Abstract
Beckwith-Wiedemann syndrome spectrum (BWSp) is an overgrowth disorder caused by imprinting or genetic alterations at the 11p15.5 locus. Clinical features include overgrowth, macroglossia, neonatal hypoglycaemia, omphalocele, hemihyperplasia, cleft palate, and increased neoplasm incidence. The most common molecular defect observed is hypomethylation at the imprinting centre 2 (KCNQ1OT1:TSS DMR) in the maternal allele, which accounts for approximately 60% of cases, although CDKN1C pathogenic variants have been reported in 5-10% of patients, with a higher incidence in familial cases. In this study, we examined the clinical and molecular features of all cases of BWSp identified by the Spanish Overgrowth Registry Initiative with pathogenic or likely pathogenic CDKN1C variants, ascertained by Sanger sequencing or next-generation sequencing, with special focus on the neoplasm incidence, given that there is scarce knowledge of this feature in CDKN1C-associated BWSp. In total, we evaluated 21 cases of BWSp with CDKN1C variants; 19 were classified as classical BWS according to the BWSp scoring classification by Brioude et al. One of our patients developed a mediastinal ganglioneuroma. Our study adds evidence that tumour development in patients with BWSp and CDKN1C variants is infrequent, but it is extremely relevant to the patient's follow-up and supports the high heterogeneity of BWSp clinical features associated with CDKN1C variants.