Correction: Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

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Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype–phenotype correlation

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors. Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study. Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_297

Genetic variation in apoptosis gene predicts neurocognitive impairment in children with medulloblastoma

Purpose: Medulloblastoma is the most common malignant brain tumor in children. As survival rates have risen, the importance of permanent side effects of therapy has grown. Neurocognitive impairment is one of the most prominent chronic toxicities of treatment. Age and craniospinal radiation (CSI) dose are established risk factors, however this adverse outcome cannot be predicted. We hypothesized that host genetic polymorphisms in pathways involved in the inflammatory response to radiation would be associated with neurocognitive impairment in children with medulloblastoma. ^ Experimental Design: This study included 40 children with medulloblastoma/primitive neuroectodermal tumor (PNET) seen at Texas Children\u27s Cancer Center or MD Anderson Cancer Center, who had been treated with CSI and had received a neuropsychological evaluation at least 9 months post-CSI. Subjects who had an intelligence-quotient score (full-scale, verbal, or performance) at or below 77.5 were deemed impaired. Genotyping of single nucleotide polymorphisms (SNPs) was performed using an Illumina HumanOmni1-Quad BeadChip. Only SNPs in relevant inflammation pathways were assessed. Odds ratios were estimated using unconditional logistic regression with adjustments for age group, CSI dose group, and a measure of population stratification. ^ Results: There were 19 children with neurocognitive impairment and 21 were unimpaired. In univariate analyses, these groups did not differ by demographic, disease, or therapy characteristics. No individual SNPs were associated with neurocognitive impairment in children with medulloblastoma/PNET. However, an apoptosis gene, Caspase-2 and Receptor Interacting Protein Kinase-1 Domain Containing Adaptor with Death Domain (CRADD ), haplotype (rs11107146, rs2304439, and rs12582133) was associated with the outcome in univariate and multivariable models. Subjects with an AGA haplotype were more than 7 times more likely to be impaired than those with a GAG haplotype (OR 7.8, 95%CI 1.1-53.9). ^ Conclusions: We have discovered a new association between CRADD and neurocognitive impairment in medulloblastoma/PNET. In the future, medulloblastoma patients with the at-risk genotypes may be considered for enrollment on clinical trials using reduced craniospinal radiation doses and/or novel anti-apoptotic strategies.

Considerations for total thyroidectomy in an adolescent with mutation

Individuals with PTEN Hamartoma Tumor Syndrome (PHTS) are at greatly increased risk for developing well-differentiated thyroid cancer. Specific circumstances in which total thyroidectomies should be considered have not been defined. A 14-year-old macrocephalic female with history of developmental delay and lipoma over her left flank presented with neck swelling and was found have multinodular goiter and auto-immune thyroiditis. Asymptomatic tracheal narrowing was also detected on her initial diagnostic imaging. Later on, she developed positional dyspnea during sleep. Genetic testing revealed a heterozygous pathogenic variant in the PTEN gene (c.463T>A). A total thyroidectomy was performed. In addition to addressing the symptomology in our case, a total thyroidectomy also fortuitously eliminated the thyroid cancer risk. This case spurred us on further to identify specific clinical scenarios where total thyroidectomy may be considered as a true prophylactic measure to manage thyroid cancer risk in PHTS patients

Surveillance Recommendations for Children with Overgrowth Syndromes and Predisposition to Wilms Tumors and Hepatoblastoma

A number of genetic syndromes have been linked to increased risk for Wilms tumor (WT), hepatoblastoma (HB), and other embryonal tumors. Here, we outline these rare syndromes with at least a 1% risk to develop these tumors and recommend uniform tumor screening recommendations for North America. Specifically, for syndromes with increased risk for WT, we recommend renal ultrasounds every 3 months from birth (or the time of diagnosis) through the seventh birthday. For HB, we recommend screening with full abdominal ultrasound and alpha-fetoprotein serum measurements every 3 months from birth (or the time of diagnosis) through the fourth birthday. We recommend that when possible, these patients be evaluated and monitored by cancer predisposition specialists. At this time, these recommendations are not based on the differential risk between different genetic or epigenetic causes for each syndrome, which some European centers have implemented. This differentiated approach largely represents distinct practice environments between the United States and Europe, and these guidelines are designed to be a broad framework within which physicians and families can work together to implement specific screening. Further study is expected to lead to modifications of these recommendations. (C) 2017 AAC