A case of familial tumoral calcinosis/hyperostosis-hyperphosphatemia syndrome due to a compound heterozygous mutation in GALNT3 demonstrating new phenotypic features.

SUMMARY: A new case of familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) due to a novel compound heterozygous mutation in N-acetylgalactosaminyltransferase 3 (GALNT3) and with new phenotypic findings is presented. The response in serum phosphate and fibroblast growth factor 23 (FGF23) to medical treatment is detailed. This case expands the genotype and phenotype of FTC/HHS and gives insight into its treatment and pathophysiology. INTRODUCTION: FTC and HHS are caused by mutations in FGF23, GALNT3, or KLOTHO. They are characterized by hyperphosphatemia, increased phosphate reabsorption, and elevated or inappropriately normal serum 1,25-dihydroxyvitamin D(3) (1,25-D(3)); FTC is associated with calcific masses, and HHS with diaphyseal hyperostosis. METHODS: A 36-year-old woman presented with abnormal dental X-rays at age 12 and was hyperphosphatemic at 22. She underwent radiographic, biochemical and genetic testing, and medical treatment. RESULTS: Serum phosphorus was 7.3 mg/dL (2.5-4.8), TmP/GFR 6.99 mg/100 mL (2.97-4.45), 1,25-D(3) 35 pg/mL (22-67). Radiographs revealed tooth anomalies, thyroid cartilage calcification, calcific masses in vertebral spaces, calcification of the interstitial septa of the soft tissue in the lower extremities, and cortical thickening of the long bones. Her total hip Z score was 1.9. C-terminus serum FGF23 was 1,210 RU/mL (20-108), but intact FGF23 was 7.4 pg/mL (10-50). DNA sequencing determined she was a compound heterozygote for mutations in GALNT3. Treatment with niacinamide and acetazolamide decreased TmP/GFR and serum phosphate, which was paralleled by a decrease in serum C-terminus FGF23. CONCLUSIONS: This case broadens the spectrum of phenotypic and genotypic features of FTC/HHS and suggests treatments to decrease renal phosphate reabsorption in the setting of a low intact FGF23.

Solitary osteosclerotic plasmacytoma: association with demyelinating polyneuropathy and amyloid deposition.

A 51-year-old man presented with a 1-year history of polyneuropathy necessitating the use of a wheelchair. Initial diagnosis was idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and associated monoclonal gammopathy. Investigations for multiple myeloma, including bone marrow aspiration and biopsy, were negative. What was initially felt to be an incidental osteosclerotic focus noted on the radiographic bone survey was eventually shown to be a solitary osteosclereotic plasmacytoma with associated amyloid. This dramatically altered treatment. This case emphasizes the importance of including osteosclerotic plasmacytoma in the differential diagnosis of a focal sclerotic bone lesion in the clinical setting of polyneuropathy. These lesions are less likely to progress to multiple myeloma than lytic plasma cell neoplasms, and the presence of polyneuropathy often results in earlier diagnosis and treatment with enhanced prospect of cure. The finding of amyloid deposition within the osteosclerotic lesion may be of prognostic importance.

Gnathodiaphyseal dysplasia: a syndrome of fibro-osseous lesions of jawbones, bone fragility, and long bone bowing.

We report an unusual generalized skeletal syndrome characterized by fibro-osseous lesions of the jawbones with a prominent psammomatoid body component, bone fragility, and bowing/sclerosis of tubular bones. The case fits with the emerging profile of a distinct syndrome with similarities to previously reported cases, some with an autosomal dominant inheritance and others sporadic. We suggest that the syndrome be named gnathodiaphyseal dysplasia. The patient had been diagnosed previously with polyostotic fibrous dysplasia (PFD) elsewhere, but further clinical evaluation, histopathological study, and mutation analysis excluded this diagnosis. In addition to providing a novel observation of an as yet poorly characterized syndrome, the case illustrates the need for stringent diagnostic criteria for FD. The jaw lesions showed fibro-osseous features with the histopathological characteristics of cemento-ossifying fibroma, psammomatoid variant. This case emphasizes that the boundaries between genuine GNAS1 mutation-positive FD and other fibro-osseous lesions occurring in the jawbones should be kept sharply defined, contrary to a prevailing tendency in the literature. A detailed pathological study revealed previously unreported features of cemento-ossifying fibroma, including the participation of myofibroblasts and the occurrence of psammomatoid bodies and aberrant mineralization, within the walls of blood vessels. Transplantation of stromal cells grown from the lesion into immunocompromised mice resulted in a close mimicry of the native lesion, including the sporadic formation of psammomatoid bodies, suggesting an intrinsic abnormality of bone-forming cells.

From the archives of AFIP. Imaging of giant cell tumor and giant cell reparative granuloma of bone: radiologic-pathologic correlation.

The radiologic features of giant cell tumor (GCT) and giant cell reparative granuloma (GCRG) of bone often strongly suggest the diagnosis and reflect their pathologic appearance. At radiography, GCT often demonstrates a metaepiphyseal location with extension to subchondral bone. GCRG has a similar appearance but most commonly affects the mandible, maxilla, hands, or feet. Computed tomography and magnetic resonance (MR) imaging are helpful in staging lesions, particularly in delineating soft-tissue extension. Cystic (secondary aneurysmal bone cyst) components are reported in 14% of GCTs. However, biopsy must be directed at the solid regions, which harbor diagnostic tissue. These solid components demonstrate low to intermediate signal intensity at T2-weighted MR imaging, a feature that can be helpful in diagnosis. Multiple GCTs, although rare, do occur and may be associated with Paget disease. Malignant GCT accounts for 5%-10% of all GCTs and is usually secondary to previous irradiation of benign GCT. Treatment of GCT usually consists of surgical resection. Recurrence is seen in 2%-25% of cases, and imaging is vital for early detection. Recognition of the spectrum of radiologic appearances of GCT and GCRG is important in allowing prospective diagnosis, guiding therapy, and facilitating early detection of recurrence.

Advanced imaging of melorheostosis with emphasis on MRI.

OBJECTIVE: To describe the CT and MR imaging appearance of both osseous and extraosseous manifestations of melorheostosis. DESIGN AND PATIENTS: We retrospectively reviewed the CT (n=7) and/or MR imaging findings (n=12) of 17 patients with characteristic radiographic findings of melorheostosis (undulating cortical hyperostosis with marked uptake on radionuclide bone scintigraphy). RESULTS: CT and MR imaging revealed cortical hyperostosis as high attenuation and low signal intensity on all MR pulse sequences, respectively. Encroachment on the marrow space was seen in all cases resulting from endosteal involvement. Thirteen patients demonstrated 14 soft tissue masses with infiltrative margins in 80% of cases and seven showed extensive mineralization on CT or MR imaging (low intensity on all pulse sequences). Seven soft tissue masses were predominantly nonmineralized with intermediate signal intensity on T1-weighted and intermediate to high signal on T2-weighted MR images corresponding to vascularized fibrous tissue with variable collagen content pathologically. Enhancement after intravenous gadolinium was seen in all patients imaged with soft tissue masses (n=2). Two patients demonstrated muscle atrophy resulting from nerve involvement. CONCLUSIONS: The osseous abnormalities in melorheostosis are identical on advanced imaging and radiographs. Mineralized or nonmineralized soft tissue masses should be recognized as another manifestation of this disease as opposed to a more ominous finding, making biopsy unwarrranted.

Imaging of musculoskeletal fibromatosis.

The musculoskeletal fibromatoses comprise a wide range of lesions with a common histopathologic appearance. They can be divided into two major groups: superficial and deep. The superficial fibromatoses are typically small, slow-growing lesions and include palmar fibromatosis, plantar fibromatosis, juvenile aponeurotic fibroma, and infantile digital fibroma. The deep fibromatoses are commonly large, may grow rapidly, and are more aggressive. They include infantile myofibromatosis, fibromatosis colli, extraabdominal desmoid tumor, and aggressive infantile fibromatosis. Radiographs typically reveal a nonspecific soft-tissue mass, and calcification is common only in juvenile aponeurotic fibroma. Advanced imaging (ultrasonography, computed tomography, and magnetic resonance [MR] imaging) demonstrates lesion extent. Involvement of adjacent structures is common, reflecting the infiltrative growth pattern often seen in these lesions. MR imaging may show characteristic features of prominent low to intermediate signal intensity and bands of low signal intensity representing highly collagenized tissue. However, fibromatoses with less collagen and more cellularity may have nonspecific high signal intensity on T2-weighted images. Local recurrence is frequent after surgical resection due to the aggressive lesion growth. It is important for radiologists to recognize the imaging characteristics of musculoskeletal fibromatoses to help guide the often difficult and protracted therapy and management of these lesions.

Benign chondroid neoplasms of bone.

Benign cartilage lesions discussed in this article include osteochondroma (solitary, epiphyseal, and multiple), chondroblastoma, periosteal chondroma, and chondromyxoid fibroma. These lesions often demonstrate imaging appearances strongly suggesting the above diagnosis, particularly the "ring and arc" mineralization characteristic of cartilage lesions, which reflects their underlying pathology. This article emphasizes the imaging spectrum of these lesions with a multimodality approach.

Enchondroma and chondrosarcoma.

Enchondroma and chondrosarcoma are two of the most commonly encountered primary bone lesions in the typical radiology practice. The purpose of this article is to review the clinical, radiological, and pathological features that distinguish conventional chondrosarcoma from enchondroma. Chondrosarcoma is almost always associated with pain and tends to present in the axial skeleton of middle aged adults. Enchondroma tends to present in young adults in the appendicular skeleton, particularly the hands, and is often an incidental finding. Although both lesions have characteristic radiographic appearances, difficulty separating these two entities most often occurs when a lesion is seen in the long tubular bones. The judicious use of computed tomography, magnetic resonance imaging, and nuclear medicine in conjunction with appropriate clinical data allows the radiologist to establish the correct diagnosis of benign or malignant medullary chondroid lesion in the majority of cases.

Alphabet soup: cystic lesions of bone.

Giant cell tumor (GCT), aneurysmal bone cyst (ABC), and simple bone cyst (SBC) represent relatively common tumors and tumorlike conditions to affect bone. This article describes the clinical presentation of these lesions, as well as the characteristic radiologic and pathologic findings of each. In addition, differential diagnoses, disease course, and various treatment options are discussed.

Angiomatous skeletal lesions.

Vascular lesions involving osseous structures are relatively common neoplasms. We will review the appearance of many musculoskeletal angiomatous lesions using the multimodality approach. Lesions to be discussed include osseous hemangioma, glomus tumor, angiomatosis and associated syndromes (Osler-Weber-Rendu, Klippel-Trenaunay-Weber, and Kasabach-Merritt), Gorham, tumor-induced osteomalacia, and aggressive vascular neoplasms (hemangioendothelioma, hemangiopericytoma, and angiosarcoma).

Langerhans' cell histiocytosis in patients older than 21 years.

In this retrospective review of 541 patients with Langerhans' cell histiocytosis, 211 (39%) patients were older than 21 years of age, whereas 330 (61%) were younger than 21 years of age. The adult patients had a mean age of 32 years (range, 21-69 years) with 159 (75%) men and 52 (25%) women, whereas the pediatric patients consisted of 176 (55%) boys and 144 (45%) girls. This male predominance in adults was statistically significant. Three adults had the Hand-Schuller-Christian variant, whereas the remaining adults (208) had eosinophilic granuloma. The rib accounted for 25% of the adult lesions and only 8% of the pediatric lesions. Spine involvement was less common in the adult group (3% versus 10%) and was predominantly thoracic. The adult patients had 40 (77%) diaphyseal lesions, 12 (23%) metaphyseal lesions, and no epiphyseal lesions. The pediatric patients had 75 (54%) diaphyseal, 59 (42%) metaphyseal, and five (4%) epiphyseal lesions. Radiographic evaluation revealed similar margin and matrix patterns in both groups, with a geographic lesion without sclerotic borders being the most common pattern. Langerhans' cell histiocytosis is considered a pediatric disease. However, this study showed a significant number (39%) of patients older than 21 years of age with this condition.

Imaging of osteochondroma: variants and complications with radiologic-pathologic correlation.

Osteochondroma represents the most common bone tumor and is a developmental lesion rather than a true neoplasm. It constitutes 20%-50% of all benign bone tumors and 10%-15% of all bone tumors. Its radiologic features are often pathognomonic and identically reflect its pathologic appearance. Osteochondromas are composed of cortical and medullary bone with an overlying hyaline cartilage cap and must demonstrate continuity with the underlying parent bone cortex and medullary canal. Osteochondromas may be solitary or multiple, the latter being associated with the autosomal dominant syndrome, hereditary multiple exostoses (HME). Complications associated with osteochondromas are more frequent with HME and include deformity (cosmetic and osseous), fracture, vascular compromise, neurologic sequelae, overlying bursa formation, and malignant transformation. Malignant transformation is seen in 1% of solitary osteochondromas and in 3%-5% of patients with HME. Continued lesion growth and a hyaline cartilage cap greater than 1.5 cm in thickness, after skeletal maturity, suggest malignant transformation. Variants of osteochondroma include subungual exostosis, dysplasia epiphysealis hemimelica, turret and traction exostoses, bizarre parosteal osteochondromatous proliferation, and florid reactive periostitis. Recognition of the radiologic spectrum of appearances of osteochondroma and its variants usually allows prospective diagnosis and differentiation of the numerous potential complications, thus helping guide therapy and improving patient management.

Primary tumors of the spine.

Primary osseous tumors of the spine are rare lesions and much less frequently encountered than metastases, multiple myeloma, and lymphoma. The interpreting radiologist must be aware of the typical radiographic appearance of the most common nonmyeloproliferative tumors of the spine because these tumors must be considered when a solitary spinal lesion is encountered. The purpose of this article is to describe the radiologic appearance and radiologic staging of the most common benign (hemangioma, enostosis, osteoid osteoma, osteoblastoma, giant cell tumor, aneurysmal bone cyst, and osteochondroma) and malignant (chordoma, chondrosarcoma, Ewing tumor, and osteosarcoma) osseous spine tumors.

Imaging features of primary lymphoma of bone.

OBJECTIVE: Our objective was to describe the imaging appearances of primary lymphoma of bone, including conventional radiographic, scintigraphic, CT, and MR imaging features. MATERIALS AND METHODS: We retrospectively reviewed 237 pathologically proven cases of primary lymphoma of bone. Evaluation included patient age, sex, lesion location, and pattern of bone destruction. Pathologic type, periosteal reaction, sequestrum, soft-tissue mass, extension across joints, and pathologic fracture were also noted. RESULTS: The study population included 151 males and 86 females (ratio 1.8:1; range, 2-88 years; mean age, 42 years). Common locations were the distal femoral diametaphysis; proximal metadiaphysis of the tibia, femur, and humerus; and femoral mid shaft. Long bones were involved more often than flat bones (71% versus 22%). Common appearances were a lytic (70%) or mixed-density (28%) lesion with most cases showing a permeative or moth-eaten pattern (74%). Periosteal reaction was seen in 58% of the long bones. Sequestra were found in 37 patients (16%). Soft-tissue masses were present in 113 patients (48%). Extension across joints was seen in nine patients (4%). Pathologic fractures occurred in 53 patients (22%). Radionuclide (n = 56), CT (n = 45), and MR (n = 20) features were usually nonspecific. Pathologic types included non-Hodgkin's (n = 223) and Hodgkin's (n = 14) lymphoma. CONCLUSION: Primary lymphoma of bone most often involves the diametaphysis of a major long bone and has an aggressive pattern of lytic bone destruction and associated soft-tissue mass. CT and MR imaging can suggest the diagnosis, particularly when a large soft-tissue mass and abnormal marrow attenuation or signal intensity is seen without extensive cortical destruction.

From the archives of the AFIP. Imaging of musculoskeletal neurogenic tumors: radiologic-pathologic correlation.

Numerous neurogenic tumors can affect the musculoskeletal system, including traumatic neuroma, Morton neuroma, neural fibrolipoma, nerve sheath ganglion, neurilemoma, neurofibroma, and malignant peripheral nerve sheath tumors (PNSTs). The diagnosis of neurogenic tumors can be suggested from their imaging appearances, including lesion shape and intrinsic imaging characteristics. It is also important to establish lesion location along a typical nerve distribution (eg, plantar digital nerve in Morton neuroma, median nerve in neural fibrolipoma, large nerve trunk in benign and malignant PNSTs). Traumatic and Morton neuromas are commonly related to an amputation stump or are located in the intermetatarsal space, respectively. Neural fibrolipomas show fat interspersed between nerve fascicles and are often associated with macrodactyly. Nerve sheath ganglion has a cystic appearance and commonly occurs about the knee. Radiologic characteristics of neurilemoma, neurofibroma, and malignant PNST at computed tomography (CT), ultrasonography, and magnetic resonance imaging include fusiform shape, identification of entering and exiting nerve, low attenuation at CT, target sign, fascicular sign, split-fat sign, and associated muscle atrophy. Although differentiation of neurilemoma from neurofibroma and of benign from malignant PNST is problematic, recognition of the radiologic appearances of neurogenic tumors often allows prospective diagnosis and improves clinical management of patients.