Genetic Drivers of Kidney Defects in the DiGeorge Syndrome

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)

Study of intestinal function in anorectal malformations: The role of bowel management in quality of life

Purpose: We aimed at investigating bowel function in children and adolescents with anorectal malformations (ARMs) and assess their quality of life (QoL), in order to define a personal program of bowel management improving both clinical condition and self-confidence. Methods: A total of 55 patients treated for ARM by Posterior Sagittal Ano-Recto-Plasty (PSARP) from 2000 to 2014 were included into the study. The parents of 41 patients answered two telephone questionnaires about the parents’ self-efficacy and about QoL (GIQLI). A modified Peña score system was used to evaluate intestinal function. Twenty patients underwent anorectal manometry. After clinical assessment, all patients underwent an individual bowel management program. A median follow-up of 91.3 months was performed. Results: A significant inverse correlation was found between Peña score and GIQLI (r:-0.93, p<0.0001). Anorectal manometry paralleled the Peña score, showing an association between megarectum and constipation and soiling subdomains, especially in patients with higher ARM. Patients who carefully followed the bowel management program had significant improvements in both continence (0.93±1.1 vs 0.45±0.9, p=0.0005) and Peña score (4.6±3 vs 3.4±2.5, p<0.0001), which positively affected their self-confidence (100±26.6 vs 110±23, p<0.0001). Conclusions: The synergy of different scores and the evaluation of anorectal physiology proved useful to define the bowel management program, which seems to significantly impact both bowel function and QoL, with specific regard to soiling. Moreover, the Peña score might be also quantitatively used, as it parallels with both anorectal manometry and GIQLI, and the latter seems to be suitable for children. Further studies are required to confirm our findings. (www.actabiomedica.it

Usefulness of intraoperative endoscopy in pediatric surgery: state of the art

Intraoperative endoscopy is a procedure that supports open and laparoscopic surgery, helping the surgeon to identify the presence of endoluminal gastrointestinal lesions which need to be treated, with a correct diagnosis and an adequate therapy

Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

BACKGROUND: The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS: We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS: We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10 CONCLUSIONS: We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.)