Diaphyseal Medullary Stenosis With Malignant Fibrous Histiocytoma

A number sign (#) is used with this entry because diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMSMFH) is caused by heterozygous mutation in the MTAP gene (156540) on chromosome 9p21.

Description

Diaphyseal medullary stenosis with malignant fibrous histiocytoma is an autosomal dominant bone dysplasia characterized by pathologic fractures due to abnormal cortical growth and diaphyseal medullary stenosis. The fractures heal poorly, and there is progressive bowing of the lower extremities. In 2 families, affected individuals also showed a limb-girdle myopathy, with muscle weakness and atrophy. Approximately 35% of affected individuals develop an aggressive form of bone sarcoma consistent with malignant fibrous histiocytoma or osteosarcoma. Thus, the disorder may be considered a tumor predisposition syndrome (summary by Camacho-Vanegas et al., 2012).

Clinical Features

Arnold (1973) described several generations of a Vermont and New York kindred demonstrating multiple areas of necrosis in the diaphyses of the large tubular bones. The radiographic appearance of this skeletal condition resembled radiation osteitis, a highly premalignant condition; however, no source of radiation exposure was found in this family. Medullary fibrosarcoma, an uncommon bone tumor, was noted in 4 of the 12 affected members. Death had occurred from widespread metastases at ages varying from 23 to 48 years. Occurrence of fibrosarcoma in idiopathic bone infarcts (Furey et al., 1960) and in an infarct in a caisson worker (Dorfman et al., 1966) has been reported. Camacho-Vanegas et al. (2012) noted that 2 affected male individuals in the family reported by Arnold (1973) died of heart disease in their early forties without other known risk factors, and suggested that this may be a manifestation of the disorder.

Hardcastle et al. (1986) gave follow-up information on the original American family and reported 2 other families, one English and the other Australian. They could find no reports of any hereditary or acquired condition similar to that in these 3 families. They suggested that the malignant change should be labeled 'malignant fibrous histiocytoma' rather than fibrosarcoma because the tumors were markedly aggressive. The malignancy occurred generally in the second to fifth decades of life. They defined the skeletal dysplasia as a diaphyseal medullary stenosis with overlying cortical bone thickening. The occurrence of fracture with minimal trauma was emphasized.

Norton et al. (1996) reported a 19-year-old boy who presented with a nontender mass on the left tibia that proved to be a pleiomorphic spindle cell sarcoma. Radiographs of the affected leg showed extensive diaphyseal cortical thickening and a medullary permeative pattern in the diaphysis. Radiographs of the patient's mother and maternal grandmother showed a similar bony dysplasia, with areas of infarction and medullary sclerosis. The lower extremities were more affected than the upper extremities in all 3 cases. Family history was significant for the death of the maternal great-grandmother at age 32 from 'metastatic osteosarcoma.' Norton et al. (1996) commented on the similarities to the families reported by Hardcastle et al. (1986) and noted that the malignant fibrous histiocytomas in this condition presumably begin at the sites of infarction within the affected bone.

Henry et al. (1958) reported a Canadian family in which 6 men had delayed healing of fractures of the long bones and later developed myopathy. Mehta et al. (2006) provided follow-up on the family reported by Henry et al. (1958); features of 8 living and 8 deceased family members with the disorder were evaluated. In this family, fractures preceded myopathy: the average age at onset of limb-girdle myopathy was 31 years, whereas that of fractures was 24 years. Fractures were primarily of the long bones of the lower limbs and were associated with poor healing and osteomyelitis, leading to amputation in some cases. Serum creatine kinase was mildly increased, and alkaline phosphatase was normal. Radiographs showed coarse trabeculation, patchy sclerosis, cortical thickening, and narrowing of the medullary cavities of the long bones. The findings were not consistent with Paget disease (see 167250). Muscle biopsies showed nonspecific myopathic changes without necrotic fibers, regenerating fibers, inflammatory infiltrates, or structural abnormalities. Many affected family members had premature graying of the hair and soft, thin skin, and 3 affected members had a clotting disorder.

Inheritance

The transmission patterns in the families with DMSMFH reported by Arnold (1973), Hardcastle et al. (1986), Norton et al. (1996), and Mehta et al. (2006) were all consistent with autosomal dominant inheritance.

Mapping

Martignetti et al. (1997, 1999) used microsatellite markers in a genome screen for the gene locus in diaphyseal medullary stenosis with malignant fibrous histiocytoma in 3 unrelated families. They linked the syndrome to a region of approximately 3 cM on 9p22-p21, with a maximum 2-point lod score of 5.49 with marker D9S171 at recombination fraction (theta) 0.05. This region of chromosome 9 is the site of chromosomal abnormalities in several other malignancies and contains a number of genes whose protein products are involved in growth regulation. Identification of the gene responsible for this rare familial sarcoma would be expected to define as well the cause of the more common nonfamilial, or sporadic, form of malignant fibrous histiocytoma, a tumor that constitutes approximately 6% of all bone cancers and is the most frequently occurring adult soft-tissue sarcoma.

To determine whether the hereditary and sporadic forms of bone dysplasia with malignant fibrous histiocytoma are genetically linked, Martignetti et al. (2000) performed loss of heterozygosity (LOH) studies of the 9p22-9p21 region and found that 71% (5/7) of informative sporadic DMSMFH specimens displayed LOH for markers within that same region. Definition of the minimal region of LOH overlap effectively limited the DMSMFH gene to a 2-cM region between markers D9S736 and D9S171.

By genomewide linkage analysis of the family reported by Henry et al. (1958) and Mehta et al. (2006), Watts et al. (2005) identified a candidate disease locus on chromosome 9p22-p21 (maximum lod score of 3.74 at marker D9S1121). Haplotype analysis refined the locus to a 15-Mb region. Genetic analysis excluded mutations in the ADAMTSL1 (609198) and TYRP1 (115501) genes. Watts et al. (2005) noted that the clinical phenotype in this family and the identified locus overlap with diaphyseal medullary stenosis with malignant fibrous histiocytoma.

Molecular Genetics

Camacho-Vanegas et al. (2012) identified 2 different heterozygous mutations affecting exon 9 of the MTAP gene (156540.0001 and 156540.0002) in affected members of 5 unrelated families with diaphyseal medullary stenosis with malignant fibrous histiocytoma. Four of the families had previously been reported by Arnold (1973), Hardcastle et al. (1986), Norton et al. (1996), and Watts et al. (2005). The mutations were found by positional cloning and examination of putative open reading frames within the candidate region. The analysis identified previously unrecognized exons in the MTAP gene, including exon 9. Both mutations affected splicing, with altered expression of MTAP isoforms. Serum samples from 2 patients showed accumulation of methylthioadenosine (MTA), whereas MTA was not present in serum from 3 controls. These findings implicated a defect in MTAP enzyme activity in the patients with mutations. DNA analysis of tumor tissue from an osteosarcoma of 1 patient showed homozygosity for the mutation with loss of heterozygosity of the wildtype allele. The findings of the study suggested that MTAP can also act as a tumor suppressor gene.