Isolated‐ and Beckwith‐Wiedemann syndrome related‐ lateralised overgrowth (hemihypertrophy): Clinical and molecular correlations in 94 individuals

Abstract

The congenital imprinting disorder, Beckwith‐Wiedemann syndrome (BWS) is associated with variable clinical features including hemihypertrophy/lateralised overgrowth (LO) and embryonal tumour predisposition. BWS‐associated (epi)genetic alterations occur in a subset of patients with isolated LO (ILO), leading to the concept of BWS spectrum disorder (BWSp). We investigated the relationship between clinical features and molecular diagnostic results in a cohort with LO using the BWSp international consensus group (BWSICG) clinical scoring system. Clinical/molecular findings in 94 previously‐unreported patients with LO referred for BWSp molecular studies were reviewed retrospectively. The BWSICG score was assigned and diagnostic rate calculated. BWSp‐associated (epi)genetic alteration was identified in 15/94 (16%). The molecular diagnostic rate by MS‐MLPA (blood DNA) for BWS‐related molecular findings in patients with LO was positively correlated with the BWSICG score. 3/48 with ILO had a molecular alteration. No individuals with ILO had developed an embryonal tumour at last follow up. Among a cohort of individuals with LO referred for BWSp molecular testing, the BWSICG score correlated with diagnostic yield. The embryonal tumour risk in children with ILO and negative molecular testing appeared very low, however longer‐ and more complete follow up is required to better define tumour risks in this group.

Characteristics Associated with Tumor Development in Individuals Diagnosed with Beckwith–Wiedemann Spectrum: Novel Tumor-(epi)Genotype-Phenotype Associations in the BWSp Population

“…There are several limitations of our study, which include potential cohort bias for the exploratory analyses, as previously discussed in the initial 2019 BWSp Cohort presentation [4]. Since this publication, multiple international cohorts have utilized these methods [19][20][21] providing strength in the methodology utilized in the present study and generalizability of our results. Furthermore, the BWS Registry is an international study and more than 10% of the cohort in this study are not from North America: 13 different countries/regions were represented in the present study cohort, including multiple countries in Europe and South America in addition to Australia and New Zealand.…”

“…The methodology for the BWS Registry database has been published previously [4], with replication of methodology applied to other BWSp cohorts [19][20][21]. A detailed description of the methodology applied for this study is available in Supplementary Appendix A; however, in brief, the BWS Registry collects longitudinal information about patients with a clinical or molecular diagnosis of BWSp through medical records and patient/family interviews as available.…”

Lateralized and Segmental Overgrowth in Children

“…However, currently few studies have evaluated what percentage of ILO cases is attributable to these specific genetic causes. Genetic testing carried out on the affected tissue (i.e., skin or muscle biopsy) rather than on leukocyte-extracted DNA allows increasing the rate of a molecular diagnosis in a relevant percentage of ILO cases [ 91 ]. Molecular tests include MS-MLPA for anomalies of the 11p15.5 region, SNP array and high-depth NGS of genes of the PI3K/AKT/mTOR and RAS/MAPK pathways; 11p15.5 methylation status testing on blood-extracted DNA allows to classify less than 6% of ILO cases as BWSp [ 91 ].…”

“…Genetic testing carried out on the affected tissue (i.e., skin or muscle biopsy) rather than on leukocyte-extracted DNA allows increasing the rate of a molecular diagnosis in a relevant percentage of ILO cases [ 91 ]. Molecular tests include MS-MLPA for anomalies of the 11p15.5 region, SNP array and high-depth NGS of genes of the PI3K/AKT/mTOR and RAS/MAPK pathways; 11p15.5 methylation status testing on blood-extracted DNA allows to classify less than 6% of ILO cases as BWSp [ 91 ]. This is likely related to both a mosaicism level lower than the sensitivity limits of the analytical method, and to an inadequate sampling of the affected tissue or a combination of both factors.…”

“…In the case of negativity to all molecular tests, a prudential clinical follow-up is adopted for such patients taking into consideration the possibility of low-expression forms of the molecular anomalies of the BWSp (i.e., the form with the highest oncogenic risk) and the related oncological implications. However, the literature indicates that ILO has a lower tumor risk than that of BWSp, with a risk ranging from 1.1% to 6% [ 91 , 92 , 93 , 94 ].…”