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.     

Beckwith-Wiedemann syndrome. Clinical comparison between patients with and without 11p15 trisomy

Thirteen previously unreported patients with Beckwith-Wiedemann syndrome are reported. They include two unrelated patients having developed nephroblastoma, and three sibs. High resolution banding techniques failed to show any evidence of trisomy 11p15 in any of these 13 patients. The clinical pictures of Beckwith-Wiedemann syndrome with and without trisomy 11p15 are compared.     

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.     

An Integrated Physical Map of 210 Markers Assigned to the Short Arm of Human Chromosome 11

Using a panel of patient cell lines with chromosomal breakpoints, we constructed a physical map for the short arm of human chromosome 11. We focused on 11p15, a chromosome band harboring at least 25 known genes and associated with the Beckwith-Wiedemann syndrome, several childhood tumors, and genomic imprinting. This underlines the need for a physical map for this region. We divided the short arm of chromosome 11 into 18 breakpoint regions, and a large series of new and previously described genes and markers was mapped within these intervals using fluorescence in situ hybridization. Cosmid fingerprint analysis showed that 19 of these markers were included in cosmid contigs. A detailed 10-Mb pulsed-field physical map of the region 11p15.3-pter was constructed. These three different approaches enabled the high-resolution mapping of 210 markers, including 22 known genes.     

Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism.

The identification of polymorphic alleles at loci coding for functional genes is crucial for genetic association and linkage studies. Since the tryptophan hydroxylase (TPH) gene codes for the rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin, it would be advantageous to identify a polymorphism in this gene. By examining introns of the human TPH gene by PCR amplification and analysis by the single-strand conformational polymorphism (SSCP) technique, an SSCP was revealed with two alleles that occur with frequencies of .40 and .60 in unrelated Caucasians. DNAs from 24 informative CEPH families were typed for the TPH intron polymorphism and analyzed with respect to 10 linked markers on chromosome 11, between p13 and p15, with the result that TPH was placed between D11S151 and D11S134. This region contains loci for several important genes, including those for Beckwith-Wiedemann syndrome and tyrosine hydroxylase.     

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.     

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.     

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.     

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.     

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.     

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.     

Further clinical delineation in trisomy 1q32 syndrome.

A male newborn with multiple congenital abnormalities was studied. Clinically, he showed prominent forehead, facial dysmorphism, ear malformations, congenital heart defect and limb anomalies. The cytogenetic studies demonstrated a karyotype 46,XY, der(18) t(1;18)(q32;p11.3)pat with partial trisomy 1q32-qter and a monosomy 18p. The patient displayed clinical features of trisomy 1q but not of monosomy 18p. There are around 80 reports of trisomy 1q32. The purpose of this paper is to describe the first case of a translocation involving 1q and 18p chromosome breakpoints. Additional findings detected in the propositus permit us a further delineation of the trisomy 1q syndrome.     

Partial trisomy 8q and partial monosomy 18p: a case report

We report clinical observations and cytogenetic studies of an inherited partial trisomy 8q and partial monosomy 18p. A full trisomy 8 syndrome (Warkany syndrome) is a clinically recognized syndrome. Partial trisomy 8q has been reported sporadically in the literature with variable phenotypes. Partial monosomy 18p, deletion of the short arm of chromosome 18, is also a well-recognized syndrome. This is the first report to the best of our knowledge of partial trisomy for distal 8q and partial monosomy for distal 18p occurring together in a patient.     

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.     

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     

Trisomy 9p syndrome in two brothers: with new clinical findings and review of the literature

We report an eleven years old boy and his fourteen years old brother who both have trisomy 9p syndrome. Their cytogenetic analysis using GTL-banding showed 46,XY,der(22)add(22)(p11) karyotype. Cytogenetic analysis of their mother and sister revealed a karyogram designated as 46,XX,t(9;22) (9pter-->9p12::22p11-->22qter). With the help of FISH technique, the derivative chromosome in the proband was further confirmed to be a translocation chromosome 22 carrying the aforementioned segments from chromosome 9 which originated from a segregation event of a mother's balanced translocation. Regarding clinical aspects of our cases, both showed similar findings of 9p trisomy syndrome but low frontal hairline, circular placement of the hair around the face and scarce, inverted eyebrows, findings not previously mentioned in the literature. We conclude that these new clinical findings could be used in the clinical diagnosis of the 9p trisomy syndrome along with the other well-documented symptoms.     

Regional mapping of the parathyroid hormone gene (PTH) by cytogenetic and molecular studies.

The locus for the human parathyroid hormone gene (PTH) was assigned to a region proximal to 11p15.4 using restriction fragment length polymorphisms and gene dose studies performed on a patient with the Beckwith-Wiedemann syndrome accompanied with a chromosome abnormality [46,XX,-14,+der(14),t(14;11)(q32.3;p15.3)pat]. Our data suggest that PTH is localized in 11p15.3----p15.1, most likely near the border of the bands 11p15.4 and 11p15.3.     

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.     

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.     

P57KIP2 targeted disruption and beckwith-wiedemann syndrome: Is the inhibitor just a contributor?

Beckwith-Wiedemann syndrome is a human congenital disorder characterized by a wide variety of growth abnormalities, including developmental defects and predisposition to certain tumors. Genetic evidence has suggested a role for p57^KIP2, a member of a family of cell cycle inhibitory genes, in Beckwith-Wiedemann syndrome. Two independent groups^(1,2) have reported the generation and characterization of mice lacking functional p57^KIP2, These mice demonstrate a number of abnormal phenotypes which overlap with, although do not completely recapitulate, Beckwith-Wiedemann syndrome. These findings advance the molecular characterization of a human disorder, and provide insight into the interplay between regulation of cell division and development.