Rare Bone Disease Research Articles

Letter to the Editor concerning “Hajdu Cheney syndrome; report of a novel NOTCH2 mutation and treatment with denosumab” by G. Adami et al. Bone 2016;92:150–156

Denosumab (Dmab), a monoclonal antibody against the receptor activator of nuclear factor-κB (RANK) ligand (RANKL) which substantially suppresses osteoclast activity, has been approved for the treatment of common metabolic bone diseases, including postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis, in which the pathway of the RANK/RANKL/osteoprotegerin is dysregulated. However, the imbalance of RANKL/RANK/osteoprotegerin is also implicated in the pathogenesis of several other rare metabolic bone diseases, including Juvenile Paget disease, fibrous dysplasia, Hajdu Cheney syndrome and Langerhans cell histiocytosis, thus rendering Dmab a potential treatment option for these diseases. Dmab has been also administered off-label in selected patients (e.g., with Paget's disease, osteogenesis imperfecta, aneurysmal bone cysts) due to contraindications or unresponsiveness to standard treatment, such as bisphosphonates. Moreover, Dmab was administered to improve hypercalcemia induced by various diseases, including primary hyperparathyroidism, tuberculosis and immobilization. The aim of this review is to summarize existing evidence on off-label uses of Dmab in metabolic bone diseases and provide opinion for or against its use, which should be always considered on an individual basis.

Modeling Hypophosphatasia in Ovies aries (sheep) using CRISPR/Cas9: Development of large animal models that phenocopy rare human bone diseases

Hypophosphatasia is a rare inherited disorder that affects the development of bones and teeth caused by mutations in the tissue‐nonspecific alkaline phosphatase (TNSALP) gene. Similar to other human disease models, the current models of HPP have been engineered exclusively in rodents – specifically mice harboring loss‐of‐function missense mutations. However, although useful for modeling some aspects of HPP, murine models harboring TNSALP mutations do not faithfully represent the broad spectrum of human HPP clinical bone and tooth (odontohypophosphatasia) phenotypes. Mice have smaller long bones with thin fragile cortices and do not remodel the skeleton by Haversian remodeling as in humans nor do mice lose their deciduous teeth. However, in sheep both bone and tooth remodeling are analogous to humans. Therefore[GD1], we hypothesized that HPP mutation‐specific replacements into the sheep genome using CRISPR/Cas9 would produce a model that accurately phenocopies the bone and tooth pathophysiology in the disorder. We have recently identified an index patient with two distinct mutations in the ALPL gene [Alanine (GCC) à Threonine (ACC) in exon 5 (c.346 G>A) and Isoleucine (ATC) à Methionine (ATG) in exon 10 (c.1077 C>G)] that has a mild bone phenotype, with the primary defects being rhizomelia and early loss of deciduous teeth. However, a knock‐in mouse model of the c.346 G>A mutation presents with odontohypophosphatasia and without tooth loss, and without any deleterious effect on the long bones. Additionally, HPP patients with mutations c.571G>A at exon 6 and c.1133A>T at exon 10 have infantile lethal clinical presentations. To develop the genetically‐modified HPP sheep models, 14 single guide RNAs targeting the four distinct HPP mutation loci in exons 5, 6, and 10 of the sheep TNSALP gene were cloned into a pSpCas9(BB)‐2A‐GFP CRISPR/Cas9 plasmid, validated, and then analyzed for cutting efficiency. Primers upstream and downstream of each exon region of interest were used to capture 2kb and sequenced to verify the loci‐specific sequences. The different CRISPR/Cas9 constructs, sgRNAs, and repair DNA templates containing orthologous HPP mutations are being used to modify sheep embryos by intracytoplasmatic microinjection. These four unique allelic variants of HPP will be used to model the human individual and compound heterozygous HPP phenotypes in sheep, allowing for the characterization and comparison of interspecies differences in the HPP bone and tooth phenotypes of mouse, sheep, and human.

Fibrogenesis Imperfecta Ossium and Response to Human Growth Hormone: A Potential Therapy.

Fibrogenesis imperfecta ossium (FIO) is a rare bone disease manifested by generalized bone pain, fragility fractures, progressive disability, and extensive mineralization defect seen in bone biopsy specimens. The pathogenesis of the disease is unknown and currently there is no effective treatment. To report on the effect of recombinant human growth hormone (rhGH) therapy in FIO. An observational study in two patients. Endocrinology clinic in an academic institution. Two siblings with FIO. rhGH was administered subcutaneously at a dose of 1 U daily for 1 year. Changes in clinical, biochemical, radiological, and bone histological (i.e., light and transmission electron microscopy, and histomorphometry) investigations. Except for an elevated serum alkaline phosphatase level, results of routine biochemical, hematological, and hormonal investigations were normal in both patients. Radiographs showed pseudofractures and bone scans revealed a "beheaded" tracer activity pattern (i.e., superscan without uptake in the skull). Bone biopsy specimens showed severe mineralization defect simulating osteomalacia with disorganized collagen fibril alignment. Treatment with rhGH was followed by clinical, biochemical, and radiological improvement in both the patients, with substantial improvement in the mineralization defect, most likely due to rhGH-induced improvement in collagen fibril arrangement. We report on two brothers with FIO and demonstrate clinical improvement and restoration of normal bone pathology with rhGH therapy. We suggest that rhGH is a potential therapy for FIO for which no effective therapy currently exists.

Osteopetroses, emphasizing potential approaches to treatment

Osteopetroses are a heterogeneous group of rare genetic bone diseases sharing the common hallmarks of reduced osteoclast activity, increased bone mass and high bone fragility. Osteoclasts are bone resorbing cells that contribute to bone growth and renewal through the erosion of the mineralized matrix. Alongside the bone forming activity by osteoblasts, osteoclasts allow the skeleton to grow harmonically and maintain a healthy balance between bone resorption and formation. Osteoclast impairment in osteopetroses prevents bone renewal and deteriorates bone quality, causing atraumatic fractures. Osteopetroses vary in severity and are caused by mutations in a variety of genes involved in bone resorption or in osteoclastogenesis. Frequent signs and symptoms include osteosclerosis, deformity, dwarfism and narrowing of the bony canals, including the nerve foramina, leading to hematological and neural failures. The disease is autosomal, with only one extremely rare form associated so far to the X-chromosome, and can have either recessive or dominant inheritance. Recessive ostepetroses are generally lethal in infancy or childhood, with a few milder forms clinically denominated intermediate osteopetroses. Dominant osteopetrosis is so far associated only with mutations in the CLCN7 gene and, although described as a benign form, it can be severely debilitating, although not at the same level as recessive forms, and can rarely result in reduced life expectancy. Severe osteopetroses due to osteoclast autonomous defects can be treated by Hematopoietic Stem Cell Transplant (HSCT), but those due to deficiency of the pro-osteoclastogenic cytokine, RANKL, are not suitable for this procedure. Likewise, it is unclear as to whether HSCT, which has high intrinsic risks, results in clinical improvement in autosomal dominant osteopetrosis. Therefore, there is an unmet medical need to identify new therapies and studies are currently in progress to test gene and cell therapies, small interfering RNA approach and novel pharmacologic treatments.

The Rare Bone Disease Working Group: report from the 2016 American Society for Bone and Mineral Research Annual Meeting

A working group on rare bone diseases was held in Atlanta, Georgia as part of the 2016 annual meeting of the American Society for Bone and Mineral Research. The meeting was organized by Matthew Drake. Given recent advances in our understanding of fibrodysplasia ossificans progressiva (FOP), the initial portion of the program was devoted to basic, translational, and clinical aspects of FOP. The remainder of the program was divided into updates on an array of rare bone diseases as detailed below. In total, there were more than 120 scientists from academia and industry in attendance.

An atypical case of craniometaphyseal dysplasia. Case report and surgical treatment.

Craniometaphyseal dysplasia is a rare hereditary bone disease presenting metaphyseal widening of the tubular bones, sclerosis of craniofacial bones and bony overgrowth of the facial and skull bones. Craniometaphyseal dysplasia occurs in an autosomal dominant (AD) and an autosomal recessive (AR) form. We present a 32-year-old patient arrived at our unit in May 2009. His main discomfort was a major limitation of the mouth opening, in the context of a craniofacial deformity. Relying on patient's medical history and the performed diagnostic tests, the diagnosis of craniometaphyseal dysplasia was made. After careful evaluation of the clinical case, in accordance with the requirements of the patient, we opted for a surgical treatment aimed at correction of functional limitation of temporomandibular joint and aesthetic improvement of the facial bones. The stability of the clinical results led us to suggest and to undertake the surgical path, also due to the lack of safe and consolidated non-surgical treatments for the specific case.

Management of pathological fracture of the humerus secondary to osteofibrous dysplasia after curettage with elastic intramedullary nail: A case report

Introduction: Fibrous dysplasia is a rare non neoplastic bone disease of unknown aetiology which has a wide spectrum of symptoms such as pain, deformity, fracture depending on the area of involvement. Cases are diagnosed within the first three decades of life, though most commonly diagnosed in children and adolescents. Fibrous dysplasia presents in two forms monostotic or polyostotic. We present a case of pathological fracture of humerus secondary to fibrous dysplasia admitted in department with a background of posttraumatic pain in the right arm. Conclusion: Pathological fracture of humerus in a child secondary to Fibrous dysplasia can be managed with curettage and bone grafting along with elastic intramedullary nail.

Hereditary multiple exostoses in a 15-year-old boy: A case report and review of literature

Background: Hereditary Multiple Exostoses (HME) is a rare bone disease, usually associated with deformity and pressure symptoms. It is an autosomal dominant disorder characterized by the development of benign tumours growing outward from the metaphyses of long bones and can lead to considerable psychosocial problems. This paper aims at reporting a case of HME with some peculiar features. Methods: A case report of a 15- year-old Nigerian male with Hereditary Multiple Exostoses is presented to highlight the clinical, radiological features and management challenges of the condition. Results: The patient presented with multiple hard, bony and ridge-like growth along the spine, scapula and para-vertebral region which gradually increased in size. These swellings were non-tender, not attached to the overlying skin and immobile, had no differential warmth and appeared to be continuous with the underlying bony structures. A striking feature was exostoses that extended from the lumbar spine towards the left scapula. He also had brachymetatarsia of the first ray of both feet. Skeletal survey confirmed the diagnosis. Conclusion: Though rare, HME do occur in our environment. The treatment is individualized, with small asymptomatic or minimally symptomatic lesions followed up and only supportive care provided. Larger symptomatic lesions may cause major physical handicap and may be resected. Keywords: Hereditary, Multiple, Exostoses, Deformity

How rare bone diseases have informed our knowledge of complex diseases.

Rare bone diseases, generally defined as monogenic traits with either autosomal recessive or dominant patterns of inheritance, have provided a rich database of genes and associated pathways over the past 2-3 decades. The molecular genetic dissection of these bone diseases has yielded some major surprises in terms of the causal genes and/or involved pathways. The discovery of genes/pathways involved in diseases such as osteopetrosis, osteosclerosis, osteogenesis imperfecta and many other rare bone diseases have all accelerated our understanding of complex traits. Importantly these discoveries have provided either direct validation for a specific gene embedded in a group of genes within an interval identified through a complex trait genome-wide association study (GWAS) or based upon the pathway associated with a monogenic trait gene, provided a means to prioritize a large number of genes for functional validation studies. In some instances GWAS studies have yielded candidate genes that fall within linkage intervals associated with monogenic traits and resulted in the identification of causal mutations in those rare diseases. Driving all of this discovery is a complement of technologies such as genome sequencing, bioinformatics and advanced statistical analysis methods that have accelerated genetic dissection and greatly reduced the cost. Thus, rare bone disorders in partnership with GWAS have brought us to the brink of a new era of personalized genomic medicine in which the prevention and management of complex diseases will be driven by the molecular understanding of each individuals contributing genetic risks for disease.

Debridement in chronic osteomyelitis with benign osteopetrosis: A case report.

Osteopetrosis is a rare bone disease caused by metabolic imbalances as a result of genetic mutations. For instance, autosomal dominant osteopetrosis is caused by a missense mutation of the C1CN7 gene. This was first reported in 1904 and is thought to be caused by osteoclastic dysfunction and an impaired bone resorption ability. An accumulation of cortical bone mass during the remodeling of the medullary bone may increase the bone density and give rise to a hard marble consistency. Osteopetrosis can be divided into benign and malignant forms; however, no curative treatment exists for benign osteopetrosis. The management of complications, such as chronic osteomyelitis and fractures, serves a key role in influencing the patient survival rates. Previous studies have demonstrated that a combined treatment of hyperbaric oxygen (HBO) lavage for debridement of the necrotic region and high-dose systemic antibiotics may be effective in the management of osteopetrosis. The present study reported a case of chronic mandible osteomyelitis and fistula occurring in association with maxillary sinusitis, who was successfully treated by through nasal endoscopy, using repeated flushing and cleaning every 2 weeks as a form of debridement, in the absence of high-dose antibiotics and HBO.

Fibrous dysplasia of bone: craniofacial and dental implications.

Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the GNAS gene, which lead to constitutive activation of adenylyl cyclase and elevated levels of cyclic AMP, which act on downstream signaling pathways and cause normal bone to be replaced with fibrous tissue and abnormal (woven) bone. The bone disease may occur in one bone (monostotic), multiple bones (polyostotic), or in combination with hyperfunctioning endocrinopathies and hyperpigmented skin lesions (in the setting of McCune-Albright Syndrome). FD is common in the craniofacial skeleton, causing significant dysmorphic features, bone pain, and dental anomalies. This review summarizes the pathophysiology, clinical findings, and treatment of FD, with an emphasis on the craniofacial and oral manifestations of the disease.

Melorheostosis: A Retrospective Clinical Analysis of 24 Patients at the Mayo Clinic

BackgroundCurrent understanding of the clinical features of persons with melorheostosis is restricted primarily to individual case reports and small case series. ObjectiveTo assess the clinical features of patients with melorheostosis treated at our institution from 1972 through 2010. DesignChart review. SettingTertiary academic medical center. ParticipantsTwenty-three patients with “definite” and one patient with “probable” melorheostosis based on radiographic criteria. MethodsThe eligible study cohort was identified through the Rochester Medical Index database. Further diagnostic confirmation of patients with melorheostosis was performed by radiographic review. Main Outcome MeasurementsWe evaluated age at first visit to our institution, gender, affected body area, number of bones affected, presenting symptoms, surgical evaluation, and therapies provided. ResultsThe average age at first evaluation at our clinic was 36.5 years (median 41.5 years, range 3-68 years). The female to male ratio was 4:1. The lower extremity was most commonly affected (66.6%), followed by upper extremity (33.3%), spine (16.6%), and head (8.3%). One-third of patients had involvement of a single bone; two-thirds had multiple bone involvement. Pain was the most common presenting concern (83.3%), followed by deformity (54.1%), limitation of movement (45.8%), numbness (37.5%), and weakness (25.0%). Most patients had a physician evaluation (87.5%); patients also underwent orthopedic surgery (45.8%), physical therapy (33.3%), and occupational therapy (12.5%). ConclusionsMelorheostosis is a rare sclerotic bone disease resulting in pain, deformity, and dysfunction. An interdisciplinary approach to care should include nonoperative and operative evaluation, as well as appropriate therapies. A prospective approach to evaluation, including imaging and physical examinations, would provide valuable longitudinal data. Level of EvidenceIV

Burden of disease in adult patients with hypophosphatasia: Results from two patient-reported surveys

BackgroundHypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutation(s) in the tissue-nonspecific alkaline (TNSALP) phosphatase gene, which manifests as rickets and/or osteomalacia with systemic complications and affects patients of all ages. The burden of disease is poorly characterized in adult patients. AimsWe assessed patient-reported burden of disease using two surveys reasonably specific for HPP symptomatology, the Hypophosphatasia Impact Patient Survey (HIPS) and the Hypophosphatasia Outcomes Study Telephone interview (HOST). MethodsPatients with HPP were invited to participate via patient advocacy groups or their medical provider. Survey questions captured demography, HPP-related medical history, mobility, and health-related quality of life (using Short Form 12 [version 2] Health Survey [SF-12v2]) via internet report (HIPS) or telephone interview (HOST). ResultsOne hundred twenty-five adults responded (mean [standard deviation, SD] age: 45 [14.3] years). Eighty-four patients (67%) reported pediatric-onset of their symptoms. Common clinical features in the study population included pain (95% of patients), fractures (86% of patients) muscle weakness (62%) and unusual gait (52%). Use of assistive devices for mobility (60%) was also prevalent. Twenty-six percent of patients reported more than 10 fractures. Seventy-four percent of patients had undergone orthopedic/dental surgical procedures. The health profile of patients responding on the SF-12 showed a broad and substantial impact of HPP on health-related quality of life, with domains related to physical ability showing the greatest decrement compared to normative data. ConclusionsIn aggregate, these data indicate that HPP can confer a high burden of illness in adulthood.

Diagnostics in osteology

Clinical diagnostics in metabolic bone diseases cover a broad spectrum of conventional and state of the art methods ranging from the medical history and clinical examination to molecular imaging. Patient treatment is carried out in an interdisciplinary team due to the multiple interactions of bone with other organ systems. Diagnosis of osteoporosis is supported by high level national guidelines. A paradigm shift concerning the clinical relevance of bone mineral density measurement renders this now to be a strong risk factor rather than a diagnostic parameter, while strengthening the value of other clinical factors for risk assessment. The impact of parameters for muscle mass, structure and function is steadily increasing in all age groups. In order to identify underlying diseases that influence bone metabolism a panel of general laboratory diagnostic parameters is recommended. Markers for bone formation and resorption and specific parameters for the regulation of calcium and phosphate metabolism should be evaluated by specialists because they require diligence in preanalytics and experience in interpretation. Genetic diagnosis is well established for rare bone diseases while diagnostic panels are not yet available for routine diagnostics in polygenetic diseases such as osteoporosis. Conventional radiologyis still very important to identify, e. g. fractures, osteolytic and osteoblastic lesions and extraosseous calcifications; however tomography-based methods which combine, e. g. scintigraphy or positron emission technologies with anatomical imaging are of increasing significance. Clinical diagnostics in osteology require profound knowledge and are subject to a dynamic evolution.

Gorham–Stout disease or new entity on the basis of vasculopathy

Gorham–Stout disease (GSD) is a rare osteolytic bone disease also known as vanishing bone disease. The pathogenesis of GSD is not well understood. Studies showed that lymphatic and blood endothelial cells in addition to macrophages secrete TNFα and IL-6 that stimulate osteoclast formation with osteolysis. Also TNFα secretion inhibits osteoblast differentiation and new bone formation. It is known that cytokines such as TNFα, IL-1 and complement system activation are responsible for inflammation and necrosis in the vessel wall at vasculitis. Both diseases have similar pathogenesis. Here, we presented a case of Gorham’s disease with involvement of bilateral humerus, systemic arterial thrombosis and mesenteric vasculitis.

631. Rankl Knock-Out Mesenchymal Stromal Cells Have an Unexpected Osteogenic Differentiation Defect Which Is Improved by a RANKL-Expressing Lentiviral Vector

Osteoclast-poor RANKL-dependent Autosomal Recessive Osteopetrosis (ARO) is a rare bone disease characterized by an increase in bone density due to the failure of bone resorption by impaired osteoclast formation. Hematopoietic stem cell transplantation is not an effective therapy for this ARO form, since in bone RANKL is produced mainly by cells of mesenchymal origin. Therefore Mesenchymal Stromal Cells (MSC) transplantation together with a gene-therapy strategy to correct RANKL defect in MSC could represent a possible effective therapy. Of note, whether also MSC, besides the osteoclasts, are affected by RANKL deficiency is unknown. To verify this, we established and characterized bone marrow derived MSC (BM-MSC) lines from the Rankl−/− (KO) mouse model, which recapitulates the human disease, and from wild type (WT) mice. No differences were found between KO and WT MSC in terms of morphology, immunophenotype and proliferation capacity. However, KO MSC displayed a reduced clonogenic potential with a decrease in stemness genes expression. KO MSC were able to normally differentiate towards the adipogenic and chondrogenic lineages, while showed a significantly impaired osteogenic differentiation capacity compared to WT MSC, as demonstrated by reduced Alizarin Red staining (ARS) and expression of osteogenic genes. To confirm that this alteration was due to the lack of functional RANKL, we developed a third generation lentiviral vector expressing human soluble RANKL (hsRL) for the genetic correction of KO MSC. We first investigated lentiviral transduction in 293T cells to optimize transduction efficiency at different multiplicity of infection (MOI) ranging from 1 to 100. hsRL production increased proportionally to the MOI and was stable over time. However, the higher the MOI the higher the cytotoxicity observed. Based on these data, we performed a lentiviral hsRL transduction in KO MSC at 20 and 50 MOI, to define the optimal transduction conditions. After transduction 99.5% of MSC were GFP+. While in Rankl−/− control cells the cytokine was not detected, in corrected cells hsRL production and secretion was measurable and comparable to sRL levels in WT mouse. KO MSC stably expressing hsRL showed an improved osteogenic differentiation capacity compared to untransduced KO MSC, as demonstrated by increased ARS and expression of osteogenic genes. Moreover, the expression of RANK receptor in both MSC suggested an autocrine role of sRL as possible mechanism. Our data suggest that restoration of RANKL production in lentiviral-transduced KO MSC might not only allow osteoclast differentiation in Rankl−/− mice upon transplantation, but also improve the osteogenic differentiation defect of KO MSC.

Galliera Genetic Bank: A DNA and Cell Line Biobank from Patients Affected by Genetic Diseases

The Galliera Genetic Bank is part of the Laboratory of Human Genetics of Galliera Hospital in Genoa and has collected samples from patients affected by genetic diseases since 1983. Presently, it stores 10,259 biospecimens and associated data from about 200 genetic disorders. The most representative disorders are chromosome disorders (Down s., Ring chromosome 14 s., Cri du chat s. and Isodicentric 15 chromosome), neurological diseases (Fragile X s., Mowat Wilson s. and Dravet s.), rare bone diseases (Crouzon s., Achondroplasia, Grieg s. and Thanathophoric dwarfism), overgrowth syndromes (Sotos s.), familial hypertrophic cardiomyopathy and other rare disease such as IPEX and Aarskog s. The biobank has been supported by Italian Telethon grants since 1993 and since 2008 is partner of the Telethon Network of Genetic Biobanks. It operates according to Italian and international regulations. Since 2008 the biobank is certified ISO 9001, and in 2010 it was officially authorized by the Liguria Region to operate as a facility in support of diagnosis and research on genetic diseases. Since its inception, the biobank has offered the following services to the biomedical community: (i) access to sample and data collection; (ii) sample processing (e.g., cell lines establishment, DNA/RNA extraction, etc); (iii) preservation of biological specimens and related data (repository service), garnering more than 110 acknowledgements in scientific articles.

Emerging treatments of rare bone diseases - relevance for the adult patient?

Emerging treatments of rare bone diseases - relevance for the adult patient?

Value of rare low bone mass diseases for osteoporosis genetics.

Osteoporosis presents as increased susceptibility to fractures due to bone loss and compromised bone microstructure. Osteoporosis mainly affects the elderly population, but it is increasingly recognized that compromised bone health with low bone mass and increased fractures may have its onset already in childhood. In such cases, genetic component is likely to contribute more than lifestyle factors to disease onset. During the last decade, our understanding of the genetic determinants of osteoporosis has significantly increased through family studies, candidate gene studies and genome-wide association studies (GWASs). GWASs have led to identification of several genetic loci associated with osteoporosis. A valuable contribution to the research field has been made through studies involving families with childhood-onset rare bone diseases such as osteogenesis imperfecta, osteoporosis-pseudoglioma syndrome and various other skeletal dysplasias with reduced bone mass. Some genes involved in rare low bone mass diseases, such as LRP5 and WNT1, participate in the Wnt/β-catenin pathway, and their discovery has underscored the importance of this pathway for normal skeletal health. The still continuing discovery of gene defects underlying various low bone mass phenotypes contributes to our understanding of normal bone metabolism and enables development of new therapies for osteoporosis.

Non-familial Cherubism – Report of a case

Introduction: The Cherubism is a rare disease that affects the middle and lower third of the face in individuals at the time of childhood. It is a rare hereditary benign bone disease with an autosomal dominant inheritance. The familial distribution may affect different generations and isolated non-familial cases have also been reported in literature. Lesions appear as cystic multilocular radiolucencies, histologically, resembles central giant cell granluloma and hyperparathyroidism brown tumor with numerous randomly distributed multinucleated giant cells and vascular spaces within a fibrous connective tissue stroma. Objectives: The aim of this study is to report the importance of the diagnosis of this pathology and the variety of treatments available in the literature, thus guiding to an individualized treatment. Case Report: Caucasian 8 years-old female, in good general condition, was referred to Service of Oral and Maxillofacial Surgery of Erasto Gaertner Hospital (EGH), Curitiba – PR, Brazil, complaining of bilateral swelling of the maxilla and mandible since 4 years-old. Apparently, the girl is the first one who developed the genetic pathology in at least 4 generation of her family. After biopsy, cherubism diagnosis was confirmed and the treatment of choice was periodic monitoring. Discussion: Cherubism studies with long-term follow-up with clinical and radiographic documentation indicate that the spontaneous resolution of bone lesions is rare. Treatment of cherubism is controversial and various modalities have been reported as the use of calcitonin, osseous plasty surgery, curettage, orthognathic surgery, liposuction and palliative treatments.