Trisomy 11p15 and Beckwith-Wiedemann syndrome. Report of two new cases

An association between trisomy 11p15 and Beckwith-Wiedemann syndrome is described in two brothers. The first presented at birth with gigantism and macroglossia, umbilical hernia and abdominal distention, hypoglycemia and atresia of the pulmonary artery, leading to the diagnosis of Beckwith-Wiedemann syndrome. Facial dysmorphism also included: a hypoplastic midface, hypertelorism, and a short nose with a flattened bridge. The karyotype showed a trisomy 11p15 with a monosomy 18p11, due to a t(11;18)(p154;p111)pat. His brother, born a year later, showed the same signs. The association between trisomy 11p15 and Beckwith-Wiedemann syndrome is in certain cases well established.     

Trisomy 11p15 and Beckwith-Wiedemann syndrome. A report of two cases

Summary Two patients with trisomy 11p15 and features of Beckwith-Wiedemann syndrome are reported. The first is a female infant with gigantism, macroglossia, abdominal hypotonia with umbilical hernia, moderate mental retardation, malformative uropathy, and atrial septal defect. Trisomy 11p15 was due to de novo duplication. The second patient was a stillborn (32–33 weeks pregnancy) with an abnormal tongue, posterior diaphragmatic eventration, inner organ congestion mainly of the adrenals. Trisomy 11p15 was due to a t(4;11)(q33;p14)pat. The association of trisomy 11p15 and Beckwith-Wiedemann syndrome is discussed with regard to cytogenetic data and the gene content of 11p, notably the genes coding for insulin and predisposition to Wilms tumour.     

Assessment of p57(KIP2) gene mutation in Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is an overgrowth disorder involving developmental anomalies, tissue and organ hyperplasia and an increased risk of embryonic tumours (most commonly Wilms' tumour). This multigenic disorder is caused by dysregulation of the expression of imprinted genes in the 11p15 chromosomal region. It may involve paternal uniparental disomy (UPD), loss of imprinting of the IGF2 gene, maternal inherited translocations and trisomy with paternal duplication. Recently, a small proportion of BWS patients has been shown to have a mutation in the paternal imprinted p57(KIP2) gene, which encodes a cyclin-dependent kinase inhibitor and negatively regulates cell proliferation. We screened for p57(KIP2) gene mutations in 21 BWS patients with no 11p15 UPD in leucocyte DNA. All patients had a phenotype typical of BWS. We analysed the entire coding sequence of p57(KIP2), including intron-exon boundaries, by direct sequencing of five PCR-amplified fragments. No mutation was found in the p57(KIP2) gene. Our results are consistent with those of previous studies showing that mutation of p57(KIP2) is infrequent in BWS. Thus, other mechanisms of p57(KIP2) silencing (imprinting errors) and/or other 11p15 genes are probably involved in the pathogenesis of BWS.     

Report of a trisomy 8p infant with carrier father.

This report describes an infant with fatal congenital heart disease, cleft palate, brain malformations, and trisomy 8p resultant from the paternal balanced reciprocal translocation, rcp(8;15) (p11;p11). Review of six previously reported trisomy 8p patients (resultant from parental balanced translocation in each instance) revealed severe mental retardation in five, short stature in all, and a variety of brain, skeletal, and cardiac defects. The features of the seven trisomy 8p patients reviewed here are not sufficiently similar to suggest a distinct dysmorphic syndrome. In addition the features differ from those in the trisomy 8 mosaicism syndrome, in which the mental retardation and malformations are generally less severe.     

Characterization of a panel of somatic cell hybrids for subregional mapping along 11p and within band 11p13

Summary The short arm of chromosome 11 carries genes involved in malformation syndromes, including the aniridia/genitourinary abnormalities/mental retardation (WAGR) syndrome and the Beckwith-Wiedemann syndrome, both of which are associated with an increased risk of childhood malignancy. Evidence comes from constitutional chromosomal aberrations and from losses of heterozygosity, limited to tumor cells, involving regions 11p13 and 11p15. In order to map the genes involved more precisely, we have fused a mouse cell line with cell lines from patients with constitutional deletions or translocations. Characterization of somatic cell hybrids with 11p-specific DNA markers has allowed us to subdivide the short arm into 11 subregions, 7 of which belong to band 11p13. We have thus defined the smallest region of overlap for the Wilms' tumor locus bracketed by the closest proximal and distal breakpoints in two of these hybrids. The region associated with the Beckwith-Wiedemann syndrome spans the region flanked by two 11p15.5 markers, HRAS1 and HBB. These hybrids also represent useful tools for mapping new markers to this region of the human genome.     

Trisomy 20p due to a paternal reciprocal translocation

A mentally retarded boy with multiple malformations was found to have trisomy for the distal two-thirds of the short arm of chromosome 20 (trisomy 20p), resulting from a paternal translocation (5;20)(p15;p11). The patient had a cleft palate, a feature not present in other trisomy 20p patients. A review of the reported trisomy 20p patients indicates that their varied features do no constitute a readily recognizable clinical syndrome.     

Normal dosage of the insulin and insulin-like growth factor II genes in patients with the Beckwith-Wiedemann syndrome.

Several patients in whom the Beckwith-Wiedemann syndrome (BWS) is associated with duplication of chromosomal region 11p15 have recently been observed. The genes encoding insulin and insulin-like growth factor II (IGF-II), proteins that affect cellular growth and pancreatic function, have been mapped to 11p15, and their increased expression might, thus, account for the physical features of BWS. To determine whether BWS is frequently associated with small duplications of 11p15, we performed dosage analyses of the insulin and IGF-II genes in somatic DNAs of seven patients with BWS. In each case, we observed apparent diploid representation of these genes. These data suggest that BWS is not frequently associated with small duplications of 11p15 material that embed the insulin and IGF-II genes.     

Paradoxical NSD1 mutations in Beckwith-Wiedemann syndrome and 11p15 anomalies in Sotos syndrome

Sotos syndrome is an overgrowth syndrome characterized by pre- and postnatal overgrowth, macrocephaly, advanced bone age, variable degrees of mental retardation, and typical facial features. Defects of the NSD1 gene account for >or=60% of cases of Sotos syndrome, whereas the disease-causing mechanism of other cases remains unknown. Beckwith-Wiedemann syndrome (BWS) is a distinct overgrowth condition characterized by macroglossia, abdominal-wall defects, visceromegaly, embryonic tumors, hemihyperplasia, ear anomalies, renal anomalies, and neonatal hypoglycemia. Deregulation of imprinted growth-regulatory genes within the 11p15 region is the major cause of BWS, whereas the molecular defect underlying a significant proportion of sporadic BWS cases remains unknown. Owing to clinical overlaps between the two syndromes, we investigated whether unexplained cases of Sotos syndrome could be related to 11p15 anomalies and, conversely, whether unexplained BWS cases could be related to NSD1 deletions or mutations. Two 11p15 anomalies were identified in a series of 20 patients with Sotos syndrome, and two NSD1 mutations were identified in a series of 52 patients with BWS. These results suggest that the two disorders may have more similarities than previously thought and that NSD1 could be involved in imprinting of the chromosome 11p15 region.     

Genetic linkage of Beckwith-Wiedemann syndrome to 11p15.

Beckwith-Wiedemann syndrome (BWS), characterized by multiorgan developmental abnormalities and predisposition to cancer, usually occurs sporadically, but small apparently dominant pedigrees have been described. Since rare patients show varying karyotypic abnormalities on the short arm of chromosome 11, it has been suggested that BWS may be related to the Wilms tumor gene on 11p13 or, alternatively, to growth factor genes on 11p15. We performed genetic linkage analysis on two BWS kindreds, using RFLPs for loci on 11p. BWS was linked to the insulin gene (11p15.5), with an overall maximum lod score of 3.60 (recombination fraction = .00). Linkage to D11S16 (11p13) could be excluded for recombination fractions less than or equal to .03. These results suggest that BWS defines a tumor-predisposition gene on 11p15.     

Molecular definition of the 11p15.5 region involved in Beckwith-Wiedemann syndrome and probably in predisposition to adrenocortical carcinoma

Summary To define more precisely, in molecular terms, the region involved in Beckwith-Wiedemann syndrome (BWS), we have studied patients with BWS and a constitutional duplication of 11p15 using eight 11p15 markers. In the first case with a de novo duplication and extra material on 11p, the region spanning pter to CALCA, excluded, was duplicated. In the second case, the rearrangement was characterized using somatic cell hybrids established with lymphocytes from the father who carried a balanced translocation t(11;18)(p15.4;p11.1). The breakpoint lay exactly in the same region. It could thus be inferred that the two sons, who were the first cases reported of BWS with dup11p15 and adrenocortical carcinoma (ADCC), carried a duplication similar to that observed in the first case. Together with evidence for specific somatic chromosomal events leading to loss of 11p15 alleles in familial cases of ADCC, it can be hypothesized that a gene involved in predisposition to ADCC maps to region 11p15.5.     

New p57KIP2 mutations in Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is characterized by numerous growth abnormalities and an increased risk of childhood tumors. The gene for BWS is localized in the 11p15.5 region, as determined by linkage analysis of autosomal dominant pedigrees. The increased maternal transmission pattern seen in the autosomal dominant-type pedigrees and the findings of paternal uniparental disomy reported for a subgroup of patients indicate that the gene for BWS is imprinted. Previously, we found p57 ^KIP2 , which is a Cdk-kinase inhibitor located at 11p15, is mutated in two BWS patients. Here, we screened for the mutation of the gene in 15 BWS patients. Received: 25 March 1997 / Accepted: 22 May 1997     

Imprinting centers, chromatin structure, and disease

Two regions that best exemplify the role of genetic imprinting in human disease are the Prader-Willi syndrome/Angelman syndrome (PWS/AS) region in 15q11-q13 and the Beckwith-Wiedemann syndrome (BWS) region in 11p15.5. In both regions, cis-acting sequences known as imprinting centers (ICs) regulate parent-specific gene expression bidirectionally over long distances. ICs for both regions are subject to parent-specific epigenetic marking by covalent modification of DNA and histones. In this review, we summarize our current understanding of IC function and IC modification in these two regions.     

Molecular characterization of Beckwith-Wiedemann syndrome (BWS) patients with partial duplication of chromosome 11p excludes the gene MYOD1 from the BWS region

The molecular characterization of two patients with features of Beckwith-Wiedemann syndrome (BWS) and chromosome abnormalities is consistent with the association of this phenotype with a duplication of a portion of chromosome 11. Quantitative Southern blot analysis of DNA from patient A defines a large inherited duplicated segment of chromosome 11. For patient B, a de novo duplication of unknown origin has been shown to contain a segment of 11p15. This chromosome segment includes the genes for insulin-like growth factor 2, beta-hemoglobin, calcitonin A (CALCA), and parathyroid hormone (PTH). However, the myogenic differentiation factor, MYOD1, is not included in the duplicated segment. This demonstrates that MYOD1 is proximal to CALCA and PTH and excludes MYOD1 as the BWS gene. These data place the BWS gene distal to MYOD1 on 11p15.     

Duplication of HRAS1, INS, and IGF2 is not a common event in Beckwith-Wiedemann syndrome

A few cases of Beckwith-Wiedemann syndrome (BWS) have in common a duplication of 11p15. Among the genes located in 11p15, c-Ha-ras 1 (HRAS1), insulin (INS), and insulin-like growth factor II (IGF2) may account for the clinical features and the increased risk for malignancy. Using eight 11p15 markers including HRAS1, INS and IGF2 we have studied eight sporadic and hereditary cases of BWS whether or not associated with a nephroblastoma. By gene dosage determination and family studies, we have shown the following: the eight patients examined had an apparent diploid representation of all of the eight markers studied, thus indicating that a microduplication of these markers or of the region characterized by these markers is not a common event in BWS; in a family with three affected sibs the genes for HRAS1 and INS/IGF2 did not cosegregate with BWS and therefore may not participate in the pathogenic processes here observed.     

Ring chromosome 11. A case report and review of the literature

A female infant with severe growth-weight retardation and with a ring chromosome 11, associated with trisomy X in 15% of metaphases, has been reported. A literature review of cases of r(11) shows that the clinical features of these patients, although showing different frequencies, are similar to those of the del(11q) syndrome. It has been suggested that the variability of the mental retardation in r(11) patients is attributable to the unstability of the ring and to the different break points in these two chromosomal rearrangements. The origin of the r(11) was also addressed by studying fragile sites of the parents at 11p15 and 11q25.     

Partial trisomy for the distal part of the short arm of chromosome 11 due to paternal translocations 11/5]

A girl with partial trisomy for the short arm of chromosome 11 resulting from an unbalanced translocation 46,XX,der 5, t(5,11) (p 15,p14) pat is described. The clinical findings are compared with those of other patients with partial trisomy 11p. The translocation in the balanced form was present in the fater, the brother, and the grandmother of the proposita.     

11p15.5-specific libraries for identification of potential gene sequences involved in Beckwith-Wiedemann syndrome and tumorigenesis.

Constitutional and somatic chromosomal abnormalities of the chromosome 11p15 region are involved in an overgrowth malformation syndrome, the Beckwith-Wiedemann syndrome (BWS), and in several types of associated tumors. The bias in parental origin for the different etiologic forms of this syndrome and for loss of heterozygosity in the tumors suggests that a gene (or genes) mapping to this region undergoes genomic imprinting. However, the precise localization of the locus (or loci) for the BWS and associated tumors is still unknown and more markers are required. We therefore isolated 11p15 markers from two libraries: the first one obtained by microdissection of the chromosome 11p15.5 region and the second one, a phage library, constructed from a hybrid cell line containing this region as its sole human DNA. Of 19 microclones isolated from the microdissection library, 11 were evolutionarily conserved. Four phage clones were isolated; one (D11S774) detected a highly informative variable number of tandem repeats (VNTR) and another (D11S773) a biallelic polymorphism. These clones were sublocalized using a panel of somatic cell hybrids that defines eight physical intervals in 11p15.5. Twenty-one clones map to the distal interval that harbors the BWS locus.     

Loss of alleles on the short arm of chromosome 11 in a hepatoblastoma from a child with Beckwith-Wiedemann syndrome

Summary The Beckwith-Wiedemann syndrome (BWS) is characterised by multiple congenital abnormalities, including exomphalos, macroglossia, and gigantism. It is also associated with an elevated risk of embryonal neoplasia and occasionally with constitutional anomalies of chromosome band 11p15. A common pathogenetic mechanism for the development of several embryonal tumours has been proposed involving the loss of somatic heterozygosity for a locus on the short arm of chromosome 11. In support of this hypothesis, we have recently reported generation of homozygosity for the c-Ha-ras-1 protooncogene in an adrenal adenoma from an adult BWS patient. In this study wer report the generation of homozygosity for a region on the short arm of chromosome 11 defined by the calcitonin (11p13-15) and insulin (11p15-15.1) genes in a hepatoblastoma from a child with BWS.     

Genetic analysis of tall stature

Tall stature is less often experienced as an important problem than short stature. However, a correct diagnosis may be of eminent importance, especially when interventions are planned, or to know the natural history. Overgrowth can be caused by endocrine disorders and skeletal dysplasias, but also by several genetic syndromes. Despite a systematic diagnostic approach, there will be patients with tall stature who do not fit a known diagnosis. In this group of patients possibilities of genetic analysis do exist, but are not common practice. The FMR1 gene should be analyzed in patients with tall stature and mental retardation, and in these patients the NSD1 gene can be considered whenever some features of Sotos syndrome do exist. In tall patients without mental retardation and some features of Sotos or Beckwith-Wiedemann syndrome it may still be useful to look for mutations in the NSD1 gene, but also for changes in the 11p15 region. The various possibilities are discussed and placed in a flowchart.