Genetic heterogeneity in Cornelia de Lange syndrome (CdLS) and CdLS-like phenotypes with observed and predicted levels of mosaicism.

BACKGROUND: Cornelia de Lange syndrome (CdLS) is a multisystem disorder with distinctive facial appearance, intellectual disability and growth failure as prominent features. Most individuals with typical CdLS have de novo heterozygous loss-of-function mutations in NIPBL with mosaic individuals representing a significant proportion. Mutations in other cohesin components, SMC1A, SMC3, HDAC8 and RAD21 cause less typical CdLS. METHODS: We screened 163 affected individuals for coding region mutations in the known genes, 90 for genomic rearrangements, 19 for deep intronic variants in NIPBL and 5 had whole-exome sequencing. RESULTS: Pathogenic mutations [including mosaic changes] were identified in: NIPBL 46 [3] (28.2%); SMC1A 5 [1] (3.1%); SMC3 5 [1] (3.1%); HDAC8 6 [0] (3.6%) and RAD21 1 [0] (0.6%). One individual had a de novo 1.3 Mb deletion of 1p36.3. Another had a 520 kb duplication of 12q13.13 encompassing ESPL1, encoding separase, an enzyme that cleaves the cohesin ring. Three de novo mutations were identified in ANKRD11 demonstrating a phenotypic overlap with KBG syndrome. To estimate the number of undetected mosaic cases we used recursive partitioning to identify discriminating features in the NIPBL-positive subgroup. Filtering of the mutation-negative group on these features classified at least 18% as 'NIPBL-like'. A computer composition of the average face of this NIPBL-like subgroup was also more typical in appearance than that of all others in the mutation-negative group supporting the existence of undetected mosaic cases. CONCLUSIONS: Future diagnostic testing in 'mutation-negative' CdLS thus merits deeper sequencing of multiple DNA samples derived from different tissues.

Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure.

Paracetamol (acetaminophen) hepatotoxicity, whether due to intentional overdose or therapeutic misadventure, is an indication for liver transplantation in selected cases. However, there is a concern that long-term outcomes may be compromised by associated psychopathology that may predispose patients to further episodes of self-harm or poor treatment adherence. We therefore undertook a retrospective analysis of patients transplanted for paracetamol-induced fulminant hepatic failure (FHF) to determine their long-term outcomes, psychiatric problems, and compliance and whether these issues could be predicted from pretransplant information. Records from patients undergoing liver transplantation for paracetamol-associated liver failure in this unit and 2 comparison groups (patients undergoing liver replacement for FHF from other causes and for chronic liver diseases) were examined. Of 60 patients transplanted for paracetamol-induced FHF between 1989 and 2007, 44 (73%) survived to discharge. Currently, 35 patients (58%) are surviving at an average of 9 years post-transplantation. The incidence of psychiatric disease (principally depression) and 30-day mortality were greatest in the paracetamol group, but for those who survived 30 days, there was no difference in long-term survival rates between the groups. Adherence to follow-up appointments and compliance with immunosuppression were lowest in the paracetamol overdose group. Poor adherence was not predicted by any identifiable premorbid psychiatric conditions. Two patients grafted for paracetamol FHF died from self-harm (1 from suicide and 1 from alcoholic liver disease after 5 years). This study suggests that, notwithstanding the shortage of donor liver grafts, transplantation is an appropriate therapy in selected patients, although close follow-up is indicated.

Anesthesia for pediatric lithotripsy.

SUMMARY BACKGROUND: We describe 7 years experience of providing anesthesia for children undergoing lithotripsy in a hospital without pediatric inpatient facilities. A pediatric team, including anesthetist, pediatric nurse along with the equipment travel across the city with the patient from the children's hospital. As a high incidence of postoperative vomiting and discomfort was observed, the effect of increasing intraoperative analgesia and the use of antiemetic medication was examined. METHODS: From 1998 to 2004, 69 children (49 boys and 20 girls) were anesthetized for 120 procedures: 67 extracorporeal shock wave lithotripsy (ESWL) and 53 endosurgical procedures, consisting of percutaneous nephrolithotomy (29), ureteroscopic laser lithotripsy (17) and percutaneous bladder litholapaxy (7). The mean age was 5.4 years (10 months to 13 years) and weight 23.7 kg (7.1-59 kg). ESWL was performed initially with a Wolf Piezolith 2300, and after 1999, a Dornier Compact Delta. RESULTS: Increased administration of intraoperative analgesia resulted in reduced postoperative analgesia requirements in all the groups, with a significant reduction (P < 0.05) in the endosurgical group. Those who required more postoperative analgesia had more vomiting significantly (P < 0.05). CONCLUSIONS: For ESWL postoperative pain is dependent on the type of lithotriptor and the resultant stone fragment size created. This study suggests that postoperative vomiting could be reduced more effectively by the increased administration of intraoperative analgesia, than by a single intraoperative dose of an antiemetic drug.