Mechanisms of in utero overgrowth

Determination of the mechanisms that lead to in utero overgrowth has proved elusive. Recently, however, our knowledge has significantly expanded as a result of the generation of experimental mouse models, engineered to disrupt the expression of one or more genes (knockout mice), and by detailed molecular and genetic analyses of infants and children with overgrowth syndromes. Studies of knockout mice have largely defined the essential roles of the insulin-like growth factors (IGF-I and IGF-II), insulin and their receptors in embryonic and fetal growth, and have provided compelling evidence that increased IGF-II gene expression and/or abundance can stimulate excessive fetal somatic growth. The IGF-II gene is usually expressed only by the paternally derived allele; however, when this imprinting is erased and IGF-II expression is biallelic, fetal overgrowth ensues. Such increased IGF-II expression would appear to explain the overgrowth in Beckwith-Wiedemann syndrome. Using the information gathered from knockout mice as a guide to human studies, detailed genetic investigations are likely to unravel the mechanisms behind other human overgrowth syndromes.     

IGF, IGF receptor and overgrowth syndromes

The insulin-like growth factors are a family of growth factors, binding proteins and receptors that are involved in normal growth as well as in a number of pathological states. Overgrowth syndromes are a group of disorders characterized by a phenotype of excessive somatic and visceral growth. In addition, patients suffering from overgrowth syndromes are predisposed to develop cancer. Several specific defects linked to the insulin-like growth factor system were elucidated for a group of these disorders, including Simpson-Golabi-Behmel syndrome, Bannayan-Ruvalcaba-Riley syndrome and Beckwith-Wiedemann syndrome. The aim of this review is to examine recent data linking the phenotype of overgrowth syndromes, visceral growth and increased risk of neoplasia, with the molecular machinery of the IGF system.     

Molecular biology of Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome associated with a predisposition to embryonal tumors, most commonly Wilms' (WT). Overlapping clinical phenotypes are seen in two other disorders, Simpson-Golabi-Behmel syndrome (SGBS) and Perlman syndrome (PS). BWS is a genetically heterogeneous disorder most often associated with normal chromosome and a negative family history. However, autosomal dominant transmission of BWS is reported, as are chromosome 11p15.5 abnormalities, uniparental paternal disomy (UPD) of chromosome 11p15.5, and altered expression of the imprinted gene insulin-like growth factor 2 (IGF2) from the normally repressed maternal allele. Crucial to our understanding of the large variety of genetic presentations in BWS is the concept of genomic imprinting, a process in which gene expression specific to parent-of-origin is observed. The current genetic and molecular data for BWS are best explained by a model assuming an imprinted domain for 11p15.5, whereby altered expression of one or more genes in this region contributes to the BWS phenotype. In this model, a defined chromatin structure is reflected in coordinated control of multiple genes in the domain, as well as specific patterns of replication timing and gene expression. Data supporting this viewpoint include the maternally derived 11p15.5 translocation breakpoints associated with BWS, and the recent finding that the normally asynchronous pattern of replication timing for the imprinted gene IGF2 can be disrupted, shifted by a BWS-associated translocation 400 kb from IGF2. As we unravel the molecular basis of the different BWS patient subgroups, we will achieve a better understanding of this overgrowth syndrome and its relationship to WT. © 1996 Wiley-Liss, Inc.     

Udział epigenetycznych i genetycznych defektów regionu 11p15 w etiologii zespołu Beckwitha i Wiedemanna

Epigenetic processes, including genomic imprinting, are important for normal human growth and development. Beckwith-Wiedemann syndrome (BWS) is a disorder characterized by pre- and postnatal overgrowth in children, abdominal wall defects, macroglossia and a high risk of tumors. BWS is caused by different molecular defects of the 11p15 region containing several imprinted genes. The genes are localized into two domains: the first one is controlled by the imprinting control region ICR1 and the second one is controlled by ICR2. Epigenetic and genetic disturbances observed in BWS include ICR1 hypermethylation, ICR2 hypomethylation, paternal uniparental disomy, deletions, duplications, translocations, inversions in the 11p15 region, and point mutations in the CDKN1C gene. In this work new findings about Beckwith-Wiedemann syndrome etiology and molecular diagnostics are presented.     

Advances in overgrowth syndromes: clinical classification to molecular delineation in Sotos syndrome and Beckwith-Wiedemann syndrome

PURPOSE OF REVIEW: The clinical importance of overgrowth syndromes in the pediatric patient population has been increasingly recognized during the past decade, but clinical overlap among overgrowth syndromes often makes diagnostic categorization difficult. Advances in the molecular delineation of overgrowth syndromes in recent years have furthered our knowledge of the phenotypic spectrum of this group of conditions. This review focuses on developments in our understanding of the molecular mechanisms and phenotype-genotype correlations in the two most common overgrowth syndromes, Beckwith-Wiedemann syndrome and Sotos syndrome. The implications of these findings with respect to clinical diagnosis, medical management, and genetic counseling are discussed. RECENT FINDINGS: Recent reports have redefined the cardinal clinical features of Sotos syndrome, and the identification of two distinct types of molecular alterations in patients with this syndrome has enabled assessment of phenotype-genotype correlations. Recent studies in patients with Beckwith-Wiedemann syndrome have further expanded our understanding of the causative molecular mechanisms of this condition and provide evidence for specific genotype-phenotype correlations, most notably with respect to tumor risk. SUMMARY: Recognition of childhood overgrowth and investigation of diagnostic causes is important in anticipating appropriate medical management and facilitating the provision of genetic counseling. New developments in our understanding of the molecular basis and phenotypic expression of overgrowth syndromes provide additional tools in this often challenging process.     

A case of Perlman syndrome presenting with hemorrhagic hemangioma

The presence of enlarged, echogenic kidneys in a newborn with generalized macrosomia points toward diagnosis of an overgrowth syndrome. These include Beckwith-Wiedemann, Perlman and Simpson-Golabi-Behmel syndromes. Perlman syndrome is an autosomal recessively inherited overgrowth syndrome characterized by fetal gigantism, visceromegaly, unusual face, bilateral renal hamartomas with nephroblastomatosis, and Wilms tumor. We report a male infant who exhibits typical features of Perlman syndrome with an unusual presentation. In this report, it is emphasized that hemangioma in neonatal period may be an unusual finding in Perlman syndrome.     

Intrauterine growth restriction--genetic causes and consequences

Intrauterine growth restriction is known to be associated with many medical problems for the baby, both before and after delivery. The mechanisms involved in fetal growth are not well understood, with an increasing range of metabolic diseases being implicated. Several key genes involved in normal embryonic and fetal growth and development are now known to be imprinted. Disruption of this parent-specific mono-allelic expression causes phenotypic changes, many of which are important for growth and development. Two growth disorders, Beckwith-Wiedemann syndrome and Silver-Russell syndrome, are discussed in detail as they represent well-characterized phenotypes that arise as a consequence of disrupted imprinting. These human models will allow us to elucidate key genes and mechanisms important in normal fetal growth.     

The search for the gene for Silver-Russell syndrome

Patients with Silver-Russell syndrome display intrauterine growth restriction and other dysmorphic features. No single genetic cause for this syndrome has been found, although there are a small number of familial cases and some patients with chromosomal rearragements. Maternal uniparental disomy of chromosome 7 has been found in approximately 7% of patients with Silver-Russell syndrome. In five of these patients exhibiting maternal uniparental disomy, no common regions of isodisomy were found, thereby ruling out the expression of a recessive allele. It is most likely that one or more imprinted genes are responsible for the phenotype of Silver-Russell syndrome. Human chromosome 7 demonstrates homology with two imprinted regions on mouse chromosomes 6 and 11, which are equivalent to human chromosome regions 7q32 and 7p11–p13, respectively. We directly analysed the imprinting status of candidate genes from chromosome 7 that mapped to homologous imprinted regions in the mouse and also had a potential role in growth. The candidates were the genes that encode the epidermal growth factor receptor and the insulin-like growth binding proteins-1 and -3. All three of these candidate genes are localized to chromosome region 7p11–p13. Using intragenic polymorphisms as markers, we found that all three genes showed biallelic expression in different fetal tissues. Therefore, it is unlikely that these candidate genes are directly involved in producing the phenotype of Silver-Russell syndrome. Other candidates are under analysis, including two newly identified genes that are known to be imprinted.     

Genotype/phenotype correlations of males affected by Simpson-Golabi-Behmel syndrome with GPC3 gene mutations: patient report and review of the literature

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome with associated visceral and skeletal anomalies. Deletions or point mutations involving the glypican-3 (GPC3) gene at Xq26 are associated with a relatively milder form of this disorder (SGBS1). GPC3 encodes a putative extracellular proteoglycan, glypican-3, that is inferred to play an important role in growth control in embryonic mesodermal tissues in which it is selectively expressed. It appears to form a complex with insulin-like growth factor-II (IGF-II), and might thereby modulate IGF-II action. We reviewed the clinical findings of all published patients with SGBS1 with GPC3 mutations to confirm the clinical specificity for the SGBS1 phenotype. Moreover, we report on a new patient with a GPC3 deletion and IGF-II evaluation.     

Serum profiles of insulin-like growth factors and their binding proteins in adults with growth hormone receptor deficiency treated with insulin like growth factor I

Six adult patients with growth hormone receptor deficiency (GHRD) (2 men, 4 women) with an identical defect in the growth hormone receptor (GHR) gene, were treated with recombinant human insulin-like growth factor I (IGF-I), 40 μgikg S.C. twice daily, for 7 days. Serum concentrations of IGF peptide and IGF binding protein-3 (IGFBP-3) were measured by specific radioimmunoassays; serum IGFBPs were also measured by Western ligand blotting. The size distribution of both IGF-I and IGF-II was measured in serum following size-exclusion fast-performance liquid chromatography. IGF-I treatment resulted in a normalization of serum IGF-I levels on days 1–7 of treatment and a decrease in serum IGF-II levels. The fall in IGF-II levels and the simultaneous rise in IGF-I levels, however, resulted in an unchanged total serum IGF level. The low IGFBP-3 values did not significantly change during treatment, whereas there was a slight increase in IGFBP-2 levels. Preliminary analysis of size-fractionated sera suggested an increase in IGF-I levels in the 40 and 150 kDa regions at the expense of IGF-II levels. The results suggest that despite the failure of IGF-I treatment to increase IGFBPs significantly, serum IGFBP concentrations were sufficient to maintain normal levels of IGF-I. 0 Laron syndrome, growth hormone receptor deficiency, insulin-like growth factors, insulin-like growth factor binding protein     

Contiguous Gene Syndromes as Multiple Anomalies Syndromes: Molecular Basis and Approach to Gene Cloning

Recent knowledge on molecular basis of several contiguous gene syndromes as multiple anomalies syndromes, such as Prader-Willi syndrome (PWS), Angelman syndrome (AS), Beckwith-Wiedemann syndrome (BWS), tricho-rhino-phalageal syndrome types I (TRPS I) and II (TRPS II or LGS), and complex glycerol kinase deficiency (CGKD), are reviewed. Based on the results of DNA deletion studies and on the evidence for the genomic imprinting mechanism of both PWS and AS, a model for the occurrence of the two syndromes is proposed. Also, a strategy of the microdissection/microcloning technique as a reverse genetics technique, i. e., direct cloning of chromosomal DNAs from a defined region of human chromosome, particularly for the cloning of the exostosis gene in TRPS, is presented.     

Multiple genetic abnormalities of 11p15 in Wilms' tumor

Wilms' tumor has served as a model of multiple genetic alterations in childhood cancer. This review summarizes work in our laboratory identifying several of these alterations. These include the localization to 11p15 of an embryonal tumor suppressor gene and at least one gene for Beckwith-Wiedemann syndrome, which predisposes to Wilms' tumor; as well as a novel mutational mechanism in man, loss of imprinting. © 1996 Wiley-Liss, Inc.     

Molecular analysis of patients with Wiedemann-Beckwith syndrome II. Paternally derived disomies of chromosome 11

In Wiedemann-Beckwith syndrome (WBS) a putative disease gene resides at the tip of the short arm of chromosome 11 in the region of the insulin growth like factor II (IGF-II) gene. Whilst changes in gene dosage in this area do not appear to be common in the syndrome, in familial cases the lesion appears to be dominant only when inherited through the female line. We undertook to examine the parental origin of the copies of chromosome 11 in a large group of WBS patients using a series of restriction fragment length polymorphisms (RFLPs) on 11p, and report here that in one sporadic case of WBS out of 14 both copies of chromosome 11 are derived from the father and are present in a normal dosage. This suggests that at least one mode of expression of the lesion is modified by genomic imprinting.     

Placental gene expression is related to glucose metabolism and fetal cord blood levels of insulin and insulin-like growth factors in intrauterine growth restriction

Despite the importance of glucose for fetal growth, placental gene expression related to the glycolytic pathway has not been studied. Insulin-like growth factors (IGFs) and insulin are known to play a critical role in fetal growth. In our study, we identified differentially expressed genes related to the glycolytic pathway using oligonucleotide microarray analysis and confirmed these genes with quantitative real-time PCR between uncomplicated pregnancies and pregnancies with intrauterine growth restriction (IUGR). We also compared the concentrations of insulin and IGFs in cord blood between the two groups. Microarray experiments identified increased expression of glycolytic enzyme-related genes, including lactate dehydrogenase C (LDHC), dihydrolipoamide S-acetyltransferase (DLAT), 6 phosphofructo-2-kinase/fructose-2, 6-biphosphatase 2 (PFKFB2), oxoglutarate dehydrogenase, phosphorylase, and insulin-like growth factor (IGF)-II and decreased expression of IGF-I in placentas from pregnancies with IUGR (p < 0.05). There were significantly lower concentrations of glucose, insulin, IGF-1, and IGF-II in the fetal cord blood of pregnancies with IUGR (p < 0.05). Microarray analysis revealed increased expression of enzyme genes related to the tricarboxylic acid cycle pathway in placentas from pregnancies with IUGR; the cause of hypoglycaemia in IUGR is attributed to increased glycolytic pathway activity in placentas from pregnancies with IUGR.     

Acute lymphocytic leukemia in a child with Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome characterized by neonatal hypoglycemia, abdominal wall defects, macroglossia, organomegaly, ear pits and creases, hemihypertrophy, and increased birthweight. Children with BWS have an increased risk of malignancy. The authors present the case of a 3-year-old boy diagnosed with both BWS and acute lymphocytic leukemia (ALL). This case report will elaborate on the possibilities as to how BWS and ALL may be associated due to abnormal genomic imprinting and IGF dysregulation.     

Insulin-Like Growth Factor II Effects Mediated through Insulin-Like Growth Factor II Receptors

ABSTRACT. Insulin-like growth factor II (IGF-II) resembles the homologous peptide insulin-like growth factor I (IGF-I) in that it stimulates cellular growth in vitro. This effect is generally believed to be mediated through IGF type 1 receptors; the role of the IGF type 2 receptor remains, as yet, unknown. IGF-II has been shown to stimulate clonal expansion in cells from the human erythroleukaemia cell line K562, which displays binding of IGF-II and insulin but not IGF-I. This IGF-II effect was dose-dependent and correlated to the amount of specific binding; IGF-I did not stimulate growth. A similar effect on clonal growth was observed in the human T-cell line Jurkat. Furthermore, IGF-II was found to stimulate the cytotoxic activity of natural killer cells (as does interleukin 2). This effect was not inhibited by addition of IGF binding protein 1. Thus, it can be concluded that IGF-II, besides demonstrating standard IGF properties, exhibits unique biological effects in certain cells.     

Targeted gene mutations define the roles of insulin and IGF-I receptors in mouse embryonic development.

Insulin-like growth factors (IGFs) and their receptors regulate embryonic and post-natal growth. Genetic evidence derived from targeted mouse mutants indicates that both the insulin receptor (IR) and IGF-I receptors (IGF-IRs) are required for mouse embryonic growth. However, the roles of IRs and IGF-IRs are functionally distinct, with IGF-IRs mediating both IGF-I and IGF-II actions, and IRs mediating IGF-II, rather than insulin, action. The combined interactions of IGF-IRs and IRs with IGF-I and IGF-II account for the entirety of the growth effects of these two ligands, and provide the molecular basis for IGFs-mediated intrauterine growth and differentiation. Genetic ablation experiments of insulin receptor substrate-1 (IRS-1) and -2 (IRS-2), two important molecules in the IR and IGF-IR signaling pathways, are also beginning to shed light onto the mechanisms accounting for the specificity of IR and IGF-IR signaling. IRS-1-deficient mice are growth retarded, while IRS-2-deficient mice develop diabetes, indicating that the two molecules play a more specific role than previously recognized in IGF-IR and IR signaling.     

Bilateral adrenal cysts and ectopic pancreatic tissue in Beckwith-Wiedemann syndrome: is a conservative approach acceptable?

Beckwith-Wiedemann syndrome is a common overgrowth syndrome associated with an increased risk of neoplasias which might be explained by the nature and localization of the genetic defect. While malignant tumors are often associated with hemihypertrophy, benign tumors are also found. We report a patient with the typical features of Beckwith-Wiedemann syndrome with two histologically different abdominal tumors, bilateral cystic adrenals and ectopic pancreatic tissue present at birth. In both tumors no malignancy could be detected. Ectopic pancreatic tissue is rarely seen and has been described in Beckwith-Wiedemann syndrome only once. After extirpation of the ectopic pancreatic tissue the cystic adrenals were left in situ since macroscopically no normal adrenal tissue could be identified and separated. Regular ultrasound examinations revealed complete resolution of the cystic adrenals within 24 months. Thus it seems that a conservative approach in selected tumors associated with the Beckwith-Wiedemann syndrome might be acceptable.