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Van Buchem disease is a rare autosomal recessive genetic disorder that causes a compromised inhibitory feedback mechanism resulting in increased bone formation and overgrowth of the skeleton leading to a variety of neurological symptoms. It has been reported in less than 50 patients most of which were in western Europe. We report the first case of this condition from the Indian subcontinent with an early presentation. This patient presented with a global delay in attaining the developmental milestones and progressive reduction in visual acuity and loss of hearing. He had dysmorphic facies, multiple cranial nerve palsies, and severe visual and auditory deficits. Imaging revealed sclerosing bone dysplasia. This case illustrates the clinical and imaging findings of this rare condition.

Sclerosteosis and van Buchem disease are two rare bone sclerosing dysplasias caused by genetic defects in the synthesis of sclerostin. In this article we review the demographic, clinical, biochemical, radiological, and histological characteristics of patients with sclerosteosis and van Buchem disease that led to a better understanding of the role of sclerostin in bone metabolism in humans and we discuss the relevance of these findings for the development of new therapeutics for the treatment of patients with osteoporosis.

Rationale: Van Buchem disease (VBD) is a very rare autosomal recessive disease. According to our review of the relevant literature, this article is the first case report of VBD in Taiwan. Patient concerns: A 54-year-old woman developed a protruding chin, frontal bossing, and macrocephaly at the age of 40 years. She noted the onset of progressive bilateral visual and hearing impairment at the age of 40 and 45 years, respectively. Intermittent headaches, peripheral facial palsy, recurrent bilateral trigeminal neuralgia, and back pain were also observed since age 40. Diagnoses: She received a diagnosis of VBD based on the phenotypic abnormalities of the skull and mandible, facial nerve involvement, radiological images of the skeleton, and her family history. Interventions: She received symptomatic treatment and surgical decompression for spinal stenosis. Outcomes: Her clinical condition did not improve satisfactorily. Lessons: We hope to promote clinician awareness of this very rare disease and its symptoms and signs. A comprehensive understanding of VBD might lead to the development of a curative therapy in the future.

Due to dull headaches and enlarged hands, feet and mandible, endocrinologist referred a 39-year-old female patient to MRI of the brain.

Fibrodysplasia ossificans progressiva (FOP) is a rare hereditary disease caused by a mutation in the intracellular domain of the activin A receptor type I and is characterized by episodes (flare-ups) of progressive heterotopic endochondral ossification (HO) in the soft tissues. The mutation alone is not sufficient for the occurrence of HO since flare-ups are triggered by inflammation and activation of the innate immune system. A number of cellular and humoral mediators have been implicated in animal and in vitro models. Observations in humans support the inflammatory nature of the condition, but data on the involved mediators are variable. We hypothesize that for induction of flare-ups in patients with FOP increase in at least one of the pro-inflammatory cytokines is both essential and sufficient to trigger the entire process of the inflammatory cells influx resulting in the novel ectopic bone formation and we suggest that C-C motif ligand 5 (CCL5), a pro- inflammatory chemokine also known as Regulated on activation, normal T-cell expressed and secreted (RANTES), might be the key candidate. CCL5 is a chemoattractant for all cellular types implicated in HO and is produced by the cells of the tissue microenvironment at the sites of HO as well as by the pro-inflammatory cellular mediators. CCL5 induces ossification in cultured human pluripotent mesenchymal cells (hMSCs) and in the primary culture of monocytes from FOP patients (but not from their healthy relatives), stimulation with lipopolysaccharide induces CCL5 expression. Finally, in a pilot study we used a panel of 23 cytokines and chemokines to screen the plasma samples of three subjects: a female patient with FOP during a flare-up ; a female patient with hyperostosis corticalis generalisata (van Buchem disease), another rare disease characterized by excessive bone formation at the sites where it regularly occurs that does not include inflammatory events ; and a healthy woman without bone disorders. There appeared a rather clear-cut signal of a 2-fold higher level of CCL5 in the FOP patient vs. the healthy subject and the van Buchem patient. Evaluation of the hypothesis would require an international prospective study, with main motivation being the lack of a conclusive treatment as the major unmet need in FOP. A treatment targeting CCL5 receptor already exists and is used in HIV- infected patients.

Differential diagnosis of facial nerve palsy in children is extensive. We report on three pediatric cases presenting with facial nerve palsy caused by hyperostosis corticalis generalisata (Van Buchem disease). This autosomal recessive disease is characterized by progressive bone overgrowth, with narrowing of the neuroforamina in the skull causing cranial neuropathies. These three new cases of Van Buchem disease are of interest because of exceptionally early presentation of symptoms. Furthermore, this is the first report describing bilateral papilledema in a child with Van Buchem disease. Head computerized tomography (CT) scan revealed thickened calvarium, skull base and mandible in all three children, with narrowed facial nerve canals. Bone mineral density (BMD) was markedly increased at all measured points and biochemical markers of bone formation were significantly elevated. Diagnosis of Van Buchem disease was genetically confirmed. The cases are unique in that these are the first well-documented pediatric cases of Van Buchem disease. (C) 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Egill Skallagrímsson, a tenth-century Viking, was a colourful warrior poet and an early anti-hero. The thickness and strength of his skull and his very ugly facial features with a prominent mandible have suggested to some authorities that Egill suffered from Paget's disease of bone. However, Paget's bone, while thickened, lacks structural integrity, infrequently involves the mandible and is prone to fractures. The more recent discoveries of sclerosing bone diseases, the elucidation of their pathophysiological abnormalities in intracellular signalling in bones and current research on the sclerostin or LRP5 genes suggest Van Buchem disease as a more probable diagnosis, although the hypothesis remains conjecture in the absence of any of his remains.

Joint Bone Spine - In Press.Proof corrected by the author Available online since mercredi 9 mars 2016

Sclerostin is an inhibitor of bone formation expressed by osteocytes. We hypothesized that sclerostin is expressed by cells of the same origin and also embedded within mineralized matrices. In this study, we analyzed (a) sclerostin expression using immunohistochemistry, (b) whether the genomic defect in individuals with van Buchem disease (VBD) was associated with the absence of sclerostin expression, and (c) whether this was associated with hypercementosis. Sclerostin was expressed by cementocytes in mouse and human teeth and by mineralized hypertrophic chondrocytes in the human growth plate. In individuals with VBD, sclerostin expression was absent or strongly decreased in osteocytes and cementocytes. This was associated with increased bone formation, but no overt changes in cementum thickness. In conclusion, sclerostin is expressed by all 3 terminally differentiated cell types embedded within mineralized matrices: osteocytes, cementocytes, and hypertrophic chondrocytes.

embers suggests a sporadic mutation affecting one f the genes responsible for bone homeostasis in this atient. Cranial nerve compression has been described in atients’ with van Buchem disease; however, cerebroascular accidents have not been identified comonly in these patients. Although the patient decribed some disturbance in facial sensation and isplayed skull bone thickening radiographically, it is ifficult to say whether the condition contributed to he cerebrovascular accidents without radiologic evience of compression of the brain or vascular canals n the skull base. Previous reports of surgical intervention on paients with van Buchem disease and ADO have ndicated normal healing although no comments have een made on longer term recurrence at surgicallyddressed sites. We were concerned about the healng capacity of the bone and carried out more limited urgery at the first intervention. These fears seem to e unfounded and, ironically with the wisdom of indsight, the history of palmidronate infusions hould have caused greater concern.

A 28-year-old man with genetically confirmed hyperostosis corticalis generalisata (Van Buchem disease) suffered from headache and progressive cognitive and sensibility disorders. Bone formation of the skull was ongoing, leading to narrowing of the intracranial space and foramen magnum. A large bilateral frontoparietal craniotomy and decompression of the foramen magnum resulted in almost complete relief of his symptoms. This is the first report on successful decompressive surgery as a treatment of cognitive impairment and dysaesthesia.

This case report presents an unusual incidental radiographic finding on a dental panoramic radiograph that caused diagnostic confusion. A 46-year-old female presented with symmetrical sclerotic cortical thickening of the anterior mandible visible on radiograph, with no other major clinical examination findings. The patient subsequently showed no change in radiographic appearance over a 6 year period. Based on this evidence, and the benign nature of the history, we propose a diagnosis of Worth syndrome. This report aims to clarify the difference in terminology and presentation of two conditions known to produce mandibular osteosclerosis: Worth syndrome and Van Buchem disease, both of which are often quoted synonymously in the literature.

Texto completo. Acesso restrito. p. 1661–1669 Submitted by Santiago Fabio (fabio.ssantiago@hotmail.com) on 2013-07-31T18:06:01Z No. of bitstreams: 1 111111111a.pdf: 683501 bytes, checksum: 978acc94ebde8e6074df25c384a75ff8 (MD5) Approved for entry into archive by Rodrigo Meirelles (rodrigomei@ufba.br) on 2013-11-01T11:57:18Z (GMT) No. of bitstreams: 1 111111111a.pdf: 683501 bytes, checksum: 978acc94ebde8e6074df25c384a75ff8 (MD5) Made available in DSpace on 2013-11-01T11:57:18Z (GMT). No. of bitstreams: 1 111111111a.pdf: 683501 bytes, checksum: 978acc94ebde8e6074df25c384a75ff8 (MD5) Previous issue date: 1999 Sclerosteosis is an uncommon, autosomal recessive, progressive, sclerosing, bone dysplasia characterized by generalized osteosclerosis and hyperostosis of the skeleton, affecting mainly the skull and mandible. In most patients this causes facial paralysis and hearing loss. Other features are gigantism and hand abnormalities. In the present study, linkage analysis in two consanguineous families with sclerosteosis resulted in the assignment of the sclerosteosis gene to chromosome 17q12-q21. This region was analyzed because of the recent assignment to this chromosomal region of the gene causing van Buchem disease, a rare autosomal recessive condition with a hyperostosis similar to sclerosteosis. Because of the clinical similarities between sclerosteosis and van Buchem disease, it has previously been suggested that both conditions might be caused by mutations in the same gene. Our study now provides genetic evidence for this hypothesis. Salvador

a c d D enetic disorders of bone homeostasis are uncomon; however, knowledge of their clinical features nd management are important for the maxillofacial urgeon. A variety of genetic abnormalities may give ise to excessive bone. The pathogenic mechanisms nderlying these conditions include: disorders of one resorption (eg, osteopetrosis), excessive bone eposition (eg, van Buchem disease or sclerostosis), nd a disturbed balance between bone resorption and ormation (eg, juvenile Paget’s disease). Progress in enetic mapping and the human genome project have nraveled the abnormalities behind many of these onditions and allowed the function of the affected enes to be described. The LRP5 gene and the SOST gene are implicated in he etiology of several conditions that have excessive one formation in the craniomaxillofacial region. an Buchem disease and autosomal dominant osteoclerosis (ADO) are such conditions, and craniomaxllofacial manifestations are responsible for the major

Van Buchem disease (VBD) is a rare bone sclerosing dysplasia caused by the lack of a regulatory element of the SOST gene, which encodes for sclerostin, an osteocyte-derived negative regulator of bone formation. We studied the demographic, clinical, biochemical, and densitometric features of 15 patients with VBD (12 adults and 3 children) and 28 related carriers of the gene mutation. The most common clinical findings in patients were facial palsy (100%) and various degrees of hearing impairment (93%); raised intracranial pressure had been documented in 20%. The clinical course of the disease appeared to stabilize in adulthood, with the majority of patients reporting no progression of symptoms or development of complications with time. Carriers of the disease had none of the clinical features or complications of the disease. Sclerostin could be detected in the serum in all but 1 VBD patients (mean 8.0 pg/mL; 95% confidence interval [CI], 4.9–11.0 pg/mL), and were lower than those of carriers (mean 28.7 pg/mL; 95% CI, 24.5–32.9 pg/mL; p

In this thesis we studie the role of sclerostin in bone metabolism. We studied patients with the rare bone sclerosing disorders sclerosteosis and van Buchem disease, both caused by sclerostin deficiency. We further studied the role of sclerostin in different bone related disorders.

Differential diagnosis of facial nerve palsy in children is extensive. We report on three pediatric cases presenting with facial nerve palsy caused by hyperostosis corticalis generalisata (Van Buchem disease). This autosomal recessive disease is characterized by progressive bone overgrowth, with narrowing of the neuroforamina in the skull causing cranial neuropathies. These three new cases of Van Buchem disease are of interest because of exceptionally early presentation of symptoms. Furthermore, this is the first report describing bilateral papilledema in a child with Van Buchem disease. Head computerized tomography (CT) scan revealed thickened calvarium, skull base and mandible in all three children, with narrowed facial nerve canals. Bone mineral density (BMD) was markedly increased at all measured points and biochemical markers of bone formation were significantly elevated. Diagnosis of Van Buchem disease was genetically confirmed. The cases are unique in that these are the first well-documented pediatric cases of Van Buchem disease. (C) 2012 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

In recent years study of rare human bone disorders has led to the identification of important signaling pathways that regulate bone formation. Such diseases include the bone sclerosing dysplasias sclerosteosis and van Buchem disease, which are due to deficiency of sclerostin, a protein secreted by osteocytes that inhibits bone formation by osteoblasts. The restricted expression pattern of sclerostin in the skeleton and the exclusive bone phenotype of good quality of patients with sclerosteosis and van Buchem disease provide the basis for the design of therapeutics that stimulate bone formation. We review here current knowledge of the regulation of the expression and formation of sclerostin, its mechanism of action, and its potential as a bone-building treatment for patients with osteoporosis.

A combination of clinical and MR examinations should be used to assess the severity of Van Buchem disease, particularly in respect to intracranial pressure.

Sclerostin is an osteocyte-derived negative regulator of bone formation. It inhibits BMP-stimulated bone formation both in vitro and in vivo but has no direct effect on BMP signaling. Instead, sclerostin inhibits Wnt signaling that is required for BMP-stimulated osteoblastic differentiation. Introduction: Sclerostin is a member of the Dan family of glycoproteins of which many members have been reported to antagonize BMP activity. Sclerostin has been shown to inhibit BMP-stimulated bone formation, but its mechanism of action seems to be different from classical BMP antagonists. In this study, we investigated the mechanism by which sclerostin inhibits BMP-stimulated bone formation. Materials and Methods: DNA electroporation of calf muscle of mice using expression plasmids for BMP and sclerostin was used to study the effect of sclerostin on BMP-induced bone formation in vivo. Transcriptional profiling using microarrays of osteoblastic cells treated with BMP in the absence or presence of sclerostin was used to find specific growth factor signaling pathways affected by sclerostin. The affected pathways were further studied using growth factor-specific reporter constructs. Results: BMP-induced ectopic bone formation in calf muscle of mice was prevented by co-expression of sclerostin in vivo. Transcriptional profiling analysis of osteoblastic cultures indicated that sclerostin specifically affects BMP and Wnt signaling out of many other growth signaling pathways. Sclerostin, however, did not inhibit stimulation of direct BMP target genes. Furthermore, we did not obtain any evidence for sclerostin acting as a direct BMP antagonist using a BMP-specific reporter construct. In contrast, sclerostin shared many characteristics with the Wnt antagonist dickkopf-1 in antagonizing BMP-stimulated bone formation and BMP- and Wnt-induced Wnt reporter construct activation. Conclusions: Sclerostin inhibits BMP-stimulated bone formation but does not affect BMP signaling. Instead, it antagonizes Wnt signaling in osteoblastic cells. High bone mass in sclerosteosis and van Buchem disease may, therefore, result from increased Wnt signaling. © 2007 American Society for Bone and Mineral Research.

The middle ear changes in Sclerosteosis and Van Buchem disease are described. Reduced bone resorption occurs due to faulty activity of the sclerostin molecule, a product of the recently discovered S

Sclerostin is an osteocyte-derived negative regulator of bone formation. It inhibits BMP-stimulated bone formation both in vitro and in vivo but has no direct effect on BMP signaling. Instead, sclerostin inhibits Wnt signaling that is required for BMP-stimulated osteoblastic differentiation. Introduction: Sclerostin is a member of the Dan family of glycoproteins of which many members have been reported to antagonize BMP activity. Sclerostin has been shown to inhibit BMP-stimulated bone formation, but its mechanism of action seems to be different from classical BMP antagonists. In this study, we investigated the mechanism by which sclerostin inhibits BMP-stimulated bone formation. Materials and Methods: DNA electroporation of calf muscle of mice using expression plasmids for BMP and sclerostin was used to study the effect of sclerostin on BMP-induced bone formation in vivo. Transcriptional profiling using microarrays of osteoblastic cells treated with BMP in the absence or presence of sclerostin was used to find specific growth factor signaling pathways affected by sclerostin. The affected pathways were further studied using growth factor-specific reporter constructs. Results: BMP-induced ectopic bone formation in calf muscle of mice was prevented by co-expression of sclerostin in vivo. Transcriptional profiling analysis of osteoblastic cultures indicated that sclerostin specifically affects BMP and Wnt signaling out of many other growth signaling pathways. Sclerostin, however, did not inhibit stimulation of direct BMP target genes. Furthermore, we did not obtain any evidence for sclerostin acting as a direct BMP antagonist using a BMP-specific reporter construct. In contrast, sclerostin shared many characteristics with the Wnt antagonist dickkopf-1 in antagonizing BMP-stimulated bone formation and BMP- and Wnt-induced Wnt reporter construct activation. Conclusions: Sclerostin inhibits BMP-stimulated bone formation but does not affect BMP signaling. Instead, it antagonizes Wnt signaling in osteoblastic cells. High bone mass in sclerosteosis and van Buchem disease may, therefore, result from increased Wnt signaling. © 2007 American Society for Bone and Mineral Research.

Objective. The purpose of this study was to evaluate the lifetime evolution of the radioclinical features in a large family with van Buchem disease. Design and patients. The study population included 13 patients, ranging between 6 and 69 years. The evolution of the clinical features has been assessed by retrospective analysis of the clinical records of the patients. The age-related evolution of the cortical hyperostosis and defective modeling at the tubular bones was evaluated by morphometric analysis of hand films in 9 patients, compared with 9 control individuals. Progression of sclerosis of the craniofacial bones was evaluated by analysis of the skull radiographs of eleven van Buchem patients, taken at different age. Results and conclusions. Radioclinical features, including sclerosis of the cranial and tubular bones and cranial nerve deficit, become more prominent in older patients. Defective modeling of tubular bones, cortical thickness and medullary width progress with age. Radioclinical abnormalities of van Buchem patients become more prominent in older patients, which suggests that the van Buchem gene is very actively involved in bone metabolism throughout life. Morphometric analysis of the plain films supports the hypothesis that the physiological function of the van Buchem gene is to inhibit bone formation and possibly to regulate bone remodeling.

We report a 56-year-old woman, mainly suffering from painful legs and the inability to run. Radiologically, marked sclerosis and hyperostosis of the skull bones is present resulting in macrocephaly. Most tubular bones of the limbs, as well as the clavicles, are affected by sclerosis. By mutation analysis of the TGFB1, SOST and LRP5 genes, we were able to exclude the diagnoses of Camurati-Engelmann disease, Van Buchem disease, sclerosteosis, high-bone-mass trait and endosteal hyperostosis (Worth type). We believe this patient represents one of the very few examples of adult craniodiaphyseal dysplasia with a mild form of the disease and moderate facial changes.

Texto completo. Acesso restrito. p. 1661–1669 Submitted by Santiago Fabio (fabio.ssantiago@hotmail.com) on 2013-07-31T18:06:01Z No. of bitstreams: 1 111111111a.pdf: 683501 bytes, checksum: 978acc94ebde8e6074df25c384a75ff8 (MD5) Approved for entry into archive by Rodrigo Meirelles (rodrigomei@ufba.br) on 2013-11-01T11:57:18Z (GMT) No. of bitstreams: 1 111111111a.pdf: 683501 bytes, checksum: 978acc94ebde8e6074df25c384a75ff8 (MD5) Made available in DSpace on 2013-11-01T11:57:18Z (GMT). No. of bitstreams: 1 111111111a.pdf: 683501 bytes, checksum: 978acc94ebde8e6074df25c384a75ff8 (MD5) Previous issue date: 1999 Sclerosteosis is an uncommon, autosomal recessive, progressive, sclerosing, bone dysplasia characterized by generalized osteosclerosis and hyperostosis of the skeleton, affecting mainly the skull and mandible. In most patients this causes facial paralysis and hearing loss. Other features are gigantism and hand abnormalities. In the present study, linkage analysis in two consanguineous families with sclerosteosis resulted in the assignment of the sclerosteosis gene to chromosome 17q12-q21. This region was analyzed because of the recent assignment to this chromosomal region of the gene causing van Buchem disease, a rare autosomal recessive condition with a hyperostosis similar to sclerosteosis. Because of the clinical similarities between sclerosteosis and van Buchem disease, it has previously been suggested that both conditions might be caused by mutations in the same gene. Our study now provides genetic evidence for this hypothesis. Salvador