IntroductionAdolescent idiopathic scoliosis (AIS) is a common musculoskeletal disorder with strong evidence for a genetic contribution. CNVs play an important role in congenital scoliosis, but their role in idiopathic scoliosis has been largely unexplored.MethodsExome sequence data from 1197 AIS cases and 1664 in-house controls was analysed using coverage data to identify rare CNVs. CNV calls were filtered to include only highly confident CNVs with >10 average reads per region and mean log-ratio of coverage consistent with single-copy duplication or deletion. The frequency of 55 common recurrent CNVs was determined and correlated with clinical characteristics.ResultsDistal chromosome 16p11.2 microduplications containing the gene SH2B1 were found in 0.7% of AIS cases (8/1197). We replicated this finding in two additional AIS cohorts (8/1097 and 2/433), resulting in 0.7% (18/2727) of all AIS cases harbouring a chromosome 16p11.2 microduplication, compared with 0.06% of local controls (1/1664) and 0.04% of published controls (8/19584) (p=2.28×10−11, OR=16.15). Furthermore, examination of electronic health records of 92 455 patients from the Geisinger health system showed scoliosis in 30% (20/66) patients with chromosome 16p11.2 microduplications containing SH2B1 compared with 7.6% (10/132) of controls (p=5.6×10−4, OR=3.9).ConclusionsRecurrent distal chromosome 16p11.2 duplications explain nearly 1% of AIS. Distal chromosome 16p11.2 duplications may contribute to scoliosis pathogenesis by directly impairing growth or by altering expression of nearby genes, such as TBX6. Individuals with distal chromosome 16p11.2 microduplications should be screened for scoliosis to facilitate early treatment.

Azole therapy is widely utilized in hematopoietic stem cell transplant (HCT) recipients for the treatment of aspergillus. Complications of voriconazole treatment related to its elevated fluoride content have been described in adults, including reports of symptomatic skeletal fluorosis. We review fluoride levels, clinical, and laboratory data in five pediatric HCT recipients on long-term voriconazole therapy, all found to have elevated serum fluoride levels. Two patients had toxic fluoride levels, one infant had symptoms of significant pain with movement and radiographs confirmed skeletal fluorosis. Monitoring fluoride levels in children, especially with skeletal symptoms, should be considered in patients on long-term voriconazole.

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Allo-HCT is the only potentially curative therapy for Chronic Myelomonocytic Leukemia (CMML). Objectives: To study the impact of allo-HCT on survival of CMML patients. Method: We compared the survival outcomes of patients who received (or not) an allo-HCT as a part of their front-line treatment strategy using The National Cancer Database (NCDB) from 2004-2015. Results: A total of 8,208 CMML patients were identified, but only 153 were allografted. Median follow-up of survivors was 33.6 months (95% CI=39.6-42.6). Allo-HCT recipients were more likely to be younger, of the male gender, had lower Charlson/Deyo co-morbidity score, had a higher median household income, being treated at an academic facility and having private insurance (Table 1). For survival analysis, we excluded 4484 patients who did not receive front-line therapy to better assess impact of allo-HCT on overall survival (OS). The median OS for patients who received chemotherapy alone or chemotherapy + allo-HCT was 13.3 (95% CI=12.7-14.0) months and 47.4 (14.5-80.4) months, respectively (p<0.001, Figure 1) After adjusting for baseline characteristics using Cox-regression modeling, allo-HCT results in better OS (HR=0.45, 95% CI=0.35-0.59, p<0.01). Age, high comorbidity score, treatment at community facility and year diagnosis before 2009 were associated with poor OS (Table 2). Positive impact of Allo-HCT on OS was maintained in a 6month landmark analysis after excluding patients who died or were lost follow-up within 6 months from diagnosis (HR= 0.59, 95% CI=0.45-0.77, p<0.01). Conclusion: Allo-HCT is an independent prognostic factor for improved OS in CMML.