[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.

Clinical characteristics and the influence of rs1800470 in patients with Camurati-Engelmann disease.

Background: Camurati-Engelmann disease (CED) is a sclerosing bone dysplasia caused by transforming growth factor ß1 (TGFB1) gene variants. Objective: We aim to summarize the clinical characteristics and the efficacy of glucocorticoids in 14 individuals with CED, and explore the correlation between the phenotype and the SNP of rs1800470 (c.29C>T). Methods: Clinical, biochemical, radiological, and therapeutic data were collected from 14 patients. DNA was extracted for TGFB1 variants detection by Sanger sequencing. Results: The median onset and record age were 3.0 and 16.1 years, respectively. All patients manifested bone pain and decreased subcutaneous fat tissue. Inflammatory markers increased in over 60% of patients, and the median erythrocyte sedimentation rate (ESR) was 1.40 (0.50~3.67) of the upper limit of normal (ULN), and the median high sensitivity C reactive protein (hsCRP) was 1.71 (0.48~12.56) of ULN. There was a positive correlation between ESR and hsCRP (rs=0.806, p=0.003). Both ESR and hsCRP were negatively correlated with the levels of hemoglobin (HGB), calcium, and creatinine, but positively correlated with the level of alkaline phosphatase. Four known variants of TGFB1 were identified, including p.Tyr171Cys, p.Arg218Cys, p.Arg218His, and p.Cys225Arg. Moreover, 35.7% and 28.6% of them carried the heterozygous and homozygous SNP of c.29C>T, called C/T and T/T groups, respectively, but 35.7% of them were without c.29C>T (C/C group). The onset age, anthropometric data, percentages of different clinical manifestations, and biochemical parameters were comparable among the three groups. But there were increasing trends in levels of HGB and calcium and decreasing trends in ESR and hsCRP among C/C, C/T, and T/T groups in turn. Glucocorticoid improves the two inflammatory markers among CED patients. Conclusion: The phenotype of CED is highly heterogeneous. There is no clear genotype-phenotype correlation, but it seems to have better trends of biochemical parameters in patients with CED carrying the T allele of rs1800470.

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.

Genetic testing is useful in adults with limited phenotypes of genetic skeletal conditions.

We show the value of genetic screening in 3 adults with limited phenotypes of three bone sclerosing genetic disease (GD): osteopetrosis (OPT), Camurati-Engelmann disease (CED) and pycnodysostosis. INTRODUCTION: OPT, CED and pycnodysostosis are three rare bone diseases often diagnosed in childhood. However, some atypical phenotypes raise the problem of delayed diagnosis in adults. Genetic tests may then be useful to establish a formal diagnosis. METHODS: We report 3 cases of adult patients with symptomatic or asymptomatic bone sclerosing lesions for whom the clinical, radiological and biological explorations were atypical and did not allow a formal diagnosis. These unusual descriptions led to the search for genetic mutations. RESULTS: These 3 cases of limited phenotypes were associated with unknown or poorly described variants of 3 rare bone genetic diseases. CONCLUSIONS: Genetic tests proved useful to establish the diagnosis and manage the condition of adults with rare bone sclerosing GD.

Angioid streaks in a case of Camurati-Engelmann disease.

Camurati-Engelmann disease (CED) is a rare autosomal dominant disease with various phenotypic expressions. The hallmark of the disease is bilateral symmetric diaphyseal hyperostosis of the long bones with progressive involvement of the metaphysis. Ocular manifestations occur rarely and mainly result from bony overgrowth of the orbit and optic canal stenosis. We report a case of CED showing angioid streaks (ASs) in both fundi with no macular involvement and discuss the possible theories of the pathogenesis of AS in this disease.

Clinical diagnosis and mutation analysis of a Chinese family with Camurati-Engelmann disease.

Camurati-Engelmann disease (CED) is a rare autosomal dominant bone disorder caused by a mutation in transforming growth factor ß1 (TGFß1). The present study aimed to identify a Chinese family with suspected CED based on the clinical symptoms, including pain in extremities, waddling gait, muscle weakness, cortical thickening of the diaphysis of the long bones, and sclerosis of the skull, facial bone, and pelvis. Molecular analysis revealed the presence of the p.Glu169Lys (E169K) mutation in exon 2 of TGFß1 in patients when compared with the controls. Therefore, the Chinese family was diagnosed with CED due to the presence of the E169K mutation. The present study emphasized the importance of clinical and genetic evidence for the diagnosis of CED. The data presented in the present study are of significance to clinicians, as well as genetic counselors, in the prenatal screening of CED.

Mild Camurati­Engelamann disease presenting with exophthalmos as the first and only manifestation: A case report.

Camurati-Engelmann disease (CED; MIM 131300), or progressive diaphyseal dysplasia, is a rare autosomal dominant bone disease, which is caused by mutations in the transforming growth factor­ß1 (TGFß1) gene on chromosome 19q13.1­13.3. Extremely variable penetrance has been reported to be associated with CED, the most common features of which are limb pain, waddling gait and muscle weakness. The present study reported on a consanguineous Chinese family with one affected individual that initially presented with exophthalmos, which has not previously been reported as an initial manifestation of CED. The proband was a 22-year-old woman that presented with progressive proptosis. Except for increased serum levels of alkaline phosphatase and C­terminal telopeptide of type I collagen, no other biochemical abnormalities were detected. Whole­body radiological and bone scintigraphic investigations revealed that hyperostosis and sclerosis predominantly affected the cranial bones, including the skull base, and only mildly affected the long bones. A heterozygous mutation involving a G to A transition at the cDNA position +653 of TGFß1 was detected in the patient only, but not in her family members, by automated DNA sequencing using an ABI DNA sequencer (Model 377). Based on the clinical, biochemical, radiological and genetic findings, a diagnosis of CED was confirmed. Considering the phenotypic variability associated with CED and the unique manifestations of the patient described in the present study, CED should be taken into account regarding the differential diagnosis of exophthalmos.

[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.

Bilateral papilloedema in Camurati-Engelmann disease.

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.

Miscellaneous Bone Disorders.

This chapter deals with a few of the important childhood bone disorders associated with high bone mass as well as conditions associated with fragility fractures and limb deformities that have not been addressed in previous chapters. A couple of skeletal dysplasias that can sometimes be confused with rickets are also dealt with in this chapter.

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: a case report]. / Doença de Camurati-Engelmann: um caso clínico.

Camurati-Engelmann disease (CED) or progressive diaphyseal dysplasia is a rare autosomal dominant hereditary disorder, characterized by symmetrical progressive sclerosis of long bones cortical diaphysis. Its presentation and progression is extremely variable. A patient of 42 years is followed in Physical Medicine and Rehabilitation (PMR) consultation for 7 years. He presented with pain in anterior thighs and legs, decreased muscle strength and functional disability. The disease was diagnosed 10 years ago based on radiological and histological examination of bone and genetic study. This patient had hypoacusis, exophthalmos and facial asymmetry, broad-based and waddling gait, and quadriceps atrophy. He has been treated with corticosteroids, non steroidal anti-inflammatory drugs (NSAIDs) and proton pump inhibitors (PPIs), and performs rehabilitation program for periods with pain symptomatic relief and mantenance of function.

Camurati-Engelmann disease with obesity in a newly identified family carrying a missense p.Arg156Cys mutation in the TGFB1 gene.

We report on a family affected by Camurati-Engelmann disease, characterized by radiological signs limited to the tibia, and associated with overweight or obesity, which is not a known feature of this disorder. The affected patients were heterozygous for a c.466C > T mutation (which predicts p.Arg156Cys) in the latency associated protein (LAP)-coding domain of the TGFB1 gene. This mutation had previously been reported once in another family with a similar, atypical phenotype, which suggests a possible phenotype/genotype relationship.

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.