Phenotype, cancer risk, and surveillance in Beckwith–Wiedemann syndrome depending on molecular genetic subgroups

Abstract

Patients with Beckwith-Wiedemann syndrome (BWS) have an increased risk to develop cancer in childhood, especially Wilms tumor and hepatoblastoma. The risk varies depending on the cause of BWS. We obtained clinical and molecular data in our cohort of children with BWS, including tumor occurrences, and correlated phenotype and genotype. We obtained similar data from larger cohorts reported in the literature. Phenotype, genotype and tumor occurrence were available in 229 of our own patients. Minor differences in phenotype existed depending on genotype/epigenotype, similar to earlier studies. By adding patients from the literature, we obtained data on genotype and tumor occurrence of in total 1,971 BWS patients. Tumor risks were highest in the IC1 (H19/IGF2:IG-DMR) hypermethylation subgroup (28%) and pUPD subgroup (16%) and were lower in the KCNQ1OT1:TSS-DMR (IC2) subgroup (2.6%), CDKN1C (6.9%) subgroup, and the group in whom no molecular defect was detectable (6.7%). Wilms tumors (median age 24 months) were frequent in the IC1 (24%) and pUPD (7.9%) subgroups. Hepatoblastoma occurred mostly in the pUPD (3.5%) and IC2 (0.7%) subgroups, never in the IC1 and CDKN1C subgroups, and always before 30 months of age. In the CDKN1C subgroup 2.8% of patients developed neuroblastoma. We conclude tumor risks in BWS differ markedly depending on molecular background. We propose a differentiated surveillance protocol, based on tumor risks in the various molecular subgroups causing BWS. © 2016 Wiley Periodicals, Inc.

Nomenclature and definition in asymmetric regional body overgrowth

“…This may allow separation of groups of affected individuals based on their molecular background or based on a pattern of concomitant subtle features that becomes evident. Such subdivisions may also indicate differences in nature, age of onset, reaction to various management schemes, prognosis, and risks for cancer in the affected individuals and their families, similar to what the recent studies in BWS have shown [Maas et al, 2016; Mussa et al, 2016]. …”

“…Recently two overviews have appeared on cancer risks and surveillance in Beckwith-Wiedemann syndrome (BWS) [Maas et al, 2016; Mussa et al, 2016]. This has prompted us as an international group of researchers to initiate a similar study of “isolated hemihyperplasia” (IHH; OMIM 23500), as IHH shares with BWS the body asymmetry and risk to develop cancer [Clericuzio and Martin, 2009].…”

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

“…100-102; Table 2), although NB is not generally considered a classic LFS tumor. In addition, patients with BWS due to mutations in CDKN1C have a 2% to 5% risk of developing NB (103,104), which is sufficiently high to warrant NB screening in these patients. Furthermore, several large studies looking broadly at somatic and germline mutations in children with cancer identified germline mutations in several other genes, including SDHB, APC, BRCA1, and BRCA2, in children with NB (105)(106)(107).…”

A Clinical Review of Generalized Overgrowth Syndromes in the Era of Massively Parallel Sequencing

“…Tumor risks were highest in the IC1 (H19/IGF2:IG-DMR) hypermethylation subgroup (28%) and pUPD subgroup (16%) and were lower in the KCNQ1OT1:TSS-DMR (IC2) subgroup (2.6%), CDKN1C (6.9%) subgroup, and in clinically diagnosed patients in whom no molecular defect was detectable (6.7%) [Maas et al, 2016].…”