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Camurati-Engelmann disease.


Camurati-Engelmann disease (CED), or progressive diaphyseal dysplasia, is a rare sclerosing dysplasia of which 250 cases have been described in the English literature.(1) The disease affects one in a million people and is autosomal dominant with variable penetrance.(2-5) It was initially described by Cockayne in 1920; Camurati was the first to suggest its hereditary nature in 1922.(6-8) A single case of muscular wasting and marked bone involvement was reported by Engelmann in 1929.(6-9) As the name suggests, there is progressive hyperostosis and predominant involvement of the diaphyses.(6-10)

The onset of the disease is usually during childhood; patients usually present by puberty and usually before age 30, with limb pain, muscular weakness, waddling gait and easy fatigue. Other symptoms and signs may include delayed growth, reduced muscle mass, anorexia and enlargement of the arms and legs.(6-11) Systemic manifestations of hepatosplenomegaly, bone marrow dysfunction (anaemia and leucopaenia) and delayed sexual development occasionally occur.(4,5,6,12,13) In a few patients, abnormal values of bone resorption and formation have been described.(10)



Radiologically, the hallmark of the disorder is bilateral, symmetrical cortical thickening of the diaphyses of the long bones(14,15) on both the periosteal and endosteal sides of the diaphyses. In decreasing order of frequency, the tibia, femur, fibula, humerus, ulna and radius are affected. CED results from disturbance of intramembranous ossification (Fig.(1)) affecting the long bones, calvaria, mandible and facial bones.(11,16) There are a few reported cases of involvement of the skull base (a site of endochondral ossification), but these occur in advanced stages.(3,11,17,18)



Radioclinical features

According to a retrospective study of 24 families done by Janssens et al.,(6) clinical symptoms were documented in 74% of the patients. The most frequent clinical symptoms were pain in the extremities (63%), easy fatigue (44%), waddling gait (48%), muscle weakness (39%), reduced subcutaneous fat (21%) and hearing loss (15%).

Radiographically, endosteal and periosteal thickening of the diaphyses of long bones (Figs. 2a-f) is seen in CED.(3,11,17,18) The result is narrowing of the medullary cavity (Figs 3a, b).(4) The metaphyses can become affected, but typically the epiphyses are spared (Figs 4a, b).(4,6) Sclerosis of the skull base (Figs 5a, b) can be present, leading to hearing impairment owing to progressive stenosis of the external auditory canal (EAC), and foraminal stenosis causing cranial nerve dysfunction.(6,11,19)

Increased osteoblastic activity detected scintigraphically with 99Tc-HMDP (hyfroxymethylene diphosphonate) is seen bilaterally symmetrical in the upper and lower limb long bones, longitudinally along the bone cortices.(6,15) Before sclerosis is seen radiologically, increased tracer uptake can be seen and is thus valuable in the early diagnosis.(6)
Table I. Classification of dysplasias with increased
bone density according to International Nomenclature
and Classifications of the Osteochondrodysplasias
(modified from Vanhoenacker FM et al.(13))

Disorder              Radiological       Mode of
                      pattern of         inheritance

                      1. Increased bone
                      density without
                      modifcation of
                      bone shape

precocious type       Generalised        AR
delayed type          Type 1 uniform     AD
intermediate type     Type 2 endobones
with renal tubular    Generalised        AR AR
acidosis              Similar other

osteomesopyknosis     Focal sclerosis    AD AR
with bamboo hair      in
Pycnodysostosis       Generalised        AR
Osteosclerosis        Cortical           AD
Stanesu type          thickening of
                      long bones,
                      defcient facial

Osteopathia striata   Radiodense         SP XLD
isolated with         striations on all
cranial sclerosis     bones with

Sponastrime           Striated           AR
dysplasia             metaphysis

Melorheostosis        Flowing            SP

Osteopoikilosis       Radiodense spots   AD

Mixed sclerosing      Combined pattern   SP
bone dysplasia

                      2. Increased bone
                      density with

Diaphyseal            Craniotubular      AD
dysplasia,            sclerosis,
Camurati-Engelmann    symmetrical

Craniodiaphyseal      Craniotubular      AR, AD

Lenz Majewski         Craniotubular      SP

Endosteal             Craniotubular
hyperostosis          sclerosis,
van Buchem type                          AR
Worth type                               AD
sclerosteosis                            AR
with cerebellar                          AR

Kenny Cafey           Diaphyseal         AD, AR
dysplasia             cortex

Osteoectasia with     Craniotubular      AR
hyperphosphatasia     sclerosis,
(juvenile Pagets)     bowing

Diaphyseal dysplasia  Diaphyseal         AR
with anaemia          cortex

Diaphyseal medullary  Diaphyseal         AD
stenosis with bone    cortex

                      3. Increased bone
                      density with

Pyle dysplasia        Erlenmeyer         AR

Craniometaphyseal     Pyle-like, but
dysplasia             cranial bones
                      more afected
severe type                              AR
mild type                                AD
other type

Frontometaphyseal     Frontal bones      XLR

Dysosteosclerosis     Generalised        AR

                      Platyspondyly      XLR

Oculodento-osseous    Craniotubular and  AD
dysplasia             mandible

Trichodento-osseous   Craniotubular      AD

                      4. Neonatal

Blomstrand            Generalised        AR

Raine dysplasia       Mild craniofacial  ?

                      long bones

Prenatal onset Cafey  Diaphyseal         ?AR
disease               cortical
                      thickening, bowed
                      long bones

AD=autosomal dominant; AR=autosomal recessive;
SP=sporadic; XLD=X-linked dominant; XLR=X-linked recessive.



Ten different mutations of the TGFB1 (transforming growth factor B1) were identified in an analysis of 46 CED families.(6, 20-27) The TGFB1 gene is located on the chromosomal region 19q13.(1).4 All investigated mutations increase the activity of TGFB1.(6) Under physiological conditions, TGFB1 has been shown to suppress bone formation and the mutation stimulates bone formation6 thus disrupting bone turnover, causing increased bone formation. TGFB1 also inhibits myogenesis, causing muscle wasting as well as lipogensis.(6)

CED is classified as a sclerosing bone dysplasia with diaphyseal involvement (Table I). The differential diagnosis is endosteal hyperostosis--van Buchem sclerosteosis, Kenny-Caffey disease or Worth type. Owing to inheritance, one can rule out van Buchem sclerosteosis (autosomal recessive (AR)), and Worth type is a more benign form and has associated mandible enlargement.(4,13)

A combination of clinical, radiological, scintigraphic and molecular data are mandatory for a definitive diagnosis.


Immunosuppressive agents such as anti-inflammatories and glucocorticosteroids have the negative side-effect of decreasing bone density; and this is used in CED as treatment. The role of the agents is to increase the apoptosis rate of osteoblasts and osteocytes and at the same time to suppress osteoblast proliferation, differentiation and bone matrix synthesis.(6) Further effects are to enhance proliferation and differentiation of osteoclast precursors(6) and also to decrease intestinal calcium absorption.(6) Glucocorticosteroids as well as counteracting bone formation exert a direct effect on TGFB expression. Prednisolone has been described as an effective treatment in a number of cases.(6)

Long-term treatment is not advisable owing to its unfavourable side-effects such as impaired growth and spinal osteoporosis. A good starting dose is 1mg/kg/day, but should be lowered in long-term treatment.

An alternative to medication is surgery. Reaming of the medullary cavity may be done to decrease the narrowing of the canal, or an osteotomy can be performed.(6,28) Further decompression in optic nerve compression has also been done. Gene therapy is a possibility in the future.


Camurati-Engelmann disease (CED), or progressive diaphyseal dysplasia, is a rare sclerosing dysplasia whose onset is usually during childhood. Patients usually present by puberty or before age 30. Radiologically, the hallmark of the disorder is bilateral, symmetrical cortical thickening of the diaphyses of the long bones occuring on both the periosteal and endosteal sides of the diaphyses.

The differential diagnosis is of CED is endosteal hyperostosis--van Buchem, sclerosteosis, Kenny-Caffey disease and Worth type. Inheritance can rule out van Buchem and sclerosteosis (AR), whereas Worth type is a more benign form and has associated mandible enlargement. A combination of clinical, radiological, scintigraphic and molecular data may be necessary for a definitive diagnosis.

(1.) Brat HG, Hamoir X, Matthijs P, et al. Camurati-Engelmann disease: A late and sporadic case with metaphyseal involvement. Eur Radiol 1999;9:159-162.

(2.) Wynne-Davies R, Hall CM, Apley AG. Engelmann's disease. In: Wynne-Davies R, ed. Atlas of Skeletal Dysplasias. Edinburgh: Churchill Livingstone 1985:488

(3.) Vanhoenacker FM, Janssens K, van Hul W, et al. Camurati-Engelmann disease: review of radioclinical features. Acta Radiologica 2003;44(4):430-434.

(4.) Simsek S, Janssens K, Kwee ML, et al. Camurati-Engelmann disease (progressive diaphyseal dysplasia) in a Moroccan family. Osteoporosis Int 2005;16:1167-1170.

(5.) Whyte MP. Primer on the metabolic bone diseases and disorders of mineral metabolism, sect VIII. Genetic, Developmental, and Dysplastic Skeletal Disorders, 5th ed. Washington, DC: American Society for Bone and Mineral Research, 2003:449-478.

(6.) Janssens K, Vanhoenacker F, Bonduelle M, et al. Camurati-Engelmann disease: review of the clinical, radiological, and molecular data of 24 families and implications for diagnosis and treatment. J Med Genet 2006;43:1-11.

(7.) Cockayne EA. Case for diagnosis. Proc R Soc Med 1920;13:132-136.

(8.) Camurati M. Di un raro caso di osteite simmetrica ereditaria degli arti inferiori. Chirurgia degli Organi di Movimento 1922;6:662-665.

(9.) Engelmann G. Ein fall von ostheopathia hyperostotica (sclerotisans) multiplex infantilis. Forschritte auf dem Gebiete der Rontgenstrahlen und der Nuklearmedizin 1929;39:1101-1106.

(10.) Smith R, Walton RJ, Corner BD, Gordon IR. Clinical and biochemical studies in Engelmann's disease (progressive diaphyseal dysplasia). QJM 1977;46:273-294.

(11.) Stasolla A, Magliulo G, Bellussi A, et al. Imaging of the temporal bone in Camurati-Engelmann dysplasia with an 11-year follow-up. Otology & Neurology. 2005;26:773-777.

(12.) Crisp AJ, Brenton DP. Engelmann's disease of bone--a systemic disorder? Ann Rheum Dis 1982;41:183-188.

(13.) Vanhoenacker FM, De Beuckeleer LH, van Hul W, et al. Sclerosing bone dysplasias: genetic and radioclinical features. Eur Radiol. 2000;10:1423-1433.

(14.) Rimoin DL. International nomenclature of constitutional diseases of bone. J Pediat 1978;93:614-616.

(15.) Momose M, Yoshida K, Yanagisawa S, et al. Camurati-Engelmann disease on a 99mTc-HMDP bone scan. Eur J Nucl Med Mol Imaging 2008;35:214.

(16.) Greenspan A. Sclerosing bone dysplasias: A target-site approach. Skeletal Radiol 1991;20:561-583.

(17.) Vanhoenacker FM, DeBeuckeleer LH, Van Hul W, et al. Sclerosing bone dysplasias: Genetic and radioclinical features. Eur Radiol 2000;10:1423-1433.

(18.) Kaftori JK, Kleinhaus U, Naveh Y. Progressive diaphyseal dysplasia (Camurati-Engelmann): Radiographic follow-up and CT findings. Radiology 1987;164:777-782.

(19.) Cheung SW, Jackler RK. Diffuse osseous lesions of the temporal bone. In: Jackler RK, Brackmann DE, eds. Neurotology. St. Louis: Mosby Year Book, 1994:1189-1202.

(20.) Campos-Xavier B, Saraiva JM, Savarirayan R, et al. Phenotypic variability at the TGFbeta1 locus in Camurati-Engelmann disease. Hum Genet 2001;109:653-658.

(21.) Wallace SE, Lachman RS, Mekikian PB, Bui KK, Wilcox WR. 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 2004;129A:235-247.

(22.) Janssens K, Gershoni-Baruch R, Guanabens N, et al. Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet 2000;26:273-275.

(23.) Kinoshita A, Saito T, Tomita H, et al. Domain-specific mutations in TGFB1 result in Camurati-Engelmann disease. Nat Genet 2000;26:19,20.

(24.) Hecht JT, Blanton SH, Broussard S, Scott A, Rhoades Hall C, Milunsky JM. Evidence for locus heterogeneity in the Camurati-Engelmann (DPD1) syndrome. Clin Genet 2001;59:198--200.

(25.) Mumm SR, Obrecht S, Podgornik MN, Whyte MP. Camurati-Engelmann Disease: New mutations in the latency-associated peptide of the transforming growth factor beta-1 gene. J Bone Miner Res 2001;16(suppl 1):S223.

(26.) Janssens K, ten Dijke P, Ralston SH, Bergmann C, Van Hul W. 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 2003;278:7718-7724.

(27.) Kinoshita A, Fukumaki Y, Shirahama S, et al. TGFB1 mutations in four new families with Camurati-Engelmann disease: confirmation of independently arising LAP-domain-specific mutations. Am J Med Genet 2004;127A:104-107.

(28.) Raffaelli P, Ronzini MF. Camurati-Engelmann's disease. A case report. Ital J Orthop Traumatol 1988;14:267-271.

Neil Bellew, MB BCh, DA (SA), FCRad Diag (SA)

Department of Radiology, Steve Biko Academic Hospital and Univerity of Pretoria

Georg Wagener, MB ChB, BSc Hon (Biochem), MMed (Rad)

Department of Radiology, Stellenbosch University
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Title Annotation:PICTORIAL ESSAY
Author:Bellew, Neil; Wagener, Georg
Publication:South African Journal of Radiology
Article Type:Disease/Disorder overview
Geographic Code:6SOUT
Date:Mar 1, 2011
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