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A case of pseudoglioma diagnosed on histopathology to be retinal tuberculosis is presented with a general review of the literature on ocular tuberculosis. The case is peculiar in that retinal tuberculosis occurred without concomitant involvement of the choroid.
Orbital abnormalities encountered in the pediatric population differ substantially from those found in adult patients. Retinoblastoma, the most serious intraocular tumor, is often difficult to diagnose, but use of computed tomography (CT) (which reveals the characteristic focal calcification) and magnetic resonance (MR) imaging allows this tumor to be differentiated from pseudogliomas, such as Coats disease, and retrolental fibroplasia. CT and MR imaging help in the differentiation of orbital cellulitis from preseptal, lacrimal, and eyelid infectious processes and of orbital pseudotumor from Graves disease. In cases of orbital trauma, CT is excellent for detecting orbital fractures and metallic foreign bodies; MR imaging is better for depicting ocular and optic nerve injuries. Both modalities allow the differentiation of rhabdomyosarcoma from dermoid, cavernous hemangioma, and lymphangioma and provide helpful information for the diagnosis of many other tumors. Since CT and MR imaging have widely expanded the capabilities of orbital imaging, it is more important than ever before for radiologists to understand pediatric orbital disease.
Ocular Toxocara canis infection causing larval granulomatosis and leading to chronic endophthalmitis and retinal detachment is a well-defined cause of unilateral leukokoria in children. The computed tomographic (CT) scan revealed a diffuse, nonenhancing, well-defined hyperdense lesion occupying most of the globe. The CT findings do not definitively differentiate the diffuse endophthalmitis of larval granulomatosis from retinoblastoma or other pseudogliomas.
The differential diagnosis between the diseases which cause leucocoria is discussed. Among them congenital cataract, persistence of the primary vitreous, retrolental fibroplasia, retinoblastoma, Coats' disease, von Hippel's disease, inflammatory pseudoglioma, Norrie's disease, and organized intraocular haemorrhage are mentioned.
Our purpose is to test linkage of human chromosome 11q12-13 to BMD variation. Chromosome 11q12-13 has been linked to three BMD-related phenotypes that are inherited as Mendelian traits in human pedigrees: an autosomal dominant high bone mass trait, autosomal recessive osteoporosis pseudoglioma, and autosomal recessive osteopetrosis. A sibling pair study with 374 sibships showed significant linkage of D11S987 to normal BMD variation, with a maximum logarithm of odds score of 3.5. However, a subsequent linkage study with a total of 595 sibling pairs demonstrated reduced significance for linkage of D11S987 to bone mineral density variation, with a logarithm of odds score less than 2.2. We genotyped five markers in a genomic region of approximately 27 cM centering on D11S987 and measured bone mineral density and other traits (weight, etc.) for 635 individuals from 53 human pedigrees. Each of these pedigrees was ascertained through a proband with bone mineral density Z-scores less than -1.28 at the hip or spine. Adjusting for age, sex, and weight as covariates, we performed two-point and multipoint linkage analyses using the variance component linkage analysis method implemented in Sequential Oligogenic Linkage Analysis Routines. We found little evidence of linkage of these five markers to bone mineral density at the spine, hip, wrist and total body bone mineral content. The maximum logarithm of odds score at these five markers was 0.25, and the maximum logarithm of odds score at D11S987 was 0.15. Therefore, although we cannot exclude the linkage of D11S987 region to bone mineral density variation, there is no evidence for linkage of the marker D11S987 on human chromosome 11q12-13 to bone mineral density variation in our study population.
Osteoporosis is a common disease with a strong genetic component. Twin studies have shown that genetic factors play an important role in regulating bone mineral density (BMD), ultrasound properties of bone, skeletal geometry, and bone turnover as well as contributing to the pathogenesis of osteoporotic fracture itself. These phenotypes are determined by the combined effects of several genes and environmental influences, but occasionally, osteoporosis or unusually high bone mass can occur as the result of mutations in a single gene. Examples are the osteoporosis-pseudoglioma syndrome, caused by inactivating mutations in the lipoprotein receptor-related protein 5 gene and the high bone mass syndrome, caused by activating mutations of the same gene. Genome-wide linkage studies in man have identified loci on chromosomes 1p36, 1q21, 2p21, 5q33-35, 6p11-12, and 11q12-13 that show definite or probable linkage to BMD, but so far, the causative genes remain to be identified. Linkage studies in mice have similarly identified several loci that regulate BMD, and a future challenge will be to investigate the syntenic loci in humans. A great deal of research has been done on candidate genes; among the best studied are the vitamin D receptor and the collagen type I alpha 1 gene. Polymorphisms of vitamin D receptor have been associated with bone mass in several studies, and there is evidence to suggest that this association may be modified by dietary calcium and vitamin D intake. A functional polymorphism affecting an Sp1 binding site has been identified in the collagen type I alpha 1 gene that predicts osteoporotic fractures independently of bone mass by influencing collagen gene regulation and bone quality. An important problem with most candidate gene studies is small sample size, and this has led to conflicting results in different populations. Some researchers are exploring the use of meta-analysis to try and address this issue and gain an accurate estimate of effect size for different polymorphisms in relation to relevant clinical endpoints, such as BMD and fracture. From a clinical standpoint, advances in knowledge about the genetic basis of osteoporosis are important, because they offer the prospect of developing genetic markers for the assessment of fracture risk and the opportunity to identify molecules that will be used as targets for the design of new drugs for the prevention and treatment of bone disease.
A major determinant of the risk of osteoporosis is peak bone mineral density (BMD), which has been shown to have substantial heritability. The genes for 3 BMD-related phenotypes (autosomal dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma, and autosomal recessives osteopetrosis) are all in the chromosome 11q12-13 region. We reported linkage of peak BMD in a large sample of healthy premenopausal sister pairs to this same chromosomal region, suggesting that the genes underlying these 3 disorders may also play a role in determining peak BMD within the normal population. To test this hypothesis, we examined the gene responsible for 1 form of autosomal recessive osteopetrosis, TCIRG1, which encodes an osteoclast-specific subunit (OC116) of the vacuolar proton pump. We identified 3 variants in the sequence of TCIRG1, but only one, single nuclear polymorphism 906713, had sufficient heterozygosity for use in genetic analyses. Our findings were consistent with linkage to femoral neck BMD, but not to spine BMD, in a sample of 995 healthy premenopausal sister pairs. However, further analysis, using both population and family-based disequilibrium approaches, did not demonstrate any evidence of association between TCIRG1 and the spine or femoral neck BMD. Therefore, our linkage data suggest that the chromosomal region that contains OC116 harbors a gene that affects peak BMD, but our association results indicate that polymorphisms in the OC116 gene do not affect peak BMD.
UNLABELLED: Three of 20 patients with juvenile osteoporosis were found to have a heterozygous mutation in the LRP5 gene. No mutations were found in the type I collagen genes. Mutations in the other family members with similar bone phenotype confirmed that LRP5 has a role in both juvenile and adult osteoporosis. INTRODUCTION: The gene encoding the low-density lipoprotein receptor-related protein 5 (LRP5) gene has recently been shown to affect bone mass accrual during growth and to be involved in osteoporosis-pseudoglioma syndrome and a high bone mass phenotype. Mutations in the type I collagen genes (COL1A1 and COL1A2) are known to cause osteogenesis imperfecta, characterized by increased bone fragility. MATERIALS AND METHODS: Here we analyzed COL1A1, COL1A2, and LRP5 for mutations in 20 pediatric patients with primary osteoporosis characterized by low BMD, recurrent fractures, and absent extraskeletal manifestations. RESULTS AND CONCLUSIONS: No mutations were detected in the type I collagen genes, but two missense mutations (A29T and R1036Q) and one frameshift mutation (C913fs) were found in the LRP5 gene in three of the patients. The frameshift mutation was also seen in the proband's father and brother, who both were found to have significant osteoporosis. R1036Q was observed in the proband's mother and two brothers, who all had osteoporosis. These results indicate that heterozygous mutations in the LRP5 gene can cause osteoporosis in both children and adults.
Osteoporosis is a leading public health problem that is responsible for substantial morbidity and mortality. A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. BMD is a complex trait that presumably is influenced by multiple genes. Recent linkage of three Mendelian BMD-related phenotypes, autosomal dominant high bone mass, autosomal recessive osteoporosis-pseudoglioma, and autosomal recessive osteopetrosis to chromosome 11q12-13 led us to evaluate this region to determine if the underlying gene(s) could also contribute to variation in BMD in the normal population. We performed a linkage study in a sample of 835 premenopausal Caucasian and African-American sisters to identify genes underlying BMD variation. A maximum multipoint LOD score of 3.50 with femoral neck BMD was obtained near the marker D11S987, in the same chromosomal region as the three Mendelian traits mentioned above. Our results suggest that the gene(s) underlying these Mendelian phenotypes also play a role in determining peak BMD in the normal population and are the first using linkage methods to establish a chromosomal location for a gene important in determining peak BMD. These findings support the hypothesis that a gene responsible for one or more of the rare Mendelian BMD traits linked to chromosome 11q12-13 has an important role in osteoporosis in the general population.
The osteopetroses are a heterogeneous group of genetic conditions characterized by increased bone density due to impaired bone resorption by osteoclasts. Within the autosomal dominant form of osteopetrosis, the radiological type I (ADOI) is characterized by a generalized osteosclerosis, most pronounced at the cranial vault. The patients are often asymptomatic but some suffer from pain and hearing loss. ADOI is the only type of osteopetrosis not associated with an increased fracture rate. Linkage analysis in two families with ADOI from Danish origin enabled us to assign the disease-causing gene to chromosome 11q12-13. A summated maximum lod score of +6.54 was obtained with marker D11S1889 and key recombinants allowed delineation of a candidate region of 6.6 cM between markers D11S1765 and D11S4113. Previously, genes causing other conditions with abnormal bone density have been identified from this chromosomal region. The TCIRG1 gene was shown to underly autosomal recessive osteopetrosis (ARO), and, recently, mutations in the LRP5 gene were found both in the osteoporosis-pseudoglioma syndrome and the high bone mass trait. Because both genes map within the candidate region for ADOI, it can not be excluded that ADOI is caused by mutations in either the TCIRG1 or the LRP5 gene.
Metabolic bone disease in children includes many hereditary and acquired conditions of diverse etiology that lead to disturbed metabolism of the bone tissue. Some of these processes primarily affect bone; others are secondary to nutritional deficiencies, a variety of chronic disorders, and/or treatment with some drugs. Some of these disorders are rare, but some present public health concerns (for instance, rickets) that have been well known for many years but still persist. The most important clinical consequences of bone metabolic diseases in the pediatric population include reduced linear growth, bone deformations, and non-traumatic fractures leading to bone pain, deterioration of motor development and disability. In this article, we analyze primary and secondary osteoporosis, rickets, osteomalacia (nutritional and hereditary vitamin D-dependent, hypophosphatemic and that due to renal tubular abnormalities), renal osteodystrophy, sclerosing bony disorders, and some genetic bone diseases (hypophosphatasia, fibrous dysplasia, skeletal dysplasia, juvenile Paget disease, familial expansile osteolysis, and osteoporosis pseudoglioma syndrome). Early identification and treatment of potential risk factors is essential for skeletal health in adulthood. In most conditions it is necessary to ensure an appropriate diet, with calcium and vitamin D, and an adequate amount of physical activity as a means of prevention. In secondary bone diseases, treatment of the primary disorder is crucial. Most genetic disorders await prospective gene therapies, while bone marrow transplantation has been attempted in other disorders. At present, affected patients are treated symptomatically, frequently by interdisciplinary teams. The role of exercise and pharmacologic therapy with calcium, vitamin D, phosphate, bisphosphonates, calcitonin, sex hormones, growth hormone, and thiazides is discussed. The perspectives on future therapy with insulin-like growth factor-1, new analogs of vitamin D, strontium, osteoprotegerin, and calcimimetics are presented.
Recently, It has been reported that the LDL receptor-related protein 5 (LRP5) regulates bone formation, and that mutations of the gene cause osteoporosis-pseudoglioma syndrome or high bone mass phenotypes. However, the mutations cannot explain a genetic trait for osteoporosis in the general population because of their rarity. From 219 Korean men aged 20-34 yr, we looked for six known polymorphisms causing amino acid changes in the LRP5 coding region, and investigated their association with bone mineral density (BMD) at the following anatomical sites: lumbar spine (L2-L4) and the left proximal femur (femoral neck, Ward's triangle, trochanter and shaft). We found that the Q89R polymorphism was significantly associated with BMD at the femoral neck and Ward's triangle (p=0.004 and <0.001, respectively). However, after adjusting for age, weight and height, a statistically significant association only occurred at the Ward's triangle (p=0.043), and a marginal association was observed at the femoral neck (p=0.098). No A400V, V667M, R1036Q and A1525V polymorphisms were found, and no statistically significant association was found between the A1330V polymorphism and BMD at any sites. Although we failed to demonstrate a clear association between the LRP5 polymorphism and peak bone mass in young men, the present study suggests that larger-scale studies on the Q89R polymorphism need to be performed.
Computed tomography (CT) constitutes a major advance in noninvasive diagnostic investigation of children with leukokoria , especially where media opacities preclude adequate visualization of the posterior segment, and, performed in conjunction with other studies such as diagnostic ultrasonography, has significantly improved diagnostic accuracy. Although retinoblastoma, the commonest life-threatening cause of leukokoria , usually presents with characteristic CT findings of intraocular calcification, during extraocular extension, the orbital portions of the tumor are non-calcific and contrast dramatically with the intraocular portion. Currently CT is also the best available technique for diagnosis of trilateral retinoblastoma. Computed tomographic features of several types of pseudogliomas (a collective term for lesions commonly mistaken for retinoblastomas) are also discussed with histopathologic correlation. In persistent hyperplastic primary vitreous, a conical density in CT corresponded to detached and dysplastic retina. A high density layered opacity corresponded to subretinal blood. In Coats' disease and sclerosing endophthalmitis homogenous intraocular CT density corresponds to vitreous and subretinal exudates radiologically indistinguishable from non-calcific retinoblastoma. Long-standing retinal detachments in children occasionally presenting with leukokoria showed subtle homogenous intraocular densities on CT.
The differential diagnosis of leukocoria (pseudoglioma) in the neonate includes multiple conditions, including malformations with retinal dysplasia as a component. Typically bilateral, retinal dysplasia is characteristically seen in microphthalmic eyes. Certain chromosomal defects have been described. The case reported herein presented in the first month of life with an enlarged eye, elevated intraocular pressure, prominent iris vasculature, and leukocoria. Family history was positive in one respect: this is the second child of a Viet Nam veteran exposed to Agent Orange. The first child, from a different mother, also had birth defects. Other than his left eye, the child is completely normal. Ultrasonography showed posterior vitreous opacities of indeterminate configuration. CT scan suggested a posterior intraocular mass. Histologically, the principal features were an anomalous, largely unformed corneoscleral angle, intraocular hemorrhage, and retinal dysplasia. Light microscopic studies were performed. The corneoscleral angle revealed an anteriorly inserted iris with an absence of trabecular meshwork and Schlemm's canal. This case is considered unique on the basis of the association of retinal dysplasia with congenital glaucoma and larger-than-normal eye. The significance of reported paternal exposure to Agent Orange in this instance is unknown.
In spite of the progress of the imagery in ophthalmology, the retinoblastoma remains in some particular cases, difficult to make. Moreover, the therapy sanction is often heavy. The lactate dehydrogenase (LDH) dosage in aqueous humor is an invasive technique conceivable when there are diagnosis problems particularly in retino-blastoma of old children and in affections simulating retino-blastoma. The purpose of this work is to lay out three observations where the LDH dosage enabled to keep the retinoblastoma diagnosis in one 8-year old child and eliminate it in two children having pseudoglioma with spontaneous evolution allowing to confirm the non-tumoral nature of the affection. Thus, the technique of LDH dosage has been reliable for the 3 cases which we have introduced. The authors compare the reliability of the different cytochemical techniques during the retinoblastoma diagnosis.
Osteoporosis is characterized by a decrease in bone mass as well as a deterioration of the bone architecture resulting in an increased risk of fracture. The disease is multifactorial, and it depends on environmental and genetic factors. Twin studies have shown that genetic factors account for 60-80% of the variance in bone mineral density, the best predictor of the risk of osteoporosis. There are different approaches to identify these genetic factors. Linkage studies in human and experimental animals have defined multiple loci that regulate bone mass but most of the genes responsible for this effect remain to be defined. The 11q12-13 locus was the first that was linked to bone mineral density of the young female and special bone diseases like high bone mass syndrome and osteoporosis-pseudoglioma syndrome. Both diseases appear to be in association with LDL receptor-related protein 5 gene mutation. The effect of LDL receptor-related protein 5 on bone metabolism had not been known only genetic methods suggested it. The effect of LRP5 in osteoporosis pathogenesis requires more investigation. Association and linkage studies have been performed in order to identify candidate genes in the pathogenesis of osteoporosis. Vitamin D receptor gene was the first candidate, however its effect is controversial. Other candidates, such as insulin like growth factor, interleukin-6, estrogen receptor alpha, transforming growth factor beta show no or small effect on bone mineral density or fracture frequency. To date only Sp1 polymorphism of collagen gene seems to have a consistent effect on bone fragility. The improved understanding of osteoporosis genetics should lead to better diagnosis of this disease and new treatment and prevention strategies.
Osteoporosis is the most common metabolic bone disease and caused by multiple nutritional, environmental and genetical factors. Bone mineral density (BMD) is rather strongly under genetical control. A number of candidate genes have been studied with respect to the impact on BMD. Also, gene loci of susceptibility genes for osteoporosis have been identified by family-based association and linkage approaches. In particular, LRP5 is an important molecule involved in the determination of BMD, because its abnormality is associated with osteoporosis-pseudoglioma syndrome or autosomal dominant syndrome characterized by high bone density. These findings may contribute to new strategy to teat patients with osteoporosis.
Single gene diseases may give us lots of clues to clarify the physiological roles of specific genes in human body. In the case of bone, extensive analysis of the pathogenetic mechanisms of systemic bone diseases may provide new important information on the factors in bone metabolism. In this manuscript, pathogenetic mechanisms of osteoporosis-pseudoglioma syndrome, osteogenesis imperfecta, homocystinuria, lysinuric protein intolerance and Menkes disease will be reviewed in relation to the pathogenesis of osteoporosis.