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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Mini Review Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) John A Martignetti Mount Sinai School of Medicine, Departments of Human Genetics and Pediatrics, 1425 Madison Ave, Box 1498, New York, NY 10029, USA (JAM) Published in Atlas Database: December 1999 Online updated version : http://AtlasGeneticsOncology.org/Kprones/DiaphysStenosID10056.html DOI: 10.4267/2042/37573 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 1999 Atlas of Genetics and Cytogenetics in Oncology and Haematology Phenotype and clinics Identity Main features include: - Bone dysplasia (100%) - Cortical growth abnormalities: diaphyseal medullary stenosis with overlying endosteal cortical thickening and scalloping, metaphyseal striations, scattered sclerotic areas symmetrically affecting the long bones; bilateral mandibular radiolucent and sclerotic lesions - Bone infarctions - Pathologic fractures: subsequent poor healing or nonunion - Progressive wasting or bowing of the lower extremities - bone pain - Pre-senile cataracts (25%) Alias: Bone dysplasia with medullary fibrosarcoma; Bone dysplasia with malignant fibrous histiocytoma; Hereditary bone dysplasia with malignant change Note: DMS-MFH is an hereditary bone dysplasia / cancer syndrome. Inheritance: Autosomal dominant; rare hereditary cancer syndrome with only four families identified worldwide; etiology unknown. Clinics Note Radiologic evidence of bone dysplasia not evident in childhood; X-ray findings become apparent during adolescence. Photograph A: Lateral X-ray view of the left tibia and fibula of an 18 year old male with DMS-MFH and MFH. Note the extensive diaphyseal cortical thickening, areas of resultant medullary stenosis, endosteal irregularities, overall permeative pattern in the medullary cavity, and metaphyseal striations. Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 219 Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) Martignetti JA Photograph B: Tibia and MFH of patient shown in Photograph A. The MFH tumor was associated with the infarcted area in the proximal tibia. Hematoxylin and eosin preparation shows removed MFH tumor from infarcted area with typical storiform arrangement of spindle cells throughout the view. and symptoms may be evident in childhood; these include unexplained bone pain and pathologic fractures; in some, crippling pain and weakness of the lower extremities ensues following the sixth decade; malignancy occurs most frequently between the second to fifth decades and is particularly aggressive; only two long-term survivors, greater than five years, are known; pre-senile cataracts have been noted as early as in the third decade. - Bone malignant fibrous histiocytoma (MFH) (35%) Diagnosis: X-ray skeletal findings are unique; however, there may be some radiologic overlap with other diaphyseal dysplasias including Camurati-Engelman and Kenny-Caffey diseases and radiation osteitis; no hematologic or urinary markers of disease have been identified; 201Thallium chloride radionucleotide scans may offer discrimination between areas of increased metabolic bone activity found in DMS-MFH patients and malignant change. Neoplastic risk Other findings Thirteen cases of osseous MFH; thirty-five per cent of DMS-MFH patients develop MFH; the age distribution has been from the second to fifth decades; no sex predilection; in its sporadic form, MFH represents approximately 6% of all bone cancers and is the most frequently occurring adult soft-tissue sarcoma. Note Collagen fibrils from the endosteal surface of bones appear frayed and unraveled (npublished results); chemical crosslink analysis of bone biopsy samples reveal altered hydroxylysylpyridinolin (HP) / lysylpyridinoline (LP) ratios (unpublished results). Treatment Genes involved and proteins No known treatment for the dysplasia; the tumors are highly aggressive - treated with surgical ablation and the same chemotherapeutic regimens as osteosarcoma; it is believed that preoperative chemotherapy improves surgical outcome. Note The gene has been mapped by linkage analysis to a 3 cM region on chromosome 9p21-22; all families used in the study generated positive LOD scores in this region and all affecteds had similar phenotypic findings consistent with the syndrome being genetically homogeneous; a number of genes in the region, Evolution The disease becomes radiologically apparent only in adolescence: however, retrospectively, clinical signs Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) 220 Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) Norton KI, Wagreich JM, Granowetter L, Martignetti JA. Diaphyseal medullary stenosis (sclerosis) with bone malignancy (malignant fibrous histiocytoma): Hardcastle syndrome. Pediatr Radiol. 1996 Sep;26(9):675-7 including p15 and p16, have been excluded as the DMS-MFH gene by DNA sequencing analysis; under the hypothesis that hereditary and sporadic MFH tumors are genetically identical, the DMS-MFH tumorsuppressor gene region has been further narrowed to 1.5 cM using loss of heterozygosity analysis; the continued search for the common minimally deleted region in MFH tumors should provide the most powerful method for gene identification. Martignetti JA, Desnick RJ, Aliprandis E, Norton KI, Hardcastle P, Nade S, Gelb BD. Diaphyseal medullary stenosis with malignant fibrous histiocytoma: a hereditary bone dysplasia/cancer syndrome maps to 9p21-22. Am J Hum Genet. 1999 Mar;64(3):801-7 Martignetti JA, Gelb BD, Pierce H, Picci P, Desnick RJ. Malignant fibrous histiocytoma: inherited and sporadic forms have loss of heterozygosity at chromosome bands 9p21-22evidence for a common genetic defect. Genes Chromosomes Cancer. 2000 Feb;27(2):191-5 References Arnold WH. Hereditary bone dysplasia with sarcomatous degeneration. Study of a family. Ann Intern Med. 1973 Jun;78(6):902-6 This article should be referenced as such: Martignetti JA. Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH). Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4):219-221. Hardcastle P, Nade S, Arnold W. Hereditary bone dysplasia with malignant change. Report of three families. J Bone Joint Surg Am. 1986 Sep;68(7):1079-89 Atlas Genet Cytogenet Oncol Haematol. 1999; 3(4) Martignetti JA 221