Limb swelling in patients who have fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva is a rare heritable disorder of connective tissue characterized by progressive heterotopic ossification of soft tissues and by congenital malformation of the great toes. Limb swelling has also been noted, yet little is known about this complication of fibrodysplasia ossificans progressiva. To determine the prevalence of limb swelling in this condition, the authors reviewed detailed medical records on 74 patients (25 males, 49 females; age range, 1-49 years) who had a documented history of fibrodysplasia ossificans progressiva. The study population included more than 90% of all patients known to have fibrodysplasia ossificans progressiva in the United States. Acute swelling of the limbs occurred in association with flareups of the condition in nearly all cases. Acute swelling in the upper limbs was focal and nodular in contrast to acute swelling in the lower limbs, which was more diffuse. Acute swelling in the upper limbs occurred in all 74 patients whereas acute swelling in the lower limbs occurred in 47 of the 74 patients (64%). Two of the 74 patients who had acute swelling in the lower limbs (4%) had a documented episode of deep vein thrombophlebitis. Chronic swelling in the upper limbs occurred in 9 of the 74 patients (12%) and was not seen before the age of 12 years. Chronic swelling in the lower limbs occurred in 36 of the 74 patients (49%) and was not seen before the age of 9 years. The intense angiogenesis and edema seen on histopathologic evaluation of preosseous fibrodysplasia ossificans progressiva lesions may play a role in the pathogenesis of the limb swelling. The data show an age related prevalence of limb swelling in fibrodysplasia ossificans progressiva and suggest a model for understanding the complex pathways leading to limb swelling in this disorder.     

Urinary basic fibroblast growth factor. A biochemical marker for preosseous fibroproliferative lesions in patients with fibrodysplasia ossificans progressiva

Angiogenesis is a prominent histopathologic feature of preosseous fibroproliferative lesions in patients who have fibrodysplasia ossificans progressiva. Basic fibroblast growth factor is an extremely potent in vivo stimulator of angiogenesis, and has been implicated in the growth of solid tumors. An enzyme linked immunosorbent assay for basic fibroblast growth factor was performed on urine samples from patients who had active (n = 28) and inactive (n = 39) fibrodysplasia ossificans progressiva, and compared with urine samples from normal age and gender matched control subjects (n = 54). Median basic fibroblast growth factor levels were 2705 pg/g of creatinine in the normal control group, 5058 pg/g of creatinine in patients with inactive fibrodysplasia ossificans progressiva (no significant difference), and 8793 pg/g of creatinine in patients with active fibrodysplasia ossificans progressiva. Female subjects, both normal and with fibrodysplasia ossificans progressiva, had higher levels of urinary basic fibroblast growth factor than did male subjects. There was no correlation of urinary basic fibroblast growth factor levels with age or severity of preexisting disability. These data document an elevation of urinary basic fibroblast growth factor during acute flareups of fibrodysplasia ossificans progressiva and provide a biochemical basis for considering antiangiogenic therapy for inhibiting endochondral osteogenesis in this disorder.     

Catastrophic falls in patients who have fibrodysplasia ossificans progressiva

There have been numerous anecdotal reports of catastrophic falls in patients with fibrodysplasia ossificans progressiva. To determine the incidence of serious morbidity and mortality associated with falls in this patient population, the authors surveyed the 135 patient members of the International Fibrodysplasia Ossificans Progressiva Association and an age and gender matched control group. Eighty-one percent of the fibrodysplasia ossificans progressiva population suffered a fall resulting in injury compared with 44% of the controls. Sixty-seven percent of the falls initiated a painful flareup of fibrodysplasia ossificans progressiva leading to permanent loss of movement in almost all patients. Fifty-four percent of all falls suffered by the fibrodysplasia ossificans progressiva group led to permanent disability compared with 4% of all falls in the control group. Although trauma to the head was a common site of injury in both groups, the injury profile in the fibrodysplasia ossificans progressiva group included traumatic brain injuries, intracranial hemorrhage and death whereas the control group suffered mostly minor soft tissue lacerations. Deficiencies in coordinate gait and protective function likely accounted for the severity of injuries especially to the head in the fibrodysplasia ossificans progressiva population. Precautions are recommended that are intended to minimize the risk of injury without compromising a patient's functional level and independence. These recommendations include limitation of high risk activities, protective head gear, safety improvements in living environments, and augmentation of stabilizing and protective functions.     

Mutational screening of the bone morphogenetic protein 4 gene in a family with fibrodysplasia ossificans progressiva

Bone morphogenetic proteins have been proposed as candidate genes for fibrodysplasia ossificans progressiva. Bone morphogenetic protein 4 is overexpressed in cells derived from these patients. The bone morphogenetic protein 4 genes from a family showing autosomal dominant inheritance of fibrodysplasia ossificans progressiva have been screened for mutations by single strand conformation polymorphism analysis and deoxyribonucleic acid sequencing. The exon coding regions and splice junctions of the bone morphogenetic protein 4 gene have been examined for polymorphisms in all five family members. However, no mutation was discovered in these messenger ribonucleic acid and protein coding regions or in the splice junctions of affected or unaffected family members. In addition, approximately 1.5 kb of upstream flanking sequences also were examined. Neutral polymorphisms were identified in the upstream flanking region of the bone morphogenetic protein 4 gene. Although this study has not identified any mutations in the bone morphogenetic protein 4 gene that are correlated with the occurrence of fibrodysplasia ossificans progressiva, the bone morphogenetic protein 4 gene cannot yet be excluded from consideration as the genetic cause of this disorder because a mutation could be present in unexamined regulatory sequences of this gene.     

Animal models of heterotopic ossification

Heterotopic ossification is often a severe clinical complication of joint arthroplasty, neurologic trauma, and muscle injury. In rare genetic disorders, such as fibrodysplasia ossificans progressiva, heterotopic ossification can be crippling and often leads to premature death. Reliable animal models of heterotopic ossifications that mimic pathologies seen in man would be invaluable for the development of new treatments to combat heterotopic ossification. Various methods used to induce heterotopic ossification in animals including the use of bone morphogenetic proteins, urinary tract epithelia, and transformed cell lines are described. Genetic animal models of heterotopic ossification and various miscellaneous examples of heterotopic ossification in animals are described. Finally, the use of transgenic mice to manipulate bone morphogenetic protein expression is discussed as a possible future animal model of heterotopic ossification.     

Fibrodysplasia (myositis) ossificans progressiva. Clinical lessons from a rare disease

Fibrodysplasia (myositis) ossificans progressiva is a rare dominantly inherited disorder, in which defects in skeletal patterning particularly affecting the big toes, are associated with progressive endochondral ossification of the large striated muscles in a specific order leading to prolonged disability. A recent series of 28 patients studied for as many as 24 years exemplifies the presentation and course of this disease. Painful swelling of muscles (myositis) leading to ossification began at a mean age of 4.6 years (range, 0-16 years) initially in the neck and upper spine (in 25 subjects) and later around the hips, other major joints, and jaw. The rate and extent of disability was unrelated to the time of onset. No form of treatment produced consistent benefit. Despite the unique clinical features, the initial diagnosis of fibrodysplasia ossificans progressiva was often wrong and usually considerably delayed. Mistaken histologic diagnoses such as soft tissue sarcoma or fibromatosis could lead to inappropriate treatment.     

Alkaline phosphatase activity in cultured skin fibroblasts from fibrodysplasia ossificans progressiva

Alkaline phosphatase activity in four strains of cultured skin fibroblasts obtained from a patient with fibrodysplasia ossificans progressiva was at the low normal range. The enzyme activity in normal fibroblasts significantly increased at late confluency. It appears that the high levels of alkaline phosphatase activity reported in biopsies of lesions are not genetically determined but are secondary events of local tissue reaction.     

Pathogenesis of human leukocyte antigen B27-positive arthritis. Information from clinical materials

In the spondyloarthropathies human leukocyte antigen (HLA) B27 confers a strong genetic predisposition to the development and to the chronicity of disease after extra-articular infection with certain gram-negative bacteria. The close relationships between infection, HLA-B27, other genetic factors, and the host immune system, however, still are unexplained. HLA-B27-positive arthritis continues to be an area of intensive investigation in basic and clinical research. New animal models with HLA-B27 transgenic mice and rats, as well as recent developments in understanding the processes involved in signal transduction, cytokine production, and human T-lymphocyte activation, contribute to the development of new pathogenic models of the spondyloarthropathies. This article summarizes the current concepts of the cause and pathogenesis of the spondyloarthropathies resulting from studies of clinical materials. The host-microbial interplay in human disease, namely in bacteria-induced reactive arthritis, may eludicate principle disease mechanisms in acute disease and in the development of chronic autoimmune arthritis or ankylosing spondylitis.     

Binding of the pili of Pseudomonas aeruginosa to a low-molecular-weight mucin and neutral cystatin of human submandibular-sublingual saliva

The HLA-B*27 group of alleles has been extensively studied due to the association of particular B*27 alleles with ankylosing spondylitis (AS). We describe here an HLA-B*27 allele (B*2712) encoding an antigen that lacks reactivity with B27 monoclonal antibodies (moabs) and alloantisera but reacts with some B40/B60 moabs and alloantisera and expresses the Bw6 public epitope. This allele was discovered by the segregation of an HLA-B allele undetectable by PCR-SSP within a Caucasian family from the British population referred for routine bone marrow transplant HLA typing and found in the haplotype A*29; B*2712; Cw*1203; DRB1*13; DQB1*0603. Serological typing showed a lack of reactivity with four B27 moabs and four alloantisera but positive reactivity with moabs and alloantisera specific for B40/B60 and Bw6 public epitopes. Subsequent sequencing showed the closest homology was with B*2708 with three mismatches in exon 2 at positions 204, 209 and 210. The intron 2 sequence was identical with other B*27 lineage alleles including a 2 base pair deletion at positions 95 and 96. The relationship between HLA-B*2712 and reported B60 associations with susceptibility to AS remains to be determined.     

Eye involvement in the spondyloarthropathies

Eye inflammation, especially uveitis, is a prominent feature of spondyloarthropathies. Uveitis associated with ankylosing spondylitis and Reiter's syndrome usually is a unilateral acute anterior uveitis with a high tendency to recur sometimes in the contralateral eye. Uveitis associated with undifferentiated spondyloarthropathy, inflammatory bowel disease, and psoriasis may be less characteristic in its presentation, with a higher tendency to posterior pole involvement, bilaterality, and chronicity. Although acute anterior uveitis is grouped into the spectrum of human leukocyte antigen B27-related disease, other genetic and environmental factors including infections by gram-negative bacteria and gut inflammation can play a role in its pathogenesis. The prognosis of uveitis usually is excellent with topical treatment, and only those with posterior pole involvement or a high tendency to recur or to chronicity might benefit from immunosuppressive therapy.     

Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis

PURPOSE: Outcomes of HLA-B27-positive and HLA-B27-negative acute anterior uveitis were assessed after a mean follow-up of nine years. Rheumatologic complications, in particular the presence and course of ankylosing spondylitis, were examined during the same period. METHODS: A hospital-based prospective study of 119 patients with HLA-B27-positive and 35 patients with HLA-B27-negative acute anterior uveitis was performed. All patients underwent a complete ophthalmologic and rheumatologic examination, including sacroiliac x-rays, and were examined again nine years later. RESULTS: No statistically significant differences in ocular complications and visual outcome were found between both patient groups with acute anterior uveitis after nine years. Posterior synechiae were observed in one half of the affected eyes. Blindness was infrequent. Rheumatologic complications, including ankylosing spondylitis, originally seen in one half of the HLA-B27-positive patients, were observed in two thirds of the patients nine years later, compared to only two of 35 HLA-B27-negative patients. When ankylosing spondylitis was evident at first examination no clinically significant deterioration was observed nine years later. CONCLUSIONS: After nine years we observed an ocular outcome equal for both patient groups. A small percentage of affected eyes became blind. Rheumatologic complications occurred in 55 (72%) of 76 HLA-B27-positive males and in 24 (56%) of 43 HLA-B27-positive females with acute anterior uveitis. The rheumatologic complications had a good prognosis.     

Spondyloarthropathy and human immunodeficiency virus infection in Zambia

OBJECTIVE: To explore the relationship between spondyloarthropathy (SpA) and infection with the human immunodeficiency virus (HIV) in black Zambians. METHODS: Consecutive patients attending an arthritis clinic in a 30 month period were assessed clinically and tested for the presence of antibodies to HIV. HLA-B27 gene was investigated by polymerase chain reaction and T cell subsets were tested in selected subgroups. RESULTS: Of 595 new attendees, 272 were diagnosed with SpA [130 reactive arthritis (ReA), 128 undifferentiated SpA (uSpA), 13 psoriatic arthritis (PsA), 1 ankylosing spondylitis] and 146 with a reactive type arthritis alone (AA) without preceding clinical trigger infection or SpA features. HIV seroprevalence was 98% in uSpA, 94% PsA, 87% ReA, 64% AA; vs approximately 50% among hospital outpatients and 30% of the adult urban population. Prevalence of SpA is calculated at approximately 180/100,000 in HIV positive and approximately 15/100,000 in HIV negative in the general population. Dysentery was the most common identified trigger. Positive HIV status correlated strongly with SpA features and aggressive sustained disease. At onset 80% of patients were in WHO clinical stage 1 (no disease or lymphadenopathy alone), with a mean CD4+ count of 279/microl. Stage 4 patients had a mean CD4+ count of 60/microl and inactive arthritis. The B27 gene was absent in 30 patients tested. CONCLUSION: ReA is the most common inflammatory joint disorder in black Zambians and is closely linked to HIV infection and not B27, even though our subjects had clinical and radiological characteristics similar to those reported in HLA-B27 positive Caucasians. The changing epidemiology of SpA in this region has important practical and educational implications.     

Decay of HIV-1 DNA in patients receiving suppressive antiretroviral therapy

HLA-B27 is associated with the etiology of ankylosing spondylitis (AS) and acute anterior uveitis (AAU). Transporter associated with antigen processing (TAP) 1 and TAP2 polymorphism influences the range of peptide presented by HLA class I molecules. In this report, contribution of TAP polymorphism to the susceptibility to AS and AAU was studied in HLA-B27-positive Japanese individuals. Patients were classified into three groups: 16 AS patients, 14 AAU patients and 22 patients with both AS and AAU. Twelve HLA-B27-positive healthy individuals were included as a control. TAP polymorphism was detected by PCR-RFLP methods. Significant differences in frequencies of TAP1 alleles were not found between patient groups. None of the TAP2 frequencies showed increased or decreased frequencies compared with HLA-B27-positive healthy controls. In comparison with a random Japanese control, TAP2D allele frequency was significantly increased in the AAU group, but failed to reach a significant level in a group consisting of the AAU-only patients and the patients with both AS and AAU. All of the patient groups were noted to have a significantly increased prevalence of the TAP2H allele as compared to random controls; however, the higher frequency of this allele was detected in HLA-B27 healthy controls as well. These observations suggest a linkage disequilibrium between TAP2D, TAP2H and HLA-B27 in Japanese.     

Spondyloarthropathies and HLA-B27 subtypes in the populations of the Russian North

The aim of the study was to investigate the role of HLA-B27 subtypes in development of ankylosing spondylitis and other seronegative spondylarthropathies. Using oligotyping techniques we studied native DNA of 219 HLA-B27 positive natives: 88 Chukotka residents and 131 Mordovians (Russian Ugro-Finnish population). Only subtypes HLA-B*2705 and B*2702 were revealed. A dominant subtype of HLA-B27 among the natives was HLA-B*2705: 99% among residents of Chukotka and 86% among Mordovians. It was established that among spondylarthropathic patients the frequency of B*2705 does not differ from its incidence in the studied populations. The data support the suggestion that several B27 subtypes and common genetic determinant of B27 gene may be involved in pathogenesis of spondylarthropathy.     

Alterations in the fecal flora of an individual frequently lacking coliforms

An individual who usually completely lacked or had very low numbers of coliforms in his stool over a period of 19 months was identified. The subject's levels of clostridia and aerobic lactobacilli were elevated as compared with those of our control group. However, these elevated populations of microorganisms were not related to the number of coliforms present in stool samples. The number of coliforms was inversely related to the number of anaerobic lactobacilli. In addition, the absence of coliforms was always accompanied by the absence of fungi. Populations of other prominent groups of intestinal flora were not significantly affected by the number of coliforms present in the intestnal tract. Since ankylosing spondylitis was the only physical abnormality of the subject, the intestinal flora of other individuals positive for histocompatibility antigen B27 who had this disease were examined but were found to be normal. The absence of coliforms from the normal flora of the intestinal tract of the subject had no apparent effect on his general health.     

Postoperative heterotopic ossification in patients with ankylosing hyperostosis on the spine (Forestier's disease)

Heterotopic ossification following hip surgery occurred in three patients with ankylosing hyperostosis of the spine. No technical difficulty during surgery was encountered in these individuals. The occurrence of this postoperative complication, coupled with the appearance of bony outgrowths at sites of ligament attachment throughout the axial and extra-axial skeleton in patients with ankylosing hyperostosis of the spine, suggests the presence of an underlying ossifying diathesis, diffuse idiopathic skeletal hyperostosis (DISH). A significant number of patients with DISH possess the second segregant series antigen, HLA-B27, a feature they share with individuals with other arthropathies characterized by abundant ossification; this gene may be closely related to one which influences bone formation. The possible association of postoperative heterotopic ossification and ankylosing hyperostosis of the spine indicates that a radiographic examination of the vertebral column in patients undergoing hip surgery may be a useful screening procedure.     

Etiopathogenesis of ankylosing spondylitis and reactive arthritis

In ankylosing spondylitis and reactive arthritis, an interplay of microbe and major histocompatibility complex initiates a sequence of events resulting in chronic inflammation. With the use of molecular probes as direct evidence and immune response patterns as indirect evidence, a strong case has been made for a central role of local microbial antigen in reactive arthritis. Cofactors such as gender, persistent gut inflammation, and antibiotic treatment may contribute to this process. Studies of transgenic rats and of familial spondylitis implicate B27 itself as the critical host variable. The results of recent studies point to intimate B27-bacteria interrelationships. HLA-B27 and proteins from enteric bacteria are structurally related, in a manner that may affect T cell response to enteric pathogens. B27 also may directly affect host-microbe interactions by modulating the invasive potential of these bacteria into target cells. Studies are in progress to apply the predictions of these in vitro systems to the in vivo situations of these diseases. The insights of research in the spondyloarthropathies may find broad applications in the rheumatic diseases.     

Use of epidural anesthesia and spontaneous ventilation during transabdominal colon and rectal procedures in selected high-risk patient groups

Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification in distinct anatomic patterns. Early preosseous lesions in FOP are clinically and histologically indistinguishable from the lesions of aggressive juvenile fibromatosis (AJF). Although the genetic defect in FOP is unknown, bone morphogenetic proteins (BMPs) 2 and 4 are plausible candidates genes. To determine if there is a difference in BMP 2/4 expression in the early fibromatous lesions of the two conditions, we performed immunohistochemical studies with a monoclonal antibody to BMP 2/4 on the earliest detectable fibromatous lesions of FOP and compared them with histologically identical lesions resected from children who had AJF. Fibromatous cells from the early FOP lesions exhibited immunostaining for BMP 2/4, whereas histologically indistinguishable fibromatous cells from AJF lesions showed no evidence of BMP 2/4 immunostaining. It is incumbent on all physicians who treat patients with suspected fibromatosis to examine the toes to rule out FOP and to avoid unnecessary diagnostic biopsies because surgical trauma induces further bone formation in patients who have FOP. However, if diagnostic confusion still exists and a biopsy is performed, immunostaining with BMP 2/4 antibody may resolve the diagnostic dilemma between FOP and AJF before the appearance of heterotopic ossification is observed in the FOP lesions. Our data suggest that the BMP 2/4 subfamily of secreted proteins may be involved in the pathogenesis of the FOP lesions.     

Ventricular tachycardia during repair of gastroschisis

This questionnaire survey of 71 patients with ankylosing spondylitis (members of the National Ankylosing Spondylitis Society of the UK) revealed that a substantial proportion of patients were apparently not told of several aspects of their illness by their doctors such as likely cause(s), familial clustering, role of HLA tissue typing and diet (appropriately). Only a small percentage (4.2%) were counselled to actively seek screening for close family members. As HLA B27 presence is not diagnostic of ankylosing spondylitis, and it cannot be prevented or arrested even if diagnosed at onset or early stages, routine screening of close family members cannot be justified at present.