Mild expression of fibrodysplasia ossificans progressiva: a report of 3 cases.

We describe 3 unusually mild cases of fibrodysplasia ossificans progressiva (FOP) in an 80-year-old man, a 44-year-old woman, and a 17-year-old woman. The man, whose daughter had classic features of FOP, lacked malformation of the great toes and experienced unusually slow progression of the disease. Both women displayed late onset heterotopic ossification. The older women displayed an unusually slow progression of the disease. All 3 patients remained ambulatory at the time of examination. Recognition of a mild form of FOP will influence diagnosis, counselling, and research in this rare condition.

Enchondroma in a patient with fibrodysplasia ossificans progressiva.

Fibrodysplasia ossificans progressiva (FOP) is a rare heritable disorder characterized by progressive heterotopic endochondral bone formation arising in ligament, tendon, and the fibrous connective tissue of skeletal muscle. The disorder is almost invariably associated with skeletal malformations of the endochondral anlage of the feet. A 25-year-old woman with FOP had a histopathologically documented phalangeal enchondroma. This common neoplasm of cartilage and bone seems not to have been previously reported in FOP; it may represent a coincidental occurrence, but in the context of the patient's genetic disorder, an enchondroma may represent an unusual and variable expression of the disease.

Chromosomal assignment of the human gene for bone morphogenetic protein 4.

Bone morphogenetic proteins (BMP) are the only known biologic factors capable of inducing endochondral ossification at an extraskeletal site. Seven members of the BMP family have been identified thus far and are involved in osteoinduction and morphogenesis. The authors established the chromosomal assignment of the gene for BMP4 on human chromosome 14 by using somatic cell hybrid panels and molecular technology. The genetic map of chromosome 14 shows that Holt-Oram Syndrome (HOS), a heritable disorder of skeletal and cardiac development, may be located also on chromosome 14. Linkage analysis studies in large families with HOS will determine if the BMP4 gene is related to HOS. In addition, analysis shows that the BMP4 gene maps to a conserved region of the mouse and human genomes. The chromosomal locus of a gene is part of human anatomy and provides a genomic landmark for studies on the pathogenesis of heritable disorders.

Genetic transmission of fibrodysplasia ossificans progressiva. Report of a family.

Fibrodysplasia ossificans progressiva is a rare connective-tissue disorder characterized by congenital malformation of the great toes and by progressive heterotopic ossification of the tendons, ligaments, fasciae, and skeletal muscles. We document the genetic transmission of fibrodysplasia ossificans progressiva from a sporadically affected father to each of his three children: two daughters and a son. Previous consideration of a genetic etiology was based on the fact that the disease has been reported in several sets of monozygotic twins, that an increased paternal age has been associated with sporadic occurrences of the disorder, and that there have been several reports of genetic transmission in the remote past. Although an autosomal-dominant genetic transmission has long been suspected, the findings in the family reported on here provide confirmation for such inheritance and a basis for the diagnosis and counseling of patients who have this disease.

The natural history of heterotopic ossification in patients who have fibrodysplasia ossificans progressiva. A study of forty-four patients.

Forty-four patients who had fibrodysplasia ossificans progressiva responded by mail to a questionnaire regarding the age at the onset of heterotopic ossification at fifteen commonly involved anatomical sites. The average age of the patients when they responded to the questionnaire was twenty-seven years (range, three to sixty-nine years). The average age at the onset of ossification was five years (range, birth to twenty-five years). The most common sites of early heterotopic ossification were the neck, spine, and shoulder girdle. Thirty-five (80 per cent) of the patients had had some restrictive heterotopic ossification by the age of seven years. By the age of fifteen years, forty-two (more than 95 per cent) of the patients had severely restricted mobility of the upper limbs. In these patients, heterotopic ossification proceeded in a direction that was axial to appendicular, cranial to caudad, and proximal to distal; this pattern appeared typical for fibrodysplasia ossificans progressiva.

The histopathology of fibrodysplasia ossificans progressiva. An endochondral process.

In order to better characterize the biological features of fibrodysplasia ossificans progressiva, we reviewed the histopathological specimens from eleven patients (twelve biopsies) who had a confirmed diagnosis of the disease. All of the biopsies had been performed in children, to exclude the diagnosis of a malignant lesion. In no instance was the diagnosis of fibrodysplasia ossificans progressiva considered before the biopsy. The results of a lesional biopsy in all eleven patients revealed normal endochondral osteogenesis at heterotopic sites. The results of biopsy of an early lesion in six children were misinterpreted as revealing a diagnosis of fibromatosis or sarcoma before the roentgenographic appearance of ossification. Immunohistochemical studies of sections of the earliest lesion demonstrated S-100 antigen positivity before the histological appearance of differentiated osteochondral tissue. The presence of congenital malformation of the great toes and of postnatal heterotopic endochondral osteogenesis strongly suggests that fibrodysplasia ossificans progressiva is a disorder of defective induction of endochondral osteogenesis. This study established the predominant histopathological findings associated with fibrodysplasia ossificans progressiva and can serve as a basis for postulation of a candidate gene in the pathogenesis of the disorder. A lesional biopsy is not needed to make the diagnosis; biopsy uniformly exacerbates the condition and should be avoided.

Bone morphogenetic protein: chromosomal localization of human genes for BMP1, BMP2A, and BMP3.

Bone morphogenetic protein (BMP) induces endochondral bone formation in vivo. The human genes have been cloned for a group of proteins containing BMP activity (BMP1, BMP2A, and BMP3). Two of the proteins are members of the transforming growth factor-beta supergene family (BMP2A and BMP3), while BMP1 is a novel regulatory protein. Using somatic cell hybrid lines, cDNA probes were used to map BMP1 to chromosome 8, BMP2A to chromosome 20, and BMP3 to the p14-q21 region of chromosome 4. This analysis reveals that the BMP2A and BMP3 genes map to conserved regions between mouse and human, while the BMP1 gene does not. The locations of the BMP genes were found to overlap with the loci for several disorders of cartilage and bone formation.

Fibrodysplasia ossificans progressiva: a clue from the fly?

Fibrodysplasia (myositis) ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by symmetrical congenital malformations of the blastemal anlage of the hands and feet and by progressive heterotopic chondrogenesis and ossification of the soft connective tissues. There is neither an established pathogenesis nor an effective treatment for this disabling disorder. We reevaluated the published data on the natural history of FOP and discovered an array of developmental gradients (characteristic patterns of disease expression) similar to developmental anomalies induced by pleiotropic mutations of the decapentaplegic (dpp) locus in Drosophila melanogaster. The protein encoded by the dpp locus is a member of the transforming growth factor-beta (TGF-beta) family of molecules. It shares 75% sequence homology with the c-terminal region of two recently cloned human bone morphogenetic proteins (BMP-2A, BMP-2B), also members of the TGF-beta family. The striking sequence identity across so large an evolutionary distance suggests that the BMP-2 genes in man and the dpp gene in the fly may be derived from a common ancestral gene. BMP is the only molecule discovered thus far that is capable of inducing endochondral ossification in vivo. Expression of endochondral bone formation is the basis for limb formation in embryogenesis, longitudinal bone growth in postnatal life, and local bone regeneration (fracture healing) following injury. We believe that FOP is a genetic disorder characterized by a disturbed developmental expression of this endochondral program and may represent a mutation resulting in a dominant gain of function. The developmental similarities between decapentaplegic in the fly and FOP in man suggest a useful model for the study of FOP. The use of such a model might be especially fruitful in suggesting a molecular basis for FOP.