Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and Kallmann Syndrome

The genetic basis is unknown for ∼60% of normosmic hypogonadotropic hypogonadism (nHH)/Kallmann syndrome (KS). DNAs from (17 male and 31 female) nHH/KS patients were analyzed by targeted next generation sequencing (NGS) of 261 genes involved in hypothalamic, pituitary, and/or olfactory pathways, or suggested by chromosome rearrangements. Selected variants were subjected to Sanger DNA sequencing, the gold standard. The frequency of Sanger-confirmed variants was determined using the ExAC database. Variants were classified as likely pathogenic (frameshift, nonsense, and splice site) or predicted pathogenic (nonsynonymous missense). Two novel FGFR1 mutations were identified, as were 18 new candidate genes including: AMN1, CCKBR, CRY1, CXCR4, FGF13, GAP43, GLI3, JAG1, NOS1, MASTL, NOTCH1, NRP2, PALM2, PDE3A, PLEKHA5, RD3, and TRAPPC9, and TSPAN11. Digenic and trigenic variants were found in 8/48 (16.7%) and 1/48 (2.1%) patients, respectively. NGS with confirmation by Sanger sequencing resulted in the identification of new causative FGFR1 gene mutations and suggested 18 new candidate genes in nHH/KS

Win or lose, nighttime transcystic laparoscopic common bile duct exploration is a win

Objectives Although controversial, recent data suggest nighttime versus daytime laparoscopic cholecystectomy (LC) have comparable outcomes. Laparoscopic common bile duct exploration (LCBDE) for choledocholithiasis decreases length of stay (LOS) as compared with LC with endoscopic retrograde cholangiopancreatography (ERCP) but increases case complexity/time. The influence of time of day on LCBDE outcomes has not been evaluated. Our aim was to examine outcomes and LOS for nighttime (PM) compared with daytime LC+LCBDE (DAY).Methods Consecutive patients who underwent LCBDE were reviewed. Demographics, operative duration, success of LCBDE, time to postoperative ERCP (if required), LOS, and complications were compared. PM procedures were defined as beginning 19:00–07:00 hours.Results Between 2018 and 2022, sixty patients underwent LCBDE (PM 42%). Groups had equivalent age/sex and preoperative liver function tests (LFTs). LCBDE success was 69% PM versus 71% DAY (p=0.78). Operative duration did not differ (2.8 IQR: 2.2–3.3 hours vs. 2.8 IQR: 2.3–3.2 hours, p=0.9). LOS was compared, and PM LOS was shorter (p=0.03). Time to ERCP after a failed LCBDE at night was compared with daytime (13.8 IQR: 10.6–29.5 hours vs. 19.9 IQR: 18.7–54.4 hours, p=0.07). LOS for failed PM LCBDE requiring ERCP was similar to successful DAY LCBDE (p=0.29). One complication (transient hyperbilirubinemia) was reported in the DAY group, none in PM.Conclusion PM LCBDE cases are equivalent in safety and success rate to DAY cases but have reduced LOS. Widespread adoption of acute care surgery-driven management of choledocholithiasis via LCBDE during cholecystectomy may decrease LOS, especially in PM cases.Level of evidence Level IV