotics use for this population decreased from 52% to 10%. Conclusion Through a multi-faceted, multidisciplinary QI study, we improved resource stewardship and value-based care by reducing unnecessary hospitalizations and antibiotics in low risk patients with a first episode of febrile neutropenia. Next steps include iterations to the guideline to increase impact along with sustainability planning. This work can easily be adopted by other pediatric and community sites caring for children.