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Introduction: Camurati-Engelmann disease (CED) is a rare autosomal dominant disease. It is characterized by hyperostosis of the long bones and the skull, Clinically patient will have limb pain, proximal muscle weakness a wide-based gait. The gene causing CED is located on chromosome 19, this region contains the gene encoding the TGF Beta -1. The diagnosis of CED is established in a proband with the characteristic radiographic findings and molecular genetic testing for TGF Beta-1 mutation. Treatment is with corticosteroids and Losartan., Materials: A 40 year old lady presented with complaints of Left lower limb pain for 1 year duration. On examination there was tenderness of left greater trochanter, proximal and distal femur was present. Blood investigations showed high PTH and low Vitamin-D3. Imaging showed non specific sclerotic lesions in femur. As patient brother had limp since childhood genetic disorders were and a provisional diagnosis of sclerotic bone disease probable Progressive diaphyseal dysplasia was considered. PET-CT was done which revealed abnormal osteoblastic activity in both femurs, focal hyperostosis in humeral diaphysis suggestive of CED. She was tested Positive for TGF beta 1 mutation consistent with CED. He was started on LOSARTAN. On follow up patient is pain free., Result: Her brother was also evaluated in view of his limp and he was also diagnosed as CED., Conclusion: The diagnosis in this case was based on the clinical history, family history and characteristic radiological findings and genetic testing which confirmed TGF Beta-1 mutation. Family history is crucial in this case which led to diagnosis. References Van Hul W, Boudin E, Vanhoenacker FM, et al. Camurati Engelmann disease. Calcif Tissue Int 2019;104(5):554-560. Camurati-Engelmann Disease. NORD (National Organization for Rare Disorders); 2022., (© Journal of the Association of Physicians of India 2011.)

Camurati-Engelmann Disease (CED) is a rare sclerosing bone disease, sometimes associated delayed puberty. The treatment effect of glucocorticoid and angiotensin II receptor blocker (ARB) in bone health and puberty development remain unclear. We report a case of an 18-year-old girl who presented for a history of an enlarged head, pain of lower limbs, and no menstrual onset or breast development. Radiographs revealed thickening of skull and cortices in the diaphysis but sparse bone trabeculae in the spine and metaphysis. Sanger sequencing detected a mutation of c. 652C>T (p. R218C) in the gene TGFB1 and confirmed the diagnosis of CED. After treatment of a medium-to-small dosage of prednisone and losartan for 28 months, we observed improvement of bone mass in spine and hip and body fat mass and found initiation of puberty development. By a systemic review of current treatment strategies in patients with CED, we found that most cases reported relief of bone pain with treatment of glucocorticoid or ARB, but none has reported the outcome of hypogonadotropic hypogonadism. We propose that long-term use of glucocorticoid combined with ARB may inhibit the activation of TGFβ1 in CED, improve adipogenesis, and thus initiate puberty development and improve the bone mass in spine and hip., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cui, Li, Guan, Yu, Li, Xia and Jiang.)

Background: To investigate the clinical characteristics and molecular diagnosis of Camurati-Engelmann disease (CAEND) in Chinese individuals., Methods: We recruited six patients aged 14 to 45 years in three unrelated families with CAEND, including five females and one male. Clinical manifestations, biochemical tests, and radiographic examinations were analyzed. The TGFB1 gene variants were further identified by Sanger sequencing. In addition, one female patient was followed up for 5 years., Results: The onset age of the patients ranged from 1 to 6 years. All of them had family histories and consisted of an autosomal dominant inheritance pattern. Gait disturbance, fatigue, progressive bone pain, muscle atrophy, and weakness were the main complaints. Laboratory examinations revealed that the inflammatory markers were at high levels, in addition to the increased bone metabolism indicators. The thickened diaphysis of long bones and the narrowed medullary cavity was observed by radiography. Furthermore, bone scintigraphy detected abnormal symmetrical radioactive concentrations in the affected regions of bone. Sanger sequencing identified a missense heterozygous variant in exon 4 of the TGFB1 gene in families 1 and 2, resulting in Arg218Cys, which confirmed CAEND. Moreover, one novel variant c.669C > G in exon 4 of the TGFB1 gene harboring Cys223Trp was detected in family 3. Subsequent bioinformatics software predicted that the novel variant was pathogenic. Of interest, III:2 in family 3 experienced heart valve defects and tachycardia at birth, which had never been reported in CAEND patients before. Moreover, the response to drug treatment is also full of contradictions and is worthy of further study., Conclusion: Besides the typical CAEND manifestations, the new phenotypic characteristics of tachycardia and heart valve defects were first reported in one woman carrying the novel variant p.Cys223Trp in TGFB1 the gene. In addition, we demonstrated that increased bone metabolism indicators and inflammatory markers may possess auxiliary diagnosis for CAEND., (© 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Camurati-Engelmann disease (CED) is a rare autosomal-dominant skeletal dysplasia caused by mutations in the transforming growth factor-β1 (TGFB1) gene. In this study, a retrospective review of patients with CED evaluated at Peking Union Medical College Hospital in Beijing, China, between November 30, 2000 and November 30, 2020 was conducted. Data including demographic data, manifestations, and examination results were characterized. Furthermore, bone geometry, density, and microarchitecture were assessed and bone strength was estimated by HR-pQCT. Results showed the median age at onset was 2.5 years. Common manifestations included pain in the lower limbs (94%, 17/18), abnormal gait (89%, 16/18), genu valgum (89%, 16/18), reduced subcutaneous fat (78%, 14/18), delayed puberty (73%, 8/11), muscle weakness (67%, 12/18), hearing loss (39%, 7/18), hepatosplenomegaly (39%, 7/18), exophthalmos or impaired vision or visual field defect (33%, 6/18), and anemia (33%, 7/18). Twenty-five percent (4/16) of patients had short stature. Serum level of alkaline phosphatase was elevated in 41% (7/17) of patients whereas beta-C-terminal telopeptide was elevated in 91% of patients (10/11). Among 12 patients, the Z-scores of two patients were greater than 2.5 at the femur neck and the Z-scores of five patients were lower than -2.5 at the femur neck and/or lumbar spine. HR-pQCT results showed lower volumetric BMD (vBMD), altered bone microstructure and lower estimated bone strength at the distal radius and tibia in patients with CED compared with controls. In addition, total volume bone mineral density and cortical volumetric bone mineral density at the radius were negatively correlated with age in patients with CED, but positively correlated with age in controls. In conclusion, the largest case series of CED with characterized clinical features in a Chinese population was reported here. In addition, HR-pQCT was used to investigate bone microstructure at the distal radius and tibia in nine patients with CED, and the alteration of bone density, microstructure, and strength was shown for the first time. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Case: A 40-year-old Colombian woman presented with a 7-year history of progressive lower-limb pain. Sclerosis of the diaphyseal tibia and femur was observed in her latest x-ray images. A narrowing of the medullary canal is observed in Camurati-Engelmann disease (CED), a rare and progressive diaphyseal dysplasia that was confirmed in this patient by genetic testing. Medical treatment was unsuccessful; thus, surgical treatment consisted of decompression by drilling of the medullary canal was performed, achieving successful pain release., Conclusion: Surgical treatment should be considered for patients with CED when the medical treatment is unsuccessful because doing so reduces bone overgrowth, leading to pain relief., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSCC/B557)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Camurati-Engelmann disease (CED) is a rare, progressive diaphyseal dysplasia characterized as diaphyseal hyperostosis and sclerosis of the long bones. Corticosteroids, bisphosphonates, and losartan have been reported to be effective systemic medications used to reduce CED symptoms. There are no reports of osteoblastoma in patients with CED, and osteoblastoma in the distal radius is rare. We present a patient diagnosed with CED, based on radiological and histological examinations, at 11 years old. At 22 years old, she experienced severe pain in her right forearm and was treated with bisphosphonate, losartan, and prednisolone; however, the pain continued. An expansive and sclerotic lesion at the distal radius was observed on radiography. A follow-up plain radiograph indicated that the lesion was growing. Fluorodeoxyglucose positron emission tomography revealed solitary, intense radiotracer uptake, and a biopsy and surgical resection were performed due to suspected malignancy. Pathologic analysis showed anastomosing bony trabeculae rimmed by osteoblasts observed in a loose fibrovascular stroma. The lesion was diagnosed as an osteoblastoma. Following bone excision and artificial bone grafting, the patient's severe pain almost completely disappeared. At final follow-up, no evidence of osteoblastoma recurrence was noted. To our knowledge, this is the first case report of osteoblastoma arising in a patient with CED. Bone excision and artificial bone grafting may be a treatment option for local symptomatic osteoblastoma in patients with CED.

Introduction: Camurati-Engelmann disease is a rare autosomal dominant bone dysplasia belonging to the group of craniotubular hyperostoses. Genetic analysis classically shows mutation on TGFβ1 gene., Case Report: A young woman was hospitalized with intense pain in lower limbs, associated to radiographic hyperostosis and sclerosis of the long bones., Results: Mutation on LRP6 has recently been associated to high bone mass. In this case report, a rare missense variant on LRP6 gene was associated to radiographic features of Camurati-Engelmann., Conclusions: More studies should be conducted to assess the pathological role of this variant in Camurati-Engelmann-like disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Competing Interests: All authors have disclosed no conflicts of interest.

Case: A 44-year-old woman presented with easy fatigability, diplopia, dizziness, and a 2-year history of pelvic, hip, and lower extremity aching and pain. Radiograph, magnetic resonance imaging, computed tomography, and histopathologic imaging studies were obtained. Hypersclerosis of the affected bones led to the initiation of a sclerotic bone dysplasia workup and sequencing of the transforming growth factor beta 1 gene located on chromosome 19q13 revealed a heterozygous rare missense variant in exon-4, leading to a final diagnosis of Camurati-Engelmann disease (CED). Medical treatment thus far has had a minimal effect on her symptoms, and the patient continues to be followed., Conclusions: This specific mutation has been reported only once previously in a patient with CED. This case report expands the typical phenotype associated with CED in association with the c.667T>C, p.Cys223Arg variant.

Camurati-Engelmann disease (OMIM 31300) is a rare cranio-tubular bone dysplasia characterized by osteosclerosis of the long bones and skull caused by dominantly-inherited mutations in the transforming growth factor beta 1 (TGFB1) gene. A wide variation in phenotype has been recognized, even within families carrying the same mutation. In addition, aspects of the natural history of the disorder, in particular whether it is always progressive or can remit spontaneously, remain uncertain. In a large kindred carrying a TGFB1 gene mutation (c.653G > A; p.R218H) we have attempted to clarify the extent of phenotypic variability and the natural history of the disease through detailed individual histories of symptoms, and skeletal imaging by both radiography and scintigraphy. Only one subject had the classical childhood onset with bone pain in the legs and gait disturbance. Eight subjects reported the onset of leg pain in their teenage years that, by their early 20s, had either resolved or persisted at a low level. Two of these eight later developed cranial nerve palsies. There was a wide variation in the radiographic appearance in adults, but disease extent and activity in long bones, as assessed by scintigraphy, was inversely correlated with age (p < 0.025). In younger subjects the radiographic and scintigraphic appearances were concordant, but in older subjects the scintigram could be quiescent despite florid radiographic changes. Sequential scintigrams in two subjects showed reduced activity in the later scan. One subject had suffered meningoencephalitis in early childhood that resulted in paresis of one arm. The affected arm showed markedly less disease involvement, implicating mechanical or growth factors in its etiology. Our data suggest that the natural history of Camurati-Engelmann disease can be benign, and that disease activity commonly attenuates in adulthood. Severe cases of childhood onset and/or with cranial nerve involvement, may occur only in a minority of mutation carriers. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Camurati-Engelmann disease or progressive diaphyseal dysplasia is a rare autosomal dominant sclerosing bone dysplasia. Mainly the skull and the diaphyses of the long tubular bones are affected. Clinically, the patients suffer from bone pain, easy fatigability, and decreased muscle mass and weakness in the proximal parts of the lower limbs resulting in gait disturbances. The disease-causing mutations are located within the TGFβ-1 gene and expected to or thought to disrupt the binding between TGFβ1 and its latency-associated peptide resulting in an increased signaling of the pathway and subsequently accelerated bone turnover. In preclinical studies, it was shown that targeting the type I receptor ameliorates the high bone turnover. In patients, treatment options are currently mostly limited to corticosteroids that may relieve the pain, and improve the muscle weakness and fatigue. In this review, the clinical and radiological characteristics as well as the molecular genetics of this condition are discussed.

Rationale: Multiple diaphyseal sclerosis (MDS), known as Ribbing disease, is a rare congenital bone disease resulting from autosomal recessive inheritance. The case study involved a 22-year-old female patient who had been diagnosed with chronic sclerosing osteomyelitis due to lack of knowledge about MDS. Previous studies reported rarely on this condition., Patient Concerns: A 22-year-old female with MDS was analyzed., Diagnoses: MDS is characterized radiographically by a fusiform widening of the diaphyseal portion of the long bones, which is caused by a thickening of the cortex with obstruction of the medullary cavity. The pathologies are observed utilizing diagnostic imagery and are often difficult to identify., Intervention: The patient was following a suggested regimen of oral celecoxib capsules at 200 mg/day for 6 days., Outcomes: The patient's diagnosis was revised to the rare condition of Ribbing disease by reviewing the clinical history and distinctive radiography images and because the symptoms were alleviated by celecoxib capsule. We also present a review of the literature on the diagnosis and differential diagnosis of MDS based on clinical and imaging features., Lessons: MDS is rare and may often be initially misdiagnosed as another type of sclerosing bone dysplasia, thus, it is important to be aware of the existence of MDS. Once MDS is suspected, differential diagnosis should be performed to exclude other sclerosing bone dysplasias, taking into account clinical history, distinctive radiographic appearance, distribution, and laboratory and histopathologic findings. Laboratory evaluation and pathologic findings are nonspecific but assist in excluding other diagnoses. More evidence is needed to illustrate the effectiveness of medical or surgical treatments for patients with MDS.

Background: Camurati-Engelmann disease is an extremely rare disease characterized by hyperostosis of multiple long bones. This condition is caused by heterozygous mutations in the TGFB1 gene., Methods: We describe the clinical and genetic characteristics of 4 Korean patients with this rare disease diagnosed at Asan Medical Center in Korea between June 2012 and May 2016, to increase awareness about this condition among general physicians and orthopedists. The presenting features, biochemical findings, radiographic and nuclear imaging findings, molecular analysis, and treatment outcomes of 4 patients were reviewed retrospectively., Results: Two patients had sporadic disease, whereas the other 2 were familial cases. The average age at symptom onset was 8.8 ± 5.5 (4-14) years. Symptoms included waddling gait or leg pain. Bone pain and easy fatigability were documented in all patients. Skeletal deformities such as osteoporosis, genu valgum, and severe scoliosis were observed. Visual and otologic manifestations presenting as exophthalmos, retinal detachment, and vestibulopathy were found in 3 patients. Skeletal survey showed diaphyseal expansion with diffuse cortical thickening of long bones in all patients. Bone scintigraphy images showed increased uptake of radioactive material in the calvarium and diaphysis of long bones. The mean erythrocyte sedimentation rate was 46.5 ± 22.2 (20-72) mm/h. Sequence analysis of TGFB1 revealed the previously reported mutations p.Arg218His, p.Arg218Cys, and p.Glu169Lys. Corticosteroid was effective in relieving pain, and losartan was used as maintenance therapy., Conclusions: Our experience suggests that this rare condition can be suspected in patients with characteristic symptoms and skeletal findings. Considering the presence of effective medical treatment, efforts are needed to identify more cases.

Case: We review the case of a 44-year-old man with Camurati-Engelmann disease, who presented with chronic right hip pain that did not improve following intra-articular hip injections. He was functionally debilitated because of the worsening pain. Routine radiographs demonstrated severe right hip osteoarthritis and severe diaphyseal sclerosis of the femur. To address the narrowed medullary cavity, appropriate reaming of the diaphysis and broaching to fill the metaphysis were performed. The patient underwent an uncemented total hip arthroplasty that resulted in an excellent recovery with no complications., Conclusion: Uncemented total hip arthroplasty serves as a good option for patients with hip osteoarthritis secondary to Camurati-Engelmann disease. Anticipation of potential operative challenges is the key to avoiding complications and achieving an optimal, durable outcome.

Background Ribbing disease, or multiple diaphyseal sclerosis, is a rare benign bone dysplasia. Purpose To systematically review the literature to determine the clinical and radiological presentation of patients with Ribbing disease as well as the effects of attempted treatments. Material and Methods We considered individual patient data of patients diagnosed with Ribbing disease derived from patient reports and patient series. All stages of the review were performed by two reviewers independently. Standard descriptive statistics were used for quantitative analyses and mixed model analyses were used when appropriate Results The literature search yielded 420 unique hits of which 23 studies were included, covering a total of 40 patients of whom 29 had bilateral involvement. The mean age at diagnosis was 35 years and the mean time between diagnosis and onset of symptoms, mostly pain, was five years (range = 1-16 years). The tibial diaphysis was the most commonly involved bone in 35 of 36 patients. Non-surgical treatment consisted of non-steroidal anti-inflammatory drugs (NSAIDs), prednisone, and bisphophonates with mixed results. Surgical treatment consisted of intramedullary reaming and fenestration and was very effective to reduce pain. Conclusion The clinical presentation and imaging findings of patients with Ribbing disease are becoming more apparent. However, there is paucity of evidence on the natural disease progression and effectiveness of treatment modalities.

Camurati-Engelmann (CE) is a very rare disease affecting one in every million persons worldwide. It is characterized by an enlargement of long bones. We aimed to assess bone characteristics in three siblings with different tools. Even if there was an excess of bone density, quality seemed to be deteriorated., Introduction: CE disease is a rare monogenic disorder affecting approximately one in every million persons worldwide. It is mainly characterized by a progressive hyperostosis of the periosteum and endosteum of the diaphysis of long bones. Limited data are available about bone characteristics in these patients. In three siblings with CE disease, we aimed to assess bone mineral density (BMD) and trabecular bone score (TBS) by dual-energy X-ray absorptiometry (DXA) and material characteristics at tissue level using bone impact reference point indentation., Methods: Clinical data were collected and a general laboratory workup was performed. At the lumbar spine and hip, BMD and TBS were measured using DXA imaging. Bone material strength index (BMSi) was measured by bone impact microindentation using an Osteoprobe instrument., Results: All three cases had densitometric values consistent with high bone mass (sum of Z-score at the lumbar spine and hip > 4). Hip BMD was extremely high in all three siblings at both total hip and femoral neck, while at the lumbar spine, two of them had normal values but the third again had very high BMD. TBS values were in the normal range. In contrast, BMSi measurements were at low or very low levels, compared with normal controls., Conclusion: Despite strikingly increased BMD and normal microarchitecture, BMSi is affected in patients with CE. Microindentation could be an appropriate tool for assessing bone fragility in these patients. Bone disease in this group of patients requires further study to better understand the underlying regulatory mechanisms and their alterations.

Rationale: Camurati-Engelmann disease (i.e., progressive diaphyseal dysplasia) is an extremely rare autosomal dominant bone disorder. The most common clinical manifestations were chronic skeletal pain, waddling gait, muscular weakness., Patient Concerns: We described that a 27-year-old male with a 1-year history of intermittent tetany was referred for bone scintigraphy. The whole body bone scan images showed abnormal increased uptake of the tracer in the long bones of the upper and lower extremities as well as in the skull., Diagnoses: Combined the family history, the findings of the images and the genetic study, the diagnosis of Camurati-Engelmann disease was confirmed., Interventions and Outcomes: The patient responded well to the treatment of calcium gluconate., Lessons: Bone scintigraphy would be helpful in the diagnosis and assessing the severity of Camurati-Engelmann disease.

Objective and Importance: Camurati-Engelmann disease (CED) is a rare, autosomal-dominant genetic disorder resulting in hyperostosis of the long bones and skull. Patients often develop cranial nerve dysfunction and increased intracranial pressure secondary to stenosis of nerve foramina and hyperostosis. Surgical decompression may provide symptomatic relief in select patients; however, a small number of reports document the recurrence of symptoms due to bony regrowth. We present a patient who had been treated previously with bilateral frontal and parietal craniotomy who experienced recurrence of symptoms due to reossification of her cranial bones. This report underscores the progressive nature of CED and its influence on surgical management. Furthermore, we propose a novel surgical approach with multiple craniectomies and titanium mesh cranioplasties that could potentially offer long-term symptomatic relief., Clinical Presentation: A 46-year-old female patient with CED who was treated with ventriculoperitoneal shunting, posterior fossa decompression, and multiple craniotomies 2 decades prior presented with signs and symptoms of increased intracranial pressure. Studies of the skull at presentation demonstrated rethickening of cranial bones that resulted in severely decreased intracranial volume., Intervention: A radical craniectomy, requiring 4 separate bone flaps made up of bilateral frontal and parietal bones, was performed. The remaining coronal and sagittal bony struts were drilled to approximately 1 cm thick. Cranioplasties with 4 separate titanium meshes were performed to preserve the natural contour of the patient's skull., Conclusions: Although surgical decompression could provide some patients with CED symptomatic relief, clinicians should consider managing CED as a chronic condition. To the authors' knowledge, this is one of few case reports documenting the recurrence of symptoms in a patient with CED treated by surgical intervention. Furthermore, we propose that multiple craniectomies with titanium mesh cranioplasties confer more permanent symptomatic control, and, more importantly, lower the risk of recurrence secondary to cranial hyperostosis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Ribbing disease, or multiple diaphyseal sclerosis, is a rare diaphyseal sclerosis of unknown etiology. Patients with this pathology usually present with asymmetric pain limited to the lower extremities. Though all efforts are made to relieve the progressive pain associated with Ribbing disease, no medical or surgical treatments have been established yet. In this case report, we followed up a Ribbing case with sclerotic bone fenestration for 5 years. The radiological changes and the clinical effects are described, and the different Ribbing treatments are then briefly reviewed.

Background: Camurati-Engelmann disease (CED) is a rare genetic skeletal disorder characterized by limb pain, muscle emaciation and weakness, and cortical thickening of the diaphysis of long bones. It is caused by mutations in the transforming growth factor beta 1 (TGFB1) (type I) or other unknown gene(s) (type II). We present 8 consecutive patients with type I CED., Methods: We retrospectively reviewed medical records and radiographs of type I CED patients with special reference to the mode of presentation, process of diagnostic work-up, and disease course. They were 4 sporadic patients, and two pairs of mother and son., Results: We categorized the mode of presentation into three groups. Group I had 4 patients who mainly presented with motor disturbances in young age. They drew medical attention for waddling gait, awkward ambulation or running, difficulty in going upstairs, or a positive Gower's sign at age 4 to 6 years. Subsequent development of limb pain and radiographic abnormality led to the diagnosis of CED at age 6 to 29 years. Group II had 3 patients who mainly presented with limb pain at age 15, 20, and 54 years, respectively. Radiographic evaluation and molecular genetic test led to the diagnosis of CED. The remaining 1 patient (group III) was asymptomatic until age 9 years when bony lesions at the tibiae were found incidentally. For the last 10 years, he intermittently complained of leg pain in the morning or after sports activities, which did not interfere with daily life. All the patients in group I showed a body mass index in the underweight range (< 18.4 kg/m 2 ). At the latest follow-up, 4 patients in groups I and II required medication for the limb pain., Conclusions: CED presents with a wide range of severity. Awareness of this rare disease entity may be the key to timely correct diagnosis. This disease entity should be considered in the differential diagnosis of limb pain or motor disturbance in children to avoid unnecessary diagnostic work-up., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.

Sclerosing bone disorders are uncommon diseases and represent a diagnostic challenge. Osteocondensation is a bone alteration, involving both acquired and hereditary conditions. Multiple diaphyseal sclerosis (Ribbing disease) is an inherited condition. It is characterized by excessive proliferation of endosteal and periosteal osseous tissue at the diaphyses of long bones, especially of tibias and femurs. The conventional radiology depicts cortical thickening of diaphyses of long bones while bone scintigraphy shows characteristically an abnormal tracer concentration in the involved diaphyses. The magnetic resonance imaging (MRI) examination confirms the presence of sclerosis and reveals bone marrow edema in the diaphyses of the afflicted bones. Due to the lack of knowledge of the pathophysiology, the treatment is empirical with glucocorticoids or bisphosphonates. Concerning bisphosphonates, the literature reports are conflicting. We report the case of a patient that showed lack of response to intravenous neridronate within 1 year of treatment, both in terms of pain and persistence of bone marrow edema at MRI.

A 23-year-old woman presented with bilateral papilloedema in a setting of Camurati-Engelmann disease (CED). She was investigated with neuroimaging showing no optic nerve canal stenosis or jugular vein canal compromise. Her MRI venogram was normal. Her opening pressure at lumbar puncture and serum alkaline phosphatase were raised. Her papilloedema resolved with long-term use of acetazolamide. We believe that our patient suffered from raised intracranial pressure directly as a result of decreasing intracranial volume secondary to CED., (2015 BMJ Publishing Group Ltd.)

Camurati-Engelmann disease (CED, OMIM 131300), or progressive diaphyseal dysplasia, is a rare autosomal dominant skeletal dysplasia, caused by mutations in the transforming growth factor-β1 (TGFβ1) gene. We describe the first Indian CED family with genetic confirmation and presenting manifestations. The proband is a 17-year-old woman who presented with lower limb pain and proximal muscle weakness. Skeletal radiographs of the long bones revealed cortical, periosteal, and endosteal thickenings, predominantly affecting the diaphyses of the long bones. On detailed evaluation, there was a strong family history of bone disorder with similar symptoms of pain and radiological findings in several family members. Exon sequencing of the TGFβ1 gene was performed in available family members. Based on clinical and radiographic studies and its familial nature, a diagnosis of CED was made and confirmed by mutation analysis. A heterozygous G to A transition in exon 4 of the TGFβ1 gene (R218H) was detected in 5 out of 10 available family members, including 4 affecteds and 1 asymptomatic individual. Many of our affected individuals responded to glucocorticoids and cortical windowing. CED is a rare genetic disease with variable clinical manifestations and incomplete penetrance. CED needs to be considered in the differential diagnosis of nonspecific limb pain and waddling gait in all young individuals.

The aim of the present study was to investigate the clinical characteristics and major causative gene in pediatric patients with Camurati‑Engelmann disease (CED). Biochemical and radiographic examinations, bone scintigraphy and genetic analyses were performed in two affected males and their parents. The two patients experienced waddling gait, muscular weakness and growth developmental delay. X-ray radiography revealed typical fusiform thickening of the diaphyseal portions of the long bones. The abnormal uptake of tracer Tc-99m was visualized in the skull and both sides of the upper humeri, ulnas, radii, femurs and tibias using bone scintigraphy. Serum levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) and the bone resorption marker β‑isomerized C-terminal cross-linked telopeptide of type I collagen (β-CTX) in the 6-year-old patient were significantly increased compared with the normal value range, while only the β-CTX levels were elevated in the 16-year-old patient. A heterozygous missense mutation p.Arg218Cys in exon 4 of the transforming growth factor β1 (TGFβ1) gene was detected in the two patients, while their parents had normal wild‑type genotypes. In conclusion, the p.Arg218Cys mutation was shown to contribute to the clinical phenotypes in two pediatric patients with CED. The results of this study suggest that abnormal bone turnover marker levels, typical radiological findings and mutations in the TGFβ1 gene are three important factors in the diagnosis of sporadic CED cases.

Objective: A case report of a patient diagnosed with Camurati-Engelmann Disease (CED) in association with the functional hypothalamic amenorrhea disturbances. CED is a very rare genetically determined disorder classified as a type of bone dysplasia., Design: Case report., Setting: Department of Gynecological Endocrinology, 3rd grade Medical University Hospital., Patient: Twenty-one years old female patient with CED admitted to the hospital because of primary amenorrhea. Her history revealed skeletal deformities and hearing impairment., Methods: Clinical examination, ultrasound, laboratory evaluations (including serum gonadotropins (FSH, LH) at basal state and after stimulation with gonadotropin-releasing hormone, serum basal estradiol) radiological studies (X-ray of the head, the lumbar spine and lower extremities; a computed tomography of the head), G-banding karyotype, polymerase chain reaction and DNA sequencing. Hormonal serum evaluations were made using an enzyme-linked immunosorbent assay. The exon 4 of the transforming growth factor beta 1 gene was amplified by a polymerase chain reaction and the product was directly sequenced., Results: The hormonal analysis was characteristic for the hypogonadotropic hypogonadism. Radiological and molecular analyses confirmed CED diagnosis., Conclusions: The hypothalamic amenorrhea in a patient with CED may be explained as a consequence of fat hypotrophy and very low body mass index. Therefore, impairment within hypothalamic-pituitary axis in patients with CED should be treated with special attention.

We report a 32-year-old man and his 59-year-old mother with a unique and extensive variant of Camurati-Engelmann disease (CED) featuring histopathological changes of osteomalacia and alterations within TGFβ1 and TNFSF11 encoding TGFβ1 and RANKL, respectively. He suffered leg pain and weakness since childhood and reportedly grew until his late 20s, reaching 7 feet in height. He had deafness, perforated nasal septum, torus palatinus, disproportionately long limbs with knock-knees, low muscle mass, and pseudoclubbing. Radiographs revealed generalized skeletal abnormalities, including wide bones and cortical and trabecular bone thickening in keeping with CED, except that long bone ends were also affected. Lumbar spine and hip BMD Z-scores were + 7.7 and + 4.4, respectively. Biochemical markers of bone turnover were elevated. Hypocalciuria accompanied low serum 25-hydroxyvitamin D (25[OH]D) levels. Pituitary hypogonadism and low serum insulin-like growth factor (IGF)-1 were present. Karyotype was normal. Despite vitamin D repletion, iliac crest histology revealed severe osteomalacia. Exon 1 of TNFRSF11A (RANK), exons 2, 3, and 4 of LRP5, and all coding exons and adjacent mRNA splice junctions of TNFRSF11B (OPG), SQSTM1 (sequestosome 1), and TNSALP (tissue nonspecific alkaline phosphatase) were intact. His asymptomatic and less dysmorphic 5'11″ mother, also with low serum 25(OH)D, had milder clinical, radiological, biochemical, and histopathological findings. Both individuals were heterozygous for a novel 12-bp duplication (c.27&#95;38dup, p.L10&#95;L13dup) in exon 1 of TGFβ1, predicting four additional leucine residues in the latency-associated-peptide segment of TGFβ1, consistent with CED. The son was also homozygous for a single base transversion in TNFSF11, predicting a nonconservative amino acid change (c.107C > G, p.Pro36Arg) in the intracellular domain of RANKL that was heterozygous in his nonconsanguineous parents. This TNFSF11 variant was not found in the SNP Database, nor in published TNFSF11 association studies, but it occurred in four of the 134 TNFSF11 alleles (3.0%) we tested randomly among individuals without CED. Perhaps the unique phenotype of this CED family is conditioned by altered RANKL activity., (Copyright © 2011 American Society for Bone and Mineral Research.)

We report here on a 25-year follow-up of cranio-meta-diaphyseal dysplasia in a 31-year-old Caucasian male, who was reported in the literature at the age of 8 years [Langer et al. (1991); Skeletal Radiol 20:37-41]. He has hyperostotic craniofacial features with protruding lower jaw and midface hypoplasia. He has the typical radiographic features of wide long tubular bones without normal metaphyseal flaring and wide short tubular bones without normal diaphyseal constriction. We describe here his clinical and radiological findings and compare his case with those published in the literature. He is the oldest reported patient with this disorder giving some insight into the natural history of this rare skeletal dysplasia.

This case report describes an enchondroma of the distal phalanx of the right little finger in a 37-year-old woman with Camurati-Engelmann disease. Curettage of the tumor and artificial bone grafting were performed in May 2004. Surgical treatment resulted in a good clinical outcome with no evidence of recurrence at 5-year follow-up. The genetic relationships between Camurati-Engelmann disease and benign chondroid tumors are discussed.

We report four sporadic and three familial patients with Camurati-Engelmann disease. One patient had follow-up examinations over 8 years. Pain in the extremities and muscle weakness were common clinical symptoms. Most patients also had cranial nerve impairment, hepatosplenomegaly, a waddling gait, and elevated serum alkaline phosphatase levels. Long bones were affected in all. We discuss the differential diagnosis for this interesting bone entity.

Camurati-Engelmann disease (CED) is an autosomal dominant progressive diaphyseal dysplasia caused by mutations in the transforming growth factor-beta1 (TGFB1) gene. We report the first Korean family with an affected mother and son who were diagnosed with CED. The proband is a 19-yr-old male with a history of abnormal gait since the age of 2. He also suffered from proximal muscle weakness, pain in the extremities, and easy fatigability. Skeletal radiographs of the long bones revealed cortical, periosteal, and endosteal thickenings, predominantly affecting the diaphyses of the upper and lower extremities. No other bony abnormalities were noted in the skull and spine and no remarkable findings were seen on laboratory tests. The patient's mother had a long-standing history of mild limb pain. Under the impression of CED on radiographic studies, we performed mutation analysis. A heterozygous G to A transition at cDNA position +653 in exon 4 of the TGFB1 gene (R218H) was detected in the patient and his mother.

Camurati-Engelmann disease (CED) [OMIM 131300] is a rare autosomal dominant disorder characterized by bone pain and osteosclerosis affecting the diaphysis of long bones. It has been previously reported that CED is caused by mutations of the transforming growth factor beta 1 (TGF beta1) gene on chromosome 19q13.1-q13.3. Until now, seven mutations (LLL12-13ins, Y81H, R156C, R218C, R218H, H222D, C225R) in Australian, French, Belgian, Japanese, and European families have been reported and these data showed that there was no correlation between the nature of the mutations and the variability of the clinical manifestations. In this study, we found a Chinese family with CED and observed some intra-familial clinical variability and symptoms that became more severe with the age. A new TGF beta1 mutation (E169K) in exon 2 was identified in the Chinese family using polymerase chain reaction, direct sequencing analysis of PCR products and single-strand conformation polymorphism analysis. This mutation has not been previously reported in other countries in the world.

We describe a rare syndrome characterized by severe craniofacial hyperostosis, sclerosis, obliteration of paranasal sinuses and foramina of skull base, in a 10-year-old female child who presented with abnormal facial features and recurrent dacryocystitis due to narrowing of nasolacrimal duct.

Gnathodiaphyseal dysplasia (GDD) is an orthopedic condition involving cemento-osseous lesions of jaw bones, sclerosis, bowing of tubular bones, and overall bone fragility. This is a case report of GDD in which an 18-year-old female presented with a several-year history of bony abnormalities of the jaw and long bones. Radiographs demonstrated endosteal thickening, bowing of long bones, and abnormalities of the skull. These findings, along with the patient's known maxillary region cementoma, led to a diagnosis of GDD.

Diaphyseal medullary stenosis (DMS) is an extremely rare hereditary bone dysplasia, which was first described by Arnold in 1973. DMS has a high incidence of pleomorphic malignant fibrous histiocytoma (MFH). In this paper, we report the imaging findings of DMS with pleomorphic MFH of the bone, mainly describing 99mTc hydroxymethylenediphosphonate (HMDP) and thallium-201 (201Tl) chloride scintigraphy findings. On 99mTc HMDP scintigraphy, focal increased uptake area of the right femur corresponded to the area of bone marrow invasion of the tumor and bone infarction. The mechanism of the uptake of 99mTc HMDP to the extraosseous lesion was not clear. On 201Tl chloride scintigraphy, the increased uptake of the periphery of the mass seemed to reflect the aggressiveness of invasion and the cellularity.

Purpose: To report a rare case of craniodiaphysial dysplasia (CDD) that resulted in a profound loss of vision in both eyes., Design: Observational case report., Methods: A 2-year-old girl presented with midfacial anomaly. Marked thickening and sclerosis in the calvaria and facial bones were detected on the plain x-rays, which were compatible with CDD. Two years later, she visited our clinic because of visual loss in both eyes., Results: The visual acuity was light perception in both eyes. The optic disk swelling with temporal pallor was observed in her both eyes. Orbital computed tomography scan revealed near-total obliteration of the optic canal in both eyes., Conclusions: CDD is a severe bone disorder characterized by massive generalized hyperostosis and sclerosis, especially involving the facial bones. Bony encroachment on the cranial foramina causes optic nerve compression, and this may lead to progressive visual impairment and ultimately to blindness.

Camurati-Engelmann disease (CED) is a rare autosomal dominant type of bone dysplasia. This review is based on the unpublished and detailed clinical, radiological, and molecular findings in 14 CED families, comprising 41 patients, combined with data from 10 other previously reported CED families. For all 100 cases, molecular evidence for CED was available, as a mutation was detected in TGFB1, the gene encoding transforming growth factor (TGF) beta1. Pain in the extremities was the most common clinical symptom, present in 68% of the patients. A waddling gait (48%), easy fatigability (44%), and muscle weakness (39%) were other important features. Radiological symptoms were not fully penetrant, with 94% of the patients showing the typical long bone involvement. A large percentage of the patients also showed involvement of the skull (54%) and pelvis (63%). The review provides an overview of possible treatments, diagnostic guidelines, and considerations for prenatal testing. The detailed description of such a large set of CED patients will be of value in establishing the correct diagnosis, genetic counselling, and treatment.

Objective: To report a case of Camurati-Engelmann disease (CED) in conjunction with hypogonadism, an association that has not been previously described., Methods: We present the clinical, laboratory, and histopathologic features of our case. In addition, we review the molecular genetics of CED., Results: CED is a rare autosomal dominant disorder of the skeleton, characterized by bilaterally symmetric, progressive dysplasia of the bones. The typical features of this disorder are hyperostotic and sclerotic changes in the bones, primarily of the extremities. Our patient, a 49-year-old male resident of a nursing home, presented with muscle weakness, waddling gait, bone pain, and increased fatigability, usual features of CED (which had been formally diagnosed when he was 8 years old). He also had hyponatremia, hyperkalemia, and almost undetectable serum testosterone. The gene responsible for CED has been mapped to the same locus as the gene for the synthesis of transforming growth factor (TGF-b 1). Mutations in the TGF b 1 gene have been identified in patients with CED. TGF-b 1 also has an important role in reproductive function, both during embryogenesis and in adulthood. It has predominant effects on steroidogenesis as well as spermatogenesis. We discuss the hormonal and histopathologic changes in our patient and postulate that the association of CED with hypogonadism could be attributable to the impaired regulation of gonadal growth and steroidogenesis, in which TGF-b 1 has an important role., Conclusion: We propose that the association of CED with hypogonadism could be explained on the basis of a common underlying mutation in the TGF b 1 gene, leading to accumulation of excessive TGF-b 1.

We report on a 46-year-old mother of Moroccan origin, suffering mainly from painful, swollen legs, and her 26-year-old son who had experienced intense pain in his legs, without fever, for approximately 3 years. They did not have dysmorphic features or abnormal gaits. Radiographic studies of the mother revealed diaphyseal sclerosis of the tibia and spondylosis of the thoracal and lumbar vertebrae. The son had sclerosis of the diaphyses of the metacarpalia of the left hand, the femur and the fibula. The other parts of the skeleton were normal. Several osteosclerotic/hyperostotic disorders, such as melorheostosis (present mostly in sporadic cases and affecting lower extremities) and van Buchem's disease (autosomal recessive and commonly affecting the mandible) were considered as a diagnosis in the proposita. However, similar symptoms in the son of the proposita suggested an autosomal dominant inheritance pattern. This brought us to the diagnosis of progressive diaphyseal dysplasia (PDD) or Camurati-Engelmann disease (CED), an autosomal dominant disorder characterized by limb pain, reduced muscle mass, weakness, a waddling gait, progressive periosteal and endosteal sclerosis of the diaphyses of the long bones and sclerosis of the skull base. Mutations in the transforming growth factor (TGF)-beta1 gene on chromosome 19q13.1 have been reported to cause this disorder. The diagnosis of PDD/CED in this family was confirmed at the molecular level by detection of a C-to-T transition at position 466, leading to an arginine-to-cysteine amino acid change (position 156) in exon 2 of the transforming growth factor-beta1 (TGFB1) gene.

Ghosal-type hematodiaphyseal dysplasia has been first described in 1986, as a steroid-dependent anemia with endosteal broadening of the long bone's diaphyses and metaphaphyses, which makes a distinction with the periosteal reaction in Camuratti-Engelmann's disease and with Caffey's disease. Extreme pallor is first noticed and leads to search for palpable thick long bones that are not always clinically obvious. The transmission of this rare entity seems to be autosomal recessive, with a common racial background from the Middle East and the Indian subcontinent. Anemia is considerably improved by steroids, which allow to avoid blood cells transfusions, but a minimum maintenance dose is necessary to keep the hemoglobin at a normal level probably during the whole life, involving iatrogen complications. The mechanism of anemia and the genetic cause of the disease are yet unknown.