heparitin-sulfate and Syndrome

From 1999-2003, Oxford GlycoSciences (OGS) ran a successful drug discovery oncology programme to discover small molecule inhibitors of the Heparanase I enzyme (HPSE1). HPSE1 at the time was widely regarded as being the sole mammalian enzyme capable of cleaving Heparan Sulfate (HS). A second family protein member however called Heparanase 2 (HPSE2) including splice forms was subsequently discovered by PCR analysis based on EST sequences. HPSE2 was found to be expressed mainly in smooth muscle containing tissues, particularly bladder and brain. HPSE2 is poorly expressed in haematopoietic cells and placenta which contrasts with the HPSE1 distribution pattern. HPSE2 binds more strongly to HS than HPSE1 and is believed to out compete for substrate binding and so in effect act as a tumor suppressor. So far, all attempts to show specific HPSE2 endoglycosidase activity against HS have failed suggesting that the enzyme may act as a pseudoenzyme that has evolved to retain only certain non-catalytic heparanase like functions. A breakthrough in the elucidation of functional roles for HPSE2 came about in 2010 with the linkage of HPSE2 gene deletions and mutations to the development of Ochoa/Urofacial Syndrome. Future work into the mechanistic analysis of HPSE2's role in signalling, tumor suppression and bladder/nerve functioning are needed to fully explore the role of this family of proteins.

Topics: Animals; Cloning, Molecular; Facies; Glucuronidase; Heparitin Sulfate; Humans; Syndrome; Urologic Diseases

Stewart-Bluefarb syndrome (SBS), also known as acroangiodermatitis or pseudo-Kaposi, is a condition rarely encountered. It involves skin lesions that are clinically similar to Kaposi sarcoma but are histologically different, and are usually secondary to an underlying arteriovenous fistula. Treatment of this disease usually involves the correction of the underlying vascular abnormality, with the mainstay of therapy ranging from compression devices for venous stasis, limited oral medications (dapsone and erythromycin) and local wound care including topical steroids. Different methods of treatment showed varied success but none is ideal. We report a case of a lower extremity ulcer in a 22-year-old male recently diagnosed with SBS successfully treated with heparan sulphate (Cacipliq20®).

Topics: Acrodermatitis; Arteriovenous Fistula; Chronic Disease; Heparitin Sulfate; Humans; Leg Ulcer; Male; Syndrome; Young Adult

Accomplishing a successful percutaneous coronary intervention in a patient with a suspected or diagnosed heparin-induced thrombocytopenia (HIT) requires the selection of an appropriate alternative anticoagulant and a thorough assessment of bleeding and thrombotic risks. In this review, we suggest an evidence-based management algorithm that takes into account the clinical phase of HIT (acute, recent, and remote HIT) and the associated risk when patients present with acute coronary syndrome. The algorithm also integrates preventive measures directed at decreasing the bleeding risk associated with the antithrombotic and invasive therapies used for HIT and percutaneous coronary intervention.

Topics: Algorithms; Angioplasty, Balloon, Coronary; Anticoagulants; Arginine; Chondroitin Sulfates; Comorbidity; Dermatan Sulfate; Drug Therapy, Combination; Fibrinolytic Agents; Fondaparinux; Heparin; Heparinoids; Heparitin Sulfate; Hirudins; Humans; Myocardial Infarction; Peptide Fragments; Pipecolic Acids; Polysaccharides; Recombinant Proteins; Sulfonamides; Syndrome; Thrombocytopenia; Vitamin K

Collagen XVIII is a component of basement membranes (BMs) with the structural properties of both a collagen and a proteoglycan. Proteolytic cleavage within its C-terminal domain releases a fragment, endostatin, which has been reported to have anti-angiogenesis effects. Molecular studies demonstrated binding of the endostatin domain to heparan sulfate and to BM components like laminin and perlecan, but the functional role of these interactions in vivo remains unknown. Insights into the physiological function of collagen XVIII/endostatin have recently been obtained through the identification of inactivating mutations in the human collagen XVIII/endostatin gene (COL18A1) in patients with Knobloch syndrome, characterized by age-dependent vitreoretinal degeneration and occipital encephalocele. That collagen XVIII/endostatin has an essential role in ocular development and the maintenance of visual function is further demonstrated by the ocular abnormalities seen in mice lacking collagen XVIII/endostatin. Age-dependent loss of vision in these mutant mice is associated with pathological accumulation of deposits under the retinal pigment epithelium, as seen in early stages of age-related macular degeneration in humans. In addition, recent evidence suggests that lack of collagen XVIII/endostatin predisposes to hydrocephalus formation. These recent findings demonstrate an important role for collagen XVIII/endostatin in cell-matrix interactions in certain tissues that may be compensated for in other tissues expressing this collagen.

Topics: Aging; Animals; Basement Membrane; Blindness; Ciliary Body; Collagen Type XVIII; Encephalocele; Endostatins; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Iris; Laminin; Mice; Mice, Knockout; Mutation; Neovascularization, Physiologic; Pigment Epithelium of Eye; Retina; Retinal Degeneration; Retinal Vessels; Syndrome

Topics: Animals; Body Patterning; Cell Membrane; Drosophila Proteins; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Membrane Glycoproteins; Models, Molecular; Molecular Structure; Polysaccharides; Proteoglycans; Signal Transduction; Syndrome

The past decade has seen many important advances in the pathogenesis, clinical and laboratory diagnosis, and management of heparin-induced thrombocytopenia (HIT), one of the most common immune-mediated adverse drug reactions. HIT is caused by IgG antibodies that recognize complexes of heparin and platelet factor 4, leading to platelet activation via platelet Fc gamma IIa receptors. Formation of procoagulant, platelet-derived microparticles, and, possibly, activation of endothelium generate thrombin in vivo. Thrombin generation helps to explain the strong association between HIT and thrombosis, including the newly recognized syndrome of warfarin-induced venous limb gangrene. This syndrome occurs when acquired protein C deficiency during warfarin treatment of HIT and deep venous thrombosis leads to the inability to regulate thrombin generation in the microvasculature. The central role of HIT antibodies in causing HIT, as well as refinements in laboratory assays to detect these antibodies, means that HIT should be considered a clinicopathologic syndrome. The diagnosis can be made confidently when one or more typical clinical events (most frequently, thrombocytopenia with or without thrombosis) occur in a patient with detectable HIT antibodies. The central role of thrombin generation in this syndrome provides a rationale for the use of anticoagulants that reduce thrombin generation (danaparoid) or inhibit thrombin (lepirudin).

Topics: Antibodies; Anticoagulants; Antithrombin III; Chondroitin Sulfates; Dermatan Sulfate; Drug Combinations; Fibrinolytic Agents; Gangrene; Heparin; Heparinoids; Heparitin Sulfate; Hirudin Therapy; Hirudins; Humans; Immunoglobulin G; Leg; Platelet Activation; Platelet Factor 4; Protein C Deficiency; Receptors, IgG; Recombinant Proteins; Retrospective Studies; Syndrome; Thrombin; Thrombocytopenia; Venous Thrombosis; Warfarin

Diverse cardiac abnormalities have been reported in patients with the Simpson-Golabi-Behmel syndrome (SGBS), and it is suspected that they are related to the apparently high incidence of early death. To clarify the incidence and significance of the various cardiac abnormalities, we reviewed 101 SGBS patients (89 from the literature, 12 new). All were male, except for one clearly affected female patient with translocation X;1 [Punnett, 1994: Am J Med Genet 50: 391-393]. Ninety-six of 99 (97%) patients had the classic phenotype of macrosomia and typical "coarse" face. Thirty-six patients (36%) had a cardiac abnormality, of whom 26 (26%) had a cardiovascular malformation (CVM). After excluding 24 patients with insufficient clinical data, these percentages among the 77 informative cases were 47% and 34%, respectively. When grouped according to a mechanistic classification, most cases (20/ 26, or 77%) were class II CVMs (attributed to altered embryonic intracardiac flow). Other cardiac abnormalities included cardiomyopathy (n = 4) and electrocardiogram (ECG) conduction or rhythm abnormalities (n = 12); three of the affected patients (25%) also had a CVM. Among 92 informative cases, there were 29 (32%) deaths, a figure that excludes seven elective terminations. Among the 25 patients younger than 3 years, death was associated with a cardiac abnormality in six (23%). GPC3 mutation analysis using Southern blot testing and polymerase chain reaction amplification was performed for 37 of 101 (37%) patients. A mutation was detected in 26 of the 37 patients tested (70%), 12 of whom (46%) had a cardiac abnormality. We conclude that cardiac abnormalities of any type are common in SGBS (almost one-half of informative cases), with CVMs seen in one-third of cases. The heterogeneous ECG abnormalities in this survey must be viewed with caution, since they may represent a genuine component of the syndrome or reporting bias. Determining the true prevalence and natural history of cardiac abnormalities in SGBS will require a larger number of patients and more consistent prospective cardiac evaluations. There are sufficient data to recommend a baseline echocardiogram and ECG in SGBS patients. Data are insufficient to define a cardiac phenotype/molecular correlation.

Topics: Adolescent; Adult; Child; Child, Preschool; DNA Mutational Analysis; Female; Fetal Death; Glypicans; Heart Defects, Congenital; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Infant; Male; Mutation; Proteoglycans; Syndrome

A safe and effective alternative is needed for patients in whom unfractionated heparin (UFH) or protamine is contraindicated (e.g., those with heparin-induced thrombocytopenia or allergy to protamine). Furthermore, choice of anticoagulant may influence graft patency in coronary surgery and may therefore be important even when there is no contraindication to UFH. Direct thrombin inhibitors have several potential advantages over UFH, demonstrated in acute coronary syndromes. However, there are also potential difficulties with their use related to lack of reversal agents and paucity of clinical experience in monitoring their anticoagulant activity at the levels required for cardiac surgery with cardiopulmonary bypass (CPB). In the first prospective randomized trial of an alternative to heparin in cardiac surgery, we compared bivalirudin (a short-acting direct thrombin inhibitor) with UFH in 100 patients undergoing off-pump coronary artery bypass (OPCAB) surgery. Blood loss for the 12 hours following study drug initiation in the bivalirudin group was not significantly greater than in the heparin group. Median graft flow was significantly higher in the bivalirudin group. We concluded that anticoagulation for OPCAB surgery with bivalirudin was feasible without a clinically important increase in perioperative blood loss. A larger study is needed to investigate the impact of improved graft patency on other clinical outcomes after cardiac surgery.

Topics: Ancrod; Angiography; Anticoagulants; Chondroitin Sulfates; Coronary Artery Bypass; Dermatan Sulfate; Drug Combinations; Heparin; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Hirudins; Humans; Peptide Fragments; Prospective Studies; Protamines; Recombinant Proteins; Regional Blood Flow; Syndrome; Thrombin; Time Factors; Treatment Outcome

Heparan sulfate belongs to the group of glycosaminoglycans (GAGs), highly sulfated linear polysaccharides. Heparan sulfate 2-O-sulfotransferase 1 (HS2ST1) is one of several specialized enzymes required for heparan sulfate synthesis and catalyzes the transfer of the sulfate groups to the sugar moiety of heparan sulfate. We report bi-allelic pathogenic variants in HS2ST1 in four individuals from three unrelated families. Affected individuals showed facial dysmorphism with coarse face, upslanted palpebral fissures, broad nasal tip, and wide mouth, developmental delay and/or intellectual disability, corpus callosum agenesis or hypoplasia, flexion contractures, brachydactyly of hands and feet with broad fingertips and toes, and uni- or bilateral renal agenesis in three individuals. HS2ST1 variants cause a reduction in HS2ST1 mRNA and decreased or absent heparan sulfate 2-O-sulfotransferase 1 in two of three fibroblast cell lines derived from affected individuals. The heparan sulfate synthesized by the individual 1 cell line lacks 2-O-sulfated domains but had an increase in N- and 6-O-sulfated domains demonstrating functional impairment of the HS2ST1. As heparan sulfate modulates FGF-mediated signaling, we found a significantly decreased activation of the MAP kinases ERK1/2 in FGF-2-stimulated cell lines of affected individuals that could be restored by addition of heparin, a GAG similar to heparan sulfate. Focal adhesions in FGF-2-stimulated fibroblasts of affected individuals concentrated at the cell periphery. Our data demonstrate that a heparan sulfate synthesis deficit causes a recognizable syndrome and emphasize a role for 2-O-sulfated heparan sulfate in human neuronal, skeletal, and renal development.

Topics: Adolescent; Alleles; Biopsy; Bone and Bones; Child; Child, Preschool; Corpus Callosum; Developmental Disabilities; Extracellular Matrix; Extracellular Signal-Regulated MAP Kinases; Family Health; Female; Fibroblasts; Genetic Variation; Heparitin Sulfate; Humans; Iduronic Acid; Infant, Newborn; Kidney; Male; Pedigree; Phenotype; Sulfotransferases; Syndrome; Urogenital Abnormalities

Topics: Aged; Anticoagulants; Chondroitin Sulfates; Computed Tomography Angiography; Dermatan Sulfate; Diagnosis, Differential; Female; Heparin; Heparitin Sulfate; Humans; Platelet Count; Syndrome; Thrombectomy; Thrombocytopenia; Thrombosis

Glypicans are a family of heparan sulfate proteoglycans whose members are bound to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. Loss-of-function mutations in GPC3, one of the six mammalian glypicans, causes the Simson-Golabi-Behmel Syndrome. This is a disorder characterized by pre- and post-natal overgrowth, a broad spectrum of visceral and skeletal abnormalities, and an increased risk for the development of embryonic tumors. GPC3-null mice also display significant overgrowth. We have recently reported that GPC3 acts as a negative regulator of Hedgehog signaling during development, and that the overgrowth caused by the lack of functional GPC3 is due, at least in part, to the hyperactivation of Hedgehog signaling. Here we discuss the rationale that led us to hypothesize that GPC3 could be a negative regulator of Hedgehog signaling, and speculate about the implications of our discovery regarding the role of GPC3 in some cancer types. We also discuss our recent results of experiments that investigated the role of the core protein, the heparan sulfate chains, and the GPI anchor in GPC3 function. Finally, we propose an explanation for the tissue-specific function of GPC3.

Topics: Abnormalities, Multiple; Animals; Body Size; Glycosylphosphatidylinositols; Glypicans; Hedgehog Proteins; Heparitin Sulfate; Mice; Neoplasms; Signal Transduction; Syndrome; Wnt Proteins

n patients with Kasabach-Merritt syndrome (KMS), local activation of coagulation commonly results in disseminated intravascular coagulation (DIC). Progress of DIC is associated with 30-40% mortality as a result of uncontrollable hemorrhage. A 39-year-old woman with an enlarging giant liver hemangioma was diagnosed as having KMS with DIC. To control the hemorrhagic diathesis, we commenced combination therapy for DIC with danaparoid (1,250 Ux2/day, intravenously (IV)) and tranexamic acid (0.5 g x 3/day, peros (PO). Rapid improvement of the bleeding tendency and coagulopathy occurred in response to this treatment - that is, DIC was controlled without removing the giant hemangioma. The therapy did not restrict the behavior of the patient by continuous drip and angiography could be performed without bleeding. Such therapy may be beneficial in chronic DIC with activation of fibrinolysis.

Topics: Adult; Antifibrinolytic Agents; Blood Proteins; Chondroitin Sulfates; Dermatan Sulfate; Disseminated Intravascular Coagulation; Drug Therapy, Combination; Female; Hemangioma; Hemorrhagic Disorders; Heparitin Sulfate; Hepatic Artery; Humans; Ligation; Liver Neoplasms; Syndrome; Tranexamic Acid

Heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is an immune-mediated drug reaction that occurs 5-14 d after initiation of heparin therapy and is a potentially life-threatening thrombotic complication. The antibody-heparin-PF4 complexes cause platelet activation and generation of platelet microparticles. The need for anticoagulant treatment in asymptomatic thrombocytopenia is uncertain. However, treatment is warranted in HITTS, as illustrated in the case reported here. Danaparoid, r-Hirudin and argatroban are effective drugs. Danaparoid has a 10-50% in vitro cross-reactivity rate with the HIT antibodies, but has been proven to be clinically efficacious even in these cases. Here, we report a case of in vivo cross-reactivity with danaparoid, the patient showed an excellent recovery with r-Hirudin.

Topics: Aged; Antibodies; Anticoagulants; Chondroitin Sulfates; Cross Reactions; Dermatan Sulfate; Drug Combinations; Factor Xa; Heparin; Heparitin Sulfate; Hirudin Therapy; Humans; International Normalized Ratio; Male; Platelet Count; Syndrome; Thrombocytopenia; Thrombosis

Deletions in the heparan sulphate proteoglycan encoding glypican 3 (GPC3) gene have recently been documented in several Simpson-Golabi-Behmel syndrome (SGBS) families. However, no precisely defined SGBS mutation has been published. We report here a 13 base pair deletion which causes a frameshift and premature termination of the GPC3 gene in the Dutch-Canadian SGBS family in whom the trait was originally mapped. Our analysis shows that a discrete GPC3 disabling mutation is sufficient to cause SGBS. Furthermore, our finding of a GPC3 normal daughter of an SGBS carrier with skeletal abnormalities and Wilms tumour raises the possibility of a trans effect from the maternal carrier in SGBS kindreds.

Topics: Bone and Bones; Canada; Chromosomes, Human, Pair 11; Female; Frameshift Mutation; Glypicans; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Male; Pedigree; Proteoglycans; Sequence Analysis, DNA; Sequence Deletion; Syndrome; Wilms Tumor; X Chromosome

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

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked overgrowth syndrome with associated visceral and skeletal abnormalities. Alterations in the glypican-3 gene (GPC3), which is located on Xq26, have been implicated in the etiology of relatively milder cases of this disorder. Not all individuals with SGBS have demonstrated disruptions of the GPC3 locus, which raises the possibility that other loci on the X chromosome could be responsible for some cases of this syndrome. We have previously described a large family with a severe form of SGBS that is characterized by multiple anomalies, hydrops fetalis, and death within the first 8 wk of life. Using 25 simple tandem-repeat polymorphism markers spanning the X chromosome, we have localized the gene for this disorder to an approximately 6-Mb region of Xp22, with a maximum LOD score of 3.31 and with LOD scores <-2.0 for all of Xq. These results demonstrate that neither the GPC3 gene nor other genes on Xq26 are responsible for all cases of SGBS and that a second SGBS locus resides on Xp22.

Topics: Abnormalities, Multiple; Chromosome Mapping; Female; Genetic Variation; Genotype; Glypicans; Haplotypes; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Hydrops Fetalis; Lod Score; Male; Pedigree; Polymorphism, Genetic; Proteoglycans; Recombination, Genetic; Syndrome; Tandem Repeat Sequences; X Chromosome

Simpson-Golabi-Behmel syndrome (SGBS) is one of the overgrowth syndromes. Microdeletions of the glypican-3 (GPC3) gene were described by Pilia et al. (1996). Glypican-3 encodes a putative extracellular proteoglycan which is expressed in embryonic mesodermal tissues and plays an important role in embryonal growth. We report a Japanese patient with SGBS who had a single base deletion in the exon 7 of the GPC3 gene. This is the first report of a single base deletion of the GPC3 gene.

Topics: Abnormalities, Multiple; Amino Acid Sequence; Base Sequence; Exons; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Hernia, Diaphragmatic; Humans; Infant, Newborn; Male; Proteoglycans; Radiography; Sequence Deletion; Syndrome

Topics: Abnormalities, Multiple; Animals; Glypicans; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Insulin-Like Growth Factor II; Mice; Mice, Knockout; Proteoglycans; Somatomedins; Syndrome

Simpson-Golabi-Behmel Syndrome (SGBS) is an X-linked disease characterized by pre- and postnatal overgrowth. Recently, we have shown that mutations in the glypican family gene, GPC3, cause SGBS. This gene is predominantly expressed in the same mesoderm-derived tissues that overgrow in its absence. To investigate the basis for promoter function, 3.3kb of GC-rich DNA 5' of the transcribed region were fused to a luciferase cDNA, transfected into Caco-2 and NT2 cells, and assayed for activity. Deletion analysis identified a 218-bp fragment upstream of the transcription start site that conferred more than 80% of maximal reporter gene activation. This fragment contains five putative Sp1 binding sites, three of which (centered at nt -14, -34, and -92) were active when assessed by DNaseI footprinting and gel shift/supershift assays. Additionally, Sp1 specifically transactivated transcription in Sp1-deficient Drosophila SL2 cells, demonstrating the functionality of Sp1 on the GPC3 promoter. A full-length promoter construct was also highly active in HeLa cells, which do not express endogenous GPC3. These results indicate that the GPC3 promoter is dependent on Sp1 for proper activation, but tissue-specific repression in non-expressing cells must involve either DNA that lies outside the region tested or auxiliary structural features of chromatin.

Topics: Animals; Base Sequence; Binding Sites; Caco-2 Cells; Cell Line; DNA; Drosophila; Gene Expression Regulation; Glypicans; Growth Disorders; HeLa Cells; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Molecular Sequence Data; Mutation; Oligonucleotide Probes; Promoter Regions, Genetic; Proteoglycans; Sp1 Transcription Factor; Syndrome; Transcriptional Activation

Interest in glypican-3 (GPC3), a member of the glypican-related integral membrane heparan sulfate proteoglycans (GRIPS) family, has increased with the finding that it is mutated in the Simpson-Golabi-Behmel overgrowth syndrome (Pilia et al. [1996] Nat. Genet. 12:241-247). The working model suggested that the membrane-bound protein acts locally to limit tissue and organ growth and that it may function by interacting with insulin-like growth factor 2 (IGF2) to limit its local effective level. Here we have tested two predictions of the model. In situ hybridization with the mouse gene cDNA was used to study the expression pattern during embryonic and fetal development. In agreement with predictions, the gene is expressed in precisely the organs that overgrow in its absence; and the patterns of expression of Gpc3 and those reported for Igf2 are strictly correlated.

Topics: Abnormalities, Multiple; Animals; Blotting, Northern; Ectoderm; Gene Expression Regulation, Developmental; Gigantism; Glypicans; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; In Situ Hybridization; Mesoderm; Mice; Phenotype; Proteoglycans; Syndrome

Topics: Animals; Chromosome Mapping; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; In Situ Hybridization, Fluorescence; Proteoglycans; Rats; Syndrome; X Chromosome

To identify the proportion and type of deletions present in the glypican 3 (GPC3) gene in a group of patients with Simpson-Golabi-Behmel syndrome (SGBS).. PCR analysis using primer pairs which amplify fragments from each of the eight exons of the GPC3 gene was carried out in a series of 18 families with SGBS (approximately half of reported cases).. Deletions were detected in only five families (one reported previously). We found deletions in all exons of the gene except exon 3.. Our results suggest that large scale deletions may be less common in SGBS than was originally thought. One patient, with an exon 4 and 5 deletion, lacked the characteristic facial dysmorphic features. This raises the possibility of involvement of GPC3 gene defects in a wider range of overgrowth disorders.

Topics: Abnormalities, Multiple; Child; Exons; Face; Genetic Linkage; Glypicans; Growth Disorders; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Male; Phenotype; Polymerase Chain Reaction; Proteoglycans; Sequence Deletion; Syndrome; X Chromosome

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

Simpson-Golabi-Behmel syndrome (SGBS) is an X-linked condition characterized by pre- and postnatal overgrowth with visceral and skeletal anomalies. To identify the causative gene, breakpoints in two female patients with X;autosome translocations were identified. The breakpoints occur near the 5' and 3' ends of a gene, GPC3, that spans more than 500 kilobases in Xq26; in three families, different microdeletions encompassing exons cosegregate with SGBS. 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. Initial western- and ligand-blotting experiments suggest that glypican 3 forms a complex with insulin-like growth factor 2 (IGF2), and might thereby modulate IGF2 action.

Topics: Abnormalities, Multiple; Amino Acid Sequence; Animals; Base Sequence; Cell Line; Chromosome Aberrations; Chromosome Disorders; Chromosome Mapping; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 16; Cloning, Molecular; DNA Primers; Female; Gene Deletion; Genetic Linkage; Glypicans; Growth Disorders; HeLa Cells; Heparan Sulfate Proteoglycans; Heparitin Sulfate; Humans; Immunologic Techniques; Insulin-Like Growth Factor II; Male; Mice; Molecular Sequence Data; Pedigree; Protein Binding; Proteoglycans; Sequence Homology, Amino Acid; Syndrome; Translocation, Genetic; Tumor Cells, Cultured; X Chromosome

Vitamin A decreased the urinary excretion of total mucopolysaccharides in a patient with Hurler-Scheie compound (type IH-S mucopolysaccharidosis). Vitamin A was administered orally in daily doses of 1,000 to 2,000 IU/kg body weight for 10 years. Adverse clinical responses such as irritability, bone pain, dizziness, vomiting and diarrhea appeared in the patient and were controlled by reduction of the dose administered. No clinical improvement was observed, although it is possible that the clinical course of the disease may have been retarded.

Topics: Adolescent; Chondroitin Sulfates; Dermatan Sulfate; Dose-Response Relationship, Drug; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Mucopolysaccharidosis I; Syndrome; Vitamin A

Newer biochemical understanding of the mucopolysaccharidoses now allows a better classification of these diseases. The dermatan and keratan sulfate-storing diseases have corneal clouding. The heparan sulfate-storing diseases have retinal changes and usually central nervous system manifestations.

Topics: Child; Corneal Diseases; Dermatan Sulfate; Glycosaminoglycans; Heparitin Sulfate; Humans; Keratan Sulfate; Mucopolysaccharidoses; Syndrome

Morphological and biochemical autopsy findings of a 12 year old girl with mucopolysaccharidosis type III (Sanfilippo's syndrome). The clinically suspected diagnosis was biochemically ascertained before the patients death. The autopsy findings obtained by biochemical and by light and electron microscopic investigations of different organs are compared with the results of other authors.

Topics: Autopsy; Central Nervous System; Child; Female; Fibroblasts; Genotype; Glucuronidase; Glycosaminoglycans; Heparin; Heparitin Sulfate; Hexosaminidases; Humans; Hydrolases; Intellectual Disability; Liver; Microscopy, Electron; Mucopolysaccharidoses; Syndrome

Topics: Amniocentesis; Amniotic Fluid; Cells, Cultured; Female; Fetal Diseases; Fetus; Fibroblasts; Glycoside Hydrolases; Heparitin Sulfate; Humans; Inclusion Bodies; Intellectual Disability; Liver; Lyases; Microscopy, Electron; Mucopolysaccharidoses; Pregnancy; Prenatal Diagnosis; Sulfur Radioisotopes; Syndrome

Topics: Child; Child, Preschool; Chondroitin; Consanguinity; Corneal Opacity; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Male; Mucopolysaccharidoses; Syndrome