Development of the Serum α-Fetoprotein Reference Range in Patients with Beckwith-Wiedemann Spectrum.

OBJECTIVE: To establish reference ranges for serum α-fetoprotein (AFP) at various ages in patients with Beckwith-Wiedemann spectrum (BWSp), to better predict the risk for hepatoblastoma in this population. STUDY DESIGN: A retrospective analysis of AFP measurements collected from patients with BWSp was performed. Factors including sex, prematurity, molecular diagnosis of patients, and performing laboratory were evaluated for significant differences. In total, 1372 AFP values were collected from 147 patients and the predictive AFP values at various ages were calculated to establish reference ranges. Mixed-effects polynomial regression models were used to study various potential factors affecting log(AFP) values. RESULTS: Overall, predicted AFP values declined to normal range for age (<10 ng/mL) by 14 months old. Patient sex and performing laboratory were found not to influence values. A significant difference was demonstrated between premature and nonpremature patients, and separate reference values were established. Significant differences in the predicted AFP value were not broadly apparent between molecular subtypes; however, interpretation was limited due to the small sample size of some of these subtypes. CONCLUSIONS: Predictive AFP values were created for premature and nonpremature patients with BWSp to aid with interpretation and monitoring of the risk for hepatoblastoma. Further analysis is needed to determine whether AFP values differ within the less common molecular subtypes of patients with BWSsp.

Cancer Risk in Beckwith-Wiedemann Syndrome: A Systematic Review and Meta-Analysis Outlining a Novel (Epi)Genotype Specific Histotype Targeted Screening Protocol.

OBJECTIVE: To compare tumor risk in the 4 Beckwith-Wiedemann syndrome (BWS) molecular subgroups: Imprinting Control Region 1 Gain of Methylation (ICR1-GoM), Imprinting Control Region 2 Loss of Methylation (ICR2-LoM), Chromosome 11p15 Paternal Uniparental Disomy (UPD), and Cyclin-Dependent Kinase Inhibitor 1C gene (CDKN1C) mutation. STUDY DESIGN: Studies on BWS and tumor development published between 2000 and 2015 providing (epi)genotype-cancer correlations with histotype data were reviewed and meta-analysed with cancer histotypes as measured outcome and (epi)genotype as exposure. RESULTS: A total of 1370 patients with BWS were included: 102 developed neoplasms (7.4%). Tumor prevalence was 2.5% in ICR2-LoM, 13.8% in UPD, 22.8% in ICR1-GoM, and 8.6% in patients with CDKN1C mutations. Cancer ORs were 12.8 in ICR1-GoM, 6.5 in UPD, and 2.9 in patients with CDKN1C mutations compared with patients with ICR2-LoM. Wilms tumor was associated with ICR1-GoM (OR 68.3) and UPD (OR 13.2). UPD also was associated with hepatoblastoma (OR 5.2) and adrenal carcinoma (OR 7.0), and CDKN1C mutations with neuroblastic tumors (OR 7.2). CONCLUSION: Cancer screening in BWS could be differentiated on the basis of (epi)genotype and target specific histotypes. Patients with ICR1-GoM and UPD should undergo renal ultrasonography scanning, given their risk of Wilms tumor. Alpha feto protein monitoring for heptaoblastoma is suggested in patients with UPD. Adrenal carcinoma may deserve screening in patients with UPD. Patients with CDKN1C mutations may deserve neuroblastoma screening based on urinary markers and ultrasonography scanning. Finally, screening appears questionable in cases of ICR2-LoM, given low tumor risk.