Camurati–Engelmann Disease

  • Wim Van HulEmail author
  • Eveline Boudin
  • Filip M. Vanhoenacker
  • Geert Mortier


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


Camurati–Engelmann disease TGFB-1 Progressive diaphyseal dysplasia 



Research relevant for this review was supported by a Grant from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (G031915N) to WVH. EB holds a postdoctoral Grant (12A3814N) with the research foundation Flanders (FWO Vlaanderen).


  1. 1.
    Boudin E, Van Hul W (2018) Sclerosing bone dysplasias. Best Pract Res 32:707–723CrossRefGoogle Scholar
  2. 2.
    De Ridder R, Boudin E, Mortier G, Van Hul W (2018) Human genetics of sclerosing bone disorders. Curr Osteoporos Rep 16:256–268CrossRefGoogle Scholar
  3. 3.
    Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, Nishimura G, Sangiorgi L, Savarirayan R, Sillence D, Spranger J, Superti-Furga A, Warman M, Unger S (2015) Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet 167A:2869–2892CrossRefGoogle Scholar
  4. 4.
    Boudin E, Fijalkowski I, Hendrickx G, Van Hul W (2016) Genetic control of bone mass. Mol Cell Endocrinol 432:3–13CrossRefGoogle Scholar
  5. 5.
    Cockayne EA (1920) Case for diagnosis. Proc R Soc Med 13:132–136Google Scholar
  6. 6.
    Camurati M (1922) Di un raro caso di osteite simmetrica ereditaria degli arti inferiori. Chirurgia degli Organi di Movimento 6:662–665Google Scholar
  7. 7.
    Engelmann G (1929) Ein fall von ostheopathia hyperostotica (sclerotisans) multiplex infantilis. Forschritte auf dem Gebiete der Röntgenstrahlen der Nuklearmedizin 39:1101–1106Google Scholar
  8. 8.
    Janssens K, Vanhoenacker F, Bonduelle M, Verbruggen L, Van Maldergem L, Ralston S, Guanabens N, Migone N, Wientroub S, Divizia MT, Bergmann C, Bennett C, Simsek S, Melancon S, Cundy T, Van Hul W (2006) Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment. J Med Genet 43:1–11CrossRefGoogle Scholar
  9. 9.
    Makita Y, Nishimura G, Ikegawa S, Ishii T, Ito Y, Okuno A (2000) Intrafamilial phenotypic variability in Engelmann disease (ED): are ED and Ribbing disease the same entity? Am J Med Genet 91:153–156CrossRefGoogle Scholar
  10. 10.
    Wallace SE, Lachman RS, Mekikian PB, Bui KK, Wilcox WR (2004) Marked phenotypic variability in progressive diaphyseal dysplasia (Camurati-Engelmann disease): report of a four-generation pedigree, identification of a mutation in TGFB1, and review. Am J Med Genet 129A:235–247CrossRefGoogle Scholar
  11. 11.
    Yuldashev AJ, Shin CH, Kim YS, Jang WY, Park MS, Chae JH, Yoo WJ, Choi IH, Kim OH, Cho TJ (2017) Orthopedic manifestations of type I Camurati-Engelmann disease. Clin Orthop Surg 9:109–115CrossRefGoogle Scholar
  12. 12.
    Gupta S, Cheikh IE (2005) Camurati-Engelmann disease in conjunction with hypogonadism. Endocr Pract 11:399–407CrossRefGoogle Scholar
  13. 13.
    Meczekalski B, Czyzyk A, Podfigurna-Stopa A, Rydzewski B, Sroczynski J, Lipinska M, Sokalski J, Krawczynski M, Jamsheer A, Katulski K, Genazzani A (2013) Hypothalamic amenorrhea in a Camurati-Engelmann disease–a case report. Gynecol Endocrinol 29:511–514CrossRefGoogle Scholar
  14. 14.
    Carlson ML, Beatty CW, Neff BA, Link MJ, Driscoll CL (2010) Skull base manifestations of Camurati-Engelmann disease. Arch Otolaryngol Head Neck Surg 136:566–575CrossRefGoogle Scholar
  15. 15.
    Wong T, Herschman Y, Patel NV, Patel T, Hanft S (2017) Repeat intracranial expansion after skull regrowth in hyperostotic disease: technical note. World Neurosurg 102:555–560CrossRefGoogle Scholar
  16. 16.
    Spranger J, Brill P, Hall C, Nishimura G, Superti-Furga A, Unger S (2018) Bone dysplasias: an atlas of genetic disorders of skeletal development, 4 edn. Oxford University Press, New YorkCrossRefGoogle Scholar
  17. 17.
    Clybouw C, Desmyttere S, Bonduelle M, Piepsz A (1994) Camurati-Engelmann disease: contribution of bone scintigraphy to genetic counseling. Genet Couns 5:195–198Google Scholar
  18. 18.
    Kumar B, Murphy WA, Whyte MP (1981) Progressive diaphyseal dysplasia (Engelmann disease(: scintigraphic-radiographic-clinical correlations. Radiology 140:87–92CrossRefGoogle Scholar
  19. 19.
    Sparkes RS, Graham CB (1972) Camurati-Engelmann disease. Genetics and clinical manifestations with a review of the literature. J Med Genet 9:73–85CrossRefGoogle Scholar
  20. 20.
    Saraiva JM (1997) Progressive diaphyseal dysplasia: a three-generation family with markedly variable expressivity. Am J Med Genet 71:348–352CrossRefGoogle Scholar
  21. 21.
    Neuhauser EB, Shwachman H et al (1948) Progressive diaphyseal dysplasia. Radiology 51:11–22CrossRefGoogle Scholar
  22. 22.
    Kaftori JK, Kleinhaus U, Naveh Y (1987) Progressive diaphyseal dysplasia (Camurati-Engelmann): radiographic follow-up and CT findings. Radiology 164:777–782CrossRefGoogle Scholar
  23. 23.
    Vanhoenacker FM, De Beuckeleer LH, Van Hul W, Balemans W, Tan GJ, Hill SC, De Schepper AM (2000) Sclerosing bone dysplasias: genetic and radioclinical features. Eur Radiol 10:1423–1433CrossRefGoogle Scholar
  24. 24.
    Freyschmidt J, Freyschmidt-Paul P (2001) SKIBO diseases: a concept to avoid bloody diagnostic procedures in ambiguous skeletal lesions. Eur Radiol 11:1729–1742CrossRefGoogle Scholar
  25. 25.
    Leri A, Joanny J (1922) Une affection non décrite des os hyperostose “en coulée” sur toute la longeur d’un member ou “melorhéostose”. Bull Mem Soc Med Hosp Paris 46:1141–1145Google Scholar
  26. 26.
    Nistala S (2014) “Whirl” in the abdomen: beware. Indian J Gastroenterol 33:492CrossRefGoogle Scholar
  27. 27.
    Arora R, Aggarwal S, Deme S (2015) Ghosal hematodiaphyseal dysplasia-a concise review including an illustrative patient. Skelet Radiol 44:447–450CrossRefGoogle Scholar
  28. 28.
    Whyte MP, Tau C, McAlister WH, Zhang X, Novack DV, Preliasco V, Santini-Araujo E, Mumm S (2014) Juvenile Paget’s disease with heterozygous duplication within TNFRSF11A encoding RANK. Bone 68:153–161CrossRefGoogle Scholar
  29. 29.
    Brueton LA, Winter RM (1990) Craniodiaphyseal dysplasia. J Med Genet 27:701–706CrossRefGoogle Scholar
  30. 30.
    Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van Maldergem L, Vanhoenacker F, Verbruggen L, Van Hul W (2000) Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet 26:273–275CrossRefGoogle Scholar
  31. 31.
    Kinoshita A, Saito T, Tomita H, Makita Y, Yoshida K, Ghadami M, Yamada K, Kondo S, Ikegawa S, Nishimura G, Fukushima Y, Nakagomi T, Saito H, Sugimoto T, Kamegaya M, Hisa K, Murray JC, Taniguchi N, Niikawa N, Yoshiura K (2000) Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet 26:19–20CrossRefGoogle Scholar
  32. 32.
    Chen Y, Xie W, Hu F, Chen J, Zheng H, Zhou H, Ni B, Li W, Zhou J (2017) Clinical diagnosis and mutation analysis of a Chinese family with Camurati-Engelmann disease. Mol Med Rep 15:235–239CrossRefGoogle Scholar
  33. 33.
    Whyte MP, Totty WG, Novack DV, Zhang X, Wenkert D, Mumm S (2011) Camurati-Engelmann disease: unique variant featuring a novel mutation in TGFbeta1 encoding transforming growth factor beta 1 and a missense change in TNFSF11 encoding RANK ligand. J Bone Miner Res 26:920–933CrossRefGoogle Scholar
  34. 34.
    Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, Springer TA (2011) Latent TGF-beta structure and activation. Nature 474:343–349CrossRefGoogle Scholar
  35. 35.
    Miyazono K, Hellman U, Wernstedt C, Heldin CH (1988) Latent high molecular weight complex of transforming growth factor beta 1. Purification from human platelets and structural characterization. J Biol Chem 263:6407–6415Google Scholar
  36. 36.
    Wakefield LM, Thompson NL, Flanders KC, O’Connor-McCourt MD, Sporn MB (1988) Transforming growth factor-beta: multifunctional regulator of cell growth and phenotype. Ann N Y Acad Sci 551:290–297; discussion 297–298CrossRefGoogle Scholar
  37. 37.
    Wrana JL, Attisano L, Wieser R, Ventura F, Massague J (1994) Mechanism of activation of the TGF-beta receptor. Nature 370:341–347CrossRefGoogle Scholar
  38. 38.
    ten Dijke P, Miyazono K, Heldin CH (2000) Signaling inputs converge on nuclear effectors in TGF-beta signaling. Trends Biochem Sci 25:64–70CrossRefGoogle Scholar
  39. 39.
    Campos-Xavier B, Saraiva JM, Savarirayan R, Verloes A, Feingold J, Faivre L, Munnich A, Le Merrer M, Cormier-Daire V (2001) Phenotypic variability at the TGF-beta1 locus in Camurati-Engelmann disease. Hum Genet 109:653–658CrossRefGoogle Scholar
  40. 40.
    Saraiva JM (2000) Anticipation in progressive diaphyseal dysplasia. J Med Genet 37:394–395CrossRefGoogle Scholar
  41. 41.
    Nishimura G, Nishimura H, Tanaka Y, Makita Y, Ikegawa S, Ghadami M, Kinoshita A, Niikawa N (2002) Camurati-Engelmann disease type II: progressive diaphyseal dysplasia with striations of the bones. Am J Med Genet 107:5–11CrossRefGoogle Scholar
  42. 42.
    Massague J (1990) The transforming growth factor-beta family. Annu Rev Cell Biol 6:597–641CrossRefGoogle Scholar
  43. 43.
    Seyedin SM, Thomas TC, Thompson AY, Rosen DM, Piez KA (1985) Purification and characterization of two cartilage-inducing factors from bovine demineralized bone. Proc Natl Acad Sci USA 82:2267–2271CrossRefGoogle Scholar
  44. 44.
    Janssens K, ten Dijke P, Janssens S, Van Hul W (2005) Transforming growth factor-beta1 to the bone. Endocr Rev 26:743–774CrossRefGoogle Scholar
  45. 45.
    Tang Y, Wu X, Lei W, Pang L, Wan C, Shi Z, Zhao L, Nagy TR, Peng X, Hu J, Feng X, Van Hul W, Wan M, Cao X (2009) TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat Med 15:757–765CrossRefGoogle Scholar
  46. 46.
    Qin Y, Tang S, Zhen G, Ding Q, Ding S, Cao X (2018) Bone-targeted delivery of TGF-beta type 1 receptor inhibitor rescues uncoupled bone remodeling in Camurati-Engelmann disease. Ann N Y Acad Sci 1433:29–40CrossRefGoogle Scholar
  47. 47.
    Massague J, Cheifetz S, Endo T, Nadal-Ginard B (1986) Type beta transforming growth factor is an inhibitor of myogenic differentiation. Proc Natl Acad Sci USA 83:8206–8210CrossRefGoogle Scholar
  48. 48.
    Ignotz RA, Massague J (1985) Type beta transforming growth factor controls the adipogenic differentiation of 3T3 fibroblasts. Proc Natl Acad Sci USA 82:8530–8534CrossRefGoogle Scholar
  49. 49.
    Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W (2003) Transforming growth factor-beta 1 mutations in Camurati-Engelmann disease lead to increased signaling by altering either activation or secretion of the mutant protein. J Biol Chem 278:7718–7724CrossRefGoogle Scholar
  50. 50.
    Bas F, Darendeliler F, Petorak I, Sadikoglu B, Bilir A, Bundak R, Saka N, Gunoz H (1999) Deflazacort treatment in progressive diaphyseal dysplasia (Camurati-Engelmann disease). J Paediatr Child Health 35:401–405CrossRefGoogle Scholar
  51. 51.
    Wallace SE, Wilcox WR (1993) Camurati-Engelmann Disease. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A (eds) GeneReviews((R)). University of Washington, SeattleGoogle Scholar
  52. 52.
    Verbruggen LA, Bossuyt A, Schreuer R, Somers G (1985) Clinical and scintigraphic evaluation of corticosteroid treatment in a case of progressive diaphyseal dysplasia. J Rheumatol 12:809–813Google Scholar
  53. 53.
    Lindstrom JA (1974) Diaphyseal dysplasia (Engelmann) treated with corticosteroids. Birth Defects Orig Artic Ser 10:504–507Google Scholar
  54. 54.
    Ayyavoo A, Derraik JG, Cutfield WS, Hofman PL (2014) Elimination of pain and improvement of exercise capacity in Camurati-Engelmann disease with losartan. J Clin Endocrinol Metabol 99:3978–3982CrossRefGoogle Scholar
  55. 55.
    Simsek-Kiper PO, Dikoglu E, Campos-Xavier B, Utine GE, Bonafe L, Unger S, Boduroglu K, Superti-Furga A (2014) Positive effects of an angiotensin II type 1 receptor antagonist in Camurati-Engelmann disease: a single case observation. Am J Med Genet 164A:2667–2671CrossRefGoogle Scholar
  56. 56.
    Cohn RD, van Erp C, Habashi JP, Soleimani AA, Klein EC, Lisi MT, Gamradt M, ap Rhys CM, Holm TM, Loeys BL, Ramirez F, Judge DP, Ward CW, Dietz HC (2007) Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic states. Nat Med 13:204–210CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalAntwerpBelgium
  2. 2.Department of Medical GeneticsUniversity of AntwerpEdegemBelgium
  3. 3.AZ Sint-Maarten, Antwerp University Hospital and Ghent UniversityMechelenBelgium

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