BECKWITH–WIEDEMANN SYNDROME (EMG SYNDROME AND IGF2 OVERGROWTH DISORDER)
This syndrome, with an estimated incidence of 1 in 14,000, is characterized by major (pre- and/or postnatal overgrowth, anterior abdominal wall defects (diastasis recti, umbilical hernia, or exomphalos), and macroglossia) and minor features (earlobe grooves or helical rim pits, facial nevus flammeus, visceromegaly (liver, kidney, spleen), neonatal hypoglycemia, hemihypertrophy, renal anomalies, cryptorchidism, and, infrequently, cardiac defects). In addition, embryonal Tumours occur in ~8 % of patients (though the risk depends on the underlying specific genetic/epigenetic abnormality) (Wiedemann et al. 1983; Hatada et al. 1996; Koufos et al. 1989).
There are no consensus clinical diagnostic criteria for Beckwith– Wiedemann syndrome (BWS). Strict diagnostic criteria were suggested by Elliott and Maher (1994) that required the presence of (1) three major features or (2) two major features plus three minor features (from ear creases or pits, hypoglycemia, nephromegaly, or hemihypertrophy), but less strict diagnostic criteria have also been proposed, for example, at least two from (a) positive family history; (b) macrosomia (height and weight >97 percentile); (c) anterior linear earlobe creases/posterior helical ear pits; (d) macroglossia; (e) exomphalos/umbilical hernia; (f) visceromegaly involving one or more intra-abdominal organs including liver, spleen, kidneys, adrenal glands, and pancreas; (g) embryonal Tumours (e.g., Wilms Tumours, hepatoblastoma, rhabdomyosarcoma) in childhood; (h) hemihypertrophy; (i) adrenocortical cytomegaly; (j) renal abnormalities including structural abnormalities, nephromegaly, and nephrocalcinosis; and (k) cleft palate (rare) and one from (a) polyhydramnios, (b) neonatal hypoglycemia, (c) facial nevus flammeus, (d) hemangioma, (e) characteristic facies including midfacial hypoplasia and infraorbital creases, (f ) cardiomegaly/structural cardiac anomalies/rarely cardiomyopathy, and (g) diastasis recti and advanced bone age (http://www. geneclinics.org). However, molecular genetic testing can diagnose most cases (Cooper et al. 2005).
The characteristic craniofacial dysmorphological features of Beckwith– Wiedemann syndrome (BWS) are most apparent before the age of 3 years, and after the age of 5 years, there are often only minor dysmorphisms. The differential diagnosis of BWS includes Perlman syndrome, Simpson–Golabi–Behmel syndrome, and other overgrowth disorders, such as Weaver or Sotos syndrome.
The genetics of BWS are complex (Choufani et al. 2010; Lim and Maher 2010). Most cases are sporadic but ~15 % of cases are familial. The inheritance pattern of familial cases is dependent on the nature of the genetic cause, but in most cases, it will be an autosomal dominant trait with parent-of-origin effects such that the penetrance is more complete when the mother is the transmitting parent, and examples of transmitting males with affected children are rare. As there is wide variation in expression of the disease and the features of BWS tend to become less apparent with age, it is likely that some familial cases of BWS are misdiagnosed clinically as sporadic cases because minor manifestations in relatives are overlooked.
Though characterization of the molecular pathology in an individual case may indicate whether the disorder is likely to be sporadic or familial, careful examination of close relatives (particularly the mother) should be performed.
An association between twinning and BWS has been recognized. Thus a greater than expected number of twins have been described among BWS children, and these are usually female monozygotic twins that are discordant for BWS (Bliek et al. 2009).
The parent-of-origin effects on the penetrance and expression of familial BWS suggested a genomic imprinting disorder, and molecular tests have confirmed that BWS results from abnormal function/expression of imprinted genes (in particular the paternally expressed growth factor IGF2 and the maternally expressed growth suppressor CDKN1C) contained within a cluster of imprinted genes at chromosome 11p15.5. Interestingly, the frequency of BWS and some other genomic imprinting disorders appears to be increased in children conceived by assisted reproductive technologies (both ICSI and in vitro fertilization) (DeBaun et al. 2003; Maher et al. 2003; Lim et al. 2009). Though the relative risk of having a child with BWS is increased after BWS (probably up to tenfold), the absolute risk appears to be small (less than 1 in 1,000).
BWS may result from chromosomal rearrangements (duplications or translocations/inversions of distal chromosome 11p), uniparental disomy of 11p15.5, mutations, or epimutations directly involving the two 11p15.5 imprinting control regions (IC1 and IC2). In addition, germline mutations in CDKN1C or inactivation of NLRP2 in the mother can cause familial BWS (Cooper et al. 2005; Choufani et al. 2010; Lim and Maher 2010).
Chromosome 11p15.5 was first implicated in BWS by the finding of paternally derived duplications of 11p15.5 in BWS patients. Subsequently maternally inherited balanced rearrangements of 11p15 were also demonstrated to be associated with BWS. It is estimated that up to 3 % of BWS patients have a cytogenetically visible chromosome duplication or rearrangement. Chromosome 11 paternal uniparental disomy is found in approximately 20 % of sporadic cases of BWS. Typically uniparental disomy in BWS is mosaic paternal isodisomy, and although the disomic region always includes the imprinted gene cluster at 11p15.5, the involvement of more centromeric regions of 11p and of 11q is variable. A few patients diagnosed with BWS have been demonstrated to have whole genome paternal uniparental disomy, and these cases appear to have an increased risk of neoplasia (e.g., pheochromocytoma, hepatoblastoma) (Romanelli et al. 2011).
Epigenetic errors at two putative imprinting control regions within 11p15.5 (IC1 and IC2) have also been implicated in BWS. Thus, 5 % of BWS patients have an imprinting defect at the distal imprinting center (IC1) such that the maternal IGF2 and H19 alleles display a paternal epigenotype (hypermethylation and silencing of H19 and biallelic IGF2 expression). In up to 50 % of cases, there is the loss of paternal methylation at IC2 (KvDMR1) that is associated with silencing of CDKN1C expression and variable loss of imprinting (biallelic expression) of IGF2. Cases associated with assisted reproductive technologies and those that occur in twins are very likely to have loss of paternal methylation at IC2 (KvDMR1). In general the risk of recurrence after a child with an imprinting center epimutations is very low if an in cis duplication or deletion has been excluded. However, in rare cases, an epimutation may result as an in trans effect of maternal homozygosity for a NALP2 mutation (Meyer et al. 2009).
Germline inactivating CDKN1C mutations occur in about half of familial cases and 5 % of sporadic cases (Lam et al. 1999). CDKN1C is expressed from the maternal allele (though there is a small level of paternal allele expression), and so a paternally transmitted mutation has minimal effect on the children who inherit the mutation. In contrast, a maternally inherited CDKN1C mutation will cause BWS (Maher and Reik 2000).
Genotype-phenotype correlations have been described for hemihypertrophy and exomphalos. Most cases with hemihypertrophy have mosaic uniparental disomy. There is a high incidence of exomphalos in patients with CDKN1C mutations and IC2 imprinting center defects, but exomphalos is infrequent in patients with uniparental disomy or IC1 imprinting center defects. In addition to patients with classical BWS, Morison et al. (1996) reported that some patients with overgrowth and nephromegaly or Wilms Tumours may have biallelic IGF2 expression, and they coined the term “IGF2 overgrowth disorder” to describe these patients (Gicquel et al. 2003).
Patients with BWS have an increased risk of neoplasia. Wiedemann (1983) reviewed 388 children with BWS and found 29 children (7.5 %) with 32 Tumours. Most Tumours (26/29) were intra-abdominal (including 14 Wilms Tumours, 5 adrenal carcinomas, and 2 hepatoblastomas). Most Tumours occur before the age of 5 years. A clinical association between hemihypertrophy and neoplasia in BWS was noted, and among patients with BWS, the risk of Wilms Tumours is highest in those with uniparental disomy and IC1 imprinting center defect, and the risk of Wilms Tumours appears minimal in those with IC2 imprinting center defects and CDKN1C mutations (Engel et al. 2000; Weksberg et al. 2003; DeBaun et al. 2002; Cooper et al. 2005). Thus, in one study the risk of embryonal Tumours was 9 % at age of 5 years in all cases but 24 % in those with uniparental disomy (Cooper et al. 2005). As the risk of Wilms Tumours appears to be very low in children with IC2 imprinting defects and CDKN1C mutations, there is no indication for Wilms Tumours surveillance (e.g., 3-monthly renal ultrasonography) in such cases. However, hepatoblastoma can occur in children with IC2 defects, and though the absolute risk of hepatoblastoma is low and the utility of screening for hepatoblastoma alone is unproven, some parents may request surveillance by serum alpha-fetoprotein measurements.