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Fibrous Dysplasia and McCune-Albright
FD/MAS: General Studies
Drs. Collins and Boyce’s article is an incredible resource for those interested in understanding FD/MAS on a technical and scientific level as well as those wondering about where the science may lead researchers next. Not all readers will be interested in such in-depth analysis. Endocrine Reviews, Volume 41, Issue 2, April 2020, Pages 345–370, https://doi.org/10.1210/endrev/bnz011
In 2018, FDF sent this article to every researcher and clinician in our contacts. This updated comprehensive look at FD and MAS diagnosis, cause, clinical description, malignancies, skeletal descriptions, endochrine issues, genetic issues, skeletal treatments. Boyce AM, Florenzano P, de Castro LF, et al. Fibrous Dysplasia/McCune-Albright Syndrome. 2015 Feb 26 [Updated 2019 Jun 27]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available
A comprehensive article about MAS including diagnosis, cause, clinical description, malignancies, skeletal descriptions, endochrine issues, genetic issues, skeletal treatment, and drugs (bisphosphonates). Excellent illustrations. Orphanet Encyclopedia, August 2004, Claudia Dumitrescu & Michael T. Collins.
FD-related bone pain is among the highest concerns of FD/MAS patients. Bone pain has been reported in up to 81% of adults and 49% of children. Unfortunately, many doctors are misinformed that FD lesions are painless. This article reviews pain management options and theorizes the mechanism behind FD lesion pain.
A chapter in a publication. The chapter covers cause and course of FD/MAS, clinical features, and management and treatment. It contains some excellent illustrations. Chapter 76 Fibrous Dysplasia, American Society of Bone and Mineral Research, 2003, Michael T. Collins and Paolo Bianco
This European study used date from 64 patients with FD, PFD and MAS at 11 participating centers. This extensive (27 pages) article includes many pictures of x-rays. The five main points noted in the abstract were: 1) there are significant diagnostic pitfalls with monostotic FD and to a lesser extent with PFD. There is a need for stringent diagnostic criteria., 2) MFD in the proximal femur carries significant risk of fracture, but tendency to progress is restricted., 3) The profile of FD in tibia is markedly different than FD in femur., 4) MAS patients have the most extensive disease and require surgical treatment. For femur fractures treatment with internal fixation using intramedullary nails provide stabilization and prevents future fractures and deformity. Conservative treatment of femoral fractures or curettage and cancellous bone grafting , or fixation with side screws and plates are not indicated and should be discouraged., 5) Evaluation of patients with FD should include a through evaluation of endochrine profile and phosphate metabolism, and proper pathological and radiographic (i.e. x-ray, bone scan, bone density) assessment. Journal of Pediatric Orthopaedics Volume 12(3) May 2003 pp. 155-177 Ippolito, Ernesto, Bray, Edward W., Corsi, Alessandro; DeMaio, Fernando; Exner, Ulrich; Robey, Pamela Gehron; Grill, Franz; Lala, Roberto; Massobrio, Marco; Pinggera, Oswald; Riminucci, Mara; Snela. Slawomir; Zambakidis, Christos; Bianco, Paolo.
This very accessibly written article reviews the literature concerning the evaluation, detection and treatment options for people suffering with Fibrous Dysplasia. The authors explain the genetic basis of the disease, the nature of typical FD lesions, and necessary tests to achieve a proper diagnosis. The authors describe the application of biophosphonates to reduce pain, lower the risk of fractures and increase function and discuss current surgical practices to reinforce weak and damaged bone. The article contains numerous radiographic images and histological slides to illustrate the conceptual discussion. It should be required reading for newly diagnosed patients, their caregivers and their primary physicians. Journal of Bone and Joint Surgery, 87: 1848-1864, 2005, Matthew DiCaprio & William Enneking.
This article examined patients from the National Institute of Health with craniofacial FD (n=91) to study the impact of FD encasement on the optic nerve. Researchers concluded that there is minimal link between craniofacial FD and blindness. Investigators also found individuals with craniofacial FD tend to have an increased amount of Growth Hormone (GH). Researchers recommend that all patients diagnosed with craniofacial FD have their GH levels tested, because appropriate treatments are available. Neurosurgery, 59: 1011-1018, 2006, Carolee Cutler, et. al.
This article describes clinical follow-up of 15 patients (13 female – 2 male) with MAS. Fractures occurred only during childhood. Hearing impairment due to temporal bone involvement occurred in four of six cases. Four females with precocious puberty had normal range final heights; they developed regular menes, and two had children. Persistent hyperthyroidism occurred in three cases. JAMA Vol. 256 No. 21, 1986, Peter A. Lee, M.D., Ph.D., Cornelis Van Dop, PhD., M.D., Claude J. Migeon, M.D.
A study of the pathology of 25 cases of FD utilizing microscopic slides of sample tissue. This study delineates some of the cellular abnormalities present in FD and details some of the criteria for the pathological diagnosis of FD. Archives of Pathology, Vol. 75, May 1963, Richard J. Reed, M.D.
Fifty-six adults and 22 children with FD enrolled in an NIH natural history study were assessed for their disease burden and perceived quality of life. The amount of bone affected by FD correlated strongly with physical impairment. Physical function for both adults and children with FD was comparable to other chronic diseases – rheumatoid arthritis and asthma, respectively. Mental health and social function scores for affected adults and children were comparable to the general US adult and child populations. However, parents with children with FD experienced greater worry than the general population. Bone vol: pages, 2005, Kelly, Marilyn H.; Brillante, Beth; Kushner, Harvey; Robey, Pamela Gehron and Collins, Michael.
The Journal of Bone and Joint Surgery, 87:2489-2494, 2005, Lietman, Steven A.; Ding, Changlin; and Levine, Michael A.
Pediatric Endocrinology Reviews, 4 (4): 2007, Lietman, Steven A.; Schwindinger, William F.; Levine, Michael A.
This study involved 22 patients with FD of the proximal part of the femur. Those with MFD had fewer microfractures, less deformity, and stronger bone. Those with PFD had more microfractures, more deformity, including shepherd’s crook, and often bone that could not support internal fixation. Curettage and cancellous or cortial bone-grafting did not appear to have any advantage as all bone grafts were resorbed with FD. Deformity of the proximal femur is best treated with osteotomy and internal fixation early in the course of the disease according to this study. The Journal of Bone and Joint Surgery Vol. 80-A. No. 5, May 1998, James T. Guille, M.D., S. Jay Kumar, M.D., G. Dean MacEwen, M.D.
This study looked at the use of graft with cortical bone in 15 patients with fibrous dysplasia of the femoral neck. They noted that grafts using cacellous bone and curettage (scrapping) were unsatisfactory in most patients with the graft being overtaken by dysplastic (FD) bone. In this study they reasoned that autogenous (from yourself) cortical (out part of the bone) bone from non-FD fibula would be less likely to be taken over by the FD bone. The goal was to repair fatigue fractures, prevent deformity and additional fractures without aggressive surgery. They restricted use of this method to patients who had normal bone in femoral head and in distal end of femur. The objective of pain relief, union of fracture and prevention of deformity was achieved in all 15 patients. The Journal of Bone and Joint Surgery. Vol. 68-A. No. 9, December 1986, William F. Enneking, M.D., Peter F. Gearen, M.D.
This study examined the fracture history of 35 patients at the National Institutes of Health with FD/MAS. The peak incidence of fractures occurred in the first decade of life (six to ten years old), followed by a decrease thereafter. Phosphaturia was associated with an earlier incidence and increased frequency of fractures. Journal of Bone and Mineral Research, Vol. 19, Number 4, 2004, Arabella Leet, Caroline Chebli, Harvey Kushner, Clara C. Chen, Marilyn H. Kelly, Beth A. Brillante, Pamela G. Robey, Paolo Bianco, Shlomo Weintraub, Michael T. Collins.
This article is concerned with the evaluation of patient function in a sample of 20 children up to age 16 participating in an NIH sponsored long term study of polyostotic FD. This investigation explored the extent of patient’s skeletal deformities as well as patient’s physical activity and happiness. Researchers examined radiographs, patients’ medical charts and parents and children completed questionnaires. Important findings include: (1) The disease has its major burden in the lower extremities which affects the functional activity of children. (2) Femoral neck shaft angle correlates strongly with involvement in sports. (3) There is an unusual correlation between happiness, pain and sports, perhaps indicating that physical activity may increase well being despite causing micro-fractures.
Report from a study conducted in Australia of five children with MAS. They were treated with a combination of bisphosponates and implantation of intramedullary rods in the femur or tibia. This treatment was successful in all patients, as indicated by improvement in quality of life, a decreased in pain, an improvement in the fracture rate, and improved walking ability. Journal of Pediatric Orthopaedics, 22:255-260 © 2002 , Mark O’Sullivan. M.B.B.S., F.R.A.C.S. and Margaret Zacharin, M.B.B.S., F.R.A.C.S.
In this study of 43 patients with FD, patients with upper extremity FD had satisfactory results with non-operative treatment. Age was a factor in patients with FD in lower extremities. For those over 18 satisfactory results were achieved in 8 of 9 cases with curettage and bone grafting. Those under 18 with lower extremity disease had unsatisfactory results with curettage and bone grafting. Those under 18 treated with internal fixation had satisfactory results. Journal of Bone and Joint Surgery, Vol. 69-A, No. 3, March 1987, Robert B. Stephenson, M.D., Michael D. London, M.D., Fred M. Hankin, M.D., and Herbert Kaufer.
Fibrous dysplasia of bone frequently involves the anterior base of the cranium and results in encasement of the optic-nerve canals. It has been assumed that such encasement leads to constriction and eventual blindness. This was a study of 38 patients with fibrous dysplasia of the lesser wing of the sphenoid bone. The patients underwent a detailed neuro-ophthalmologic examination and computed tomography of the face and skull. The results were compared with those of 38 age and sex-matched controls. Encasement of the optic canal in fibrous dysplasia causes narrowing of the canal, but that in itself does not result in visual loss. Therefore, prophylactic decompression of the optic nerve does not appear to be indicated on the basis of the presence of fibrous dysplasia on diagnostic images alone, since it does not correlate with visual loss.November 21, 2002, Janice S. Lee, D,D.S., M,D., Edmond FitzGibbon, M.D., John A. Butman, M,D., Ph.D., Craig R. Dufresne, M.D., Harvey Kushner, Ph.D., Shlomo Wientraub, M.D., Pamela G. Robey, Ph.D., and Michael T. Collins, M.D.
Twenty-three men and 39 women in an NIH natural history study were examined using bone scans and radiography. Bone scans established the presence of spinal lesions in 63% of the sample. This was much higher than was generally believed likely. Bone scans also reliably established the presence of scoliosis; however, radiography resulted in a more accurate measure of the degree of curvature. Phosphaturia and hyperparathyroidism were associated with scoliosis; location of café-au-lait spots or precocious puberty were not. Authors recommend that patients with PFD be surveyed for spinal involvement using bone scans and if scoliosis is detected, then radiography be sued to refine the diagnosis. Journal of Bone and Joint Surgery 86 (3): 531-537, 2004, Leet, Arabella; Magur, Edward; Lee, Janice S.; Wientroub, Shlomo; Robey, Pamela G. and Collins, Michael T.
This study investigated IL-6 expression in FD pathology samples and its relationship to the actual patterns of osteoclastogenesis (the creation of cells that break down bone) within the abnormal tissue. The authors found that unlike normal bone, osteoclastogenesis is not spatially restricted to bone surfaces in FD, but occurs to a large extent ectopically in the fibrous tissue. The authors also observed that an autocrine/ paracrine loop may contribute to osteoclastogenesis in vivo in FD, as in some other diseases, including Paget’s disease. Using “wild type” and mutated stromal cells taken from FD lesions, the authors established a direct link between GNAS1 mutations in stromal cells and IL-6 production. However, they also discovered that the local and systematic context – non-osteogenic cells, proportions of “wild type” and mutated cells, and systemic hormones – contribute to patterns of osteoclastogenesis and bone resorption. Bone 33: 434-442, 2003, Riminucci, M.; Kuznetsov, S. A.; Cherman, N.; Corsi, A.; Bianco, P. and Robey, P. G.
This study shows (1) that GSa gene expression and its mRNA is critically up-regulated during maturation of precurser osteogenic cells to normal osteoblast cells (cells that build-up bone) and (2) that this pattern of expression is maintained in Fibrous Dysplasia. The authors argue that the convention view that FD is a disease of cells in the osteogenic lineage related to affects of excess cAMP on bone function is wrong. The authors discovered that the fibrous component of the dysplastic lesion is composed of cells with features of early pre-osteoblastic, rather than fibroblastic cells. Cells populating the fibrotic areas of FD express alkeline phosphatase activity, which indicates their relationship to osteogenic lineage and their divergence from nonosteogenic fibroblasts. American Jounral of Pathology 151 (6): 1587-1600, 1997, Riminucci, Mara; Fisher, Larry W.; Shenker, Andrew; Spiegel, Allen M.; Bianco, Palo and Robey, Pamela Gehrom.
This was a study of nine patients with moderate to severe fibrous dysplasia who were treated with intravenous pamidronate. They were treated over a period of six months to three and a half years. Bone pain and gait abnormality due to pain disappeared after two or three cycles of the drug treatment. Cranial asymmetry and limb length differences remained unchanged. An increase in bone density was also reported. Elevated levels of alkaline phosphatase and urine hydroxyproline were reduced by the treatment. Long term implications are unknown. Acta Paediatr, 89:188-93 2000, R. Lala, P. Matarazzo, S. Bertelloi, F. Buzi, F. Rigaon, C de Sanctis
The aim of this study was to assess the long term effects of intravenous pamidronate in FD. The severity of bone pain and the number of painful sites appears to be significantly reduced. Al biochemical markers of bone remodeling were substantially lowered. They observed a radiographic response in 9 (of 20) patients with refilling of osteolytic lesions. A mineralization defect was observed in one case and four had stress lines but no fractures. Journal of Bone and Mineral Research, Vol. 12 Number 10, 1997, Roland D. Chapurlat, Pierre D. Delmas, Daniel Liens, Pierre J. Meunier
Nine patients with FD were treated with intravenous pamidronate and were followed for 18-48 months. The major effect was decreased bone pain. Positive radiological changes were seen in four patients. The Lancet, Vol. 343, April 16, 1994, Daniel Liens, Pierre D. Delmas, Pierre J. Meunier
Report from a Canadian study of 18 children and adolescents with FD. Patients had bone biopsies before and after treatment with high dose pamidronate. Levels of serum alkaline phosphatase and urinary collagen type I N-telopeptide decreased continuously over the first three years of the study. There was no radiographic evidence of filling of lesions or thickening of the bone cortex surrounding the lesions in any patient. The study concluded that pamidronate therapy appears to be safe for children and adolescents, but there was no clear evidence that pamidronate had any positive effect on dysplastic lesions. This is perhaps the best study to date, in terms of the quality of the design of the study, on the use of bisphosphonates in FD. The Journal of Clinical Endocrinology & Metabolism, 88(10):4589-4575, 2003, Horacio Plotkin, Frank Rauch, Leonid Zeitlin, Craig Munns, Rose Travers, And Francis H. Glorieux
This study followed 3 male children with MAS and polyostotic FD – starting ages 2.5-5 – while they received treatments with biophosphonates (pamidronate). The period of treatment lasted 8-10.5 years. The authors found that the treatment controlled pain effectively, but it did not reduce or limit the size of dysplastic lesions in the children’s bone. Journal of Pediatric Endocrinology and Metabolism, 19: 75-80, 2006, Chan, Brendan and Zacharin, Margaret.
This article examined 5 patients with fibrous dysplasia with an excess in Growth Hormone (GH). Participants were given pegvisomant, a GH receptor antagonist for a 12 week period. It is an antagonist that was expected to block the binding of certain proteins, decreasing GH levels in the blood. The pegvisomant effectively lowered IGF-1 & IGFBP-3 levels which are binding proteins, essentially lowering the level of GH in the blood. Unfortunately, pegvisomant did not resolve other factors linked to individuals with FD and GH excess, such as fatigue and sweating. Journal of Clinical Endocrinology and Metabolism, 91 (8): 2960-2966, 2006, Sunday Akintoye, et. al.
This is a study of 42 patients with FD/MAS seen at the NIH. The investigators evaluated how phosphorus is controlled in patients with FD/MAS. They concluded that abnormal phosphorus metabolism is common (48%), and the likely cause is a circulating factor (hormone) made by the fibrous dysplastic bone. This has implications for the evaluation and treatment of FD/MAS patients, as low blood phosphorus is associated with worsening of FD. Vol. 16, Number 5, 2001, Michael T. Collins, Caroline Chebli Janet Jones, Harvey Kushner, Mark Consugar, Piero Rinaldo, Shlomo WientroubPaolo Bianco,and Pamela Gehron Robey.
This study identifies fibroblast growth factor –23 (FGF-23) as the factor (hormone) that is made by FD bone that causes the abnormalities in phosphorus metabolism that are associated with FD. The Journal of Clinical Investigation, Vol. 112, Number 3, September 2003, Mara Riminucci, Michael T. Collins, Neal S. Fedarko, Natasha Cherman, Alessandro Corsi, Kenneth E. White, Steven Waguespack, Anurag Gupta, Tamara Hannon,8 Michael J. Econs, Paolo Bianco, and Pamela Gehron Robey
The authors compare a variety of imaging techniques used for the purpose of diagnosing cherubism. Key findings include: “CT clearly depicted bilateral osseous involvement and expansive remodeling.” “CT also accurately delineated the extent of involvement and was especially useful in characterizing osseous matrix.” “MRI provides an anatomic outline that allows accurate determination of lesion extent and location.” CT results “provided clear evidence of lesion extension and involvement in the mandibular condyle” (not previously detectable through panorex) The results suggest using multiple imaging technologies before starting invasive treatment. American Journal of Radiology, 182: 1051-1054, 2004, Beaman, Francesca; Bancroft, Laura W.; Peterson, Jeffrey J.; Kransdorf, Mark J.; Murphey, Mark D.; Menke, David M.
The authors of this article examine and describe the microscopic features of bone lesions associated with cherubism. They document cherubism’s histological (cellular) similarity to giant-cell reparative granuloma and histological difference from fibrous dysplasia. The article has good diagnostic images of cherubism, including a panoramic radiograph of the jaws, CT scan of the jaws, and photomicrographs of cells in cherubic lesions. Skeletal Radiology 28: 350-353, 1999, Yamaguchi, Dorfman & Eisig.
This article provides a detailed description of the characteristics of radiographic, MRI and CT images of cherubism found in a 5 year old Indian girl. The article includes numerous images from all three sources. The authors report that MRI images were particularly useful for “elucidating the exact anatomical location and extent of the cherubism lesions, particularly their relationship to the orbits and the optic nerves.” The MRI also showed involvement in the condoyle of the mandible, which “was not apparent on radiographs or CT images.” Pediatric Radiology 36: 1099-1104, 2006, Jain, Vaibhav and Sharma, Raju.
The authors followed 7 cherubism patients of various ages for an average of 8.5 years. For each, they characterized histopathological parameters as absent, few, moderate or marked. These parameters included the density of giant multinucleated cells, interstitial hemorage, inflammatory activity, and the density of fibrous tissue. In addition, the authors assessed the progression of the disease (improved, no change, modest progression, marked progression). The authors argue for a conservative approach to treatment: “surgical treatment appears to be unnecessary for grade 1 and 2 cases [involvement of only the mandibular ascending rami or the mandibular ascending rami and involvement of the maxillary tuberosities] in the absence of secondary disturbances,” but it may be necessary in aggressive cases. Their recommendation is curettage with remodeling of the cortical layer as others have found bone grafts may result in spreading of the disease. The article provides good radiographic and photographic images showing the progression of the disease. Journal of Oral and Maxillofacial Surgeons 64: 924-930, 2006, Penarrocha, Miguel; Minguez, Juan; Bagan, Jose Vincente; Minguez, Ignacio
The authors study 4 English children of two brothers known to be cherubs: three had aggressive cherubism affecting the maxilla and mandible and the fourth had minimal radiographic evidence. The article provides detailed discussion of the methodology and results of invitro bone resorption studies, cytogenetic studies and biochemical analysis. The authors also gave calcitonin to the three severely affected children and discussed the feasibility of using this treatment to halt the progression of lesions. These results were inconclusive. Journal of Clinical Pathology 51: 831-837,1998, Southgate, John; Sarma, Usha; Townend, John V. and Flanagan, Adrianne M.
This article provides a good overview of the state of clinical, genetic and histopathological knowledge about cherubism. It also briefly outlines the case of 2 Indian siblings with the condition. Journal of the Canadian Dental Association 69 (3): 150-154, 2003, Ongole, Ravikiran; Pillai, Rajeev S.; Pai, Keerthilatha M.
The authors document how CT scans can detect maxillary lesions of cherubism that do not appear as radiolucent regions in panoramic radiography. They also discuss the presence of maxillary lesions found in the temporal bone of a 10 year old Brazilian girl, a region of the maxilla previously undocumented in published literature. Brazilian Dental Journal 15 (1), 2004, Fonseca, Luciana Cardoso; Freitas, Joa batista de; Maciel, Pedro Hernane; Cavalcanti, Marcelo Gusmao Paraiso.
This article reviews the nature of radiographic, histopathological and biochemical results for 24 cases of familial and non-familial cherubism in Chinese nationals with various ages of onset. The authors review the various grading systems developed to classify cherubism and the importance of separating aggressive fast growing lesions from others. Based on what is known of the natural course of the disease, the authors recommend conservative treatment: “curettage of the affected tissue, preserving the teeth as long as possible” and surgical recontouring when necessary. International Journal of Oral Maxillofacial Surgery 34: 350-356, 2005, Meng, W. M. ; Yu, S. F, and Yu, G. Y.
Treatment of Cherubism with Locally Aggressive Behavior Presenting in Adulthood: Report of Four Cases and a Proposed New Grading System
The author describes 4 cases of cherubism in an Iranian family, in which onset was late in 3 (patients were in their 20s) and typical in the fourth. The author noted the inability to classify the patients according to Arnott’s (1979) grading scale and proposed an alternative: Grades I –V specify the location of lesions in the mandible and maxilla and the extent of root resorption caused by the lesions. Classes 1-5 within the grades specify whether the lesions are solitary or multiple and the location of the lesions within the affected bones. Subclasses A-D designate the “mandibular involvement within anyone of the 4 grades.” The author argues that it is critical to recognize the impact that root resorption has on permanent dentition in patients. They emphasize as well the need to test relatives of patients who receive clinical diagnoses of cherubism, given its hereditary nature. This article presents a framework for discussing the variability of penetrance of the disease in individuals sharing the same genetic mutation. Journal of Oral and Maxilliofacial Surgeons 56:1336-1342, 1998, Motamedi, Mohammad Hosein Kalantar.
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This article describes the progression of 8 Brazilian cases of cherubism in females and males from childhood, through adolescence and into adulthood. This article offers good photographs and radiographs of individuals at various stages of disease progression. Using the classical grading system for cherubism, the authors associate different patterns of remission (regression) with the location of the cherubic lesions in the jaws. Typically regression occurs in the mandible before the maxilla. The authors also discuss the nature of surgical interventions. Journal of Oral Maxillofacial Surgery. 65: 517-522, 2007, Silva, Edgard Carvalho; Carvalho, Guilherme Costa; Vieira, Tainab Couto.
This article describes the spontaneous remission / regression of cherubism lesions in the adolescence of two boys who were followed between ages 6 and 23 and 6 and 25. The authors provide photographs and radiographs of the individuals pre and post remission, clearly showing the filling in of the fibrous lesions with bone. (These cases are included within Silva 2007.) British Journal of Oral and Maxillofacial Surgery. 2006, Silva, Guilherme Costa Carvalho; Gomez Ricardo Santiago; Vieira, Tainah Couto and Silva, Edgard Carvalho.
This article describes the genetic basis for cherubism. It reviews the recently published findings that mapped cherubism to chromosome band 4p16 and to specific genes. The authors’ examination of genetic material from a Canadian family with cherubism led them to find a new mutation in the SH3BP2 gene. To date, they note that 13 ethnically diverse families with cherubism all show a mutation in a stretch of 6 amino acids on the 9th exon. They argue that cherubism is due to a de novo mutation. American Journal of Medical Genetics 121:37-40, 2003, Lo, Faiyaz-Ul-Haque, Kennedy, Aviv, Tsui & Teebi
The authors genetically evaluated an 11 member Turkish family in tandem with a radiographic examination. They found a new amino acid change ( a point mutation) in the SH3BP2 gene, a known cherubism mutation hotspot in 5 members, of which 2 showed no clinical evidence of cherubism. The authors also discuss the theoretical connection between cherubism mutations and development of 2nd and 3rd molars. Unique in this study is a male with the cherubism mutation who exhibited no clinical signs of the disease, contrary to the frequently reported 100% penetrance of cherubism in boys/men. Oral Surgery, Oral medicine, Oral Pathology, Oral Radiology, and Endontology 103 (3): 378-381, 2007, Lange, Jan de; van Maarle, Merle C.; Akker, Hans P. van den and Redeker, Egbert J. W.
This article establishes a linkage between clinical, radiographic and histological evidence of cherubism and the genotyping data of two families in the UK (10 individuals). It locates the gene for cherubism on the 4p16.3 chromosome. Family A also appears in the Southgate article (1998). American Journal of Human Genetics 65:151-157, 1999, Mangion, Jonathan, et al.
This article establishes a linkage between clinical, radiographic and histological evidence of cherubism and the genotyping data of three Brazilian and 1 German family (15 individuals). It locates the gene for cherubism on the 4p16 chromosome. American Journal of Human Genetics 65:158-166, 1999, Tiziani, Valdenize, et. al.
The authors studied 15 families: 66 individuals clinically diagnosed with cherubism, 4 “obligate carriers,” and 79 unaffected individuals. Using a linkage and haplotype analysis of 12 families, the authors defined the cherubism locus to a 1.5-megebase interval between D4S127 and D4S115. Sequencing genomic DNA from affected and unaffected family members, they detected point mutations causing amino acid substitutions in the SH3-binding protein SH3BP2 in 12 of the families. The authors conclude that a different genetic mutation other than SH3BP2 causes the cherubism symptoms in the remaining 3 families. Nature Genetics 28: 125-126, 2001, Ueki, Yasuyoshi, et. al.
This article provides background information about Cherubism. It includes previous research that has been conducted as well as an introduction to some of the most recent and promising research that has been carried out. Novack and Faccio give some important basics concerning Cherubism: it is a dominantly inherited disease that is the result of a point mutation that codes for a proline to arginine substitution in the Sh3bp2 gene, which in turn results in a mutated Sh3bp2 protein. The protein Sh3pb2 is a scaffold protein, meaning that it is essential to mediating other proteins in a signaling pathway. The authors summarize “Increased Myeloid Cell Responses to M-CSF and RANKL Cause Bone Loss and Inflammation in SH2BP2 ‘Cherubism’ Mice” written by Yasuyoshi Ueki, et al.. They explain the knock-in mouse experiment as well as the crossing experiments (please see article summary for Ueki et. al) and they give the general findings of the article, but more importantly they explain why the findings are significant: The crossing experiments show that myeloid cells, and not lymphocytes, are critical to the expression of the disease. Myeloid cells are cells which are derived from bone marrow, and osteoclasts are derived from the myeloid cells. Osteoclasts play a very important role in Cherubism—they are the cells that are responsible for the extensive bone resorption seen in the jaw. RANK is an activator protein that sits on the surface of osteoclasts and activates them upon being stimulated by its progenitor, RANKL. RANKL is a tumor necrosis factor (TNF) that is dependant on a number of stimulating and signaling pathways which require further experimentation to determine their exact role. Another tumor necrosis factor (TNF-α) is absolutely essential to the activation of the osteoclasts. When mutated mice with Cherubism-like characteristics were with a TNF-α lacking background, the offspring showed no bone loss or inflammation. Novack and Faccio point out that this is an extremely important discovery that needs to be explored further because there are already existing anti-TNF therapies in existence for arthritis patients. Further experimentation is needed to determine if this could potentially be an effective treatment for Cherubism patients. Cell 128, January 12, 2007, Deborah Veis Novack and Roberta Faccio.
Previous to this 2007 article, Ueki and others had conducted experiments to determine where the causal mutation of Cherubism occurs. The gene for protein Sh3bp2 was mapped to chromosome 4p (the short arm of chromosome 4). The most common mutation that results in Cherubism in humans is a point mutation, that is, a single letter change in the genetic code, which leads to the amino acid arginine being produced in place of proline. In order to conduct experiments concerning the disease, Ueki et al. introduced the same point mutation into mice. This is referred to as a knock-in mouse experiment. Though the disease does not act in an autosomal dominant manner while in mice, as it does in humans, it still demonstrated some of the key components of Cherubism such as bone loss and inflammation. However, it was not limited to the face and jaw—instead it was spread throughout the skeleton. It is therefore necessary to recognize that the human form of the disease must depend on other factors as well. To determine the dependence of the disease on different types of cells present, the mutant mice were crossed with mice deficient in Rag-1 (meaning that they had non-functional lymphocytes) and also op-deficient mice (which are lacking in myeloid cells). The disease was only apparent in those that lacked lymphocytes (Rag-1 deficient). This implies that the disease depends on myeloid cells, and not lymphocytes, to function. Osteoclasts are derived from myeloid cells (that is cells that are derived from bone marrow). Not only did knock-in mice bones showing signs of deterioration, but there was also a marked increase in the number of osteoclasts—multinucleated cells that are responsible for the extensive bone resorption seen in Cherubism patients—in them. The researchers found that mutant mice also had osteoclasts with an increased number of nuclei. They found that when incubated with activators M-CSF and RANKL (M-CSF influences hemopoietic cells like osteoclasts to differentiate while RANKL activates osteoclasts) osteoclasts became even larger with more nuclei, and with less RANKL than is required for wild-type (non-mutant) cultures of osteoclasts. This implies that the mutant osteoclasts will resorb an abnormal amount of bone. Researchers measured the levels of TNF-α in serum of wild-type and knock-in mice with the Cherubism mutation. Tumor necrosis factor- alpha (TNF-α) is meant to regulate immune cells, however when it is overproduced it has been implicated as the cause of a number of diseases, including cancers. It was found that there was an increased level of TNF-α was found in the serum of those mice that had the Cherubism characteristics. To determine how much TNF-α influences the expression of Cherubism symptoms the researchers crossed the mutant mice with TNF-α null mice—that is mice that lack TNF-α. The result was that all of the offspring were void of the lymph node abnormalities, systemic inflammation, as well as bone loss. Basically all of the symptoms of Cherubism disapated when the TNF-α was removed. This shows that Cherubism is entirely dependent on TNF-α. It is clear that Cherubism depends on both myeloid cells and TNF-α. More research needs to be done in both areas to better understand their pathways and why it is that they induce the symptoms of Cherubism. This does bring a great deal of hope to people who have Cherubism—anti- TNF-α therapies have the potential to be used as treatment of the disease. Anti- TNF-α therapies have already proved as useful for other bone disorders such as rheumatoid arthritis. Cell 128, 71–83, January 12, 2007, Yasuyoshi Ueki, Chin-Yu Lin, Makoto Senoo, Takeshi Ebihara, Naoki Agata, Masahiro Onji, Yasunori Saheki, Toshihisa Kawai, Padma M. Mukherjee, Ernst Reichenberger, and Bjorn R. Olsen
The authors note the close association between clinical aspects of cherubism and tooth formation: (1) the visible development of lesions and the normal development of 2nd and3rd molars; (2) the coincidence of regression with the “conclusion of molar odontogenesis: and (3) the skyward gaze (orbital involvement) and excessive tissue formation associated with highly placed dental germs of 2nd molars at 2-3 years. They hypothesize “the underlying genetic defect of cherubism [ mutations in the SH3BP2 gene] disturbing normal development of these teeth and disregulating the associated bone formation.” Specifically, “SH3BP2- dependent signal transduction chains interact with regulatory pathways temporarily determining jaw morphogenesis.” This hypothesis accounts for the development of large cell granuloma, root resorption and lymph node swelling. Journal of Cranio-Maxillofacial Surgery, 33: 61-68, 2005, Hyckel, Peter; Berndt, Alexander; Schleier, Peter; Clement, Joachim; Beensen, Volkmar; Peters, Harmut; Kosmehl, Hartwig.
Human Mutation in Brief #904, 2006, Lietman, Steven; Kalinchinko, Natasha; Deng, Xichao; Kohanski, Roland; Levine, Michael A.
Biochemical and Biophysical Research Communications. 371: 644-648, 2008, Lietman, Steven; Yin, Lihong; Levine, Michael A.
The Journal of Clinical Investigation http://www.jci.org 2008, Allprantis.et. al.
Adaptor Protein 3BP2 and Cherubism
The authors synthesize current genetic and microbiological studies on cherubism. They first review the structure and function of 3BP2, identifying the consequences of deletions and mutations in different zones of the gene (PH, PR1, PR2, PR3, SH2). In this section, they summarize the 11 mutations in Arg, Pro, Asp and Gly and one deletion of Arg that researchers have associated with cherubism. The second section describes the physiological function of 3PP2 on T cells, B cells, NK cells and Mast cells. The third and forth sections discuss the “implications of 3BP2 mutations in the pathogenesis of cherubism” and the possibility of intervention in the disease cycle through selective inhibition of 3BP2. , Current Medicinal Chemistry 15: 549-554, 2008, Hatani, Tomoko and Sada, Kiyonao.
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This case report describes a procedure to debulk orbital and maxillary lesions in a 7 year old with extensive involvement of cherubism in these regions. The surgeons viewed the “potential risk of compressive optic neuropathy” as justification to undertake the intervention. Clinical and Experimental Ophthalmology 29: 38-40, 2001, Caroll, Andrew L. and Sullivan, Timothy J.
This article describes surgery conducted to alter cherubism in the orbits. Cherubic lesions in this reason are a cosmetic concern, but can pose a threat to sight. The orbital lesions developed after lesions in the mandible and maxilla regressed spontaneously in this 27 year-old woman. The article reviews the small published literature on cherubism in the orbits. The article provides good photos of the patient and diagnostic images of cherubism, including CT scans and photomicrographs. American Academy of Opthamology 1884-1888, 2001, Colombu, Cursiefen, Neukam, & Holbach.
This case report involves a 27 year old woman: her cherubism was diagnosed at age 4, it did not regress after puberty and she underwent 3 maxillary and mandibular osteoplasties between ages 18 and 24. Severe visual symptoms did not emerge with the onset of the disease, but later in adulthood. The authors describe the visual distortions associated with the patient’s orbital lesions, the surgical treatments that were undertaken to alleviate the symptoms, and the results. Ophthalmology 110 (9): 1846-1849, 2003, Font, Ramon L; Blanco, Gonzalo; Soparker, Charles N.; Patrinely, James R.; Ostrowski, Mary L.
These authors describe a case of maxillary cherubism that extended into the orbit with “documented visual loss secondary to optic neuropathy and macular chorioretinal folds/ scarring directly attributable to compression from fibro osseous growth within the orbit.” They provide a detailed discussion of the surgical intervention they performed on the 31 year old woman and photographic images of the fundus and cranial CTs taken before and after the surgery. Archives of Ophthalmology 121: 570-573, 2003, Ahmadi, A.J.; Pirinjian, Goarik E; Sires, Bryan S.
The authors describe their procedure for creating over dentures for a 21 year old with cherubism who was missing maxillary canines and second and third molars and all teeth but the right canine and 1st and 2nd premolars and left 1st and 2nd premolars in the mandible. Implants were ruled out due to the extent of lesions and porosity of the bone and partial dentures were ruled out due to lack of abutment teeth. The Journal of Prosthetic Dentistry 96 (5): 313-316, 2006, Yilmaz, Burak; Ozan, Oguz; Karaagaclioglu, Lale; Ersoy, A. Ersan.
Two Stage Surgical Treatment of Severe Cherubism
This article discusses the treatment of 8 patients (ages 6-15) exhibiting “severe cherubism” in a 2 stage surgical “debulking” operation performed by Cassio Menezes Raposo-Amaral between 1987 and 2005. All patients had “massivly growing, aggressive and extensively deforming juvenile lesions involving maxilla and mandible [and in some cases] orbits,” stage 5 and 6 on a modified Motamedi grading scale. Stage 1, performed in 5 cases: the anterior wall of the maxilla was osteotomized and removed, the cherubic lesion was curetted from maxilla and orbits, and the maxilla was recontoured and orthotopically fitted with wires. Stage 1, performed in 3 cases: corticle bone windows were created, the maxilla and orbital lesions were curetted, and the maxilla was infractured and recontoured in situ with manual pressure. Six month later, stage 2 was undertaken: the mandible was recountoured using “bony access windows and manual infracture.” The authors report satisfactory esthetic results in all patients. The article provides detailed discussion and photographic and diagrammatic representation of the procedures as well as CT images documenting the extent of the cherubism in these “severe” cases. Annals of Plastic Surgery 58 (6): 645-651, 2007, Raposo-Amaral, Cassio Eduardo; Guidi, Marcelo de Campos; Warren, Stephen; Almeida, Ana Beatriz; Amstalden, Elaine M. Ingrid; Tiziane, Valdenize and Raposo-Amaral, Cassio Menezes.
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