Bone resorption in syndromes of the Ras/MAPK pathway.

Disorders of the Ras/mitogen-activated protein kinase (MAPK) pathway have an overlapping skeletal phenotype (e.g. scoliosis, osteopenia). The Ras proteins regulate cell proliferation and differentiation and neurofibromatosis type 1 (NF1) individuals have osteoclast hyperactivity and increased bone resorption as measured by urine pyridinium crosslinks [pyridinoline (Pyd) and deoxypyridinoline (Dpd)]. Pyd and Dpd are hydroxylysine-derived crosslinks of collagen found in bone and cartilage and excreted in the urine. Dpd is most abundant in bone. The aim of this study was to evaluate if other syndromes of the Ras/MAPK pathway have increased bone resorption, which may impact the skeletal phenotype. Participants were individuals with Noonan syndrome (n = 14), Costello syndrome (n = 21), and cardiofaciocutaneous (CFC) syndrome (n = 14). Pyridinium crosslinks from two consecutive first morning urines were extracted after acid hydrolysis and analyzed by high performance liquid chromatography. Three separate analyses of covariance were performed to compare Pyd, Dpd, and Dpd/Pyd ratio of each group to controls after controlling for age. Data were compared to 99 healthy controls. The Dpd and the Dpd/Pyd ratio were elevated (p < 0.0001) in all three conditions compared to controls suggesting that collagen degradation was predominantly from bone. The data suggest that the Ras/MAPK signal transduction pathway is important in bone homeostasis.

Etiology of idiopathic scoliosis: current trends in research.

Current population studies characterize idiopathic scoliosis as a single-gene disorder that follows the patterns of mendelian genetics, including variable penetrance and heterogeneity. The role of melatonin and calmodulin in the development of idiopathic scoliosis is likely secondary, with indirect effects on growth mechanisms. Reported abnormalities of connective tissue, skeletal muscle, platelets, the spinal column, and the rib cage are all thought to be secondary to the deformity itself. Although no consistent neurological abnormalities have been identified in patients with idiopathic scoliosis, it is possible that a defect in processing by the central nervous system affects the growing spine. The true etiology of idiopathic scoliosis remains unknown; however, it appears to be multifactorial.

Scleroderma in childhood: a 35-year history of cases and review of the literature.

Scleroderma is a connective tissue disease with a variety of clinical presentations. The purpose of our study was to review representative cases of scleroderma in childhood to determine the initial presentation, course of the disease, orthopaedic manifestations, and the necessity and success of surgical intervention. Records from the four medical centers were retrospectively reviewed to identify the patients who were diagnosed with scleroderma over the past 35 years. Data on disease presentation, course, treatment, and response were collected. Seventeen cases representing the variety of clinical presentations are presented. Scleroderma characteristically presents with asymmetric lesions involving the extremities and remains a diagnostic and therapeutic challenge. Treatment must be individualized to the patient and his or her specific limitations brought about by the disease. Early diagnosis, supportive care, and physical therapy combined with early orthopaedic surgical intervention to release joint contractures are among the most efficacious treatments.

Attempted limb lengthenings beyond twenty percent of the initial bone length: results and complications.

In response to historic guidelines suggesting limits to the amount of limb lengthening, we report the results and complications of those patients in whom the initial goal of lengthening exceeded 20% of the initial segment length. Thirty-one patients underwent a total of 35 attempted lengthenings with a mean follow-up of 38.6 months. Limb-length discrepancy was the primary indication in all but one case. With an average goal of 35% of the original bone length, we achieved a mean gain of 33%. Lengthening to within 2.5 cm was achieved in 31 (89%) of 35 cases, and significantly more successful with goals extending < or =55% of the initial bone length (p<0.05). Treatment times extended a mean of 8.7 months with a healing index of 37 days/cm. By Paley's classification scheme, all had problems, in addition to an average of 1.3 obstacles and 0.9 complications per segment lengthened. In 23 patients with extended follow-up, good to excellent results were achieved in 78%, and were significantly more successful with goals < or =55% (< or =0.05).

Accurate needle placement by the suction-bubble technique for hip arthrography.

We present a novel, effective method for verifying intraarticular needle placement for hip aspiration and arthrography. The vacuum created by hip-joint distraction induces an easily visualized movement of air bubbles in attached tubing, thereby confirming accurate localization. The suction-bubble technique is safe, objective, and reproducible in even inexperienced hands. We report no complications of erroneous extracapsular injection of contrast in >50 cases.

Heterozygous mutations in the gene encoding noggin affect human joint morphogenesis.

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.

Localization of a multiple synostoses-syndrome disease gene to chromosome 17q21-22.

Multiple synostoses syndrome is an autosomal dominant disorder characterized by premature onset of joint fusions, which initially affect the interphalangeal joints, by characteristic facies, and by deafness. We performed linkage analysis on a large Hawaiian family with multiple synostoses syndrome. Because another autosomal dominant disorder, proximal symphalangism, shares some clinical symptoms with multiple synostoses syndrome and has been linked to markers at loci at chromosome 17q21-22, we tested the hypothesis that multiple synostoses syndrome is linked to the same chromosomal region. Using polymorphic markers from the proximal symphalangism interval, we conducted linkage analysis and showed that the multiple synostoses-syndrome phenotype is linked to the same chromosomal region. A maximum LOD score of 3.98 at recombination fraction of .00 was achieved for the marker at locus D17S787. Further genetic analysis identified individuals with recombinant genotypes, allowing localization of the disease gene within the interval D17S931-D17S792, a 16-cM region. These data provide evidence that multiple synostoses syndrome and proximal symphalangism may be allelic disorders.

Scoliosis in twins. A meta-analysis of the literature and report of six cases.

STUDY DESIGN: This study is a meta-analysis of the world's literature on adolescent idiopathic scoliosis in monozygotic and dizygotic twins. Additionally, six previously unreported cases of scoliosis in twins are presented. OBJECTIVES: To compare and contrast the concordance, severity, and curve patterns in monozygotic and dizygotic twins with adolescent idiopathic scoliosis in an attempt to document a genetic etiology and delineate inheritance patterns for adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: There are numerous case reports of twins sets with adolescent idiopathic scoliosis. However, this data has not been previously analyzed as a single data base. METHODS: The literature was searched for cases of twins with adolescent idiopathic scoliosis, and six cases of patients treated by authors were added. One hundred cases of sets of twins were discovered, 68 of which had sufficient data for comparative analysis. Each set was evaluated for monozygosity, concordance of scoliosis, curve pattern, and severity of curve. RESULTS: Thirty-seven sets of twins were monozygous, and 31 sets were dizygous. Concordance was 73% among monozygous twins and 36% among dizygous twins. The difference is statistically significant at P < 0.003. Curve severity could be compared in 20 sets of monozygous twins and 16 sets of dizygous twins. Among monozygous twins, there was a correlation coefficient of r = 0.399 (P < 0.126). Curve pattern comparison was not statistically significant. CONCLUSIONS: Monozygous twins have a significantly higher rate of concordance than dizygous twins, and the curves in monozygous twins develop and progress together. Based on these data, there is strong evidence for a genetic etiology for adolescent idiopathic scoliosis.

Ilizarov applications in the pediatric foot.

We applied the Ilizarov technique and apparatus to the correction of 24 severe foot deformities in 21 children. We were able to achieve a serviceable plantigrade foot in all cases, with nine feet achieving an excellent result, 12 achieving a good result, three being fair, and none poor. Ilizarov's technique and apparatus offer an excellent adjunct for treating carefully selected severe foot deformities in children.

Cytokine mRNA repertoire of articular chondrocytes from arthritic patients, infants, and neonatal mice.

Articular chondrocytes from nine arthritic patients, five infants, and Balb/c neonatal mice were analyzed for the presence of various cytokine mRNAs by a reverse transcriptase polymerase chain reaction (RT-PCR). Four cytokine mRNAs, interleukin (IL)-6, IL-8, IL-11, and macrophage colony stimulating factor (M-CSF), were detected in all human chondrocytes, regardless of source. IL-10, IL-12p35, and tumor necrosis factor alpha (TNF-alpha) transcripts were found in at least 12 of the 14 human samples. IL-13, granulocyte colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), and TNF-beta mRNAs were found more predominantly in infant samples and in samples from patients with rheumatoid arthritis (RA) compared with samples from patients with osteoarthritis (OA). Another group of cytokine mRNAs, IL-1 (alpha, beta), IL-4, IL-5, and IL-7, were only weakly expressed in some human samples. The cytokine transcripts that were not found were IL-2, IL3, and interferon gamma (IFN-gamma). Because of the large array of cytokine transcripts detected, human chondrocyte preparations were further purified by reacting them with a monoclonal antibody specific to chondrocyte differentiation antigen and subjecting them to fluorescent-activated cell sorting. A similar array of cytokines was found between the sorted and unsorted chondrocytes, although TNF-alpha, G-CSF and GM-CSF transcripts appeared to be upregulated during the sorting process. Human chondrocytes that dedifferentiated into fibroblasts (a 40-day and a 77-day culture) no longer expressed mRNAs for IL-1, G-CSF, GM-CSF, and TNF-alpha, but all other cytokine mRNAs remained detectable. Although certain phenotypic characteristics were lost, including reactivity to chondrocyte-specific monoclonal antibodies and morphological features, chondrocytes in long-term culture still expressed cytokine mRNAs. As expected, more consistent results were obtained when seven preparations of chondrocytes from neonatal Balb/c mice were examined using available cytokine primers. They contained IL-1, IL-5, IL-6, IL-7, IL-12, GM-CSF, M-CSF, transforming growth factor beta (TGF-beta), TNF-alpha, and TNF-beta mRNAs but lacked IL-2, IL-3, IL-4, IL-10, and IFN-gamma mRNAs. Future experiments to define conditions by which these cytokine protein products are expressed are needed to help assess their roles in chondrocyte biology and in disease states.

Early diagnosis and treatment of hinge abduction in Legg-Perthes disease.

A review of 106 cases of Legg-Perthes disease disclosed 26 in whom a particularly poor radiographic appearance was seen. Hinge abduction was detected in 19 of these patients and was suspected but not proven in the remainder. Hinge abduction was found to occur early in the course of Legg-Perthes, and hinging frequently occurred about an unossified portion of femoral head, making detection difficult. Failure of movement of the lateral corner of the epiphysis under the edge of the acetabulum on an internally rotated and abducted radiograph is prima facie evidence of hinge abduction. Confirmation is easily obtained by arthrography. Hinging must be relieved if guidance of femoral head growth by the healthy acetabulum is to be possible. Both clinical and radiographic outcomes were worse in patients with unrelieved hinge abduction. Relief of hinging can frequently be accomplished by traction, and containment can then be maintained by appropriate surgery.

Unilateral duplication of the great toe with anterolateral tibial bowing.

A syndrome consisting of unilateral duplication of the great toe in association with anterolateral bowing of the tibia is described. Patients with this syndrome have significant pedal difficulties after surgical management, but the tibial bowing spontaneously resolves without treatment. Tibial shortening is noted relative to the fibula. Associated clinodactyly and dysharmonic maturation of carpals and metacarpals are also seen. Current data are most consistent with a developmental rather than a genetic etiology.

Toxic shock syndrome as a complication of orthopaedic surgery.

Toxic shock syndrome (TSS) was initially described by Todd et al. in 1978. TSS as a complication of orthopaedic surgery was reported in 1984. There have been previously a total of nine cases of TSS reported in orthopaedic patients. These patients presented at an average of 13 days postoperatively compared to 2 days for general surgical patients. Patients with external fixators, however, presented an average of 25 days postoperatively. Menstrual TSS and nonmenstrual TSS present similarly; however, the fatality rate is reported as 10 and 50%, respectively. There was a 27% case fatality rate in orthopaedic patients. Because TSS is not a septicemia but a toxemia, the treatment depends on aggressive hemodynamic stabilization rather than antibiotic therapy. The classical presentation of TSS is not often seen in patients with TSS complicating orthopaedic surgery. Wounds rarely have any signs of infection. This presentation may be even more difficult to identify due to the occasionally long latency period between surgery and the development of TSS. It appears that external fixators may be left in place if there are no signs of infection. This requires further study.

Acquired radial clubhand deformity due to osteomyelitis.

We reviewed nine cases of acquired radial clubhand due to osteomyelitis. Goals were cosmetic improvement, maintenance of any wrist mobility, and a stable, painless wrist and forearm. All patients achieved these goals, although residual forearm shortening ranged from 4-8 cm. Treatment of acquired radial clubhand is difficult. The options and guidelines for treating the congenital variety may not be applicable in the treatment of the acquired type. Surgical options include interposition bone grafting, centralization, and radioulnar transposition. Recently the circular external fixator has been used for correction of this complex deformity.

Thumb duplication, 66 years' experience--a review of surgical complications.

Fifty-four supernumerary thumbs excisions were followed for an average of 9 years for results of their surgical management, which consisted of simple excision (16 patients), reconstructive procedures (33 patients), or central wedge resections (5 patients). Half of all simple excisions and reconstructive procedures gave unacceptable results, most were salvaged. These were primarily joint deviations, joint instabilities, and bony prominences. All of our central wedge resections gave unacceptable results that were not salvageable--short, stiff, fat thumbs with nail deformities. We feel this procedure should probably be reserved for cases where both digits of the supernumerary thumbs are severely hypoplastic.

A large family with features of pseudoachondroplasia and multiple epiphyseal dysplasia: exclusion of seven candidate gene loci that encode proteins of the cartilage extracellular matrix.

We have identified a large family with a dominantly inherited chondrodysplasia characterized by a waddling gait, short limbs, and early onset osteoarthritis. The radiographic presentation resembles pseudoachondroplasia in childhood and multiple epiphyseal dysplasia in adults. Electron microscopic examination of cartilage reveals accumulation of material within the rough endoplasmic reticulum similar to that seen in pseudoachondroplasia and the Fairbank type of multiple epiphyseal dysplasia. By linkage analysis, we have excluded the genes for aggrecan, decorin, hexabrachion (tenascin), type II procollagen, the alpha 1 chain of type XI procollagen, the alpha 1 chain of type IX procollagen, and link protein, candidate genes that encode structural components of the cartilage extracellular matrix, as the disease locus for this disorder.

Congenital constriction band syndrome: a seventy-year experience.

Seventy-one cases of congenital constriction band syndrome (CCBS) were reviewed. The year of birth, sex, ethnic background, gestational history, family history, and concurrent diagnoses were obtained. The anatomic patterns of involvement, degree of impairment, and number and type of surgical interventions were recorded. The incidence of CCBS appears to be rising. The average patient had three involved limbs, with a predilection for distal, central digits of the upper extremity. Abnormal gestational histories were found in 60% of the cases; 50% had concurrent diagnoses, and nearly one-third had club-feet. The average patient had a 20% whole body impairment and required three reconstructive procedures. Distraction osteogenesis and free osteocutaneous transfer were useful. We feel that the term "early amnion rupture sequence" more accurately reflects the true pathogenesis of CCBS.

Genetic linkage of mild pseudoachondroplasia (PSACH) to markers in the pericentromeric region of chromosome 19.

Pseudoachondroplasia (PSACH) is a dominantly inherited form of short-limb dwarfism characterized by dysplastic changes in the spine, epiphyses, and metaphyses and early onset osteoarthropathy. Chondrocytes from affected individuals accumulate an unusual appearing material in the rough endoplasmic reticulum, which has led to the hypothesis that a structural abnormality in a cartilage-specific protein produces the phenotype. We recently identified a large family with a mild form of pseudoachondroplasia. By genetic linkage to a dinucleotide repeat polymorphic marker (D19S199), we have localized the disease gene to chromosome 19 (maximum lod score of 7.09 at a recombination fraction of 0.03). Analysis of additional markers and recombinants between the linked markers and the phenotype suggests that the disease gene resides within a 6.3-cM interval in the immediate pericentromeric region of the chromosome.

Ossific nucleus eccentricity in congenital dislocation of the hip.

We studied plain films, arthrograms, and clinical courses of patients with congenital dislocation of the hip to examine the relationship of ossific nucleus eccentricity (ONE) of the femoral head to the shape of the cartilaginous femoral head and the prognosis of these findings. No statistically significant correlation of ONE and cartilaginous femoral head shape was noted, nor was correlation noted for early femoral head shape and subsequent clinical course. Only the association of ONE in an older subgroup of patients with a complicated clinical course was statistically significant (p less than 0.05).

Tibial fractures of young children.

Tibial fractures are relatively frequent injuries of young children. These fractures are occasionally the cause of a childhood gait disturbance. Additionally, tibial fractures may be the result of child abuse. Consequently, the pediatrician should have knowledge concerning these injuries. In this paper, we present a review of tibial fractures in hospitalized children and describe their associations with nonaccidental trauma (NAT). Finally, we provide suggestions for improving nonmenclature clarity for isolated spiral fractures of the tibia.