Beckwith-Wiedemann Syndrome: Growth Pattern and Tumor Risk according to Molecular Mechanism, and Guidelines for Tumor Surveillance

Abstract

Background: Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with an increased risk of pediatric tumors. The underlying molecular abnormalities may be genetic (CDKN1C mutations or 11p15 paternal uniparental isodisomy, pUPD) or epigenetic (imprinting center region 1, ICR1, gain of methylation, ICR1 GOM, or ICR2 loss of methylation, ICR2 LOM). Aim: We aimed to describe a cohort of 407 BWS patients with molecular defects of the 11p15 domain followed prospectively after molecular diagnosis. Results: Birth weight and length were significantly higher in patients with ICR1 GOM than in the other groups. ICR2 LOM and CDKN1C mutations were associated with a higher prevalence of exomphalos. Mean adult height (regardless of molecular subtype, n = 35) was 1.8 ± 1.2 SDS, with 18 patients having a final height above +2 SDS. The prevalence of tumors was 8.6% in the whole population; 28.6 and 17.3% of the patients with ICR1 GOM (all Wilms tumors) and 11p15 pUPD, respectively, developed a tumor during infancy. Conversely, the prevalence of tumors in patients with ICR2 LOM and CDKN1C mutations were 3.1 and 8.8%, respectively, with no Wilms tumors. Conclusion: Based on these results for a large cohort, we formulated guidelines for the follow-up of these patients according to the molecular subtype of BWS.

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

“…4,[9][10][11]13,[27][28][29] In this study we further investigated these correlations providing data on a large cohort of fully characterized BWS patients with 11p15 region molecular defects. Our analysis evidences in the four BWS molecular subtypes differences in the incidence of many phenotypic traits, such as growth pattern, prevalence and severity of abdominal wall defects, macrosomia, nevus flammeus, ear signs, renal malformations, ureteral anomalies, organ enlargement, polyhydramnios, cancer incidence, and histotypes.…”

“…39 As concerns tumor risk, the overall prevalence of cancer approximates 8%, consistent with other studies. 10 It is well established that patients with telomeric defects (IC1-GoM/UPD) have a major risk of tumors, especially Wilms' tumor, whereas patients with defects of the centromeric domain (IC2-LoM/CDKN1C variant) have a lower risk. 4,9,10,40 Our data also point to a gradient of oncogenic risk between the three main molecular subgroups.…”

“…10 It is well established that patients with telomeric defects (IC1-GoM/UPD) have a major risk of tumors, especially Wilms' tumor, whereas patients with defects of the centromeric domain (IC2-LoM/CDKN1C variant) have a lower risk. 4,9,10,40 Our data also point to a gradient of oncogenic risk between the three main molecular subgroups. At one end of the spectrum, patients with IC2-LoM have a very low risk of tumors and can develop histotypes seen in both IC1-GoM and IC2-LoM cases; furthermore, UPD cases show a previously unreported predisposition to hepatoblastoma, the second more common histotype of BWS, occurring in 1.6% of BWS patients, that is, 6% of UPD cases.…”

“…We did not observe hepatoblastoma in the other molecular subgroups, but cannot conclude that hepatoblastoma occurs only in UPD cases, as three cases have been described in IC2-LoM patients previously. 4,10 Few data are available on benign neoplasms in BWS; [40][41][42] interestingly, their incidence is a gradient across the molecular subtypes paralleling that of malignancies: highest (~13%) in IC1-GoM, intermediate (~7%) in UPD, and lower (~4%) in IC2-LoM patients. Among benign histotypes observed, hepatic angiomas were prevailing, and no differences were detectable across the molecular subgroups.…”

“…4,[9][10][11]13,[27][28][29] Some aspects emerge as new: in particular, the significant association between hepatoblastoma and UPD may have relevant implications for cancer screening, the association between IC2-GoM and uretheral defects and polyhydramnios may have implications for the neonatal nephrourological management, the higher incidence of benign neoplasm paralleling the distribution of the malignant ones should be taken into considerations during patients' follow-up. Finally, IC2-LoM/CDKN1C variant patients display a higher rate of postnatal overgrowth, poorly studied before; as in these molecular subgroups neonatal macrosomia is rarer than in UPD/IC1-GoM ones 13 clinicians should be aware that these molecular subtypes of BWS may display specific growth patterns after the neonatal period.…”