Alternative lengthening of telomeres (ALT) in pediatric high-grade gliomas can occur without ATRX mutation and is enriched in patients with pathogenic germline mismatch repair (MMR) variants.

BACKGROUND: To achieve replicative immortality, most cancers develop a telomere maintenance mechanism, such as reactivation of telomerase or alternative lengthening of telomeres (ALT). There are limited data on the prevalence and clinical significance of ALT in pediatric brain tumors, and ALT-directed therapy is not available. METHODS: We performed C-circle analysis (CCA) on 579 pediatric brain tumors that had corresponding tumor/normal whole genome sequencing through the Open Pediatric Brain Tumor Atlas (OpenPBTA). We detected ALT in 6.9% (n = 40/579) of these tumors and completed additional validation by ultrabright telomeric foci in situ on a subset of these tumors. We used CCA to validate TelomereHunter for computational prediction of ALT status and focus subsequent analyses on pediatric high-grade gliomas (pHGGs) Finally, we examined whether ALT is associated with recurrent somatic or germline alterations. RESULTS: ALT is common in pHGGs (n = 24/63, 38.1%), but occurs infrequently in other pediatric brain tumors (<3%). Somatic ATRX mutations occur in 50% of ALT+ pHGGs and in 30% of ALT- pHGGs. Rare pathogenic germline variants in mismatch repair (MMR) genes are significantly associated with an increased occurrence of ALT. CONCLUSIONS: We demonstrate that ATRX is mutated in only a subset of ALT+ pHGGs, suggesting other mechanisms of ATRX loss of function or alterations in other genes may be associated with the development of ALT in these patients. We show that germline variants in MMR are associated with the development of ALT in patients with pHGG.

Use of occipital bone graft in pediatric posterior cervical fusion: an alternative paramedian technique and review of the literature.

An alternative method of bone grafting for pediatric posterior cervical and occipitocervical fixation is presented in detail. Full-thickness autografts from small craniectomies of the occipital bone are used to augment posterior segmental fusion in pediatric patients. Twelve patients have been treated successfully without bone graft donor site complications. The technical differences from previously reported uses of calvarial autograft in spine fusion are reviewed.

Treatment of pediatric atlantoaxial instability with traditional and modified Goel-Harms fusion constructs.

There are several treatment options for rigid fixation at C1-C2 including Brooks and Gallie type wired fusions and C1-2 transarticular screws. The use of a Goel-Harms type fusion, a construct with C1 lateral mass screws and C2 pedicle screws, has not been extensively described in pediatric patients. Here, we describe its relatively safe and effective use for treating pediatric patients by retrospective chart review of patients treated by the senior author for atlantoaxial instability with a Goel-Harms-type constructs during a 3-year period (2005-2007). Six patients were treated using Goel-Harms-type constructs. Five patients were treated utilizing a construct containing C1 lateral mass screws and C2 pedicle screws; one patient was treated using construct containing C1 lateral mass screws and C2 trans-laminar screws. The patients ranged in age from 7 to 17 years old (mean 12.7). All patients had findings of an os odontoideum on CT scans and three of the six patients had T2 hyperintensity on MRI. Three of the six patients presented with transient neurologic deficits: quadraplegia in two patients and paresthesias in two patients. In each patient C1 lateral mass and C2 screws were placed and the subluxation was reduced to attain an anatomical alignment. No bone grafts were harvested from the iliac crest or rib. Local morsalized bone and sub-occipital skull graft was used. All patients tolerated the procedure well and were discharged home on post-operative day 3-4. The patients wore a hard cervical collar and no halo-vests were needed. All patients had solid fusion constructs and normal alignment on post-operative imaging studies performed on average 14 months post-operatively (range: 7-29). The results demonstrated that Goel-Harms fusions are a relatively safe and effective method of treating pediatric patients with atlantoaxial instability and are not dependent on vertebral anatomy or an intact ring of C1. Follow-up visits and studies in this limited series of patients demonstrated solid fusion constructs and anatomical alignment in all patients treated.