Interstitial deletion 4p15.32p16.1 and complex chromoplexy in a female proband with severe neurodevelopmental delay, growth failure and dysmorphism.

Complex chromosomal rearrangements involve the restructuring of genetic material within a single chromosome or across multiple chromosomes. These events can cause serious human disease by disrupting coding DNA and gene regulatory elements via deletions, duplications, and structural rearrangements. Here we describe a 5-year-old female with severe developmental delay, dysmorphic features, multi-suture craniosynostosis, and growth failure found to have a complex series of balanced intra- and inter-chromosomal rearrangements involving chromosomes 4, 11, 13, and X. Initial clinical studies were performed by karyotype, chromosomal microarray, and FISH with research-based short-read genome sequencing coupled with sanger sequencing to precisely map her breakpoints to the base pair resolution to understand the molecular basis of her phenotype. Genome analysis revealed two pathogenic deletions at 4p16.1-p15.32 and 4q31.1, accounting for her developmental delay and dysmorphism. We identified over 60 breakpoints, many with blunt ends and limited homology, supporting a role for non-homologous end joining in restructuring and resolution of the seminal chromoplexy event. We propose that the complexity of our patient's genomic rearrangements with a high number of breakpoints causes dysregulation of gene expression by three-dimensional chromatin interactions or topologically associating domains leading to growth failure and craniosynostosis. Our work supports an important role for genome sequencing in understanding the molecular basis of complex chromosomal rearrangements in human disease.

Feeding and nutrition in children with medical complexity.

Providing adequate and appropriate nutrition to children with medical complexity (CMC) is often a challenging task. These patients are a diverse group whose varying nutritional needs must be carefully assessed and monitored. Optimal feeding and nutrition strategies in CMC require an individual approach and may include oral, enteral (gastric or jejunal), or parenteral provision of nutrients. Complications of enteral feeding, including those associated with medical devices such as feeding tubes, are common, and provider familiarity with some of the more common complaints is helpful. We provide here a summary of different feeding approaches, with exploration of the rationale for each, as well as discussion of common complications and some practical troubleshooting tips.

Expanding the phenotype, genotype and biochemical knowledge of ALG3-CDG.

Congenital disorders of glycosylation (CDGs) are a continuously expanding group of monogenic disorders of glycoprotein and glycolipid biosynthesis that cause multisystem diseases. Individuals with ALG3-CDG frequently exhibit severe neurological involvement (epilepsy, microcephaly, and hypotonia), ocular anomalies, dysmorphic features, skeletal anomalies, and feeding difficulties. We present 10 unreported individuals diagnosed with ALG3-CDG based on molecular and biochemical testing with 11 novel variants in ALG3, bringing the total to 40 reported individuals. In addition to the typical multisystem disease seen in ALG3-CDG, we expand the symptomatology of ALG3-CDG to now include endocrine abnormalities, neural tube defects, mild aortic root dilatation, immunodeficiency, and renal anomalies. N-glycan analyses of these individuals showed combined deficiencies of hybrid glycans and glycan extension beyond Man5 GlcNAc2 consistent with their truncated lipid-linked precursor oligosaccharides. This spectrum of N-glycan changes is unique to ALG3-CDG. These expanded features of ALG3-CDG facilitate diagnosis and suggest that optimal management should include baseline endocrine, renal, cardiac, and immunological evaluation at the time of diagnosis and with ongoing monitoring.

Alternate waiting list strategies for heart transplantation maximize donor organ utilization.

BACKGROUND: Alternate waiting list strategies have been promoted as a means to offer the benefit of heart transplantation to a greater number of candidates. We undertook the current study to evaluate our experience with transplantation in alternate list (AL) candidates. METHODS: Adults undergoing heart transplantation from January 1, 2001, through April 15, 2004, were evaluated. Selected patients who did not meet criteria for standard listing for heart transplantation were offered alternate listing. Primary posttransplant outcomes included 30-day, 90-day, and more than 90-day mortality, and determinants of perioperative morbidity. RESULTS: Thirty-seven patients (14.3%) met alternate list criteria. Among these alternate list patients, contraindications to standard listing included age greater than 65 years, amyloidosis, severe diabetes mellitus and peripheral vascular disease, human immunodeficiency virus, and high-risk retransplant. The average age of alternate list donors was 41.2 +/- 13.9 years. Survival analysis revealed no posttransplant survival advantage for standard list recipients However, mean ventilatory support time was significantly (p < 0.001) longer in the alternate list group (5.7 +/- 9.3 days) compared with the standard group (2.3 +/- 4.2 days), and significantly more sternal wound infections (p = 0.03) were observed in the alternate list group (6 [16.2%]) compared with the standard group (13 [5.9%]). CONCLUSIONS: The alternate list patients demonstrated comparable survival with standard list patients, but did exhibit more ventilatory dependence and sternal wound infections. More than half of alternate list donor organs in the future could be considered for standard list candidates as well. Use of the alternate list reinforces the assertion that, even today, our donor criteria remain too stringent.

Magnetic resonance imaging to detect acute cerebral events in on-pump and hybrid-pump patients.

BACKGROUND: Conventional cardiopulmonary bypass results in cerebral ischemic sequelae that may be reduced with hybrid pump technologies, such as the CardioVention system (CardioVention, Santa Clara, CA, USA). CardioVention differs from conventional bypass in that it has a novel air elimination module and reduced membrane surface area and priming volume. This preliminary study tested whether this pump confers neurological safety advantages over conventional bypass. METHODS: Ten patients were studied, with 6 assigned to on-pump coronary artery bypass grafting and 4 to the CardioVention system. No patients had any stroke history. Within 72 hours postsurgery, each underwent diffusion-weighted magnetic resonance imaging, a sensitive test for cerebral ischemic events. RESULTS: Two on-pump patients (33%) had postoperative findings on imaging, but none of the CardioVention patients demonstrated comparable changes ( P =.47). No patients had symptoms of acute stroke. CONCLUSION: Postoperative magnetic resonance imaging showed a trend toward a greater rate of ischemic events in patients undergoing traditional on-pump surgery. These preliminary findings suggest that hybrid pump technologies, such as the CardioVention system, may attenuate the risk of short-term neurological complications. Future studies are indicated to confirm these subclinical ischemic changes and to correlate them with long-term neurocognitive changes.

Effects of changes in UNOS policy regarding left ventricular assist devices.

Over the last 6 years, 161 patients underwent implantation of HeartMate single-lead vented electric (SLVE) devices as a bridge to transplantation. SLVE patients were retrospectively analyzed before and after United Network for Organ Sharing (UNOS) policy changes, and designated SLVE-1 and SLVE-2, respectively. Mean support time decreased significantly from 79.7 +/- 72.0 days to 55.3 +/- 60.5 days (p = 0.022). Although not statistically significant, rate of successful bridging to transplant increased from 70.3% to 74.7%, and post-transplant 1- and 3-year survival increased from 90.0% and 86.0%, respectively, to 92.9% and 87.3%, respectively.

Bridging to transplant with the HeartMate left ventricular assist device: The Columbia Presbyterian 12-year experience.

OBJECTIVE: Implantation of a left ventricular assist device as a bridge to transplantation has become an acceptable approach for patients with end-stage heart failure. Our long-term results with 3 Thoratec HeartMate devices are presented to outline improvements in successful bridging to transplantation and post-transplant survival. METHODS: From August 1990 through January 2003, 243 patients underwent implantation of Thoratec HeartMate devices as a bridge to transplantation. This included 52 (21.4%) pneumatic devices, 17 (7.0%) dual-lead vented electric devices, and 174 (71.6%) single-lead vented electric devices. RESULTS: Mean age was 49.7 +/- 13.7 years. Mean support time was 78.1 +/- 82.9 days (0-541). Bridging success increased from 63.5% (n = 33) for pneumatic devices to 64.7% (n = 11) for dual-lead vented electric devices and 72.4% (n = 126) for single-lead vented electric devices (P =.005). Posttransplant 1-, 3-, and 5-year actuarial survival increased from 87.5%, 78.1%, and 71.9% in patients with pneumatic devices to 91.5%, 86.9%, and 81.3%, respectively, for patients with single-lead vented electric devices. Device infection and malfunction occurred in 17.7% (n = 43) and 12.8% (n = 31) of patients, respectively. CONCLUSIONS: Successful bridging to transplantation and posttransplant survival has improved over time. Left ventricular assist devices have become increasingly more effective in bridging patients with end-stage heart failure to transplantation. This is likely due to a combination of better patient selection, improvements in clinical practice, and evolution in device design.

Early and medium-term results for repair of Ebstein anomaly.

OBJECTIVES: We evaluated the early and medium-term single-center results for primary repair of Ebstein anomaly in both adults and children. METHODS: The records were reviewed of patients undergoing repair of Ebstein anomaly at the Children's Hospital of New York from September 1990 to September 2002. Functional, demographic, and echocardiographic parameters were studied both preoperatively and postoperatively, along with functional status and adverse events. The repair technique involved vertical plication of the atrialized ventricle and valve leaflet reimplantation after clockwise rotation. RESULTS: A total of 25 patients (19 children and 6 adults) underwent repair. The average age was 14.2 +/- 15.9 years, and the average follow-up was 4.1 +/- 3.4 years. Three patients required reoperation for right ventricular overload (1 child) and progressive, severe tricuspid regurgitation (2 adults); both adults received tricuspid valve replacements, one at 4 years and the other at 8 years post-repair. Three patients had radiofrequency ablation procedures performed intraoperatively. Ten patients (40%) had moderate-to-severe tricuspid regurgitation perioperatively. However, 18 children (95%) and 5 adults (83%) demonstrated significant improvement in exercise capacity late postoperatively. Two children died suddenly 11 months and 4 years after repair. DISCUSSION: Ebstein repair has good functional outcomes in children despite residual tricuspid regurgitation, likely because of reduction in right ventricular volume loading and relative annular and ventricular plasticity. Adult patients did not demonstrate the same durability of valve repair and frequently required tricuspid valve replacement. Intraoperative radiofrequency ablation represents an important adjunctive treatment for intractable arrhythmias, which may now represent relative indications for operative intervention.