heparitin-sulfate and Beckwith-Wiedemann-Syndrome

Beckwith-Wiedemann syndrome (BWS), a human overgrowth syndrome with a complex genetic basis, is caused by alterations to chromosome 11p15, a region subject to genomic imprinting. These alterations include translocations, duplications, single gene mutations of p57KIP2, and increased expression of insulin-like growth factor 2 (IGF2). A phenotypically related X-linked overgrowth syndrome, Simpson Golabi Behmel syndrome (SGBS), is caused by alterations in glypican-3 (GPC3), a molecule that may interact with the gene products identified to be important in generating the BWS phenotype, that is, IGF2 and p57KIP2. The crucial defect in these overgrowth syndromes is likely to be an imbalance in contributions of growth-promoting genes versus growth-inhibitory genes in critical tissues at specific developmental stages. Murine models have been used to study the effects of targeted deletions of the genes p57KIP2 and GPC3, as well as overexpression of IGF2. At this time, there are still many issues which remain to be explored before we can fully understand the molecular basis of BWS and SGBS.

Topics: Animals; Beckwith-Wiedemann Syndrome; Chromosome Mapping; Chromosomes, Human, Pair 11; Cyclin-Dependent Kinase Inhibitor p57; Disease Models, Animal; Genomic Imprinting; Glypicans; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Mice; Nuclear Proteins; Proteoglycans

Glypicans are a family of heparan sulfate proteoglycans that are linked to the cell surface through a glycosyl-phosphatidylinositol anchor. One member of this family, glypican-3 (Gpc3), is mutated in patients with the Simpson-Golabi-Behmel syndrome (SGBS). These patients display pre- and postnatal overgrowth, and a varying range of dysmorphisms. The clinical features of SGBS are very similar to the more extensively studied Beckwith-Wiedemann syndrome (BWS). Since BWS has been associated with biallelic expression of insulin-like growth factor II (IGF-II), it has been proposed that GPC3 is a negative regulator of IGF-II. However, there is still no biochemical evidence indicating that GPC3 plays such a role.Here, we report that GPC3-deficient mice exhibit several of the clinical features observed in SGBS patients, including developmental overgrowth, perinatal death, cystic and dyplastic kidneys, and abnormal lung development. A proportion of the mutant mice also display mandibular hypoplasia and an imperforate vagina. In the particular case of the kidney, we demonstrate that there is an early and persistent developmental abnormality of the ureteric bud/collecting system due to increased proliferation of cells in this tissue element. The degree of developmental overgrowth of the GPC3-deficient mice is similar to that of mice deficient in IGF receptor type 2 (IGF2R), a well characterized negative regulator of IGF-II. Unlike the IGF2R-deficient mice, however, the levels of IGF-II in GPC3 knockouts are similar to those of the normal littermates.

Topics: Abnormalities, Multiple; Animals; Beckwith-Wiedemann Syndrome; Body Weight; Cell Division; Female; Genotype; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Insulin-Like Growth Factor II; Kidney Tubules, Collecting; Male; Mandible; Mice; Mice, Inbred C57BL; Mice, Knockout; Organ Size; Phenotype; Proteoglycans; Syndrome

We present the case of a male infant, born prematurely (at 33 weeks gestation) with macrosomia, disproportionate macrocephaly, facial dysmorphism, short penis and a small umbilical defect. He had a large ASD and was ventilated from birth for respiratory distress syndrome. He died at 12 hours of age despite neonatal ITU care. Post-mortem examination showed highly lobulated kidneys with nodules of blastema and foci of hamartomatous change in the medulla. Prominence of pancreatic islet cells and expansion of hepatic portal tracts were also noted. His mother has minor cervical spine abnormalities. We discuss the differential diagnosis and the difficulty in confidently assigning a diagnosis to this patient, as considerable overlap is becoming evident between Simpson-Golabi-Behmel syndrome and Perlman syndrome.

Topics: Abnormalities, Multiple; Beckwith-Wiedemann Syndrome; Chromosomes, Human, Pair 11; Face; Female; Glypicans; Growth Disorders; Heart Septal Defects, Atrial; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Infant, Newborn; Kidney; Liver; Male; Pancreas; Pregnancy; Proteoglycans; Syndrome

Topics: Abnormalities, Multiple; Animals; Beckwith-Wiedemann Syndrome; Gigantism; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Insulin-Like Growth Factor II; Proteoglycans; Receptor, IGF Type 2; Syndrome