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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.

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

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.

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

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.

Summary Van Buchem disease is a hereditary sclerosing dysplasia of bone. Both dominant and autosomal recessive modes of transmission have been described. The dominant form tends to be a benign disorder and symptoms are usually confined to those associated with the enlargement of the jaw. The recessive forms tend to have a greater morbidity and symptoms arise from pressure on cranial nerves by hyperostotic bone at the base of the skull. Patients of the dominant families have often had a torus palatinus. No haematological changes are found. The alkaline phosphatase may be raised—even if the total level is not elevated, the bone fraction may be increased. The radiological appearances are regarded as characteristic. The jaw is enlarged and thickened to an extent not seen in other bone dysplasias such as osteopetrosis. The cortices of the diaphyses are thickened and the medullary cavities are encroached upon but not obliterated. Abnormal modelling of the bone ends is not found in van Buchem disease. In long bones the distribution is predominantly diaphyseal but the bone ends are also affected.

First described in 1955, Van Buchem disease is an infrequently occurring hereditary sclerosing bone dysplasia. It is more properly called hyperostosis corticalis generalisata. The most striking feature is an unusual enlargement of the mandible with a normal dental occlusion. Skull base, spine, and pelvic bone involvement is also seen. The defect appears to be an increase in cortical bone thickness or sclerosis. The condition first appears around puberty in the autosomal recessive type and in early childhood with the autosomal dominant type. Reported here is a family with Van Buchem disease, in which surgical recontouring of the mandible was performed for one of the members. The surgery was performed by a combined intraoral/extraoral technique with good aesthetic results and minimal morbidity. A differential diagnosis and workup is also presented.

(1955). An uncommon familial systemic disease of the skeleton: Hyperostosis corticalis generalisata familiaris. Acta Radiologica: Vol. 44, No. 2, pp. 109-120.

Van Buchem disease (hyperostosis corticalis generalisata; OMIM 239100 [http://www3.ncbi.nlm.nih. gov:80/htbin-post/Omim/dispmim?239100]) is an autosomal recessive disorder characterized by hyperostosis of the skull, mandible, clavicles, ribs, and diaphyseal cortices of the long bones. The most striking clinical features are the enlargement of the jaw and the thickness of the skull, which may lead to facial nerve palsy, hearing loss, and optic atrophy. Increased formation, by osteoblasts, of qualitatively normal bone has been proposed as the underlying pathological mechanism, but the molecular defect is unknown. We studied 11 van Buchem patients and their highly inbred family, who live in The Netherlands in a small ethnic isolate, that had a common ancestor approximately 9 generations ago. A genomewide search with highly polymorphic microsatellite markers showed linkage to marker D17S1299 on chromosome 17q12-21 (maximum LOD score of 8.82 at a recombination fraction [straight theta] of .01). Analysis of additional markers from that region delineated a candidate region of

We have examined 50 persons with sclerosteosis in the Afrikaner community of South Africa and 15 individuals with van Buchem disease in Holland. The clinical and radiographic manifestations of these conditions are very similar, the only notable differences being greater severity and syndactyly in the majority of the patients with sclerosteosis. The Afrikaners have Dutch antecedants and it seems likely that these autosomal recessive disorders result from homozygosity of the same faulty genes. The phenotypic variation may be due to the epistatic effect of modifying genes in the Afrikaner population.

Six of 41 presumed cases of Van Buchem disease described in the literature fit uniform diagnostic criteria. Segregation analysis of these 6 cases, in addition to another the authors report, supports a recessive mode of inheritance. Genetic heterogeneity is confirmed by the demonstration of a dominantly-inherited phenotype resembling Van Buchem disease. The probable etiology is a defect in the endochrondral modulatory step regulating transformation of osteoclast to osteoblast.

In this paper we report a 7.5-year-old physically normal boy with van Buchem disease (endosteal hyperostosis). Vague complaints of headache were the indication for X-ray examination. At the age of 2 months a left-side peripheral facial nerve palsy suddenly occurred in this boy. Skull X-rays gave normal results at that age, suggesting that encroachment of the cranial nerves in van Buchem disease may occur as early as in the postnatal period, even before sclerosis of the skull has become radiologically visible.