Beckwith-Wiedemann syndrome is an overgrowth multiple malformation disorder [3] with a predisposition for developing embryonal tumors (most commonly Wilms’ tumor or nephroblastoma). Its estimated prevalence [5] may be too low because of the marked variability in the syndome’s presentation and the difficulties in diagnosis when the clinical features are less prominent and likely to be ignored [8]. Consensus diagnostic criteria for BWS do not exist, although it is generally accepted that diagnosis requires the presence of at least three characteristic findings, two major and one minor [3] (Table 1). Our patient 1 had three major and three minor signs, while patient 2 had two major and three minor signs. None of our patients had neonatal hypoglycemia, which is a minor criterion. Clinically, BWS must be distinguished from other overgrowth disorders, particularly the Simpson-Golabi-Behmel, the Sotos, the Weaver and the Perlman syndromes, each of which is characterized by distinctive facial features and other signs [9].

Eighty-five percent of BWS cases are sporadic, while 15% result from vertical transmission. Beckwith-Wiedemann syndrome is associated with abnormal transcription and regulation of genes in the imprinted domain on chromosome 11p15.5 [6,7,10], which includes genes encoding growth factors and tumor suppressor genes. The paternally expressed genes (maternally imprinted) have growth enhancing activity and the maternally expressed genes (paternally imprinted) have growth suppressing activity. This region is organized into a telomeric domain which includes the IGF2 (Insulin Growth Factor II) and H19 genes, and a centromeric domain that includes the CDKN1C (Cyclin DependEnt Kinase Inhibitor 1C), KCNQ1 (potassium voltage-gated channel, subfamily Q, member 1) and KCNQ1OT1 (KCNQ1-Overlapping transcript 1) genes. Each domain is controlled by its own imprinting center (IC1 and IC2 for the telomeric and centromeric domains, respectively) [7].

Beckwith-Wiedermann syndrome can be caused by a variety of defects. Cytogenetic abnormalities account for 1-2% of the cases and consist of maternally inherited translocations or inversions and trisomy with paternal duplication. Various molecular abnormalities in the 11p15 region have been reported [11-14]: 1) 11p15 paternal uniparental disomy (UPD), the maternal allele is lost and the paternal allele is duplicated. This occurs in approximately 20% of cases. 2) Mutations in the CDKN1C gene for a maternally expressed cell-cycle regulator occur in about 5% of patients [15]. The phenotype is typical and includes a very high frequency of exomphalos. Mutation of the CDKN1C gene account for 60% of familial BWS cases.

Epigenetic abnormalities also occur in BWS: 1) hypermethylation of the H19 gene is found in 10% of cases. 2) Demethylation of KvDMR, a differentially methylated region at the 5' end of the KCNQ1OT1 gene, is involved in 55 to 60% of patients. The KCNQ1OT1 gene (also known as LIT1 or KvLQT1-AS) encodes an antisense transcript of the KCNQ1 gene and is normally expressed from the paternal allele [15-19]. 3) Microdeletions within IC1 (H19 DMR) [20] or IC2 (Intermediate Chain 2) [21] account for some BWS cases with hypermethylation of H19 or demethylation of KCNQ1OT1.

Management of patients with BWS requires the surgical cure of exomphalos, monitoring and eventual treatment of hypoglycemia in the neonatal period, treatment of macroglossia, and screening for embryonal tumor. For patient 2, we recommended surgical treatment for his macroglossia at a future time and screening for an embryonal tumor. The risk of recurrence in a family depends on the genetic cause of BWS present in the proband.