[Ribbing disease: apropos of a case]. / Enfermedad de Ribbing: a propósito de un caso.

Ribbing's disease is a rare form of sclerosing bone dysplasia characterized by exuberant yet benign endosteal bone, and periosteum formation in the diaphysis of long bones. Diagnosis relies on exclusionary criteria, as the primary clinical manifestations entail progressive pain unresponsive to analgesic therapy, accompanied by serological markers within normal ranges. Pain management constitutes the cornerstone of treatment, with surgery appearing to offer the most efficacious approach, despite the absence of a standardized therapeutic algorithm. The diagnostic and therapeutic delays associated with Ribbing's disease, reaching up to 16 years, exert a profound impact on patients' quality of life. Hence, the purpose of our work is to present a case report of Ribbing's disease and conduct a comprehensive literature review on the subject matter.

La enfermedad de Ribbing es una forma rara de displasia ósea esclerosante caracterizada por una formación exuberante, aunque benigna, de hueso endóstico y periostio en la diáfisis de los huesos largos. El diagnóstico se basa en criterios de exclusión, ya que las manifestaciones clínicas principales implican dolor progresivo que no responde a analgésicos, acompañado de marcadores serológicos normales. El manejo del dolor constituye la piedra angular del tratamiento y la cirugía parece ofrecer el enfoque más efectivo, a pesar de no contar con un algoritmo terapéutico estandarizado. Los retrasos diagnósticos y terapéuticos asociados con la enfermedad de Ribbing, que pueden alcanzar hasta 16 años, impactan profundamente en la calidad de vida de los pacientes. Por lo tanto, el propósito de nuestro trabajo es presentar un reporte de caso de la enfermedad de Ribbing y realizar una revisión bibliográfica exhaustiva sobre el tema.

Improvement of Bone Health and Initiation of Puberty Development in Camurati-Engelmann Disease With Glucocorticoid and Losartan Treatment: A Case Report and Review of Literature.

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 TGFß1 in CED, improve adipogenesis, and thus initiate puberty development and improve the bone mass in spine and hip.

Looking for the skeleton in the closet-rare genetic diagnoses in patients with diabetes and skeletal manifestations.

AIMS: The precision medicine approach of tailoring treatment to the individual characteristics of each patient has been a great success in monogenic diabetes subtypes, highlighting the importance of accurate clinical and genetic diagnoses of the type of diabetes. We sought to describe three unique cases of childhood-onset diabetes in whom skeletal manifestations led to the revelation of a rare type of diabetes. METHODS : Case-scenarios and review of the literature. RESULTS: Case 1: A homozygous mutation in TRMT10A, a tRNA methyltransferase, was identified in a 15-year-old boy with new-onset diabetes, developmental delay, microcephaly, dysmorphism, short stature and central obesity. The progressive apoptosis of pancreatic beta cells required insulin replacement therapy, with increased demand due to an unfavorable body composition. Case 2: Congenital generalized lipodystrophy type 1 was suspected in an adolescent male with an acromegaloid facial appearance, muscular habitus, and diabetes who presented with a pathological fracture in a cystic bone lesion. A homozygous mutation in AGPAT2, an acyl transferase which mediates the formation of phospholipid precursors, was identified. Leptin replacement therapy initiation resulted in a remarkable improvement in clinical parameters. Case 3: A 12-year-old boy with progressive lower limb weakness and pain was diagnosed with diabetic ketoacidosis. Diffuse diaphyseal osteosclerosis compatible with the diagnosis of Camurati-Engelmann disease and a heterozygous mutation in TGFß1 were identified. Preservation of euglycemia by insulin replacement relieved pain, suggesting that the diabetic milieu may have augmented TGFß1 overexpression. CONCLUSION: Unraveling the precise genetic cause for the clinical manifestations led to the prediction of phenotypic manifestations, and enhanced the clinical outcomes.

Bone pain management with opioid medication in a patient with Camurati-Engelmann disease: a case report / Manejo del dolor óseo con medicación opioide en una paciente con enfermedad de Camurati-Engelmann: reporte de un caso

Introduction: Camurati-Engelman Disease is a rare genetic sclerosing bone dysplasia with periosteal and endosteal thickening of the cortical of the long bones. It generates pain secondary to the reduction of the medullary canal that is usually controlled with corticosteroids and, in severe cases, with surgical decompression. Case history: We present the case of a woman with a genetic diagnosis of Camurati-Engelman Disease with poor pain control with corticosteroid management and surgical procedures throughout her childhood and early adulthood. In whom optimal pain control was achieved with pain regimen with hydrocodone analgesic management. This is the first case described in the literature for adequate pain control using an opioid drug. Discussion: CE disease is an extremely rare genetic entity with little more than 300 cases reported in the world. It is generated by an alteration in the gene for growth factor-beta 1 (TGF-B1); it has a varied clinical presentation that can begin with bone alterations accompanied by muscle weakness, joint angular alterations, headache, and nerve compressions. It has a differential diagnosis with some genetic entities that may present clinical similarity, but its morphological and radiological characteristics are distinctive. The usual management of bone pain generated by this entity is based on corticosteroids, in addition to losartan or surgical intervention aimed at reducing cortical changes. The intervention with opioid analgesics accompanied by a rehabilitation plan is not a frequent report, this being a case of success due to the refractoriness of the symptoms in a patient with chronic pain, with a positive impact on her functionality and quality of life. Conclusion: It is considered that analgesic management with opioids may be a treatment option in patients with Camurati-Engelman disease refractory to corticosteroid management and surgical interventions.(AU)

Introducción: La enfermedad de Camurati-Engelman (CE) es una displasia ósea esclerosante rara, de causa genética. Se presenta con engrosamiento perióstico y endóstico de la cortical de los huesos largos. Genera dolor secundario a la reducción del canal medular, que habitualmente se controla con corticoides y en casos severos, con descompresión quirúrgica. Historia del caso: Presentamos el caso de una mujer con diagnóstico genético de enfermedad de Camurati-Engelman, con mal control del dolor, con manejo de corticosteroides y procedimientos quirúrgicos a lo largo de su niñez y adultez temprana. Se logró un control óptimo del dolor con un régimen con manejo analgésico con hidrocodona. Este es el primer caso descrito en la literatura de un adecuado control del dolor con un medicamento opioide. Discusión: La enfermedad de CE es una entidad genética extremadamente rara, con poco más de 300 casos reportados en el mundo. Se genera por una alteración en el gen del factor de crecimiento beta 1 (TGF-B1). Tiene una presentación clínica variada que puede iniciar con las alteraciones óseas acompañado de debilidad muscular, alteraciones angulares articulares, cefalea y compresiones nerviosas. Tiene diagnóstico diferencial con algunas entidades genéticas que pueden presentar similitud clínica, pero su característica morfológica y radiológica es distintiva. El manejo usual del dolor óseo generado por esta entidad se basa en corticoesteroides, además de losartán o intervenciones quirúrgicas orientadas a disminuir los cambios corticales. La intervención con analgésicos opioides, acompañada de un plan de rehabilitación, no es un reporte frecuente, siendo este un caso de éxito ante la refractariedad de los síntomas en una paciente con dolor crónico, impactando de manera positiva en su funcionalidad y calidad de vida.(AU)

Efficacy of denosumab therapy after alendronate treatment for a 66-year-old woman with Camurati-Engelmann disease and osteoporosis: a case report.

Camurati-Engelmann disease (CED) is characterized by hyperostois of multiple long bones. Although several treatments for CED complicated with osteoporosis have been described, it remains controversial whether such therapy is suitable for osteoporotic CED patients. We retrospectively enrolled a 66-year-old female patient with osteoporosis in CED who underwent denosumab therapy for 14 months. Denosumab was commenced after 3 years of alendronate treatment. Fourteen months later, lumbar and total hip bone mineral density showed gains of 5.9% and 6.4%, respectively. Bone turnover markers were also improved during follow-up. No fractures or other complications were recorded during the observational period. This is the first study describing denosumab treatment for an osteoporotic CED patient. Our findings indicate that denosumab is an effective therapy option for osteoporosis in CED.

Bone-targeted delivery of TGF-ß type 1 receptor inhibitor rescues uncoupled bone remodeling in Camurati-Engelmann disease.

Camurati-Engelmann disease (CED) is a genetic bone-modeling disorder mainly caused by mutations in the gene that encodes transforming growth factor-ß1 (TGF-ß1). Symptoms of CED include bone pain, fractures, and dysplasia. Currently, effective therapies for bone fracture and dysplasia in CED are urgently needed. We have demonstrated that TGF-ß1 is a coupling factor for bone remodeling and is aberrantly activated in CED. Daily injection of TGF-ß type 1 receptor inhibitor (TßR1I) attenuated CED symptoms, but this systemic administration caused serious side effects. In this study, we created a conjugate linking TßR1I and alendronate, which delivered TßR1I specifically to bone. After weekly injection of the conjugate for 8 weeks, normal bone morphology and remodeling in CED mice was maintained with a minimum effective dose 700 times lower than TßR1I injection. Additionally, we found that the conjugate restored normal bone turnover by reducing the number of osteoblasts and osteoclasts, maintained a regular osteogenic microenvironment by regulating the formation of CD31 and Endomucin double-positive vessels, and preserved ordinary bone formation via inhibition of the migration of leptin-receptor-positive cells. Thus, targeting delivery of TßR1I to bone is a promising therapy for CED and other uncoupled bone remodeling disorders.

Imaging features and differential diagnosis of multiple diaphyseal sclerosis: A case report and review of literature.

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.

Pain improvement in Camurati-Engelmann disease after anti-TNFα therapy.

Camurati-Engelmann disease (CED) is a rare disorder included in the group of craniotubular hyperostosis diseases. Corticosteroids are used for pain management in CED, but in refractory or corticosteroid-non-tolerant patients, pain management is limited. We report the case of a woman with CED diagnosed in early infancy whose initial complaints included persistent bone pain associated with progressive functional disability. She was treated with steroids but over time became dependent on higher doses with only mild pain relief. In her third decade, she was diagnosed with ulcerative colitis (UC) and was treated with mesalazine, azathioprine and prednisolone. Due to recurrent exacerbations of UC, treatment was changed to infliximab, an antitumour necrosis factor-alpha (TNFα). Remission of UC was achieved and CED-associated pain also improved with infliximab. This is the first report showing a possible role of anti-TNFα in pain management in CED with unsatisfactory response to steroids.

Camurati-Engelmann disease-a rare cause of tetany identified on bone scintigraphy: A case report.

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.

Enfermedad de Camurati-Engelmann / Camurati-Engelmann disease

No disponible

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.

Elimination of pain and improvement of exercise capacity in Camurati-Engelmann disease with losartan.

BACKGROUND: Camurati-Engelmann disease (CED) is a rare disorder, with approximately 250 described cases in the literature. Treatment options are limited and have been suboptimal so far. PATIENT AND METHODS: A prepubertal girl aged 9 years was diagnosed with CED. Treatment with losartan was initiated at a daily dose of 0.75 mg/kg. Over a period of 12 weeks, the dose was gradually increased to 1.0 mg/kg/d. The patient was reviewed in clinic regularly and underwent thorough clinical assessments 9, 17, and 38 months after treatment initiation. RESULTS: The patient experienced marked clinical improvements with losartan. In particular, losartan treatment led to the complete elimination of the previously severe and incapacitating pain, with an increased ability to walk and perform physical activities. There was also a considerable improvement in body composition with increased lean and adipose tissue. Notably, the improvement in fat deposition had not been previously observed with other treatments in CED. Hematology, liver, and renal function tests were within normal ranges at presentation and remained so over the course of treatment. CONCLUSIONS: In light of our findings, losartan may be a useful option in CED management.

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.

Treatment responses in five patients with Ribbing disease including two with 466C>T missense mutations in TGFß1.

OBJECTIVE: To assess 5-year treatment responses and TGFB1 gene abnormalities in five patients with ribbing disease. METHODS: PCR analysis and bidirectional sequencing of TGFß1 exons 1 through 7 were performed in all five patients. RESULTS: The five patients, four women and one man with a mean age of 34 years at symptom onset, shared the following features: severe diaphyseal pain predominating in the lower limbs with diaphyseal hyperostosis; increased radionuclide uptake at sites of pain and, in some cases at other cortical sites; asymmetric or asynchronous lesions; long symptom duration (5-18 years) despite a variety of treatments; and a delay of several years (2-15) between symptom onset and the diagnosis. Of our five patients, two had a heterozygous missense mutation in exon 2 of TGFß1 (c.466C>T, p.Arg156Cys, previously described in Camurati-Engelmann syndrome) and three had commonly found TGFß1 polymorphisms. Intravenous bisphosphonate therapy was used in all five patients but induced substantial improvements in a single patient. Of the three patients given bolus methylprednisolone therapy, two experienced a lasting response; the exception was one of the two women with a TGFß1 mutation. CONCLUSION: Considerable heterogeneity in the clinical presentations, genetic abnormalities, and treatment responses contribute to the diagnostic challenges raised by ribbing disease. Detailed genetic studies are needed.

Camurati-Engelmann disease--a rare cause of bone pain.

OBJECTIVE: Camurati-Engelmann disease or progressive diaphyseal dysplasia is a rare autosomal dominant disease characterized by cortical thickening of the long-bone diaphyses accompanied by waddling gait, muscular weakness, hearing loss and chronic skeletal pain. We describe two cases of Camurati-Engelmann disease with differing presentations and review of the literature on several therapeutic options. METHODS: We present two cases of Camurati-Engelmann disease which responded to different medical therapies. Various diagnostic tests including radiographs, bone scan and genetic analysis are also described. RESULTS: These cases responded differently to the treatment options and provide an insight into the variable response of the disease. CONCLUSION: Diagnosis of this disorder is based on the clinical history, family history, clinical examination and imaging results. Recently genetic testing has become available for TGF-beta1 mutation Several therapeutic agents including biphosphonates, NSAIDs, prednisone and losartan have been described as therapeutic options with mixed results, as described in our cases.

Ribbing disease: a case report and literature review.

Ribbing disease (RD) is a rare bone dysplasia characterized by benign endosteal and periosteal new bone formation confined to the diaphysis of the long bones of the lower extremities in young adults. The etiology and optimal treatment for the disease are unknown. It is often initially diagnosed as a low-grade osteomyelitis or a bone-forming neoplasia. It may also be confused with other causes of increased bone density. The onset is usually after puberty and the most common presenting symptom is pain that does not resolve with medical treatment and sometimes is intolerable. We report the case of a 22-year old woman with clinical and radiological manifestations of RD. In spite of different medical treatment modalities, pain did not resolve and the patient consulted multiple physicians. Intramedullary reaming of the tibia was performed to relieve the severe pain. To the authors' knowledge, in this report we present a case of RD for the third time in the orthopaedic literature and also she is the second case in the English literature to undergo a definite surgical treatment modality as intramedullary reaming for the solution of her pain. Owing to the rarity of the disease we aimed to report the complete findings of our encounter with the disease and to emphasize the role of an orthopaedic surgeon in consultation and intervention for the treatment of intolerable pain which is the most important symptom of this disease.