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SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n=50, mean age=8.5±7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41=49%) with a progressive decline in weight (95% CI=-2.3 to -1.1, p

e17001 Background: Prostate cancer is thought of as an immunologically cold tumor, however a small proportion of patients treated with immunotherapy have impressive responses. Studies into the effect of autoimmune disease on risk of prostate cancer have yielded contradictory results and little is known about the survival of patients with concurrent autoimmune disease and prostate cancer. This study compared outcomes in patients with prostate cancer with and without autoimmune disease. Methods: This study was a retrospective analysis of patients from the SEER-Medicare databases from 2007-2014 with prostate cancer. Patients with a history of autoimmune disease were identified using ICD-9 codes. The effects of autoimmune disease on overall survival (OS) and cancer-specific survival (CSS) were estimated using multivariable Cox regression and Gray’s method respectively controlling the effects of age, race and chronic kidney disease (CKD). The cumulative CSS was estimated taking death as a competing risk. Results: The overall prevalence of investigated autoimmune diseases among the 172,061 patients with prostate cancer was 23.74%. The most common autoimmune diseases identified were rheumatoid arthritis (RA) (20.93%), psoriasis (2.43%) and ulcerative colitis (UC) (0.91%). In stage IV prostate cancer, OS (p = 0.018) and CSS (p < 0.001) were significantly higher in patients with autoimmune disease, with a median OS of 55 months compared to 48 months in patients without autoimmune disease. After adjusting for the effects of age, race, and CKD, autoimmune disease was still predictive of higher OS (HR: 1.41, 95% CI: 1.33 – 1.5, p < 0.0001) and CSS (HR: 1.30, 95% CI: 1.21 – 1.39, p < 0.0001). Patients with autoimmune disease and stage II and III prostate cancer had lower OS (p values < 0.0001) compared to patients without autoimmune disease. Conclusions: The study showed higher prevalence of RA, Crohn disease, UC, and systemic lupus erythematosus in patients with prostate cancer compared to cohorts of similar age ranges in the general population. History of autoimmune disease predicted significantly higher OS and CSS in patients with stage IV prostate cancer even when age, race and CKD were controlled for. It is possible that an improvement in OS with a history of autoimmune disease was evident in stage IV but not in stages II and III because anti-tumor autoimmune activity plays a larger role when prostate cancer effects regional lymph nodes or has distant metastases.

Aminoacyl-tRNA synthetases (ARSs) are crucial enzymes for protein translation. Mutations in genes encoding ARSs are associated with human disease. Tyrosyl-tRNA synthetase is encoded by YARS which is ubiquitously expressed and implicated in an autosomal dominant form of Charcot-Marie-Tooth and autosomal recessive YARS-related multisystem disease. We report on a former 34-week gestational age male who presented at 2 months of age with failure to thrive (FTT) and cholestatic hepatitis. He was subsequently diagnosed with hyperinsulinemic hypoglycemia with a negative congenital hyperinsulinism gene panel and F-DOPA positron-emission tomography (PET) scan that did not demonstrate a focal lesion. Autopsy findings were notable for overall normal pancreatic islet size and morphology. Trio whole exome sequencing identified a novel homozygous variant of uncertain significance in YARS (c.611A > C, p.Tyr204Cys) with each parent a carrier for the YARS variant. Euglycemia was maintained with diazoxide (max dose, 18 mg/kg/day), and enteral dextrose via gastrostomy tube (G-Tube). During his prolonged hospitalization, the patient developed progressive liver disease, exocrine pancreatic insufficiency, acute renal failure, recurrent infections, ichthyosis, hematologic concerns, hypotonia, and global developmental delay. Such multisystem features have been previously reported in association with pathogenic YARS mutations. Although hypoglycemia has been associated with pathogenic YARS mutations, this report provides more conclusive data that a YARS variant can cause hyperinsulinemic hypoglycemia. This case expands the allelic and clinical heterogeneity of YARS-related disease. In addition, YARS-related disease should be considered in the differential of hyperinsulinemic hypoglycemia associated with multisystem disease.

e21500 Background: Half of patients (pts) with melanoma (mel) develop central nervous system (CNS) metastases (mets), leading to death in over 90% in the pre-immune checkpoint inhibitor (ICI) era. Overall survival (OS) has improved in the ICI era for those with CNS mets, yet the association of survival with ICI treatment for those with tumors harboring genomic variants (var) remains unclear. Methods: We retrospectively reviewed our electronic medical records to identify pts with mel and CNS mets who received ICI from 2010 to 2018. Treatment history, systemic and CNS responses, and genomic data were recorded. Genomic var were categorized as BRAFV600E (BRAF), NRAS, cKIT, other var, and no var. Concurrent RT (CRT) was defined as RT to CNS mets within 30 days of ICI. OS was calculated from date of first ICI or RT to date of death or last follow up, and comparison analyses made using Kaplan-Meier estimate. Fisher's exact or Chi-squared tests were used to compare categorical variables and Wilcoxon or Kruskal-Wallis tests to compare continuous variables. A two-sided p-value of < 0.05 was considered statistically significant. Results: A total of 49 pts were identified; 37 had var results available. BRAFV600E was the most common var identified (32%), followed by NRAS (19%), cKIT (5%), and other (5%); 38% had no var. BRAFV600K was not identified. Pts with BRAF had lower rates of CNS progression on ICI at 3 and 6 months than all other pts (17% vs 50%, p< 0.01 and 12.5% vs 40%, p< 0.01, respectively). Of 38 pts (10 BRAF) who had CNS mets at the start of ICI, 6-month OS was 50% in pts with BRAF, compared to 0% in pts with non-BRAF var ( p= 0.01) and 36% in pts with no var ( p= 0.7). 4 of the 10 pts with BRAF who had CNS mets at start of ICI received BRAF-targeted therapy after ICI. On ICI, only 30% of pts with BRAF developed new CNS mets, compared to 57% of all other pts ( p= 0.08). Pts who developed new CNS mets on ICI had worse OS than pts who did not (median OS (mOS) 314 days vs 662 days, p= 0.04). A majority of pts (55%) received anti-CTLA4 monotherapy as first ICI, and 39% received anti-CTLA4 plus anti-PD1. Pts with BRAF were just as likely to receive dual anti-CTLA4/PD-1 as pts without BRAF (33% vs 40%, p= 0.74). 40 pts underwent RT for CNS mets, of whom 22 received CRT. There was no difference in mOS between pts who received CRT and non-concurrent RT/no RT (468 days vs 314 days, p= 0.8). Rates of CRT between pts with BRAF and pts without BRAF were similar ( p> 0.9), and there was no difference in mOS between these groups (400 days vs 536 days, p= 0.9). Conclusions: Pts with BRAF-mutated mel with CNS mets receiving ICI had lower rates of progression in CNS and improved OS compared to other var. CRT was not associated with improved survival over non-concurrent RT. There has been significant improvement in OS of pts with mel CNS mets in the era of ICI and additional studies are warranted to understand the biology of BRAF var and the host immune system response in the CNS.