Proband and the Brother.

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.

Significant Improvement After Surgery for a Symptomatic Osteoblastoma in a Patient with Camurati-Engelmann Disease: Case Report and Literature Review.

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.

Camurati-Engelmann Disease.

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 TGFß-1 gene and expected to or thought to disrupt the binding between TGFß1 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.

Ribbing disease: a systematic review.

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.

Discrepancy between bone density and bone material strength index in three siblings with Camurati-Engelmann disease.

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.

Treatment of Ribbing disease with 5-year follow-up and literature review.

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.

Latent TGF-ß structure and activation.

Transforming growth factor (TGF)-ß is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-ß1 requires the binding of α(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-ß binding proteins. Crystals of dimeric porcine proTGF-ß1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between α(v)ß(6) integrin and the prodomain is insufficient for TGF-ß1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-ß family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.

A Rare Sporadic Case of Camurati-Engelmann Disease With Jaw Involvement.

Camurati-Engelmann disease (CED), or progressive diaphyseal dysplasia, is an uncommon bone dysplasia that is inherited in an autosomal-dominant pattern. The disease mainly affects the diaphyses of the long bones but can induce sclerotic changes to the facial skeleton and skull base. The diagnosis of CED is based on clinical and radiologic features. This article presents the clinical and radiologic characteristics of the jaws as visualized on cone-beam computed tomograms of a 46-year-old woman diagnosed with CED.

Reduced Dentin Matrix Protein Expression in Camurati-Engelmann Disease Transgenic Mouse Model.

UNLABELLED: Overexpression of transforming growth factor-ß1 (TGF-ß1) has been shown to lead to mineralization defects in both the enamel and dentin layers of teeth. A TGFB1 point mutation (H222D), derived from published cases of Camurati-Engelmann disease (CED), has been shown to constitutively activate TGF-ß1, leading to excess bone matrix production. Although CED has been well documented in clinical case reports, there are no published studies on the effect of CED on the dentition. The objective of this study was to determine the dental manifestations of hyperactivated TGF-ß1 signaling using an established mouse model of CED-derived TGF-ß1 mutation. Murine dental tissues were studied via radiography, micro-CT, immunohistochemistry, and qRT-PCR. Results showed that initial decreased dental mineralized tissue density is resolved. Proliferation assays of incisor pulp and alveolar bone cell cultures revealed that cells from transgenic animals displayed a reduced rate of growth compared to alveolar bone cultures from wild-type mice. TGF-ß family gene expression analysis indicated significant fold changes in the expression of Alpl, Bmp2-5, Col-1, -2, -4, and -6, Fgf, Mmp, Runx2, Tgfb3, Tfgbr3, and Vdr genes. Assessment of SIBLINGs revealed downregulation of Ibsp, Dmp1, Dspp, Mepe, and Spp1, as well as reduced staining for BMP-2 and VDR in mesenchymal-derived pulp tissue in CED animals. Treatment of dental pulp cells with recombinant human TGF-ß1 resulted in increased SIBLING gene expression. CONCLUSIONS: Our results provide in vivo evidence suggesting that TFG-ß1 mediates expression of important dentin extracellular matrix components secreted by dental pulp, and when unbalanced, may contribute to abnormal dentin disorders.

Multiple diaphyseal sclerosis (Ribbing disease): what about neridronate?

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.

[Camurati-Engelmann disease].

Camurati-Engelmann disease (CAEND, OMIM 131300) is a rare autosomal dominant, progressive diaphyseal dysplasia, which is characterized by hyperosteosis and sclerosis of the diaphyses of long bones. Estimated number of patients with CAEND in Japan is approximately 50-60 by our epidemiological survey. We have reported that domain-specific mutations in transforming growth factor-ß1 gene(TGFB1) cause CAEND. Mutations in latency associated peptide(LAP) domain of TGF-ß1 destabilize the complex and may hyperactivate TGF signal pathway. We tried to establish CAEND model mice by gene-targeting, but could not because of spermatogenesis defects in chimera mice. We also failed using CRISPR/Cas9 system. Alternatively, we established CAEND patient-derived iPS cells, and are advancing research with them to develop novel therapeutic agents for CAEND.

Camurati-Engelmann disease (progressive diaphyseal dysplasia): reports of an Indian kindred.

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-ß1 (TGFß1) 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 TGFß1 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 TGFß1 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.

Positive effects of an angiotensin II type 1 receptor antagonist in Camurati-Engelmann disease: a single case observation.

Camurati-Engelmann disease is characterized by hyperostosis of the long bones and the skull, muscle atrophy, severe limb pain, and progressive joint contractures in some patients. It is caused by heterozygous mutations in the transforming growth factor ß1 (TGFß1) believed to result in improper folding of the latency-associated peptide domain of TGFß1 and thus in increased or deregulated bioactivity. Losartan, an angiotensin II type 1 receptor antagonist, has been found to downregulate the expression of TGFß type 1 and 2 receptors. Clinical trials with losartan have shown a benefit in Marfan syndrome, while trials are underway for Duchenne muscular dystrophy and other myopathies associated with TGFß1 signaling. We hypothesized that due to its anti-TGFß1 activity, losartan might be beneficial in Camurati-Engelmann disease. This report concerns a boy who presented at age 13 years with severe limb pain and difficulty in walking. Clinical and radiographic evaluation results were compatible with Camurati-Engelmann disease and the diagnosis was confirmed by mutation analysis (c.652C > T [p.Arg218Cys]). The boy underwent an experimental treatment with losartan at a dosage of 50 mg/day, orally. During the treatment period of 18 months, the intensity and frequency of limb pain decreased significantly (as shown by a pain diary), and muscle strength improved, allowing the boy to resume walking and climbing stairs. No obvious side effects were observed. We cautiously conclude that TGFß1 inhibition with losartan deserves further evaluation in the clinical management of Camurati-Engelmann disease.

Camurati-Engelmann disease in a family from Croatian Island: an old bone scan confirmed pattern of inheritance.

34-year old patient had history of muscular wasting, easy fatigability, pain in extremities and waddling gait since age of four. During the time, neuromuscular disease was suspected, but not confirmed. Elevated bone alkaline phosphatase as well as other bone turnover markers (osteocalcin, procollagen, telopeptide) indicated further skeletal evaluation. Symmetrical enhanced uptake on technetium methylene diphosphonate [99mTc]MPD bone scintigraphy at diaphyses of longitudinal bones and scull matched cortical thickening of long bones and sclerosis of the scull seen at radiograms. Those findings pointed to Camurati-Engelmann disease misdiagnosed for the long time. This rare genetic autosomal dominant disorder was retrospectively diagnosed in asymptomatic father too on the basis of bone scans done long time ago. Old family member scans confirmed heredity pattern of the disease.

Unveiling the uncommon: diagnostic journey of camurati-engelmann disease in a pediatric patient.

BACKGROUND: Camurati-Engelmann disease (CED), also known as progressive diaphyseal dysplasia, is a rare genetic disorder characterized by abnormal thickening of the long bones' diaphysis. This condition is caused by mutations in the transforming growth factor beta-1 (TGFB-1) gene and is typically inherited in an autosomal dominant pattern. Patients with CED often present with symptoms such as chronic bone pain, muscle weakness, fatigue, and difficulty walking. CASE PRESENTATION: We report a 30-month-old boy who presented with gait abnormality. Initially, toxic synovitis was considered, and non-steroidal anti-inflammatory (NSAI) treatment was administered. The patient did not respond to NSAI treatment. Direct radiographs showed diaphyseal thickening, especially in the long bones. Radiologically, CED was suspected, and clinical exome sequencing identified a TGFB-1: c1121C > G (Pro374Arg) heterozygous mutation, which was interpreted as a possible pathogenic variant for CED. A clinical, radiologic, and genetic diagnosis of CED was made. CONCLUSION: Due to its rarity and variable clinical presentation, the diagnosis of CED can be challenging and often requires a high index of suspicion. Early and accurate diagnosis is crucial for managing symptoms and improving patients' quality of life.

Osteosclerotic disease and bone cyst in a prehispanic burial from Las Cañadas del Teide (Tenerife, Canary Islands).

Skeletal remains of two prehispanic male adult individuals (antiquity ≈ 550 BP) recovered from a burial cave located in Montaña Blanca (Las Cañadas del Teide) at an altitude of 2450 m above sea level, in the highlands of Tenerife (Canary Islands) showed some unusual features. Femora and tibiae of both individuals showed increased bone density, with irregular thickening of the midshaft diaphyses. One individual showed a cystic lesion in the distal third of the left femoral diaphysis, surrounded by a subtle sclerotic reaction of the spongiosa and a thin cortex that was partially fractured. Periosteal thickening was present, but not around the cystic lesion. A thoracic vertebra with rachischisis was also recovered. The bone density of vertebrae and iliac bones were normal, and one recovered jaw was also normal. The tibiae of one individual showed an abnormal location of the foramen nutritium. Hypoplasia of the lesser trochanter and an abnormally thin left femoral neck were also observed. It is possible that both individuals were affected by diaphyseal dysplasia (possibly Camurati Engelmann or Ribbing disease). One of them also showed a lesion compatible with a unicameral bone cyst. The alternative possibility of a Klippel-Trenaunay-Weber disease, with a bone aneurysmal cyst, also exists.