Unusual case of septic arthritis of the hip: spread from adjacent adductor pyomyositis.

Distinguishing intracapsular and extracapsular hip infections may be clinically difficult. Because of this difficulty in diagnosis, the spread of an extracapsular infection into the hip joint may be missed and lead to significant joint destruction. The case of a patient who suffered from the spread of adductor pyomyositis to the hip joint is reported. The delay in diagnosis of an intracapsular hip infection led to significant intra-articular destruction and ultimately necessitated a Girdlestone resection arthroplasty. The patient's hip function was salvaged with a total hip arthroplasty. The presence of an extracapsular hip infection should mandate serial physical examinations and aggressive evaluation to rule out intracapsular spread. A delay in diagnosis of an intracapsular hip infection can lead to catastrophic results.

The human bone morphogenetic protein 4 (BMP-4) gene: molecular structure and transcriptional regulation.

Bone morphogenetic protein 4 (BMP-4) is a vital regulatory molecule that functions throughout human development in mesoderm induction, tooth development, limb formation, bone induction, and fracture repair and is overexpressed in patients who have fibrodysplasia ossificans progressiva. The human gene encoding bone morphogenetic protein 4 (BMP-4) has been isolated and its structural organization characterized. The complete DNA sequence of an 11.2 kb region has been determined. BMP-4 mRNA is transcribed from four exons, although there is evidence that alternate first exons may be used. Transcript initiation occurs at variable positions within a GA-rich region of the DNA. The promoter region is GC-rich with no obvious TATA or CAAT consensus sequences, and contains both positive and negative transcriptional regulatory elements within the 3 kb 5' flanking region of the RNA start site. Comparison of the human and murine BMP-4 genes reveals highly conserved sequences not only in the exon-coding regions but also within the introns and 5' flanking regions. BMP-4 localizes to human chromosome 14q21 by fluorescence in situ hybridization, a location more centromeric than that recently reported. These studies provide a foundation for understanding the genetic regulation of this important gene in human development.

Treatment of patients who have fibrodysplasia ossificans progressiva with isotretinoin.

Retinoids are a plausible family of therapeutic agents for fibrodysplasia ossificans progressiva due to their ability to inhibit differentiation of mesenchymal tissue into cartilage and bone. A prospective study was conducted to assess the efficacy of isotretinoin (13-cis-retinoic acid) in the prevention of heterotopic ossification in patients who had fibrodysplasia ossificans progressiva. Eleven anatomic regions were assessed in each of 21 patients by clinical examination, radiographs, and bone scans. An anatomic region was considered to be involved if there was clinical, radiographic, or radionuclide evidence of orthotopic or heterotopic ossification anywhere in the region. There were 143 involved anatomic regions and 88 uninvolved anatomic regions at the beginning of the study. Only one of the 88 anatomic regions that was completely uninvolved at the beginning of the study became involved during isotretinoin therapy. However, 16 of the 21 patients (76%) had major flare ups develop in 38 of 143 (27%) previously involved anatomic regions while administered isotretinoin therapy. Isotretinoin at steady state doses of 1 to 2 mg/kg per day decreased the incidence of heterotopic ossification at uninvolved anatomic regions compared with an external control group, as long as the medication was started before the appearance of any orthotopic or heterotopic ossification in that anatomic region. The data did not allow the determination of whether isotretinoin was effective or detrimental in preventing disease flareups in regions that had even minimal orthotopic or heterotopic ossification at the time the therapy began. Extreme caution should be exercised when using this medication in patients who have fibrodysplasia ossificans progressiva.

Pseudomalignant heterotopic ossification.

Pseudomalignant heterotopic ossification is a rare, self limited connective tissue disorder of unknown origin that may occur atypically during childhood and can simulate either soft tissue sarcoma or fibrodysplasia ossificans progressiva. A complex constellation of diagnostic features usually enable the differentiation of pseudomalignant heterotopic ossification from extraosseous osteosarcoma and fibrodysplasia ossificans progressiva during a time span of approximately 8 to 12 weeks. Orthopaedic surgeons who treat children with connective tissue tumors should be familiar with pseudomalignant heterotopic ossification and its differential diagnosis. The occasional mild and variable expression of fibrodysplasia ossificans progressiva rarely may make it more difficult to distinguish from pseudomalignant heterotopic ossification. It is possible that pseudomalignant heterotopic ossification is a form fruste of fibrodysplasia ossificans progressiva.

Severe restriction in jaw movement after routine injection of local anesthetic in patients who have fibrodysplasia ossificans progressiva.

OBJECTIVE: To determine the relationship of dental procedures to immediate ossification and ankylosis of the jaw in patients who have fibrodysplasia ossificans progressiva. STUDY DESIGN: A mail survey was conducted of the 60 patient-members of the International Fibrodysplasia Ossificans Progressiva Association. All 41 patients (18 males, 23 females) who responded were examined. Instantaneous exact hazard rates for ossification of the jaw were calculated by the Weibull model. RESULTS: Thirty-six patients had dental procedures performed. Twenty-one (58%) patients had received an injection of local anesthetic. Five (24%) patients had an immediate flare-up of fibrodysplasia ossificans progressiva with ossification and permanent ankylosis of the jaw (expected occurrence, 0.031; p < 0.0001). None of the 12 patients who had comparable dental work without injections developed heterotopic ossification (expected occurrence, 0.019; not significant). CONCLUSION: Injections of local anesthetic during dental procedures pose serious and immediate risk for inciting heterotopic ossification and ankylosis of the jaw in patients who have fibrodysplasia ossificans progressiva and should be assiduously avoided.

BMP-1 sublocalization on human chromosome 8. Molecular anatomy and orthopaedic implications.

Bone morphogenetic proteins are capable of inducing mesenchymal tissue to form mature bone. Bone morphogenetic protein 1 (BMP-1) has a structure unique from the other bone morphogenetic proteins and may be involved in activation of other bone morphogenetic proteins. Localization of the human BMP-1 gene to chromosome 8 led to its consideration as a candidate gene for Langer-Giedion syndrome. Individuals with Langer-Giedion syndrome (also known as trichorhinophalangeal syndrome Type II) exhibit several skeletal abnormalities, including multiple exostoses and cone-shaped epiphyses of the hands and feet. The genetic locus responsible for this disease has been localized to the long arm of human chromosome 8 at 8q24.1. Somatic-cell hybrid and molecular biology techniques were used to sublocalize the BMP-1 gene to the short arm of chromosome 8 within the 8p22-cen region. Although this locus falls outside the Langer-Giedion syndrome region, and therefore excludes BMP-1 as a candidate gene for this disorder, BMP-1 gene sublocalization establishes a chromosomal landmark for evaluating other possible disease associations with BMP-1.

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.

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.

A bone morphogenetic protein subfamily: chromosomal localization of human genes for BMP5, BMP6, and BMP7.

Bone morphogenetic proteins (BMPs) were originally identified by the ability of a demineralized bone extract to induce endochondral osteogenesis in vivo. Seven BMP cDNAs (BMP1 through BMP7) have been recovered through molecular cloning. Recombinant protein products from six of these clones (BMP2 through BMP7) are members of the transforming growth factor beta (TGF-beta) superfamily of regulatory molecules. Based upon a high degree of amino acid sequence homology, BMP5, BMP6, and BMP7 constitute a subfamily within the BMPs. Using human-rodent somatic cell hybrid lines and cDNA probes, we mapped the three members of this subfamily of genes to the human chromosomes. BMP5 and BMP6 are syntenic on human chromosome 6, while BMP7 is syntenic with previously localized BMP2 on human chromosome 20. This analysis reveals that BMP6 maps to a conserved region between the mouse and human genomes. Sequence analysis suggests that the Drosophila 60A gene is the dipteran homolog of this BMP subfamily and may provide clues to the physiologic functions of the products of these genes in human biology.