DNA replication-associated mutations are repaired by two components: polymerase proofreading and mismatch repair. The mutation consequences of disruption to both repair components in humans are not well studied. We sequenced cancer genomes from children with inherited biallelic mismatch repair deficiency (bMMRD). High-grade bMMRD brain tumors exhibited massive numbers of substitution mutations (>250/Mb), which was greater than all childhood and most cancers (>7,000 analyzed). All ultra-hypermutated bMMRD cancers acquired early somatic driver mutations in DNA polymerase ɛ or δ. The ensuing mutation signatures and numbers are unique and diagnostic of childhood germ-line bMMRD (P < 10(-13)). Sequential tumor biopsy analysis revealed that bMMRD/polymerase-mutant cancers rapidly amass an excess of simultaneous mutations (∼600 mutations/cell division), reaching but not exceeding ∼20,000 exonic mutations in <6 months. This implies a threshold compatible with cancer-cell survival. We suggest a new mechanism of cancer progression in which mutations develop in a rapid burst after ablation of replication repair.

Plain abdominal radiography is the current standard imaging modality for evaluation of necrotizing enterocolitis (NEC). Sonography is still not routinely used for diagnosis and follow-up, as it is not widely recognized that it can provide information that is not provided by plain abdominal radiography and that may affect the management of NEC. Like plain abdominal radiography, sonography can depict intramural gas, portal venous gas, and free intraperitoneal gas. However, the major advantages of abdominal sonography over plain abdominal radiography are that it can depict intraabdominal fluid, bowel wall thickness, and bowel wall perfusion. Sonography may depict changes consistent with NEC when the plain abdominal radiographic findings are nonspecific and inconclusive. Thinning of the bowel wall and lack of perfusion at sonography are highly suggestive of nonviable bowel and may be seen before visualization of pneumoperitoneum at plain abdominal radiography. The mortality rate is higher after perforation; thus, earlier detection of severely ischemic or necrotic bowel loops, before perforation occurs, could potentially improve the morbidity and mortality in NEC. The information provided by sonography allows a more complete understanding of the state of the bowel in patients with NEC and may thus make management decisions easier and potentially change outcome.

Background-Maternal anti-Ro and anti-La antibodies are associated with congenital heart block (CHB). Although endocardial fibroelastosis (EFE) has been described in isolated cases of autoantibody-mediated CHB, the natural history and pathogenesis of this disease are poorly understood. Methods and Results-We retrospectively reviewed the clinical history, echocardiography, and pathology of fetuses and children with EFE associated with CHB born to mothers positive for anti-Ro or anti-La antibodies at 5 centers. Thirteen patients were identified, 6 with a prenatal and 7 with a postnatal diagnosis. Six mothers were positive for anti-Ro and anti-La antibodies, and 7 were positive for anti-Ro antibodies only. Only 1 mother had autoimmune disease. Severe ventricular dysfunction was seen in all fetal and postnatal cases. Four fetal and 3 postnatal cases had EFE at initial presentation. However, 2 fetal and 4 postnatal cases developed EFE 6 to 12 weeks and 7 months to 5 years from CHB diagnosis, respectively, even despite ventricular pacing in 6 postnatal cases. Eleven (85%) either died (nϭ9) or underwent cardiac transplantation (nϭ2) secondary to the EFE. Pathologic assessment of the explanted heart, available in 10 cases, revealed moderate to severe EFE in 7 and mild EFE in 3 cases, predominantly involving the left ventricle.