RARE DISEASE
Camurati-Engelmann disease
Camurati-Engelmann disease
Camurati-Engelmann disease
Synonyms: Progressive diaphyseal dysplasia
Synonyms: Progressive diaphyseal dysplasia
Synonyms: Progressive diaphyseal dysplasia
Drug discovery
1
drug
With orphan designation
Overview
Camurati-Engelmann disease (CED) is a rare autosomal dominant skeletal dysplasia caused by TGFB1 gene mutations, leading to progressive hyperostosis of long bones, skull, and pelvis. Clinically, it manifests with limb pain, muscle weakness, waddling gait, and potential cranial nerve compression causing vision/hearing loss. Symptom onset typically occurs before age 30, with variable penetrance. Management includes corticosteroids for symptom relief, losartan for TGFβ-1 inhibition, and physical therapy, though no curative therapies exist [1][3][9][10][17].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare genetic diseases
Research Papers
84 drug discovery papers about Camurati-Engelmann disease, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
84 drug discovery papers about Camurati-Engelmann disease, with 1 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-06-17 | Camurati-Engelmann Disease: A Narrative Review of Clinical Features, Molecular Pathogenesis, Diagnosis, and Emerging Targeted Therapies
Camurati-Engelmann Disease (CED) is a very rare, autosomal-dominant type sclerosing bone dysplasia that is characterised by progressive diaphyseal hyperostosis, cortical thickening of long bones, along with variable involvement of skull-base. This narrative review synthesises the current evidence regarding clinical features, molecular basis, diagnosis, as well as management strategies of CED. Clinically, patients having CED, usually present in childhood or adolescence age with chronic pain in limbs, proximal muscle weakness, fatigability, along with a waddling gait, while cranial hyperostosis may lead to hearing impairment, cranial nerve deficits, or raised intracranial pressure. Pathogenic heterozygous mutations in Transforming Growth Factor Beta 1 (TGFB1), also less commonly Transforming Growth Factor Beta 1 (TGFB2), can cause disruption of the latency-associated peptide domain of TGF-β, which can result in excessive TGF-β activation along with downstream dysregulation of bone remodeling pathways. Diagnosis of CED primarily depends upon identification of typical clinical features, characteristic imaging findings of symmetric diaphyseal sclerosis, also definitive confirmation although is done using genetic testing. Management of CED is usually symptomatic, which is inclusive of analgesics, glucocorticoids, and emerging usage of angiotensin II receptor blockers such as losartan. Surgical decompression is usually reserved only for few cases which present with skull-base complications. Novel therapeutic strategies that target TGF-β axis, including receptor inhibitors, ligand traps, as well as Rho-GTPase pathway modulators, also represent promising options as disease-modifying treatment. Improved understanding of various molecular mechanisms for CED along with long-term clinical outcomes is essential for enhancing patient care and quality of life. This narrative review article focuses on uniquely merging updated molecular insights on dysregulated TGF-β signalling along with contemporary diagnostic algorithms, emerging targeted therapies, thus providing a consolidated, clinically oriented framework which is currently lacking in existing literature about CED.
2026-04-08 | Camurati-Engelmann disease with bilateral proptosis and optic neuropathy: a case report and literature review.
Camurati-Engelmann disease (CED) is a rare autosomal dominant skeletal disorder caused by mutations in the TGFB1 gene and is characterized by progressive diaphyseal widening and cortical thickening of long bones. A 29-year-old woman presented with bilateral proptosis, hypothyroidism and a 15-year history of hearing loss and limb pain. Superior visual field defects were detected on automated perimetry. Orbital computed tomography demonstrated orbital apex crowding and narrowing of the optic canals caused by skull hyperostosis, raising concern for compressive optic neuropathy. Imaging revealed systemic skeletal abnormalities, including macrocephaly, mandibular overgrowth, and cortical thickening of multiple bones. Genetic testing confirmed a pathogenic TGFB1 mutation, establishing the diagnosis of CED. Treatment with zoledronic acid, methotrexate, and hormone replacement therapy improved bone metabolism and relieved bone pain at the six-month follow-up. At one-year follow-up, optical coherence tomography showed reduced peripapillary retinal nerve fiber layer thickness (mean 66 μm in both eyes), accompanied by mild progression of visual field defects. Orbital apex decompression with possible optic canal decompression was considered if visual function declined further. This case highlights the potential for orbital involvement and compressive optic neuropathy in CED and underscores the importance of multidisciplinary management and regular ophthalmologic monitoring.
2025-08-13 | Identification of a novel TGFB1 variant in a patient with Camurati-Engelmann disease responsive to alendronate
Whole genome sequencing and alendronate may be of value in diagnosing and managing CED, respectively.
2025-04-10 | Transforming growth factor, beta-2 gene mutation causes autosomal dominant Camurati-Engelmann disease, type 2 (OMIM % 606631).
Camurati-Engelmann disease, type 1 (CED1, OMIM # 131300) is the rare autosomal dominant skeletal dysplasia caused by select heterozygous loss-of-function defects within the gene TGFB1, which encodes transforming growth factor beta 1 (TGFB1). CED1 mutations are found in TGFB1 exons 1-4 that form the latency-associated peptide (LAP) of pro-TGFB1. Consequently, skeletal action of TGFB1 increases and thereby enhances bone formation manifest clinically as "progressive diaphyseal dysplasia". Beginning 24 years ago negative TGFB1 analysis suggested rare genetic heterogeneity for CED, and Online Mendelian Inheritance In Man designated, of unknown etiology, "CED2" (OMIM % 606631). In 2024, three sporadic occurrences considered CED2 were reported to harbor either of two mutations of TGFB2, which encodes the LAP of transforming growth factor beta 2 (TGFB2). Herein, three adults (father, son, daughter) having the CED2 phenotype in a Peruvian family revealed a novel missense variant (c.108G > T, p.R36S) within the TGFB2 LAP domain. Debilitating painful skeletal disease featuring hyperostosis of entire long bones, worse in the men, presented early in childhood. Aminobisphosphonate therapy seemed helpful. Their TGFB2 variant was within a highly conserved domain across species, absent in the gnomAD database, "possibly damaging" by Polyphen-2, not tolerated by SIFT, homologous with TGFB1 at the same amino acid position (R36) as one reported TGFB2 mutation, co-segregated as autosomal dominant, and "likely pathogenic" per ACMG guidelines.
2024-07-17 | Heterozygous mutations in the straitjacket region of the latency-associated peptide domain of TGFB2 cause Camurati-Engelmann disease type II.
Camurati-Engelmann disease (CED) is an autosomal dominant bone dysplasia characterized by progressive hyperostosis of the skull base and diaphyses of the long bones. CED is further divided into two subtypes, CED1 and CED2, according to the presence or absence of TGFB1 mutations, respectively. In this study, we used exome sequencing to investigate the genetic cause of CED2 in three pedigrees and identified two de novo heterozygous mutations in TGFB2 among the three patients. Both mutations were located in the region of the gene encoding the straitjacket subdomain of the latency-associated peptide (LAP) of pro-TGF-β2. Structural simulations of the mutant LAPs suggested that the mutations could cause significant conformational changes and lead to a reduction in TGF-β2 inactivation. An activity assay confirmed a significant increase in TGF-β2/SMAD signaling. In vitro osteogenic differentiation experiment using iPS cells from one of the CED2 patients showed significantly enhanced ossification, suggesting that the pathogenic mechanism of CED2 is increased activation of TGF-β2 by loss-of-function of the LAP. These results, in combination with the difference in hyperostosis patterns between CED1 and CED2, suggest distinct functions between TGFB1 and TGFB2 in human skeletal development and homeostasis.
antibodies
2025-03-17 | P454: Improvement in refractory bone pain with infliximab in an adolescent with Camurati-Engelmann disease
Diagnostic Workup: Brain MRI identified significant cortical dysplasia and cortical thickening with absence of normal sulcation of left hemisphere.EEG revealed status epilepticus on multiple occasions.Biochemical labs included plasma amino acids, urine organic acids, and an acylcarnitine profile.All were non-diagnostic.Newborn screening #1 was normal, though #2 was positive for congenital adrenal hyperplasia and congenital hypothyroidism.Genetic testing included a rapid proband-only genome sequence analysis.Positive results include a pathogenic variant in PTEN (c.388C>T), a likely pathogenic variant in WDR19 (c.3652dup) and 2 VUS in WDR19 (c.2365G>A and c.2671C>T).Secondary findings were declined by the family.
2024-11-27 | Phenotypic Variability in Camurati-Engelmann Disease: A Case Report of a Family with the c.653G>A Pathogenic Variant in the TGFB1 Gene.
Camurati-Engelmann Disease (CED), or Progressive Diaphyseal Dysplasia, is a rare autosomal dominant disorder caused by heterozygous mutations in the TGFB1 Gene, essential for bone regeneration. This study examines the genotype-phenotype relationship in a family diagnosed with CED, specifically focusing on a missense variant (c.653G>A, p.Arg218Cys). The family comprised a mother and her two children, all of whom were found to carry the same disease-causing variant. The second child exhibited severe symptoms by age six, including progressive weakness and joint pain, leading to wheelchair dependency. The mother displayed milder symptoms with preserved independence. The firstborn son, initially asymptomatic, developed gait abnormalities and pain during adolescence. Clinical evaluations revealed characteristic hyperostosis of long bones, with significant variability in symptom onset and severity among family members, potentially indicative of genetic anticipation. This case underscores the importance of genetic testing and interdisciplinary management in CED, as traditional treatments, including corticosteroids and NSAIDs, often yield limited efficacy and notable side effects. Our findings contribute to the understanding of CED's pathophysiology and highlight the necessity for tailored therapeutic approaches. The identification of the common TGFB1 variant in this family reinforces the critical role of TGFB1 in bone metabolism and suggests avenues for further research into targeted therapies. Such reports enhance awareness and provide valuable insights for healthcare professionals managing rare genetic disorders.
2019-06-17 | 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.
2018-07-05 | 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.
2014-02-03 | Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling
During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy.
small molecules
2026-06-17 | Camurati-Engelmann Disease: A Narrative Review of Clinical Features, Molecular Pathogenesis, Diagnosis, and Emerging Targeted Therapies
Camurati-Engelmann Disease (CED) is a very rare, autosomal-dominant type sclerosing bone dysplasia that is characterised by progressive diaphyseal hyperostosis, cortical thickening of long bones, along with variable involvement of skull-base. This narrative review synthesises the current evidence regarding clinical features, molecular basis, diagnosis, as well as management strategies of CED. Clinically, patients having CED, usually present in childhood or adolescence age with chronic pain in limbs, proximal muscle weakness, fatigability, along with a waddling gait, while cranial hyperostosis may lead to hearing impairment, cranial nerve deficits, or raised intracranial pressure. Pathogenic heterozygous mutations in Transforming Growth Factor Beta 1 (TGFB1), also less commonly Transforming Growth Factor Beta 1 (TGFB2), can cause disruption of the latency-associated peptide domain of TGF-β, which can result in excessive TGF-β activation along with downstream dysregulation of bone remodeling pathways. Diagnosis of CED primarily depends upon identification of typical clinical features, characteristic imaging findings of symmetric diaphyseal sclerosis, also definitive confirmation although is done using genetic testing. Management of CED is usually symptomatic, which is inclusive of analgesics, glucocorticoids, and emerging usage of angiotensin II receptor blockers such as losartan. Surgical decompression is usually reserved only for few cases which present with skull-base complications. Novel therapeutic strategies that target TGF-β axis, including receptor inhibitors, ligand traps, as well as Rho-GTPase pathway modulators, also represent promising options as disease-modifying treatment. Improved understanding of various molecular mechanisms for CED along with long-term clinical outcomes is essential for enhancing patient care and quality of life. This narrative review article focuses on uniquely merging updated molecular insights on dysregulated TGF-β signalling along with contemporary diagnostic algorithms, emerging targeted therapies, thus providing a consolidated, clinically oriented framework which is currently lacking in existing literature about CED.
2026-04-08 | Camurati-Engelmann disease with bilateral proptosis and optic neuropathy: a case report and literature review.
Camurati-Engelmann disease (CED) is a rare autosomal dominant skeletal disorder caused by mutations in the TGFB1 gene and is characterized by progressive diaphyseal widening and cortical thickening of long bones. A 29-year-old woman presented with bilateral proptosis, hypothyroidism and a 15-year history of hearing loss and limb pain. Superior visual field defects were detected on automated perimetry. Orbital computed tomography demonstrated orbital apex crowding and narrowing of the optic canals caused by skull hyperostosis, raising concern for compressive optic neuropathy. Imaging revealed systemic skeletal abnormalities, including macrocephaly, mandibular overgrowth, and cortical thickening of multiple bones. Genetic testing confirmed a pathogenic TGFB1 mutation, establishing the diagnosis of CED. Treatment with zoledronic acid, methotrexate, and hormone replacement therapy improved bone metabolism and relieved bone pain at the six-month follow-up. At one-year follow-up, optical coherence tomography showed reduced peripapillary retinal nerve fiber layer thickness (mean 66 μm in both eyes), accompanied by mild progression of visual field defects. Orbital apex decompression with possible optic canal decompression was considered if visual function declined further. This case highlights the potential for orbital involvement and compressive optic neuropathy in CED and underscores the importance of multidisciplinary management and regular ophthalmologic monitoring.
2025-08-13 | Identification of a novel TGFB1 variant in a patient with Camurati-Engelmann disease responsive to alendronate
Whole genome sequencing and alendronate may be of value in diagnosing and managing CED, respectively.
2025-04-10 | Transforming growth factor, beta-2 gene mutation causes autosomal dominant Camurati-Engelmann disease, type 2 (OMIM % 606631).
Camurati-Engelmann disease, type 1 (CED1, OMIM # 131300) is the rare autosomal dominant skeletal dysplasia caused by select heterozygous loss-of-function defects within the gene TGFB1, which encodes transforming growth factor beta 1 (TGFB1). CED1 mutations are found in TGFB1 exons 1-4 that form the latency-associated peptide (LAP) of pro-TGFB1. Consequently, skeletal action of TGFB1 increases and thereby enhances bone formation manifest clinically as "progressive diaphyseal dysplasia". Beginning 24 years ago negative TGFB1 analysis suggested rare genetic heterogeneity for CED, and Online Mendelian Inheritance In Man designated, of unknown etiology, "CED2" (OMIM % 606631). In 2024, three sporadic occurrences considered CED2 were reported to harbor either of two mutations of TGFB2, which encodes the LAP of transforming growth factor beta 2 (TGFB2). Herein, three adults (father, son, daughter) having the CED2 phenotype in a Peruvian family revealed a novel missense variant (c.108G > T, p.R36S) within the TGFB2 LAP domain. Debilitating painful skeletal disease featuring hyperostosis of entire long bones, worse in the men, presented early in childhood. Aminobisphosphonate therapy seemed helpful. Their TGFB2 variant was within a highly conserved domain across species, absent in the gnomAD database, "possibly damaging" by Polyphen-2, not tolerated by SIFT, homologous with TGFB1 at the same amino acid position (R36) as one reported TGFB2 mutation, co-segregated as autosomal dominant, and "likely pathogenic" per ACMG guidelines.
2024-07-17 | Heterozygous mutations in the straitjacket region of the latency-associated peptide domain of TGFB2 cause Camurati-Engelmann disease type II.
Camurati-Engelmann disease (CED) is an autosomal dominant bone dysplasia characterized by progressive hyperostosis of the skull base and diaphyses of the long bones. CED is further divided into two subtypes, CED1 and CED2, according to the presence or absence of TGFB1 mutations, respectively. In this study, we used exome sequencing to investigate the genetic cause of CED2 in three pedigrees and identified two de novo heterozygous mutations in TGFB2 among the three patients. Both mutations were located in the region of the gene encoding the straitjacket subdomain of the latency-associated peptide (LAP) of pro-TGF-β2. Structural simulations of the mutant LAPs suggested that the mutations could cause significant conformational changes and lead to a reduction in TGF-β2 inactivation. An activity assay confirmed a significant increase in TGF-β2/SMAD signaling. In vitro osteogenic differentiation experiment using iPS cells from one of the CED2 patients showed significantly enhanced ossification, suggesting that the pathogenic mechanism of CED2 is increased activation of TGF-β2 by loss-of-function of the LAP. These results, in combination with the difference in hyperostosis patterns between CED1 and CED2, suggest distinct functions between TGFB1 and TGFB2 in human skeletal development and homeostasis.
antibodies
2025-03-17 | P454: Improvement in refractory bone pain with infliximab in an adolescent with Camurati-Engelmann disease
Diagnostic Workup: Brain MRI identified significant cortical dysplasia and cortical thickening with absence of normal sulcation of left hemisphere.EEG revealed status epilepticus on multiple occasions.Biochemical labs included plasma amino acids, urine organic acids, and an acylcarnitine profile.All were non-diagnostic.Newborn screening #1 was normal, though #2 was positive for congenital adrenal hyperplasia and congenital hypothyroidism.Genetic testing included a rapid proband-only genome sequence analysis.Positive results include a pathogenic variant in PTEN (c.388C>T), a likely pathogenic variant in WDR19 (c.3652dup) and 2 VUS in WDR19 (c.2365G>A and c.2671C>T).Secondary findings were declined by the family.
2024-11-27 | Phenotypic Variability in Camurati-Engelmann Disease: A Case Report of a Family with the c.653G>A Pathogenic Variant in the TGFB1 Gene.
Camurati-Engelmann Disease (CED), or Progressive Diaphyseal Dysplasia, is a rare autosomal dominant disorder caused by heterozygous mutations in the TGFB1 Gene, essential for bone regeneration. This study examines the genotype-phenotype relationship in a family diagnosed with CED, specifically focusing on a missense variant (c.653G>A, p.Arg218Cys). The family comprised a mother and her two children, all of whom were found to carry the same disease-causing variant. The second child exhibited severe symptoms by age six, including progressive weakness and joint pain, leading to wheelchair dependency. The mother displayed milder symptoms with preserved independence. The firstborn son, initially asymptomatic, developed gait abnormalities and pain during adolescence. Clinical evaluations revealed characteristic hyperostosis of long bones, with significant variability in symptom onset and severity among family members, potentially indicative of genetic anticipation. This case underscores the importance of genetic testing and interdisciplinary management in CED, as traditional treatments, including corticosteroids and NSAIDs, often yield limited efficacy and notable side effects. Our findings contribute to the understanding of CED's pathophysiology and highlight the necessity for tailored therapeutic approaches. The identification of the common TGFB1 variant in this family reinforces the critical role of TGFB1 in bone metabolism and suggests avenues for further research into targeted therapies. Such reports enhance awareness and provide valuable insights for healthcare professionals managing rare genetic disorders.
2019-06-17 | 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.
2018-07-05 | 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.
2014-02-03 | Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling
During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-β during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-β alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-β or PTH signaling may reestablish coupled bone remodeling and be a potential therapy.
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Drug Discovery Landscape
1 orphan drug designation for Camurati-Engelmann disease.
1 orphan drug designation for Camurati-Engelmann disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sodium (1-hydroxy-4-(((2-((4-(2-(pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolin-7-yl)oxy)ethoxy)carbonyl)amino)butane-1,1-diyl)bis(hydrogen phosphonate) | small molecules | FDA | 2022-09-01 | — | Brise Pharmaceuticals Co., Ltd. |
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