53 - Hardcastle's Syndome

Hardcastle's Syndome; Diaphyseal Medullary Stenosis with Malignant Fibrous Histiocytoma (DMS-MFH)

Hardcastle's syndrome is a rare, autosomal dominant bony dysplasia characterized by symmetric diaphyseal medullary stenosis of long bones and a very high risk of development of Malignant Fibrous histiocytoma.

This rare disorder has been reported in four or five families worldwide. It is inherited as an autosomal dominant trait. Characteristic findings become visible on radiographs in early adult years. Transformation into Malignant Fibrous histiocytoma occurs in approximately 35 percent. Insufficiency fractures can occur in affected long bones. Following treatment, healing is slow and nonunion may result.

Radiographs show thickening of the cortex, with irregularity and loss of distinction of the endosteal surface. There may be small lucent or lytic areas within or adjacent to the cortex, which may appear to permeate a region of the bone. The metaphyseal area has striated densities that may be seen as confluent fibro-osseous bands on axial imaging. Larger seemingly lytic areas may be seen, although these may areas of normal density surrounded by more sclerotic areas. The diffuse changes seen throughout multiple long bones have the appearance of "worm-eaten wood". Fractures occur with relatively minor trauma through affected bone, and healing is slow and incomplete. Visible fracture lines persist years after surgical stabilization.

Bone scan does not show abnormal uptake in all affected areas, and uptake in areas of recent fracture is much more modest than expected.

CT scan shows the densification of the medullary space and confluent striations.

Treatment should be based on:

1) Avoidance of pathological fracture by appropriate activity modifications.

2) Treatment of pathologic fracture, with appropriate biopsy sampling of fracture areas to detect malignancy. Internal fixation, preferably by intramedullary rodding, is best. It should be expected that the rods will stay in permanently due to the lack of complete healing.

3) Ongoing monitoring for malignant transformation. One approach is to educate the patient about reporting any signs and symptoms of this event, coupled with regular scheduled exams and plain radiographs of affected bones. Serial bone scanning has been considered, but the potential carcinogenic effects of the radioisotopes are of concern in these individuals. No established monitoring protocol has been proposed, but similar monitoring is routine for other genetically-based disorders where there is an increased cancer risk.

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DMS-MFH is an hereditary bone dysplasia / cancer syndrome.

Other names

Bone Dysplasia with Medullary Fibrosarcoma Bone Dysplasia with Malignant Fibrous Histiocytoma Hereditary Bone Dysplasia with Malignant Change

Inheritance autosomal dominant; rare hereditary cancer syndrome with only four families identified worldwide; etiology unknown

radiography shows extensive diaphyseal cortical thickening, areas of resultant medullary stenosis, endosteal irregularities, overall permeative pattern in the medullary cavity, and metaphyseal striations.

Clinics Note radiologic evidence of bone dysplasia not evident in childhood; X-ray findings become apparent during adolescence

Phenotype and clinics 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 non-union progressive wasting or bowing of the lower extremities bone pain pre-senile cataracts (25%) 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.

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. Neoplastic risk 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

Treatment 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

Evolution the disease becomes radiologically apparent only in adolescence: however, retrospectively, clinical signs 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

Other findings 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)

Genes involved and Proteins 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, including p15and 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 tumor-suppressor 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