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Many lesions, termed pseudogliomas, may mimic the appearance of retinoblastoma, both clinically and on computed tomography. The appearance of Toxocara canis endophthalmitis on computed tomography is presented. The role of computed tomography in the evaluation of patients presenting with leukokoria is discussed.
The identification of a link between bone mass in humans and gain- [high bone mass (HBM) trait] or loss-of-function [osteoporosis pseudoglioma (OPPG) syndrome] mutations in the Wnt coreceptor lipoprotein receptor-related protein (LRP)5 or in the Wnt antagonist sclerostin (sclerosteosis, Van Buchem syndrome) has called the attention of academic and industry scientists and clinicians to the importance of this signaling pathway in skeletal biology and disease. Multiple genetic and pharmacological manipulations of Wnt signaling in mice have since then confirmed the central role of this pathway in both the establishment of peak bone mass and its maintenance throughout life. Wnt signaling appears to be located downstream of bone morphogenetic proteins (BMPs), itself induced by Hedgehog (Hh) signaling, suggesting that it is the successive recruitment of these three intracellular signaling cascades that allow the full expression of the genetic patterns that characterize the osteoblast, the cell responsible for the formation of bone.
LRP5 and LRP6 comprise a subfamily of lipoprotein-receptor related proteins that function as co-receptors for Wnt proteins. Mutation of human LRP5 is responsible for osteoporosis-pseudoglioma syndrome and disruption of Lrp6 in mice causes similar effects to mutation of several different Wnt genes. We have cloned Xenopus homologues of Lrp5 and Lrp6 (Xlrp5, Xlrp6) and examined their expression during embryogenesis. Both genes are expressed maternally and ubiquitously through early development. At later stages, Xlrp5 is found in the eye, forebrain, hindbrain, branchial arches and the tip of the tail bud. Xlrp6 is expressed throughout the central nervous system, branchial arches, in the eye and otic vesicle. Both genes are also expressed at the intersomitic boundary. These results suggest roles for Wnt signaling via LRP proteins in these tissues.
A familial syndrome is described in three siblings. The disease is characterized by osteoporosis, macrocephalus with wormian bones and frontal bossing, brachytelephalangy, hyperextensibility of the joints, congenital amaurosis and low grade oligophrenia. Clinically similar syndromes as Osteogenesis Imperfecta, Amaurosis Congenita Leber or the Osteoporosis-Pseudoglioma-Syndrome are discussed. The condition is thought to be an independent disease.
We report on a 46-year old white male with Norrie disease. In the right eye he had a keratotorus with non vascularized corneal scars and mature cataract. After penetrating keratoplasty a pseudoglioma with irreversible total retinal detachment was found. The left eye had phthisis bulbi with corneal pannus and band keratopathy, shallow anterior chamber, posterior synechia and mature cataract.
In the presence of leukokoria the diagnosis of retinoblastoma is usually easy when the mediae are transparent. If they are not, however, one is frequently obliged to enucleate a painful or useless eye in order to rule out this diagnosis. In a series of eight cases having undergone enucleation for this reason at the Lausanne University Eye Hospital, the histological examination revealed four pseudogliomas. These particularly instructive cases are described, together with the histological findings.
BACKGROUND: Osteoporosis is a major public health problem of largely unknown cause. Loss-of-function mutations in the gene for low-density lipoprotein receptor-related protein 5 (LRP5), which acts in the Wnt signaling pathway, have been shown to cause osteoporosis-pseudoglioma. METHODS: We performed genetic and biochemical analyses of a kindred with an autosomal dominant syndrome characterized by high bone density, a wide and deep mandible, and torus palatinus. RESULTS: Genetic analysis revealed linkage of the syndrome to chromosome 11q12-13 (odds of linkage, >1 million to 1), an interval that contains LRP5. Affected members of the kindred had a mutation in this gene, with valine substituted for glycine at codon 171 (LRP5V171). This mutation segregated with the trait in the family and was absent in control subjects. The normal glycine lies in a so-called propeller motif that is highly conserved from fruit flies to humans. Markers of bone resorption were normal in the affected subjects, whereas markers of bone formation such as osteocalcin were markedly elevated. Levels of fibronectin, a known target of signaling by Wnt, a developmental protein, were also elevated. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1 (Dkk-1), was defective in the presence of LRP5V171 and that this resulted in increased signaling due to unopposed Wnt activity. CONCLUSIONS: The LRP5V171 mutation causes high bone density, with a thickened mandible and torus palatinus, by impairing the action of a normal antagonist of the Wnt pathway and thus increasing Wnt signaling. These findings demonstrate the role of altered LRP5 function in high bone mass and point to Dkk as a potential target for the prevention or treatment of osteoporosis.
Norrie disease is an X-linked recessive disorder characterized by congenital blindness and in some cases mental retardation and deafness.(1) The variability of signs among patients often complicates diagnosis. Signs such as an ocular pseudoglioma, progressive deafness, and mental disturbance are considered classic features.(2) Only one third of patients with Norrie disease have sensorineural deafness, and approximately one half of the affected individuals exhibit mental retardation, often with psychotic features.(3) Histologic analysis has suggested that retinal dysgenesis occurs early in eye development and involves cells in the inner wall of the optic cup.(4) The gene associated with Norrie disease was identified in 1992. (5,6) We report a novel mutation identified in a patient in whom Norrie disease was diagnosed.
The low-density lipoprotein receptor-related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.
Bone is a dynamic tissue that is subject to the balanced processes of bone formation and bone resorption. Imbalance can give rise to skeletal pathologies with increased bone density. In recent years, several genes underlying such sclerosing bone disorders have been identified. The LDL receptor-related protein 5 (LRP5) gene has been shown to be involved in both osteoporosis-pseudoglioma syndrome and the high-bone-mass phenotype and turned out to be an important regulator of peak bone mass in vertebrates. We performed mutation analysis of the LRP5 gene in 10 families or isolated patients with different conditions with an increased bone density, including endosteal hyperostosis, Van Buchem disease, autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing of the LRP5 gene revealed 19 sequence variants. Thirteen of these were confirmed as polymorphisms, but six novel missense mutations (D111Y, G171R, A214T, A214V, A242T, and T253I) are most likely disease causing. Like the previously reported mutation (G171V) that causes the high-bone-mass phenotype, all mutations are located in the aminoterminal part of the gene, before the first epidermal growth factor-like domain. These results indicate that, despite the different diagnoses that can be made, conditions with an increased bone density affecting mainly the cortices of the long bones and the skull are often caused by mutations in the LRP5 gene. Functional analysis of the effects of the various mutations will be of interest, to evaluate whether all the mutations give rise to the same pathogenic mechanism.
Stature, bone size, and bone mass are interrelated traits with high heritability, but the major genes that govern these phenotypes remain unknown. Independent genomewide quantitative-trait locus studies have suggested a locus for bone-mineral density and stature at chromosome 11q12-13, a region harboring the low-density lipoprotein receptor-related protein 5 (LRP5) gene. Mutations in the LRP5 gene were recently implicated in osteoporosis-pseudoglioma and "high-bone-mass" syndromes. To test whether polymorphisms in the LRP5 gene contribute to bone-mass determination in the general population, we studied a cross-sectional cohort of 889 healthy whites of both sexes. Significant associations were found for a missense substitution in exon 9 (c.2047G-->A) with lumbar spine (LS)-bone-mineral content (BMC) (P=.0032), with bone area (P=.0014), and with stature (P=.0062). The associations were observed mainly in adult men, in whom LRP5 polymorphisms accounted for <or=15% of the traits' variances. Results of haplotype analysis of five single-nucleotide polymorphisms in the LRP5 region suggest that additional genetic variation within the locus might also contribute to bone-mass and size determination. To confirm our results, we investigated whether LRP5 haplotypes were associated with 1-year gain in vertebral bone mass and size in 386 prepubertal children. Significant associations were observed for changes in BMC (P=.0348) and bone area (P=.0286) in males but not females, independently supporting our observations of a mostly male-specific effect, as seen in the adults. Together, these results suggest that LRP5 variants significantly contribute to LS-bone-mass and size determination in men by influencing vertebral bone growth during childhood.
The purpose of this paper is to report the linkage of a genetic locus (designated "HBM") in the human genome to a phenotype of very high spinal bone density, using a single extended pedigree. We measured spinal bone-mineral density, spinal Z(BMD), and collected blood from 22 members of this kindred. DNA was genotyped on an Applied Biosystems model 377 (ABI PRISM Linkage Mapping Sets; Perkin Elmer Applied Biosystems), by use of fluorescence-based marker sets that included 345 markers. Both two-point and multipoint linkage analyses were performed, by use of affected/unaffected and quantitative-trait models. Spinal Z(BMD) for affected individuals (N = 12) of the kindred was 5.54 +/- 1.40; and for unaffected individuals (N = 16) it was 0.41 +/- 0.81. The trait was present in affected individuals 18-86 years of age, suggesting that HBM influences peak bone mass. The only region of linkage was to a series of markers on chromosome 11 (11q12-13). The highest LOD score (5.21) obtained in two-point analysis, when a quantitative-trait model was used, was at D11S987. Multipoint analysis using a quantitative-trait model confirmed the linkage, with a LOD score of 5.74 near marker D11S987. HBM demonstrates the utility of spinal Z(BMD) as a quantitative bone phenotype that can be used for linkage analysis. Osteoporosis pseudoglioma syndrome also has been mapped to this region of chromosome 11. Identification of the causal gene for both traits will be required for determination of whether a single gene with different alleles that determine a wide range of peak bone densities exists in this region.
Previous studies showed that transcripts encoding specific Wnt ligands and Frizzled receptors including Wnt4, Frizzled1 (Fzd1), and Frizzled4 (Fzd4) were expressed in a cell-specific manner in the adult mouse ovary. Overlapping expression of Wnt4 and Fzd4 mRNA in small follicles and corpora lutea led us to hypothesize that the infertility of mice null for Fzd4 (Fzd4-/-) might involve impaired follicular growth or corpus luteum formation. Analyses at defined stages of reproductive function indicate that immature Fzd4-/- mouse ovaries contain follicles at many stages of development and respond to exogenous hormone treatments in a manner similar to their wild-type littermates, indicating that the processes controlling follicular development and follicular cell responses to gonadotropins are intact. Adult Fzd4-/- mice also exhibit normal mating behavior and ovulate, indicating that endocrine events controlling these processes occur. However, Fzd4-/- mice fail to become pregnant and do not produce offspring. Histological and functional analyses of ovaries from timed mating pairs at Days 1.5-7.5 postcoitus (p.c.) indicate that the corpora lutea of the Fzd4-/- mice do not develop normally. Expression of luteal cell-specific mRNAs (Lhcgr, Prlr, Cyp11a1 and Sfrp4) is reduced, luteal cell morphology is altered, and markers of angiogenesis and vascular formation (Efnb1, Efnb2, Ephb4, Vegfa, Vegfc) are low in the Fzd4-/- mice. Although a recently identified, high-affinity FZD4 ligand Norrin (Norrie disease pseudoglioma homolog) is expressed in the ovary, adult Ndph-/- mice contain functional corpora lutea and do not phenocopy Fzd4-/- mice. Thus, Fzd4 appears to impact the formation of the corpus luteum by mechanisms that more closely phenocopy Prlr null mice.
Osteogenesis Imperfecta (OI) is characterized by bone fragility. At least seven discrete types have been described ranging from mild disease to a lethal form. In a large number of cases, mutations in one of the two genes encoding type I collagen have been found. In forms recently described (types V, VI, VII), such mutations have been excluded. In two other forms, (Bruck, and osteoporosis - pseudoglioma syndromes) defects in other proteins have been characterized. In OI, bone fragility stems from: decreased bone mass, disturbed organization of bone tissue, and altered bone geometry (size and shape). Histologic studies have shown that increased bone turnover is the rule in OI bone. This justifies using bisphosphonates in order to reduce osteoclast mediated bone resorption. Initial results are encouraging. Cyclical intravenous pamidronate administration reduces bone pain and fracture incidence, and increases bone density and level of ambulation, with minimal side effects. Effects on bone include increase in size of vertebral bodies and thickening of cortical bone. These results allow for more efficacious corrective surgery using intramedullary rodding of the long bones and paravertegral instrumentation. Specific occupational and physiotherapy programs are integral parts of the treatment protocol. This multidisciplinary approach will prevail until strategies aiming at the correction of the basic defect(s) will have come to fruition.
PURPOSE OF REVIEW: This review summarizes recent findings concerning the genomic variations of the lipoprotein receptor-related protein 5 (LPR5) in relation to bone biology. RECENT FINDINGS: Mutations in the LRP5 gene causing high bone mass (HBM) and osteoporosis-pseudoglioma (OPPG) underscored the role of the Wnt-LRP5 canonical signaling on bone formation. Additional LRP5 activating mutations have been identified in a variety of sclerosing bone dysplasias, improving the diagnostic classification of these disorders. Association of polymorphisms in LRP5 with bone mineral density indicate that LRP5 genetic variation contribute to the risk of osteoporosis. Transgenic mice carrying the LRP5 HBM mutation have improved bone biomechanical properties, and the molecular mechanisms by which this mutation exerts its effects have been clarified. A number of KO mice have shown the complex effects of the Wnt-LRP5 pathway on bone mass and skeletal morphology. In vitro studies indicate that osteoblasts produce a variety of Wnts, the LRP5 co-receptor frizzled (Fzd), as well as LRP5 and Wnt inhibitors, i.e. dickkopf (Dkk1) and frizzled-related proteins (Sfrps), respectively, and delineate the role of these molecules in regulating the commitment of mesenchymal stem cells along the osteoblastic lineage. SUMMARY: Identification of pathogenic mutations and allelic variations in LRP5 has improved our understanding of the physiology of bone mass acquisition and the pathophysiology of several bone diseases, including osteoporosis. Understanding how complex interactions between agonistic and inhibitory factors in the Wnt-LRP5 canonical pathway influence osteoblast functions has the potential of providing new anabolic treatments for osteoporosis.
We report a sibship of three sisters and two brothers who showed osteoporosis of variable severity; the propositus has incapacitating deformities following numerous fractures. Four of the sibs, including three with frequent fractures, were blind from infancy ("pseudogliomatous blindness"). In addition, two were mentally retarded. The osteoporosis-pseudoglioma syndrome is inherited as an autosomal recessive trait; similar reports from the literature support this assumption.
The low-density-lipoprotein receptor-related protein 5 (LRP5), a coreceptor in the canonical Wnt signaling pathway, has been implicated in human disorders of low and high bone mass. Loss-of-function mutations cause the autosomal recessive osteoporosis-pseudoglioma syndrome, and heterozygous missense mutations in families segregating autosomal dominant high bone mass (HBM) phenotypes have been identified. We expressed seven different HBM-LRP5 missense mutations to delineate the mechanism by which they alter Wnt signaling. None of the mutations caused activation of the receptor in the absence of ligand. Each mutant receptor was able to reach the cell surface, albeit at differing amounts, and transduce exogenously supplied Wnt1 and Wnt3a signal. All HBM mutant proteins had reduced physical interaction with and reduced inhibition by DKK1. These data suggest that HBM mutant proteins can transit to the cell surface in sufficient quantity to transduce Wnt signal and that the likely mechanism for the HBM mutations' physiologic effects is via reduced affinity to and inhibition by DKK1.
A sibship of a brother and sister with congenital bilateral pseudoglioma is described. The most prominent abnormality was a greyish-white vascularised mass in the retrolental spaces, which was noted as early as the first weeks of life. Corneal opacities, posterior synechiae, and complicated cataracts developed within 1 to 2 years age. The sibship showed normal chromosomes and had no systemic disorders, including mental and hearing impairment. The parents and other relatives were normal. Autosomal recessive disease, rather than Norrie's disease, was the most probable explanation for the dysplasia of the vitreous and retina in the sibship. This is probably the third report of familial occurrence with autosomal recessively inherited vitreoretinal dysplasia without systemic anomalies. The importance of the disease in genetic counselling is discussed.