Diagnostic efficacy and clinical impact of image-guided core needle biopsy of suspected vertebral osteomyelitis.

OBJECTIVES: The diagnostic yield and clinical impact of image-guided core needle biopsy (ICNB) of suspected vertebral osteomyelitis in adults is heterogenous in published studies owing to small sample sizes, indicating the need for large cohort studies. METHODS: A retrospective analysis of ICNBs was performed from 2010 to 2021 for patients with imaging findings consistent with vertebral osteomyelitis. For each biopsy, a series of factors were analyzed, as well as if histopathology was diagnostic of osteomyelitis and if microbiological cultures were positive. In addition, it was recorded in what way biopsy influenced clinical management regarding antimicrobial treatment. A multivariate statistical analysis was performed to evaluate the factors associated with yield. RESULTS: A total of 570 biopsies performed on 527 patients were included. A histopathologic diagnosis of osteomyelitis was made in 68.4% (359 of 525) of biopsies, and microbiological cultures were positive in 29.6% (169 of 570). Elevated erythrocyte sedimentation rate was positively associated with a histopathologic diagnosis of osteomyelitis (odds ratio [OR] =1.96, P = 0.007) and positive cultures from bone cores (OR = 1.02, P ≤0.001) and aspirate (OR = 1.02, P ≤0.001). Increased total core length was positively associated with a histopathologic diagnosis of osteomyelitis (OR = 1.81, P = 0.013) and positive cultures from bone cores (OR = 1.65, P = 0.049). Clinical management was affected by ICNB in 37.5% (214 of 570) of cases. CONCLUSIONS: In this large cohort, ICNB yielded approximately 30% positive cultures and changed clinical management in over one-third of the patients.

Diagnostic efficacy of image-guided core needle biopsy of suspected malignant osseous lesions: a retrospective cohort study from a single academic institution.

OBJECTIVES: To evaluate diagnostic yield and accuracy of image-guided core needle biopsy (ICNB) of suspected malignant osseous lesions in a large cohort of adults, evaluate what factors influence these measures, and offer technical recommendations to optimize yield. METHODS: A retrospective analysis of 2321 ICNBs performed from 2010 to 2021 was completed. The diagnostic yield and accuracy of the biopsies as well as a series of patient, lesion-related, and technical factors were retrospectively analyzed. Multivariate statistical analysis was performed to evaluate what factors were associated with yield and accuracy. Different cutoff values of total core length and core number were then tested to determine threshold values in relation to increased diagnostic yield. RESULTS: Diagnostic yield was 98.2% (2279/2321) and accuracy was 97.6% (120/123). Increased total core length (odds ratio [OR] = 2.34, 95% confidence interval [CI] (1.41-3.90), p = 0.001), core number (OR = 1.51, 95% CI (1.06-2.16), p = 0.02) and presence of primary malignancy (OR = 2.81, 95% CI (1.40-5.62), p = 0.004) were associated with improved yield. Lesion location in an extremity (OR = 0.27, 95% CI (0.11-0.68), p = 0.006) and using fluoroscopic imaging guidance (OR = 0.33, 95% CI (0.12-0.90), p = 0.03) were associated with lower yield. Cutoff thresholds in relation to increased diagnostic yield were found to be 20 mm total core length (marginal OR = 4.16, 95% CI = (2.09-9.03), p < 0.001), and three total cores obtained (marginal OR = 2.78, 95% CI (1.34-6.54), p = 0.005). None of the analyzed factors influenced diagnostic accuracy. CONCLUSIONS: ICNB has a high rate of diagnostic yield and accuracy. Several factors influence diagnostic yield; 20 mm core length and three total cores optimize yield. CLINICAL RELEVANCE STATEMENT: Image-guided core needle biopsy of suspected malignant osseous lesions is a safe procedure with a very high rate of diagnostic yield and accuracy. Obtaining 20 mm total core length and three total cores optimizes diagnostic yield. KEY POINTS: • In a retrospective cohort study, image-guided core needle biopsy of suspected osseous malignant lesions in adults was found to have very high rates of diagnostic yield and accuracy. • Increased total core length and core number of biopsies were each associated with increased diagnostic yield, and these relationships reached thresholds at 20 mm total core length and three total cores obtained. • The presence of a known primary malignancy was also associated with increased yield while using fluoroscopic imaging guidance and lesion location in an extremity were associated with decreased yield.

ACR Appropriateness Criteria® Management of Vertebral Compression Fractures: 2022 Update.

Vertebral compression fractures (VCFs) can have a variety of etiologies, including trauma, osteoporosis, or neoplastic infiltration. Osteoporosis related fractures are the most common cause of VCFs and have a high prevalence among all postmenopausal women with increasing incidence in similarly aged men. Trauma is the most common etiology in those >50 years of age. However, many cancers, such as breast, prostate, thyroid, and lung, have a propensity to metastasize to bone, which can lead to malignant VCFs. Indeed, the spine is third most common site of metastases after lung and liver. In addition, primary tumors of bone and lymphoproliferative diseases such as lymphoma and multiple myeloma can be the cause of malignant VCFs. Although patient clinical history could help raising suspicion for a particular disorder, the characterization of VCFs is usually referred to diagnostic imaging. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

ACR Appropriateness Criteria® Soft Tissue Masses: 2022 Update.

Imaging should be performed in patients with a suspected soft tissue mass that cannot be clinically confirmed as benign. Imaging provides essential information necessary for diagnosis, local staging, and biopsy planning. Although the modalities available for imaging of musculoskeletal masses have undergone progressive technological advancements in recent years, their overall purpose in the setting of a soft tissue mass remains unchanged. This document identifies the most common clinical scenarios related to soft tissue masses and the most appropriate imaging for their assessment on the basis of the current literature. It also provides general guidance for those scenarios that are not specifically addressed. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low-Density Lipoprotein Receptor-Related Protein 6.

Osteoblast Wnt/ß-catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low-density lipoprotein receptor-related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first ß-propeller of LRP5 or LRP6, thereby disassociating these cognate co-receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within LRP5 and three heterozygous mutations identified since 2019 within LRP6 prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous LRP6 missense mutation (c.719C>T, p.Thr240Ile) was present in two middle-aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm2) of the lumbar spine and total hip featured accelerated increases reaching Z-scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

ACR Appropriateness Criteria® Malignant or Aggressive Primary Musculoskeletal Tumor-Staging and Surveillance: 2022 Update.

Malignant or aggressive primary musculoskeletal tumors are rare and encompass a wide variety of bone and soft tissue tumors. Given the most common site for metastasis from these primary musculoskeletal tumors is to the lung, chest imaging is integral in both staging and surveillance. Extrapulmonary metastases are rarely encountered with only a few exceptions. Following primary tumor resection, surveillance of the primary tumor site is generally recommended. Local surveillance imaging recommendations differ between primary tumors of bone origin versus soft tissue origin. This document consolidates the current evidence and expert opinion for the imaging staging and surveillance of these tumors into five clinical scenarios. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Suspected Osteomyelitis, Septic Arthritis, or Soft Tissue Infection (Excluding Spine and Diabetic Foot): 2022 Update.

Musculoskeletal infections involve bones, joints, and soft tissues. These infections are a common clinical scenario in both outpatient and emergent settings. Although radiography provides baseline findings, a multimodality approach is often implemented to provide more detailed information on the extent of infection involvement and complications. MRI with intravenous contrast is excellent for the evaluation of musculoskeletal infections and is the most sensitive for diagnosing osteomyelitis. MRI, CT, and ultrasound can be useful for joint and soft tissue infections. When MRI or CT is contraindicated, bone scans and the appropriate utilization of other nuclear medicine scans can be implemented for aiding in the diagnostic imaging of infection, especially with metal hardware and arthroplasty artifacts on MRI and CT. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer-reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer-reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Postoperative MR Imaging of the Knee Meniscus.

Surgery to treat a torn meniscus is a common orthopedic procedure, and radiologists are frequently asked to image patients with new or recurrent knee pain after meniscus surgery. However, surgery alters the MR imaging appearance of the meniscus, making the diagnosis of recurrent tear a diagnostic challenge. This article reviews relevant anatomy of the meniscus, surgical techniques used to treat meniscus tear, the roles of conventional MR imaging and MR arthrography to assess the postoperative meniscus, and the key MR imaging findings to distinguish the intact postoperative meniscus from recurrent tear.

Xanthogranulomatous epithelial tumors and keratin-positive giant cell-rich soft tissue tumors: two aspects of a single entity with frequent HMGA2-NCOR2 fusions.

Xanthogranulomatous epithelial tumor (XGET) and keratin-positive giant cell-rich soft tissue tumor with HMGA2-NCOR2 fusion (KPGCT) are two recently described neoplasms with both distinct and overlapping clinical and histopathologic features. We hypothesized that XGET and KPGCT may be related and represent a histologic spectrum of a single entity. To test this, we sought to characterize the clinical, radiographic, immunohistochemical, ultrastructural and molecular features of additional tumors with features of XGET and/or KPGCT, which we refer to descriptively as keratin-positive xanthogranulomatous/giant cell-rich tumors (KPXG/GCT). The archives were searched for potential cases of KPXG/GCT. Clinical and imaging features were noted. Slides were assessed for histologic and immunohistochemical findings. Ultrastructural and next generation RNA sequencing-based analysis were also performed. Nine cases were identified arising in seven women and two men [median age of 33 years (range: 12-87)]. Median tumor size was 4 cm (range: 2.4-14.0 cm) and tumors presented in the thigh (2), buttock (1), forearm (2), groin (1), cranial fossa (1), ilium (1), and tibia (1). Morphologically, tumors were most frequently characterized by a fibrous capsule, with associated lymphoid reaction, enclosing a polymorphous proliferation of histiocytes, giant cells (Touton and osteoclast-types), mixed inflammatory infiltrate, hemorrhage and hemosiderin deposition, which imparted a variably xanthogranulomatous to giant cell tumor-like appearance. One case clearly showed mononuclear cells with eosinophilic cytoplasm characteristic of XGET. All cases expressed keratin and 7 of 9 were found to harbor HMGA2-NCOR2 fusions including cases with xanthogranulomatous appearance. One patient developed local recurrence and multifocal pulmonary lesions, which were radiographically suspicious for metastases. Shared clinical, histologic and immunohistochemical features, and the shared presence of HMGA2-NCOR2 fusions supports interpretation of KPXG/GCT as a single entity which includes XGET and KPGCT. Given limited clinical follow-up to date and rare cases with apparently aggressive findings, we provisionally regard these tumors as having uncertain biologic potential.

The pivot fracture: an unusual tibial plateau fracture found in association with acute ACL injury.

Tibial plateau fractures are common fractures which are often associated with concurrent soft tissue injury and for which accurate preoperative diagnosis is important for development of an appropriate treatment plan and outcome prediction. Here, we present an extreme manifestation of the pivot shift phenomenon with an unusual tibial plateau fracture with flipped component not described by any existing tibial plateau fracture classification system and never reported previously in conjunction with an anterior cruciate ligament injury. We describe the utilization of advanced imaging not typically utilized in the management of tibial plateau fractures in combination with clinical suspicion to diagnose the associated soft tissue injuries and develop an appropriate management plan.

ACR Appropriateness Criteria® Inflammatory Back Pain: Known or Suspected Axial Spondyloarthritis: 2021 Update.

Inflammatory back pain is a hallmark feature of axial spondyloarthritis, a heterogeneous group of inflammatory disorders which affects the sacroiliac joints and spine. Imaging plays a key role in diagnosis of this disease and in facilitating appropriate treatment. This document provides evidence-based recommendations on the appropriate use of imaging studies during multiple stages of the clinical evaluation of patients with suspected or known axial spondyloarthritis. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Qualitative study of musculoskeletal tissues and their radiographic correlates in diabetic neuropathic foot deformity.

BACKGROUND: Diabetes mellitus (DM) with peripheral neuropathy (PN) results in foot deformity increasing ulceration, joint dislocation, and amputation risk. This study describes the frequency and severity of foot and ankle musculoskeletal abnormalities and their relationship to radiographic alignment in people with DMPN with (DMPN + MCD) and without (DMPN - MCD) medial column deformity (MCD) compared to age- and body mass index-matched controls without DMPN or MDC. METHODS: DMPN + MCD (n = 11), DMPN - MCD (n = 12), and controls (n = 12) were studied. A radiologist scored foot and ankle magnetic resonance images (MRI) for abnormalities in tendons/fascia, ligaments, muscles, joints, and bones. Higher scores represent greater abnormalities. Foot alignment was measured from lateral weightbearing radiographs. Frequency of abnormalities between groups and relationships between abnormalities and foot alignment in the combined group (n = 35) were examined. RESULTS: DMPN + MCD had higher total muscle, joint, and bone scores compared to controls and higher total joint scores than DMPN - MCD. DMPN - MCD had higher total muscle scores than controls. DMPN + MCD higher bone and joint scores were driven by increased frequency of osteophytes, cartilage damage, focal bone marrow edema, new bone formation, and subchondral cysts. Significant correlations included cuboid height and total bone and joint scores (ρ = -0.37 and ρ = -0.40, respectively) and talar declination angle and total joint score (ρ = 0.38). CONCLUSION: High contrast resolution MRI allowed identification of structural lesions of the foot affecting the cartilage surfaces, bone marrow, and soft tissue supports in patients with DMPN + MCD. As expected, the presence of bone and joint lesions on MRI were strongly associated with DMPN + MCD; surprisingly, although the sample is small, lesions of the soft tissue supports were not associated with MCD. While MRI is not done routinely to investigate MCD, opportunistic use of the information from MRI done for the common clinical indications may allow early identification of the structural lesions associated with MCD and facilitate early, aggressive therapy. LEVEL OF EVIDENCE: III.

The diagnostic performance of MRI signs to distinguish Pectoralis major tendon avulsions from Myotendinous injuries.

BACKGROUND: Management of pectoralis major (PM) injuries is largely determined by the anatomic location of the injury, with tendon avulsions from the humerus requiring surgery while myotendinous (MT) injuries are typically managed non-operatively. Because physical examination cannot reliably make this distinction, MRI is often used for staging. However, correct classification can also be difficult with MRI where there is extensive soft tissue edema and distorted anatomy. OBJECTIVE: To determine the diagnostic performance of primary and secondary MRI signs of PM injury for distinguishing tendon avulsions from MT injuries in a selected sample of patients that underwent surgical repair using a practical interpretation algorithm. METHODS: In this retrospective study, 3 blinded observers independently assessed the MRI findings of 17 patients with PM injury (including 12 acute injuries, 4 chronic, and 1 of uncertain age) where subsequent surgery documented tendon avulsion (11) and MT injuries (6) by applying the primary MRI criteria of absent tendon at the humerus, retracted tendon stump, epicenter of edema, and the secondary finding of soft tissue edema contacting the anterior humeral cortex. Operative findings were used as the reference standard. Sensitivity, specificity, and positive and negative predictive value were recorded for each finding. RESULTS: The primary MRI finding of lack of a visible tendon at the insertion (sensitivity 82-100%, specificity 100%) and the secondary finding of edema contacting the anterior humeral cortex (sensitivity 64-91%, specificity 67-100%) were both useful for the distinction of tendon avulsion from MT injury, particularly in acute injuries. The presence of a retracted tendon stump and the epicenter of edema were not reliable findings. The use of a decision tree including the secondary finding of humeral edema increased the sensitivity and specificity for 2 of the 3 observers. CONCLUSION: MRI assessment of PM injury focused on the humeral insertion of the PM tendon allows accurate distinction of tendon avulsion from MT injury. CLINICAL IMPACT: This study describes a practical approach to classifying PM injuries with MRI to distinguish injuries that require surgery from those that can potentially be managed conservatively.

Ulnar shaft stress fractures in fast-pitch softball pitchers: a case series and proposed mechanism of injury.

BACKGROUND: Stress fractures of the upper extremities in athletes are important injuries for radiologists to appreciate despite being far less common than stress fractures of the lower extremities. Among upper extremity stress fractures, those involving the olecranon have been well described in overhead pitching athletes. Isolated stress fractures of the ulnar shaft however are less commonly reported in the literature and considered to be rare. We have observed a correlation between young patients with ulnar shaft stress fractures and the activity of fast-pitch softball pitching. CASE REPORTS: In this series, we present the imaging findings in four cases of ulnar shaft stress fractures in softball pitchers who presented with insidious onset forearm pain. Furthermore, a review of the literature focusing on softball pitching mechanics is provided to offer a potential underlying mechanism for the occurrence and location of these injuries. CONCLUSION: An awareness of the imaging appearance of ulnar shaft stress fractures along with an understanding of its proposed mechanism will facilitate accurate and timely imaging diagnosis of this injury by the radiologist.

Machine Learning for Supplementing Behavioral Assessment.

The Questions About Behavioral Function (QABF) has a high degree of convergent validity, but there is still a lack of agreement between the results of the assessment and the results of experimental function analysis. Machine learning (ML) may improve the validity of assessments by using data to build a mathematical model for more accurate predictions. We used published QABF and subsequent functional analyses to train ML models to identify the function of behavior. With ML models, predictions can be made from indirect assessment results based on learning from results of past experimental functional analyses. In Experiment 1, we compared the results of five algorithms to the QABF criteria using a leave-one-out cross-validation approach. All five outperformed the QABF assessment on multilabel accuracy (i.e., percentage of predictions with the presence or absence of each function indicated correctly), but false negatives remained an issue. In Experiment 2, we augmented the data with 1,000 artificial samples to train and test an artificial neural network. The artificial network outperformed other models on all measures of accuracy. The results indicated that ML could be used to inform conditions that should be present in a functional analysis. Therefore, this study represents a proof-of-concept for the application of machine learning to functional assessment.

Three-Column Classification System for Tibial Plateau Fractures: What the Orthopedic Surgeon Wants to Know.

Recent orthopedic surgical literature emphasizes a three-column approach to understand and guide the treatment of tibial plateau fractures. This three-column classification system published in 2010 relies on preoperative CT images to depict injuries to the medial, lateral, and posterior columns of the tibial plateau and improves surgical outcomes in complex tibial plateau fractures with coronal fracture planes and posterior plateau fracture fragments requiring dorsal plating. Tibial plateau fracture classification systems traditionally used by radiologists and orthopedic surgeons, including the Schatzker and the Arbeitsgemeinschaft für Osteosynthesefragen-Orthopedic Trauma Association (AO-OTA) classification systems, rely on findings at anteroposterior radiography and lack the terminology to accurately characterize fractures in the coronal plane involving the posterior tibial plateau. Incorporating elements from the contemporary three-column classification system into radiology reports will enhance radiologists' descriptions of these injuries. It is essential for radiologists to understand the role of clinical assessment and the pertinent imaging findings taken into consideration by orthopedic surgeons in their management of these injuries. This understanding includes familiarity with injury patterns and how they relate to mechanism of injury, patient demographics, and underlying pertinent comorbidities. Evaluating findings on initial radiographs is the basis of tibial plateau fracture diagnosis. Additional information provided by preoperative cross-sectional imaging, including two-dimensional and three-dimensional CT and MRI in specific circumstances, aids in the identification of specific soft-tissue injuries and fracture morphologies that influence surgical management. These specific fracture morphologies and soft-tissue injuries should be identified and communicated to orthopedic surgeons for optimal patient management. Online DICOM image stacks are available for this article. ©RSNA, 2020.

ATRAID regulates the action of nitrogen-containing bisphosphonates on bone.

Nitrogen-containing bisphosphonates (N-BPs), such as alendronate, are the most widely prescribed medications for diseases involving bone, with nearly 200 million prescriptions written annually. Recently, widespread use of N-BPs has been challenged due to the risk of rare but traumatic side effects such as atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). N-BPs bind to and inhibit farnesyl diphosphate synthase, resulting in defects in protein prenylation. Yet, it remains poorly understood what other cellular factors might allow N-BPs to exert their pharmacological effects. Here, we performed genome-wide studies in cells and patients to identify the poorly characterized gene, ATRAID Loss of ATRAID function results in selective resistance to N-BP-mediated loss of cell viability and the prevention of alendronate-mediated inhibition of prenylation. ATRAID is required for alendronate inhibition of osteoclast function, and ATRAID-deficient mice have impaired therapeutic responses to alendronate in both postmenopausal and senile (old age) osteoporosis models. Last, we performed exome sequencing on patients taking N-BPs that suffered ONJ or an AFF. ATRAID is one of three genes that contain rare nonsynonymous coding variants in patients with ONJ or an AFF that is also differentially expressed in poor outcome groups of patients treated with N-BPs. We functionally validated this patient variation in ATRAID as conferring cellular hypersensitivity to N-BPs. Our work adds key insight into the mechanistic action of N-BPs and the processes that might underlie differential responsiveness to N-BPs in people.

Early-onset Paget's disease of bone in a Mexican family caused by a novel tandem duplication (77dup27) in TNFRSF11A that encodes RANK.

Four heterozygous in-frame tandem duplications of different lengths in TNFRSF11A, the gene that encodes receptor activator of nuclear factor κB (RANK), constitutively activate RANK and lead to high turnover skeletal disease. Each duplication elongates the signal peptide of RANK. The 18-base pair (bp) duplication at position 84 (84dup18) causes familial expansile osteolysis (FEO), the 15-bp duplication at position 84 (84dup15) causes expansile skeletal hyperphosphatasia (ESH), the 12-bp duplication at position 90 (90dup12) causes panostotic expansile bone disease (PEBD), and the 27-bp duplication causes early-onset Paget's disease of bone (PDB2). The severity of the associated skeletal disease seems inversely related to the duplication's length. Additional 15- and 18-bp duplications of TNFRSF11A fit this pattern. Herein, we delineate the skeletal disease of a middle-aged man of Mexican descent who we found to harbor a novel 27-bp tandem duplication at position 77 (77dup27) of TNFRSF11A. His disorder shares features, particularly hand involvement, with the single Japanese (75dup27) and Chinese (78dup27) kindreds with PDB2 (PDB2Jpn and PDB2Chn, respectively). However, his distinct hearing loss developed later in adulthood compared to the other 27-bp families. He reported no morbidities during childhood, but in his late 20s developed unexplained tooth loss, low-trauma fractures, post-operative hypercalcemia, and painless enlargement of his fingers. Biochemical studies showed elevated serum alkaline phosphatase (ALP), bone-specific ALP, C-telopeptide, and osteocalcin consistent with rapid bone remodeling. Radiologic imaging revealed remarkably lucent bones with vertebral compression fractures, calvarial lucencies, and thinned long bone cortices. DXA showed extremely low bone mineral density. His disorder genetically and phenotypically fits best with PDB2 and can be called PDB2Mex.