Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders.

Notch signaling is an established developmental pathway for brain morphogenesis. Given that Delta-like 1 (DLL1) is a ligand for the Notch receptor and that a few individuals with developmental delay, intellectual disability, and brain malformations have microdeletions encompassing DLL1, we hypothesized that insufficiency of DLL1 causes a human neurodevelopmental disorder. We performed exome sequencing in individuals with neurodevelopmental disorders. The cohort was identified using known Matchmaker Exchange nodes such as GeneMatcher. This method identified 15 individuals from 12 unrelated families with heterozygous pathogenic DLL1 variants (nonsense, missense, splice site, and one whole gene deletion). The most common features in our cohort were intellectual disability, autism spectrum disorder, seizures, variable brain malformations, muscular hypotonia, and scoliosis. We did not identify an obvious genotype-phenotype correlation. Analysis of one splice site variant showed an in-frame insertion of 12 bp. In conclusion, heterozygous DLL1 pathogenic variants cause a variable neurodevelopmental phenotype and multi-systemic features. The clinical and molecular data support haploinsufficiency as a mechanism for the pathogenesis of this DLL1-related disorder and affirm the importance of DLL1 in human brain development.

Interval appendectomy after perforated appendicitis: what are the operative risks and luminal patency rates?

BACKGROUND: The need for interval appendectomy after nonoperative management of a perforated appendicitis is being questioned owing to recent studies that estimated recurrence rates as low as 5% because of obliteration of the appendiceal lumen. We review our experience with interval appendectomy in this subset of patients to determine the postoperative outcomes and luminal patency rates. METHODS: A retrospective review was conducted of all children treated nonoperatively for a perforated appendicitis followed by elective interval appendectomy during the past 10 years. The data collected included initial hospitalization, convalescence period, perioperative course, and luminal patency rates. RESULTS: A total of 128 patients were identified, of whom 55% were male. Their mean ± SD age was 9.1 ± 4.2 years. The mean interval from the initial presentation to appendectomy was 65.9 ± 20.3 d. All but 2 of the patients underwent laparoscopic appendectomy with 3 conversions to open surgery. The mean operative time was 43.6 ± 19.2 min. The complication rate was 9%, including 1 postoperative abscess, 1 reoperation for bleeding, and 1 readmission for Clostridium difficile infection. Six patients had a superficial wound infection, and 2 patients underwent outpatient procedures for suture granuloma. No risk factors for complications were identified. Of the specimens, 16% had obliterated lumens. CONCLUSIONS: Major postoperative morbidity for interval appendectomy after a perforated appendicitis is low and should not be a deterrent in offering interval appendectomy to this subset of patients.