Clinical Diagnosis

Features essential to the diagnosis of Camurati-Engelmann disease (CED) in a proband include the following:

• Proximal muscle weakness

• Radiographic findings of hyperostosis of one or more of the long bones. Periosteal and endosteal bony sclerosis of the diaphyses of the long bones results in uneven cortical thickening, increased bone diameter, and in some cases a narrowed medullary canal. Hyperostosis is usually restricted to the diaphyses but may progress to the metaphyses. The epiphyses are rarely, if ever, involved. Hyperostosis is usually symmetric in the appendicular skeleton but may be asymmetric.
  
  Other radiologic findings may include:

  • Skull involvement beginning at the base of the anterior and middle fossae and often including the frontal bone [Wallace et al 2004];

  • Mild osteosclerosis in the posterior neural arch of the spine and parts of the flat bones that correspond to the diaphysis.

Testing

Changes in bone and muscle histology are nonspecific.

Molecular Genetic Testing

Gene. TGFB1 is the only gene known to be associated with CED.

Other loci. The affected members of one family with CED did not share marker haplotypes at the TGFB1 locus and had no sequence alterations in TGFB1 exons 1 through 7 [Hecht et al 2001], implying genetic locus heterogeneity.

Clinical testing

• Sequence analysis. More than 90% of individuals with CED have identifiable mutations in TGFB1. The majority are missense mutations in exon 4 leading to single amino acid substitutions in the encoded protein. The three common mutant alleles, p.Arg218Cys, p.Arg218His, and p.Cys225Arg, are detailed in Table 2 along with other mutations [Janssens et al 2000, Kinoshita et al 2000, Campos-Xavier et al 2001, Hecht et al 2001, Mumm et al 2001, Janssens et al 2003, Kinoshita et al 2004, Wallace et al 2004, Janssens et al 2006].

Table 1. Summary of Molecular Genetic Testing Used in Camurati-Engelmann Disease

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
TGFB1	Sequence analysis	Sequence variants 2	>90%	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Small intragenic deletions/insertions, missense, nonsense, and splice site mutations

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband.

• Molecular genetic testing of TGFB1 may begin with sequencing of exon 4.

• If no mutation is found, the remaining exons are sequenced.

Clarification of genetic status in at-risk relatives requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

CED and Ribbing disease, representing phenotypic variations of the same disorder, are the only phenotypes currently known to be associated with mutations in TGFB1.

Natural History

Individuals with Camurati-Engelmann disease (CED) present with limb pain, proximal muscle weakness, poor muscular development, a wide-based, waddling gait, easy fatigability, and headaches. The average age of onset of symptoms in the 199 reported individuals is 14 years with a range of birth to age 76 years (see Literature Cited).

Extremities. Decreased muscle mass and weakness are most apparent in the proximal lower limbs, resulting in difficulty when rising from a sitting position. A wide-based, waddling gait is found in 64% of individuals. Joint contractures occur in 43% of individuals. Marfanoid body habitus is described in some affected individuals [Wallace et al 2004, Janssens et al 2006].

Bone pain is reported in 90% of affected individuals [Wallace et al 2004, Janssens et al 2006]. The pain is described as constant, aching, and most intense in the lower limbs. Pain often increases with activity, stress, and cold weather. Many individuals have intermittent episodes of severe pain and incapacitation. The enlarged bone shafts can also be palpable and tender on examination; 52% of affected individuals report bone tenderness with palpation [Wallace et al 2004]. Intermittent limb swelling, erythema, and warmth also occur.

Susceptibility to fracture may be reduced because of increased bone mineral density, but healing of fractures, when they occur, may be delayed [Wallace et al 2004].

Neurologic. Sclerosis of the cranial nerve foramina can lead to direct nerve compression or neurovascular compromise. Cranial nerve deficits occur in 38% of affected individuals. The most common deficits are hearing loss, vision problems, and facial paralysis.

Approximately 15% of individuals with CED have conductive and/or sensorineural hearing loss. Conductive loss can be caused by narrowing of the external auditory meatus, bony encroachment of the ossicles, or narrowing of the oval and round windows. Sensorineural hearing loss is caused by narrowing of the internal auditory canal and compression of the cochlear nerve and/or vasculature. Sensorineural loss can also occur with attempted decompression of the facial nerves.

Involvement of the orbit has led to proptosis, papilledema, epiphora, glaucoma, and subluxation of the globe.

Rarely, clonus [Neuhauser et al 1948], sensory loss, slurred speech, cerebellar ataxia, and bowel and bladder incontinence are reported.

Ribbing disease, an osteosclerotic disease of the long bones that is radiographically indistinguishable from CED and usually presents with bone pain after puberty [Makita et al 2000], is now known to be caused by mutations in TGFB1 [Janssens et al 2006]. Thus, CED and Ribbing disease represent phenotypic variations of the same disorder.

Other. Musculoskeletal involvement can lead to varying degrees of lumbar lordosis, kyphosis, scoliosis, coxae valga, genua valga, flat feet, and frontal bossing.

Rare manifestations include anemia (hypothesized to be caused by a narrowed medullary cavity), anorexia, hepatosplenomegaly, decreased subcutaneous tissue, atrophic skin, hyperhidrosis of the hands and feet, delayed dentition, extensive caries, delayed puberty, and hypogonadism [Gupta & Cheikh 2005].

Pregnancy. One individual who experienced relief with steroids also experienced decreased bone pain and improved muscle strength while pregnant, which allowed discontinuation of her steroid therapy. Scintigraphic bone imaging with MDP a few hours after delivery of her second child showed decreased uptake compared to imaging prior to pregnancy and six weeks post partum.

Genotype-Phenotype Correlations

No known correlation exists between the nature of the TGFB1 mutations and the severity of the clinical or radiographic manifestations [Campos-Xavier et al 2001].

Penetrance

Some obligate heterozygotes for CED with identified TGFB1 mutations have had normal radiographs [Wallace et al 2004]; an exact penetrance figure is not known.

Anticipation

Earlier onset of symptoms and increased severity of symptoms and bone involvement in successive generations has been reported in several families [Wallace et al 2004, Janssens et al 2006]. If these findings represent anticipation rather than ascertainment bias (the latter being more likely), the mechanism of anticipation is unknown. Although multiple copies of the amino acid leucine can be encoded by one observed mutation in exon 1, the mutation was not found in these families.

Nomenclature

Engelmann described the second reported occurrence of CED in 1929 as "osteopathic hyperostotica (sclerotisans) multiplex infantilis."

The terms Engelmann disease and diaphyseal dysplasia were commonly used until Neuhauser et al [1948] coined the term progressive diaphyseal dysplasia.

Gulledge & White [1951] suggested the term progressive diaphyseal hyperostosis, which was not widely used.

Prevalence

The prevalence is unknown. At least 200 individuals have been reported.

The disorder is pan ethnic.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Camurati-Engelmann disease, the initial evaluation should include neurologic examination, measurement of blood pressure, complete skeletal survey, ESR (erythrocyte sedimentation rate), CBC count, hearing screen, and ophthalmologic evaluation.

If acute bone pain is present, ESR and bone scan may be helpful as baseline measures of disease activity.

Treatment of Manifestations

Corticosteroids may relieve many of the symptoms of Camurati-Engelmann disease (CED). Several investigators report success with corticosteroid treatment in reducing pain and weakness, improving gait, exercise tolerance, and flexion contractures, and correcting anemia and hepatosplenomegaly [Lindstrom 1974, Bas et al 1999, Wallace et al 2004]. Unsuccessful steroid therapy was reported in one adult.

Individuals with severe symptoms can be treated with a bolus of prednisolone 1.0-2.0 mg/kg/day followed by rapid tapering to the lowest alternate-day dose tolerated. Less symptomatic individuals can be started on 0.5-1.0 mg/kg every other day. Some individuals may be able to discontinue steroid therapy during quiescent periods.

Higher-dose steroids may help with acute pain crises.

Losartan. Although no outcome data are available, losartan can be tried in symptomatic individuals who do not tolerate corticosteroids or who have concomitant hypertension. Losartan has an anti-TGFβ effect and is being tested in individuals with Marfan syndrome.

Other analgesics and non-pharmacologic methods are frequently used for alleviation of pain.

Hearing loss evaluation by an otolaryngologist should include a BAER and a CT with fine cuts through the inner ear. Reports of successful treatment of hearing loss in CED are rare. Surgical decompression of the internal auditory canals can improve hearing. However, the skull hyperostosis is progressive, and cranial nerve compression often recurs.

Corticosteroids may delay skull hyperostosis and cranial nerve impingement. Lindstrom [1974] reported no change in conductive hearing loss with steroid therapy. A 30-year-old woman with a 75-dB neurosensory hearing loss on the right and a 65-dB neurosensory hearing loss of the left experienced some improvement in hearing with prednisone. Her hearing stabilized after decompression of the right internal auditory canal.

Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis in individuals with CED.

A 71-year-old woman with bilateral conductive hearing loss and patent internal auditory canals underwent a cochlear implantation, and speech detection improved from 75 dB to 45 dB [Friedland et al 2000]. General contraindications for cochlear implants include a narrowed internal auditory canal and absence of a functioning eighth nerve, both of which can be found in individuals with CED (see also Hereditary Deafness and Hearing Loss Overview).

Prevention of Secondary Complications

Steroids may delay bone hyperostosis and prevent or delay the onset of skull involvement. Histologic studies following steroid therapy showed increased bone resorption and secondary remodeling with increased osteoblastic activity and decreased lamellar bone deposition. However, several authors reported no regression of sclerosis on radiographic evaluation [Verbruggen et al 1985] or on scintigraphic evaluation [Bas et al 1999]. Lindstrom [1974] and Bas et al [1999] reported diminished sclerosis on radiographs following steroid therapy. Verbruggen et al [1985] and Inaoka et al [2001] reported reduced radioactivity on bone scintigraphy. Long-term follow-up studies should be conducted to evaluate the success of corticosteroid therapy in preventing anemia, hepatosplenomegaly, headaches, and cranial nerve impingement.

Surveillance

After initiating corticosteroids, affected individuals should be followed monthly, with efforts to taper the steroids to the lowest tolerated dose. Blood pressure should be monitored at each visit, as hypertension can develop following the initiation of steroid therapy

When a maintenance steroid dose is achieved, yearly evaluations should include a complete neurologic exam, CBC count, blood pressure, and hearing screen.

Agents/Circumstances to Avoid

None has been reported aside from bisphosphonates (see Other).

Testing of Relatives at Risk

Testing of at-risk asymptomatic relatives is helpful to avoid potential misdiagnosis and unnecessary extremity pain later in life.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

The following therapies have proven ineffective:

• NSAIDs

• Biophosphonates. Bone pain and uptake of 99mTc methylene diphosphonate by scintigraphy increased with pamidronate in a 27-year-old woman with CED [Inaoka et al 2001]. Clodronate infusion caused increased bone pain in one individual with CED and no improvement in another individual reported by Castro et al [2005].

• Excess phosphate. Treatment with cellulose phosphate led to worsening hypocalcemia and proximal myopathy in another individual

Initiation of steroids prior to the onset of proximal muscle weakness and/or sclerotic bone changes has not been reported. Because of the variable symptomatology and decreased penetrance, treatment of asymptomatic individuals cannot be recommended.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

Camurati-Engelmann disease (CED) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with CED have an affected parent.

• A proband with CED may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.

• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a complete skeletal survey or AP radiographs of the extremities and a lateral skull film. If the radiographs are normal, molecular genetic testing should be performed because of the possibility of reduced penetrance (i.e., individuals with a disease-causing mutation may have no clinical manifestations).

Note: Although many individuals diagnosed with CED have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members.

Sibs of a proband

The risk to the sibs of the proband depends on the genetic status of the proband's parents.

• If a parent of the proband is affected or has an identified mutation in TGFB1, the risk to the sibs is 50%.

• When the parents are clinically unaffected, molecular genetic testing can be used to identify individuals who have a disease-causing mutation but no clinical manifestations.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the two possible genetic explanations are germline mosaicism in a parent or a de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband. Each child of an individual with CED has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has an identified mutation in TGFB1, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning.

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

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Revision History

• 1 June 2010 (me) Comprehensive update posted live

• 16 August 2006 (me) Comprehensive update posted to live Web site

• 25 June 2004 (me) Review posted to live Web site

• 18 march 2004 (sw) Original submission