First case of pan-suture craniosynostosis due to de novo mosaic KAT6A mutation.

A nonverbal 3-year-old male with a complex past medical history was referred to pediatric neurosurgery for evaluation of Chiari I malformation. A full clinical evaluation suggested that the "Chiari" was a secondary change caused by craniocerebral disproportion that was the result of delayed pan-sutural craniosynostosis. Given his unknown cause of craniosynostosis, whole-exome sequencing (WES) was performed. WES revealed a de novo, somatic mosaic variant in the KAT6A gene. This report discusses importance of keeping a broad differential in the setting of referral for Chiari I malformation and presents a unique case of craniosynostosis. Additionally, it emphasizes the value of utilizing genetic testing for complex craniofacial cases with unknown causes to provide clinical answers and guide clinical management.

Evolution of the phenotype of craniosynostosis with dental anomalies syndrome and report of IL11RA variant population frequencies in a Crouzon-like autosomal recessive syndrome.

In 2011, biallelic loss-of-function variants in the interleukin receptor 11 alpha gene IL11RA were found to be associated with a Crouzon-like craniosynostosis syndrome with associated dental anomalies (CRSDA). Since then, a total of 41 similar patients have been reported with IL11RA variants. We report two adult brothers diagnosed with Crouzon syndrome as children, in which the clinical diagnosis of CRSDA was made on reevaluation. Laboratory testing detected biallelic IL11RA variants, c.916_924dup (p.Thr306_Ser308dup) and c.781C > T (p.Arg261Cys), both of which have now been reported in other families. Protein modeling and conservation analysis show that these two mutation sites cluster together near a WSXWS motif that likely plays a significant role in regulating IL11RA protein function. Population analysis from gnomAD shows that Non-Finnish Europeans (similar to ethnicity of this family), have an allele frequency for p.Thr306_Ser308dup of 0.014% and p.Arg261Cys of 0.008%. We found other ethnicities have functional IL11RA missense variants at higher frequencies. With this report, we provide a summary of the clinical findings including details of middle ear anomalies associated with conductive hearing loss. We also provide data supporting the populations at risk for this condition to increase recognition and diagnosis of this rare autosomal recessive craniosynostosis syndrome.

Chemoenzymatic Total Synthesis and Structural Diversification of Tylactone-Based Macrolide Antibiotics through Late-Stage Polyketide Assembly, Tailoring, and C-H Functionalization.

Polyketide synthases (PKSs) represent a powerful catalytic platform capable of effecting multiple carbon-carbon bond forming reactions and oxidation state adjustments. We explored the functionality of two terminal PKS modules that produce the 16-membered tylosin macrocycle, using them as biocatalysts in the chemoenzymatic synthesis of tylactone and its subsequent elaboration to complete the first total synthesis of the juvenimicin, M-4365, and rosamicin classes of macrolide antibiotics via late-stage diversification. Synthetic chemistry was employed to generate the tylactone hexaketide chain elongation intermediate that was accepted by the juvenimicin (Juv) ketosynthase of the penultimate JuvEIV PKS module. The hexaketide is processed through two complete modules (JuvEIV and JuvEV) in vitro, which catalyze elongation and functionalization of two ketide units followed by cyclization of the resulting octaketide into tylactone. After macrolactonization, a combination of in vivo glycosylation, selective in vitro cytochrome P450-mediated oxidation, and chemical oxidation was used to complete the scalable construction of a series of macrolide natural products in as few as 15 linear steps (21 total) with an overall yield of 4.6%.

Sex-specific Differences in IDH1-Wildtype Glioblastoma patients in the ReSPOND Consortium.

BACKGROUND: Understanding sex-based differences in glioblastoma patients is necessary for accurate personalized treatment planning to improve patient outcomes. PURPOSE: To investigate sex-specific differences in molecular, clinical and radiological tumor parameters, as well as survival outcomes in glioblastoma, isocitrate dehydrogenase-1 wildtype (IDH1-WT), grade 4 patients. METHODS: Retrospective data of 1832 glioblastoma, IDH1-WT patients with comprehensive information on tumor parameters was acquired from the Radiomics Signatures for Precision Oncology in Glioblastoma (ReSPOND) consortium. Data imputation was performed for missing values. Sex-based differences in tumor parameters, such as, age, molecular parameters, pre-operative KPS score, tumor volumes, epicenter and laterality were assessed through non-parametric tests. Spatial atlases were generated using pre-operative MRI maps to visualize tumor characteristics. Survival time analysis was performed through log-rank tests and Cox proportional hazard analyses. RESULTS: GBM was diagnosed at a median age of 64 years in females compared to 61.9 years in males (FDR = 0.003). Males had a higher Karnofsky Performance Score (above 80) as compared to females (60.4% females Vs 69.7% males, FDR = 0.044). Females had lower tumor volumes in enhancing (16.7 cm3 Vs. 20.6 cm3 in males, FDR = 0.001), necrotic core (6.18 cm3 Vs. 7.76 cm3 in males, FDR = 0.001) and edema regions (46.9 cm3 Vs. 59.2 cm3 in males, FDR = 0.0001). Right temporal region was the most common tumor epicenter in the overall population. Right as well as left temporal lobes were more frequently involved in males. There were no significant differences in survival outcomes and mortality ratios. Higher age, unmethylated O6-methylguanine-DNAmethyltransferase (MGMT) promoter and undergoing subtotal resection increased the mortality risk in both males and females. CONCLUSIONS: Our study demonstrates significant sex-based differences in clinical and radiological tumor parameters of glioblastoma, IDH1-WT, grade 4 patients. Sex is not an independent prognostic factor for survival outcomes and the tumor parameters influencing patient outcomes are identical for males and females. ABBREVIATIONS: IDH1-WT = isocitrate dehydrogenase-1 wildtype; MGMTp = O6-methylguanine-DNA-methyltransferase promoter; KPS = Karnofsky performance score; EOR = extent of resection; WHO = world health organization; FDR = false discovery rate.

Comparison of Robotic, Laparoscopic, and Open Unilateral Repair of Non-recurrent Inguinal Hernia.

BACKGROUND: There is a paucity of data comparing open, robotic, and laparoscopic approaches on unilateral, non-recurrent inguinal hernias. Our study presents a large, retrospective triple-arm outcome analysis between robotic, laparoscopic, and open unilateral, non-recurrent inguinal hernia repairs at a single institution. METHODS: 706 patients who underwent elective, non-recurrent inguinal hernia repair performed by 8 general surgeons at a single institution from 2016 to 2019 were reviewed retrospectively. Patient baseline characteristics, operative times, resident involvement, and postoperative outcomes were analyzed for all repair types. A cost analysis of the different procedures was performed. RESULTS: There were 305 laparoscopic repairs, 207 robotic repairs, and 194 open repairs. Open and laparoscopic repairs were performed on patients who were older (p =< .001) and with a higher Charlson Comorbidity Index (p =< .001). Patient BMI was higher in minimally invasive repair than open repair (P = .021). There were no significant differences in complication rates on pairwise analysis. Robotic and open repairs had significantly longer operative times than laparoscopic repairs (P < .001). There was less resident involvement in robotic repair than with the other approaches (P < .001). Resident involvement was associated with shorter OR times (P = .001) and no significant difference in postoperative complications. There was a trend over the study period toward faster operative times and more robotic repair. Robotic repair is the most expensive repair, followed by laparoscopic and open repairs. CONCLUSION: All 3 repair techniques can be performed without significant differences in outcomes. The technique utilized should be based on surgeon preference and patient characteristics.