Differential Diagnosis of Rare Diseases Involving Bilateral Lower Extremities with Similar 99mTc-MDP Bone Scan Patterns: Analysis of a Case Series

Here, we reported a panel of rare diseases involving bilateral lower extremities with similar imaging patterns on 99mTc-MDP bone scans. Glucose-6-phosphate dehydrogenase deficiency (G-6PD deficiency), Gaucher disease (GD), steroid-induced osteonecrosis, progressive diaphyseal dysplasia (PDD), Erdheim–Chester disease (ECD) and Langerhans cell sarcoma (LCS) were included and imaging characteristics were analyzed. The rare properties of these diseases and mimicking features on 99mTc-MDP bone scans rendered differential diagnosis difficult but necessary. We believe that the rarely known imaging features of the reported diseases will undoubtedly help nuclear medicine physicians make differential diagnoses in clinical practice.


Introduction
Although frequent deformities are encountered in pediatric orthopedic departments, diseases involving bilateral lower extremities are relatively rare in clinical practice. Clinical and radiological phenotypic characterizations are the baseline tools of diagnosis. However, the expanding availability of bone scintigraphy may help the physicians to better understand these diseases. In diseases such as hyperparathyroidism, typical imaging characteristics with hypercalcemia and hypophosphatemia usually enable a definitive diagnosis. Hypertrophic pulmonary osteoarthropathy (HPO) can likely be diagnosed based on clinical symptoms (unremitting pain, edema, and erythema in the extremities) and radiographic findings (radiography reveals periosteal membrane thickening and periosteal new bone formation, and bone scintigraphy shows bracelet-like or diffusely increased uptake throughout most of the skeleton). However, the imaging features of many other diseases may be disappointingly nonspecific, and the possible diagnostic considerations initially may seem extensive. In such cases, the use of a systematic approach can help narrow down the differential diagnosis.
Diseases involving bilateral lower extremities may be classified in one of the following general diagnostic categories: metabolic bone disorders, haematological systemic disorders, genetic developmental diseases, tumors, trauma, autoimmune diseases, and inflammatory lesions. Although these categories comprise a plethora of possible diagnoses, an orderly list of differential considerations may be constructed by considering the patient's age, laboratory examination, salient imaging features, and clinical manifestations.
The current article is based on our experience with diseases involving bilateral lower extremities. It is not intended as a comprehensive review, but rather as an overview, with emphases on lesions that are more common or relatively more common and on diagnoses that may be suggested by bone scintigraphy and radiologic imaging. G-6PD deficiency is one of the most common human enzyme defects that causes many biochemical and clinical phenotypes, including neonatal jaundice, chronic haemolysis and acute haemolytic anaemia [1]. However, 99m Tc-MDP bone scan and radiological patterns of G-6PD deficiency have rarely been reported [2]. Therefore, we first reported a G-6PD deficiency case that was previously misdiagnosed as fibrous dysplasia.
Patient 1 was a 17-year-old man who complained of fatigue, back and lower limbs' pain for three years. Spleen volume and liver volume of the patient were found to be significantly enlarged upon abdominal computed tomography (CT) ( Figure 1A). To explore potential factors causing pain of the lower extremities, the patient was recommended to receive magnetic resonance imaging (MRI) and X-ray examinations. MRI showed bone marrow involvement of the bilateral femora with slightly high signal intensity (SI) on T1-weighted imaging (WI) ( Figure 1B) and significantly high SI on T2 fat saturation WI ( Figure 1C,D). A frontal radiograph of tibiae demonstrated a well-demarcated lytic lesion in the proximal end of the left tibia without a sclerotic border, endosteal erosion or associated expansion of the tibial shaft. Radiologists supposed that it was a typical nonossifying fibroma. Decreased intensity in the medullary cavities of bilateral tibiae was observed at the same time ( Figure 2A). After collecting medical history carefully, we came to know that the patient was from a malaria-endemic area and had acute hemolysis and hematuria after eating fresh fava beans 15 years ago. The patient was further recommended to take a bone scan to exclude other metabolic bone diseases. As a result, 99m Tc-MDP bone scintigraphy showed increased uptake of 99m Tc-MDP in the skull, bilateral humeral heads, bilateral iliac bones, and metaphysis around bilateral knee joints ( Figure 2B). Furthermore, 99m Tc-MDP SPECT/CT fusion images demonstrated thickening of cranium (especially in the vault of the skull) and concomitant increased uptake of radiotracer ( Figure 2C-E). Notably, medullary intensity of both tibial shafts decreased significantly, and metaphysis and normal remaining bone tissue in the middle of the right shinbone showed increased concentration of 99m Tc-MDP ( Figure 2F-H). Considering the patient once had an acute hemolytic reaction triggered by ingestion of fava beans, splenohepatomegalia, imaging features of 99m Tc-MDP SPECT/CT and MRI, a final diagnosis of G-6PD deficiency rather than fibrous dysplasia was made. A subsequent fluorescent spot test confirmed the diagnosis [3].  Hematologic abnormalities of G-6PD deficiency are exceedingly common. Besides ingestion of fava beans, drugs and infection affecting oxidative stress of red blood cells can also trigger manifestations of G-6PD deficiency [1]. This patient subsequently presented with anemia, thrombocytopenia and fatigue. The etiology can be explained by depressed hematopoiesis resulting from substitution of the bone marrow. However, hypersplenism or sequestration within the spleen can be a cause as well. Lieberman et al. have demonstrated that patients with G-6PD deficiency may exhibit splenic accumulation of 99m Tc-MDP without evidence of splenic calcification [2], but there was not any augmented uptake of radiopharmaceutical within the spleen in our case, although physical examination demonstrated a palpable and enlarged spleen further supported by abdominal CT scanning. Despite the delusive image features on MRI, fibrous dysplasia tends to demonstrate marked enhancement throughout the mass on contrast-enhanced MRI [4]. The most effective management strategy for G-6PD deficiency is to prevent hemolysis, by avoiding oxidative stressors (such as drugs and fava beans). Although acute hemolysis in G-6PD deficient individuals is usually short-lived, this patient had severe anemia caused by chronic hemolysis on follow up and then received transfusions of red blood cells after the diagnosis was established.

Gaucher's Disease (GD)
G-6PD deficiency needs to be differentiated from Gaucher's disease (GD), where the latter is the most common lysosomal storage disease resulting from accumulation of undegraded glucosylceramide in the reticuloendothelial system of the bone marrow, spleen and liver [5]. Although the clinical manifestations of GD depend on the severity of symptoms and the course of the disease, the most dramatic and debilitating symptoms arise from infiltration of the bone marrow and bone changes, which can lead to pathologic fracture in the late stages.
Patient 2 was a 22-year-old female admitted to our hospital due to suffering from left thigh pain and swelling after an accidental crash. CT scanning revealed altered bone formation, resorption as well as pathologic fracture of the left femur ( Figure S1A,B). MRI showed low SI of involved bone marrow of the bilateral femora on T1 WI and heterogenous SI on T2 fat saturation WI ( Figure S1C,D). Initial radiological diagnosis of the patient was polyostotic fibrous dysplasia and concomitant pathological fracture of the left femur. The patient then received bone grafting and internal fixation surgery, and postoperative pathology revealed Gaucher's disease ( Figure S1E). Immunohistochemical tests of the tumor tissue disclosed positive PGM-1, Kp-1 ( Figure S1F), CD163, periodic acid-Schiff ( Figure S1G), iron staining ( Figure S1H) and negative S-100, CD5, CD4, SOX10, Langerin, CD1a, CK, EMA and BRAF V600E staining.
One week ( Figure S2A,B) and one month ( Figure S2C,D) after the surgery, X-ray films were taken to assess the healing process of the fractured bone. Considering the pathology, the patient further received 18 F-FDG PET/CT examination to systematically assess the disease burden. Maximum intensity projection (MIP) image with anterior view showed diffuse abnormal FDG uptakes, especially in the bilateral upper and lower extremities. MIP also demonstrated marked hepatosplenomegaly ( Figure S3A). The infiltration of the marrow by Gaucher's cells and fracture of the left femur were confirmed by the fusion images ( Figure S3B-D). Notably, CT features in both tibiae of this patient were quite similar to those of patient 1 ( Figures S3E and 2F). Replacement of yellow marrow by Gaucher cells in the humerus also led to destruction of normal bone formation and increased glucose metabolism ( Figure S3H-J).
Giuliano et al. reported that 99m Tc-Sestamibi uptake reliably identified bone marrow infiltration by Gaucher's cells, and that scintigraphic score was highly correlated with the severity of bone marrow involvement. The series work by the authors together with others' indicated the feasibility of directly imaging bone marrow infiltration using 99m Tc-Sestamibi in the early phases of Gaucher's disease [6][7][8]. However, biodistribution of 99m Tc-Sestamibi did not seem to coincide with that of 99m Tc-MDP [9]. Although both G-6PD deficiency and GD belong to diseases of hematological system and they may have similar patterns on 99m Tc-MDP bone scan and 18 F-FDG PET/CT scan, they have totally different features on MRI images, which can help make differential diagnoses. While G-6PD tends to have high SI on both T1-and T2-weighted images, the most frequent MRI abnormality of GD is reduced SI of the bone marrow spaces on the T1-and T2-weighted images (Figure S1C,D) [10]. The decrease in SI may be caused by displacement of the hematopoietic, fat-rich marrow and proinflammatory cytokines in response to pathologic macrophages [11].

Steroid-Induced Osteonecrosis
Osteonecrosis has a large number of etiologies and multifocal osteonecrosis is an uncommon entity usually seen in the clinical setting of corticosteroid administration, connective tissue disorders, dysbarism, hemoglobin patties, arteritis/vasculitis, pancreatitis, Gaucher's disease, pregnancy and alcohol abuse [12]. We report the development of multiple-site osteonecrosis in a patient with Sjogren syndrome who had received long-term administration of corticosteroid. We know that osteonecrosis is a common finding in a long list of skeletal dysplasia, and the most common in mild and moderate types of lysosomal storage disorders especially in adult patients. Osteoporosis is one of the manifestations of Sjogren syndrome and corticosteroid is an additional factor.
A 54-year-old female (Patient 3) was admitted to our hospital for evaluation of arthralgia. After initial negative laboratory tests, the patient was recommended to have a 99m Tc-MDP bone scan. The patient had a three-month corticosteroid administration course due to having Sjogren syndrome. Anterior imaging demonstrated increased periarticular tracer uptake around both knee joints and increased uptake in the right humeral head ( Figure 3A). 99m Tc-MDP SPECT/CT fusion images revealed abnormal uptake of 99m Tc-MDP in the right humeral head, accompanied by bone destruction ( Figure    Early diagnosis of steroid-induced osteonecrosis is of great importance to prevent irreversible bone and joint destruction. It is difficult to judge whether or not increased activity on a plain 99m Tc-MDP bone scan is correlated with revascularization and healing of osteonecrosis [13]. Although it lacks specificity, SPECT/CT may be a useful adjunct in this particular situation by providing anatomic and functional information. MRI has a high sensitivity and specificity in the diagnosis of osteonecrosis, and should be used when steroid-induced osteonecrosis is suspected [13]. If patients have history of steroid intake or chemotherapy containing steroids, patients suffer from bone or joint pains following steroid regimen, or symmetric tracer uptake on the bone scintigraphy, steroid-induced osteonecrosis should be considered and further MRI imaging is definitely needed to consolidate the diagnosis [13][14][15].

Progressive Diaphyseal Dysplasia (PDD)
Progressive diaphyseal dysplasia, or Camurati-Engelmann disease (CED), is a rare autosomal dominant skeletal dysplasia caused by mutations in the transforming growth factor-b1 (TGF β 1) gene [16]. TGF β 1 interferes with the bone remodeling process by stimulating bone formation and suppressing bone resorption under physiologic conditions, therefore, mutations in the TGF β 1 gene often lead to increased intramembranous bone formation. PDD is a rare genetic disease with variable clinical manifestations, and needs to be considered in the differential diagnosis of nonspecific limb pain and waddling gait in all young individuals.
A reported case (Patient 4) presented at 30 years of age with complaints of pain over both lower limbs and increasing difficulty in walking. Laboratory studies showed that serum calcium, phosphorus and PTH were within the normal range. Alkaline phosphatase was elevated (217 U/L, normal range: 15-112 U/L). Her CTX-I was elevated as well (715 ng/L, normal range: 513 ng/L), with decreased hemoglobin (87 g/L, normal range: 113-142 g/L) and increased blood sedimentation rate. A 99m Tc-MDP bone scan revealed increased tracer uptake in the extremities and skull. The rest of the skeleton was relatively spared. Radiographs of bilateral lower limbs and upper limbs revealed thickened cortices with irregular endosteal, diaphyseal sclerosis and narrowing marrow cavity ( Figure 5B-E). The skull of the patient was thickened, and sclerosis of the tympanic portion of the skull base was observed at the same time ( Figure 5F,G). MRI images of the both femora showed thickened cortices with low SI on T1 WI ( Figure 6A) and heterogenous SI on T2 fat suppression WI ( Figure 6B,C). On detailed evaluation, there was a strong family history of bone disorders, indicating an autosomal dominant mode of inheritance ( Figure 6D). The onset of symptoms was noted after puberty in affected family members. The clinical findings, characteristic radiological appearances and family history led to a diagnosis of PDD.
Camurati first suggested the familial nature of PDD in 1922, and subsequently, Engelmann reported a single case with muscular wasting and marked bone involvement in 1929 [16]. The typical clinical features include leg pain, muscle weakness, waddling gait, hearing loss, and easy fatigability after the onset of puberty. Although quite rare, systemic manifestations of anemia, leucopenia, and hepatosplenomegaly can appear [17]. The patient reported here suffered from anemia due to the severe involvement of the marrow cavity. Generally, uptake of 99m Tc-MDP in the longitudinal bone cortices was consistent with sclerosing dysplasia on bone X-ray films [18][19][20][21].

Erdheim-Chester Disease (ECD)
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by infiltration of tissues by foamy histiocytes [22]. By June 2014, a total of 448 ECD cases had been reported [23]. This disease has a broad spectrum of clinical manifestations, and generally presents with bone pain and atypically with neurological system involvement or renal failure.
The first case reported (Patient 5) was a 51-year-old male patient who suffered from renal failure in 2011 and skin pigmentation of the anterior chest wall in 2012. Since 2013, the patient has suffered from increasing bone pain of the lower extremities. A timely 99m Tc-MDP bone scan showed abnormal symmetrical concentration of radiotracer in the distal femora and proximal tibiae ( Figure S4A). The patient further underwent a CT scan followed by CT-guided tissue biopsy of the distal left femur. CT showed diffuse osteosclerosis in the distal femur and the corresponding marrow cavity of the femur was narrowed ( Figure S4B,C). Final pathology of the patient was Erdheim-Chester disease characterized by positive CD68, CD138, Lys, Ki67 (10%) staining and negative S-100, and CD1a staining. The final diagnosis of the patient was based on radiographic findings of medullary sclerosis confined to the appendicular skeleton, 99m Tc-MDP bone scan and pathologic features.
We have encountered another two ECD cases and both patients suffered from orbital and sphenoid bone involvement and subsequent visual extinction. A 99m Tc-MDP bone scan of one of the two patients is shown in Figure 7A. The patient (Patient 6) was a 38-year-old woman presenting with a fracture of the left proximal femur after a minor injury. She had been hospitalized in the endocrinology department for central diabetes insipidus and was being treated with desmopressin. She recently complained of coughing and dyspnea. In addition, her vision deteriorated and her eyes protruded to the point that she could not close her eyelids. A 99m Tc-MDP bone scan revealed diffuse uptake of radiotracer in the skull and lower extremities ( Figure 7A). Abnormal concentration of radiotracer was also observed in bilateral humeral heads and iliac bones. A radiograph of her pelvis showed pathologic fracture of the left proximal femur, and both lytic and sclerotic lesions could be found at the right hip bone ( Figure 7B). The patient then received internal fixation of the fractured femur ( Figure 7C) and X-ray performed 3 years after surgery indicated that the fracture did heal ( Figure 7D). X-ray also revealed diffuse osteosclerosis with focal osteolysis in the diaphysis and metaphysis of the distal right femur ( Figure 7E). The multifocal nature of the patient's osseous lesions prompted a complete diagnostic workup with CT and MRI followed by tissue biopsy from two sites: the left femur and the left temporal bone. Sagittal and coronal multiplanar reconstruction CT showed lytic and sclerotic lesions in multiple vertebral bodies and enlargement of bilateral kidneys ( Figure 8A-C). In addition, axial CT showed progressive pulmonary interstitial fibrosis ( Figure 8D). Cranial CT scans showed bilateral osteosclerosis encompassing the sphenoid sinuses ( Figure 8E,F) and exophthalmos caused by bilateral retroocular infiltration ( Figure 8G). The sagittal T1 WI showed marked thickening of the mucoperiosteal lining in the sphenoid sinus and absence of a normal bright spot signal in the posterior pituitary gland ( Figure 9A). The sagittal T2 WI showed a sellar arachnoid cyst, and the pituitary gland was compressed to the bottom of the sellar ( Figure 9B). The gadolinium-enhanced sagittal T1 WI showed no enhancement of the sellar arachnoid cyst ( Figure 9C). Coronal T1-weighted gadolinium-enhanced MRI showed diffuse enhancement and thickening of skull ( Figure 9D). Microscopic examination of the biopsy specimens showed an infiltrate of foamy histiocytes with bland nuclei admixed with Touton giant cells, lymphocytes, and eosinophils ( Figure 9E). Immunocytochemistry stained positive for S-100 protein ( Figure 9F) and CD163 ( Figure 9G) and negative for CD1a ( Figure 9H). Positive staining of CD163 excluded the diagnosis of Langerhans cell histiocytosis.   The third patient (Patient 7) was a 56-year-old female who complained of interrupted fevering and paining of bilateral knee joints since 2014. The patient had Sjogren's syndrome and usually took hydroxychloroquine and prednisone when the disease was active. The patient also suffered from diabetes and anxious depression for 3 years. Because of increasing pain and stiffness of the knee joints and right finger joints, she was admitted to department of osteoporosis in our hospital for further evaluation. The results of extensive serum laboratory analyses were otherwise unremarkable. Plain film showed abnormal density of sella turcica and basalis ( Figure S5A,B), sclerosis and narrowing of marrow cavity of distal femora and proximal tibiae ( Figure S5C,D) as well as bilateral ulnar bones and radial bones ( Figure S5E). MRI imaging of lower extremities showed patchy diseased areas in the distal femora and proximal tibiae, with low SI on T1 WI ( Figure S6A) and high SI on T2 fat suppression WI ( Figure S6B). Notably the diseased areas were enhanced significantly ( Figure S6C). The pituitary was normal on brain MRI imaging. The patient further underwent 18 F-FDG PET/CT scanning to exclude tumorous diseases. MIP ( Figure S7A) and fusion images disclosed increased uptake of 18 F-FDG, mainly in the bilateral distal femora and proximal tibiae. Increased concentration of radiotracer around the knee joints coincided with thickened cortices and narrowed marrow cavity ( Figure S7B-G). From a radiological aspect we gave a possible diagnosis of ECD considering its radiological features and multiple-organ involvement. Subsequent histopathological diagnosis of ECD by bone and bone marrow biopsy was established. Clinical physicians provided four treatment options: steroid, interferon, chemotherapy and cladribine [24]. The patient and family chose interferon treatment considering the adverse effects of other options.
ECD is a rare disease first described by Jacob Erdheim and William Chester in 1930. The disease is characterized by tissue infiltration by foamy histiocytes, typically in the long bone marrow, but also in numerous other organs [25]. Common medical complications include progression to respiratory, renal, skin and cardiac failure [26]. Neurological symptoms represent a prominent feature of ECD and occur in approximately 50% of patients during the course of the disease [23]. One of our ECD patients suffered from exophthalmos and diabetes insipidus, which was the most common manifestation of neuro-ECD and was associated with thickening of the pituitary stalk, alteration of the brightness of the hypophysis or pituitary infiltration. Another patient suffered from neuropsychiatric symptoms (depression), which was observed in less than 10% of patients [23]. The diagnosis relies exclusively upon correlation of the radiographic and pathologic findings because of its nonspecific clinical presentation. Conventional radiography of ECD typically shows a bilateral symmetric pattern of medullary sclerosis involving the diametaphyses of the lower extremities with sparing of the epiphysis [27]. Radiological features of ECD are believed to be consistent with that of 99m Tc-MDP bone scans [26,[28][29][30][31]. Despite similar symmetrical patterns on the 99m Tc-MDP plain film, ECD tends to involve extremities or metaphyses, while PDD impinge diaphyses more often. However, the rarity of the disease hinders the diagnosis and necessitates extensive imaging examinations, in which bone scans, CT and MRI of the central nervous system (CNS) are essential components. Beylergil et al. reported that 18 F-FDG PET/CT may provide additional value in the assessment of orbital involvement in ECD [32]. Previous studies have reported that PET scanning had high specificity for brain ECD lesions and should be considered for the initial assessment and follow-up of ECD patients displaying pituitary involvement [23,33]. Here, we further demonstrated that 18 F-FDG PET/CT imaging can provide similar diagnostic value when assessing ECD burden without pituitary involvement.

Langerhans Cell Sarcoma
Langerhans cell tumors are generally classified into Langerhans cell histiocytosis (LCH) and Langerhans cell sarcoma (LCS), and while the former is a benign entity the latter is a rare and malignant tumor of Langerhans cells. Up to now, there are only 66 LCS cases reported in the literature [34]. Given its rarity, there is a lack of evidence regarding the medical imaging patterns for this condition.
The last patient (Patient 8) was a 47-year-old female patient initially presenting with lower leg pain. Previously, she had received surgery on the right tibia because of suspicious chronic osteomyelitis. A 99m Tc-MDP bone scan of the patient revealed diffused and symmetric uptake of radiotracer in the distal femoral bones and proximal shin bones, and increased concentration of radiotracer was also found in her hip joints, sacroiliac joints, elbow joints as well as in the middle part of the left humerus ( Figure 10A). Subsequent 18 F-FDG PET/CT further reported abnormal glucose metabolism in bone marrow of the corresponding diseased areas with a SUVmax of 4.5 ( Figure 10B-D). Our nuclear medicine physicians consistently diagnosed the case as a typical ECD. Based on her medical history and these imaging findings, pathologists suggested a consultation of her previous surgical specimens. Beyond our imagination, final pathological results showed malignant cytological features, atypia and mitoses ( Figure 10E), and positive immunohistochemical staining for Ki-67 (40%, Figure 10F), S-100 ( Figure 10G), Langerin and CD1a ( Figure 10H) protein, which were confirmatory of LCS. The expression of histiocytic marker lysozyme, Kp1, CD163, PGM1 were also positive for this patient. Histopathology also found that the tumor infiltrated cortical plate and adjacent soft tissue. Currently the patient is receiving chemotherapy, but the optimal treatment strategy and efficacy is still in debate [35,36]. LCS can present de novo or progress from antecedent LCH. Skin, lymph nodes, spleen, liver, bone marrow, thymus, lung, and kidney have been frequently involved [37]. It is notable that LCS can undergo leukemic transformation [35,[38][39][40]. Although our patient did not have bone marrow aspiration, abnormal laboratory results or splenohepatomegalia, her imaging features upon 99m Tc-MDP bone scan and 18 F-FDG PET/CT resembled that of the above-mentioned hematological diseases. LCS is unfamiliar to nuclear medicine physicians, and to our best knowledge, this is the first time that the imaging features of LCS on both 99m Tc-MDP bone scan and 18 F-FDG PET/CT are reported. However, from this specific case we come to know that differential diagnosis between LCS and ECD is quite difficult from a medical imaging perspective.

Others
Besides those rare diseases involving metaphyses/extremities of lower extremities, fibrous dysplasia, hyperparathyroidism and other metabolic bone diseases are of relatively higher incidence and may present similar bone scan patterns. Fibrous dysplasia (FD), which accounts for about 2-3% of bone-derived tumors, is a benign bone lesion characterized by the replacement of normal bone structure with abnormal fibro-osseous connective tissue [41]. It has been reported that monostotic FD accounted for 70% and polyostotic FD accounted for 30% in a Chinese population [42]. Diagnosis of fibrous dysplasia is based on clinical examination, radiographic and histopathological findings. We previously studied the bone scan findings of 42 cases of FD and found that the extremities and ribs are the most common sites of involvement in FD, and further illustrated that Paget's disease resembles FD on bone scans but the former generally contains osteolytic, osteogenic, sclerotic features on X-ray/CT [43].
Hyperparathyroidism, especially primary hyperparathyroidism (PHPT), is a frequent and potentially debilitating endocrine disorder. In up to 85% of clinical cases, PHPT is characterized by the autonomous overproduction of parathyroid hormone (PTH) by a solitary parathyroid adenoma [44]. We previously reported that 99m Tc-MIBI scintigraphy and 99m Tc-MDP bone scintigraphy are closely correlated with tumor diameter and PTH level [45]. Therefore, combination of laboratory tests, 99m Tc-MIBI planar or SPECT/CT fusion images and 99m Tc-MDP bone scintigraphy is of great value to make a differential diagnosis. In addition, super-bone-scans are observed in tumorous diseases such as agnogenic myeloid metaplasia [46], gastric cancer [47][48][49], intracranial glioma [50], prostate cancer [51,52], breast cancer [49] and even recurrent syncope [53]. In some of these cases, superscans on bone scintigraphy were caused by concomitant metastatic and metabolic bone diseases. Therefore, caution should be given when interpreting a bone scintigraphy in patients with known malignancy because the appearance of metabolic disease may obscure recognition of osseous metastases.

Conclusions
Here, we show that when symmetrical uptake of radiotracer appears on 99m Tc-MDP bone scintigraphy or 18 F-FDG PET/CT scans, other potential causes except for FD, hyperparathyroidism and metabolic bone diseases should be considered. Together with examinations including laboratory tests, X-ray, CT, MRI and medical history, it is possible to draw a correct diagnosis, despite the rare properties of these diseases. SPECT/CT is a complimentary procedure and not mandatory to every case. It can be suggested after thorough clinical and conventional phenotypic characterizations. However, whole-body bone scanning with or without SPECT/CT might show us unusual findings and help us to understand the extent of the disease.  Institutional Review Board Statement: Ethical review and approval were waived due to the retrospective nature of this study.
Informed Consent Statement: Informed consent has been waived for most patients except for those whose medical images were used in the current study.
Data Availability Statement: Not applicable.