Steven A. Lietman

Complications of irradiated allografts in orthopaedic tumor surgery.

Massive structural allografts used for replacement of bone defects after removal of bone tumors have several complications, including fracture, infection, and nonunion. To decrease the rate of infection, irradiation of selected allografts before their implantation was performed. This study evaluated the complications in patients with these irradiated grafts. Twenty-four patients were identified who had received allografts from 1987 through 1991 that were irradiated before implantation. The dosage of radiation was between 10 kGy and 30 kGy. The mean length of followup of the patients was 5 years (range, 2-9 years). These grafts were compared with a control group of grafts that were not irradiated but were implanted during the same time and used for similar diagnostic problems with defects of similar size. The outcomes of the groups differed significantly only in the incidence of allograft fracture. These findings indicate that high-dose irradiation to bone allografts is associated with a higher rate of fracture than are similar reconstructions using nonirradiated allografts.

Cherubism: best clinical practice

Cherubism is a skeletal dysplasia characterized by bilateral and symmetric fibro-osseous lesions limited to the mandible and maxilla. In most patients, cherubism is due to dominant mutations in the SH3BP2 gene on chromosome 4p16.3. Affected children appear normal at birth. Swelling of the jaws usually appears between 2 and 7 years of age, after which, lesions proliferate and increase in size until puberty. The lesions subsequently begin to regress, fill with bone and remodel until age 30, when they are frequently not detectable.Fibro-osseous lesions, including those in cherubism have been classified as quiescent, non-aggressive and aggressive on the basis of clinical behavior and radiographic findings. Quiescent cherubic lesions are usually seen in older patients and do not demonstrate progressive growth. Non-aggressive lesions are most frequently present in teenagers. Lesions in the aggressive form of cherubism occur in young children and are large, rapidly growing and may cause tooth displacement, root resorption, thinning and perforation of cortical bone.Because cherubism is usually self-limiting, operative treatment may not be necessary. Longitudinal observation and follow-up is the initial management in most cases. Surgical intervention with curettage, contouring or resection may be indicated for functional or aesthetic reasons. Surgical procedures are usually performed when the disease becomes quiescent. Aggressive lesions that cause severe functional problems such as airway obstruction justify early surgical intervention.

Soft-tissue sarcomas: Overview of management, with a focus on surgical treatment considerations

Outcomes for patients with bone sarcomas have improved dramatically over the past 40 years, and most bone sarcomas today are treated with surgery and chemotherapy. The most common clinical findings in patients with bone sarcomas are pain and an enlarging bone mass, although pain is not generally a good indicator of malignancy. In general, any patient with a bone mass with indeterminate imaging findings should be referred to an orthopedic oncologist. Bone sarcomas are diagnosed after a biopsy, which is best performed by the surgeon who will be doing the curative resection. Postresection reconstruction of the affected limb is generally done with an allograft-prosthetic composite or a modular metallic prosthetic joint replacement device. Post- therapy follow-up at frequent and regular intervals is critical to assess for recurrence and lung metastasis.

Effect of postoperative epidural analgesia on morbidity and mortality after total hip replacement surgery in medicare patients.

Background and Objectives: The effect of postoperative epidural analgesia (vs. systemic analgesia) on patient outcomes is unclear. Available randomized controlled trials (RCTs) have focused on the intraoperative period and not properly examined the effect of postoperative epidural analgesia (EA) on outcomes. Methods: A 5% nationally random sample of Medicare beneficiaries from 1994 to 1999 was analyzed to identify patients undergoing total hip arthroplasty (Common Procedural Terminology [CPT] code 27130, 27132, 27134, 27137, 27138). Patients were divided into 2 groups depending on the presence or absence of postoperative EA based on the CPT coding (01996). The rate of major morbidity (acute myocardial infarction, deep venous thrombosis, pulmonary embolism, angina, respiratory failure, heart failure, cardiac dysrhythmias, pneumonia, pulmonary edema, sepsis, acute renal failure, paralytic ileus, acute cerebrovascular event) and death at 7 and 30 days after the procedure were compared. Multivariate regression analysis was performed to determine if the presence of postoperative (EA) had an independent effect on mortality or major morbidity. Data were reported as an odds ratio with 95% confidence intervals (CI) when appropriate. Results: The unadjusted 7‐ and 30‐day death rate was significantly lower for EA versus no EA (1.9/1000 [95% CI: 0.2‐3.6] vs. 3.9/1000 [95% CI: 3.0‐6.2] at 7 days [P = .04] and 5.8/1000 [95% CI: 2.9‐8.7] vs. 9.9/1000 [95% CI: 8.6‐11.3] at 30 days [P = 0.01]). However, multivariate regression analysis revealed that there was no difference between the groups with regard to mortality or major morbidity with the exception of an increase in deep venous thrombosis in patients who received EA. Conclusions: The use of postoperative EA was not associated a lower incidence of mortality and major morbidity in Medicare patients undergoing total hip arthroplasty. However, the results should be interpreted with caution because of limitations in using the Medicare claims data for analysis. Further trials using other properly conducted and designed studies (e.g., RCTs) would be ideal to validate these results.

A Highly Sensitive Polymerase Chain Reaction Method Detects Activating Mutations of the GNAS Gene in Peripheral Blood Cells in McCune-Albright Syndrome or Isolated Fibrous Dysplasia

BACKGROUND The somatic nature of mutations in the GNAS gene in McCune-Albright syndrome and isolated fibrous dysplasia makes their identification difficult. Conventional methods for the detection of mosaic mutations of GNAS have required polymerase chain reaction analysis of genomic DNA from affected tissues or multiple rounds of tandem polymerase chain reaction and endonuclease digestion to enrich for mutant alleles in genomic deoxyribonucleic acid (DNA) from other tissues. Peptide nucleic acid (PNA) primers specifically block synthesis from the nonmutant or wild-type allele. We therefore used PNA-clamping to detect low copy numbers of mutant GNAS alleles in DNA from peripheral blood cells from patients with McCune-Albright syndrome and fibrous dysplasia. METHODS We applied the PNA-clamping method to the analysis of genomic DNA from peripheral blood cells of thirteen patients with McCune-Albright syndrome and three patients with isolated fibrous dysplasia. Polymerase chain reaction was performed in the presence and absence of PNA, and the polymerase chain reaction products were sequenced. In the absence of PNA, a strong 325 base-pair polymerase chain reaction band was generated from all samples; in the presence of PNA, there was an approximately 50% to 90% reduction in the intensity of this polymerase chain reaction product. RESULTS In the absence of PNA, direct sequencing of the polymerase chain reaction products demonstrated R201 mutations in GNAS alleles of three of the thirteen patients with McCune-Albright syndrome and none of the three patients with fibrous dysplasia. In contrast, in the presence of PNA, R201 mutations were detected in eleven of the thirteen patients with McCune-Albright syndrome and in all three of the patients with fibrous dysplasia. In mixing experiments involving the use of wild-type and mutant DNA samples, we were able to determine the presence of a mutant GNAS allele in the equivalent of one cell in 1000 to 5000 cells. CONCLUSIONS Inclusion of a specific PNA primer in the polymerase chain reaction for GNAS exon 8 allows the selective amplification of low numbers of mutant alleles, and it permits detection of activating mutations in genomic DNA from peripheral blood cells in patients with McCune-Albright syndrome and fibrous dysplasia.

Hypercalcemia in children and adolescents

Purpose of review In this review, we define hypercalcemia levels, common causes for hypercalcemia in children, and treatment in order to aid the practicing pediatrician. Recent findings One rare cause of hypercalcemia in the child is familial hypocalciuric hypercalcemia (also termed familial benign hypercalcemia). Mutations that inactivate the Ca2+-sensing receptor gene FHH have been described as an autosomal dominant disorder, but recently milder mutations in the CASR have been shown to cause hypercalcemia when homozygous. Summary Normal serum levels of calcium are maintained through the interplay of parathyroid, renal, and skeletal factors. In this review, we have distinguished the neonate and infant from the older child and adolescent because the causes and clinical features of hypercalcemia can differ in these two age groups. However, the initial approach to the medical treatment of severe or symptomatic hypercalcemia is to increase the urinary excretion of calcium in both groups. In most cases, hypercalcemia is due to osteoclastic bone resorption, and agents that inhibit or destroy osteoclasts are, therefore, effective treatments. Parathyroid surgery, the conventional treatment for adults with symptomatic primary hyperparathyroidism, is recommended for all children with primary hyperparathyroidism.

Clinical presentation and imaging of bone and soft-tissue sarcomas.

The clinical presentation of bone and soft-tissue sarcomas is varied. Constitutional symptoms are rare, and although bone sarcomas tend to be painful while soft-tissue sarcomas usually are not, there are exceptions to this general rule. A high index of suspicion is required for any unexplained mass with indeterminate imaging findings. Choosing the right imaging modality is critical to the diagnosis and management of patients with suspected sarcoma, and referring clinicians have a multitude of imaging options. After discovery of a malignant-appearing bone lesion by radiography, further imaging is obtained for better characterization of the lesion (typically with magnetic resonance imaging [MRI]) and for staging (typically with computed tomography of the chest). In contrast, radiographs are rarely helpful for evaluation of soft-tissue lesions, which almost always require MRI assessment.

Reduction in Gsα induces osteogenic differentiation in human mesenchymal stem cells

We hypothesized that a decrease in Gsα expression occurs with osteogenic differentiation and that when Gsα expression was decreased by antisense oligonucleotides or direct inhibition of protein kinase A there was a concomitant increase in Runx2/Cbfa1. We also investigated the mechanism involved in the change in Runx2/Cbfa1 levels and whether the expression of other genes known to be involved in bone formation was altered. There was a decrease in Gsα expression with osteogenic differentiation and antisense oligonucleotides, and protein kinase A inhibition led to increased expression and DNA binding of the osteoblast-specific Runx2/Cbfa1. Additionally, with decreased Gsα expression or protein kinase A inhibition, Runx2/Cbfa1 protein was serine phosphorylated and ubiquitinated less. Microarray analysis, after the addition of antisense Gsα, showed a more than 10-fold increase in collagen Type I Alpha 2 mRNA (a target of Runx2/Cbfa1). These data show that reduced expression of Gsα can induce an osteoblast-like phenotype. The results also indicate a potential pathophysiologic role in patients with heterozygous inactivating mutations in GNAS1, the gene for the alpha chain (Gsα) of the heterotrimeric G protein, present in three disorders with ectopic intramembranous bone: Albright’s hereditary osteodystrophy, progressive osseous heteroplasia, and osteoma cutis.

A Novel Loss-of-Function Mutation, Gln459Arg, of the Calcium-Sensing Receptor Gene Associated with Apparent Autosomal Recessive Inheritance of Familial Hypocalciuric Hypercalcemia

CONTEXT Mutations that inactivate one allele of the gene encoding the calcium sensing receptor (CaSR) cause autosomal dominant familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations cause neonatal severe hyperparathyroidism. OBJECTIVE We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred. DESIGN The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR. RESULTS A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The probands parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30-50% of the calcium-dependent activity of the wild-type CaSR. CONCLUSION We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions.

The role of SH3BP2 in the pathophysiology of cherubism

Cherubism is a rare bone dysplasia that is characterized by symmetrical bone resorption limited to the jaws. Bone lesions are filled with soft fibrous giant cell-rich tissue that can expand and cause severe facial deformity. The disorder typically begins in children at ages of 2-5 years and the bone resorption and facial swelling continues until puberty; in most cases the lesions regress spontaneously thereafter. Most patients with cherubism have germline mutations in the gene encoding SH3BP2, an adapter protein involved in adaptive and innate immune response signaling. A mouse model carrying a Pro416Arg mutation in SH3BP2 develops osteopenia and expansile lytic lesions in bone and some soft tissue organs. In this review we discuss the genetics of cherubism, the biological functions of SH3BP2 and the analysis of the mouse model. The data suggest that the underlying cause for cherubism is a systemic autoinflammatory response to physiologic challenges despite the localized appearance of bone resorption and fibrous expansion to the jaws in humans.