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Camurati-Engelmann Disease

Synonym: Progressive Diaphyseal Dysplasia

, MD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: October 12, 2017.

Estimated reading time: 20 minutes

Summary

Clinical characteristics.

Camurati-Engelmann disease (CED) is characterized by hyperostosis of the long bones and the skull, proximal muscle weakness, limb pain, a wide-based, waddling gait, and joint contractures. Facial features such as macrocephaly, frontal bossing, enlargement of the mandible, proptosis, and cranial nerve impingement resulting in facial palsy are seen in severely affected individuals later in life.

Diagnosis/testing.

The diagnosis of CED is established in a proband with the characteristic radiographic findings or on identification of a heterozygous pathogenic variant in TGFB1 by molecular genetic testing if radiographic findings are inconclusive.

Management.

Treatment of manifestations: Corticosteroid therapy as needed to control symptoms; losartan may be a helpful adjuvant therapy to minimize the need for steroids to control pain. Pain is also managed with analgesics and non-pharmacologic methods. Craniectomy may be needed to reduce intracranial pressure and relieve symptoms in individuals with several cranial sclerosis. Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis.

Prevention of secondary complications: Monitor blood pressure in individuals treated with corticosteroids and treat hypertension if necessary; individuals taking losartan also need regular blood pressure monitoring due to the increased risk for hypotension; taper corticosteroid dose as tolerated to reduce the risk of osteoporosis and compression fractures of the spine.

Surveillance: Following initiation of corticosteroid treatment, blood pressure should be monitored monthly; when maintenance steroid dose is achieved, yearly evaluation includes complete neurologic examination, CBC, blood pressure, audiology evaluation, ophthalmology evaluation, and bone density scan; routine monitoring of linear growth in children due to the possible side effect of delayed or stunted growth; individuals with cranial hyperostosis (including those treated surgically) should continue to be monitored for signs and symptoms of increased intracranial pressure.

Genetic counseling.

CED is inherited in an autosomal dominant manner. Penetrance is reduced. The incidence of de novo pathogenic variant is unknown. Each child of an individual with CED has a 50% chance of inheriting the TGFB1 pathogenic variant. Prenatal testing and preimplantation genetic diagnosis for pregnancies at increased risk are possible options for families in which the pathogenic variant has been identified.

GeneReview Scope

Camurati-Engelmann Disease: Included Phenotype
  • Ribbing disease

For synonyms and outdated names see Nomenclature.

Diagnosis

There are no current published guidelines for the diagnosis of Camurati-Engelmann disease.

Suggestive Findings

Camurati-Engelmann disease (CED) should be suspected in individuals with the following clinical findings:

  • Proximal muscle weakness
  • Limb pain
  • Waddling gait

Establishing the Diagnosis

The diagnosis of CED is established in a proband with the characteristic radiographic findings or, if radiographic findings are inconclusive, on identification of a heterozygous pathogenic variant in TGFB1 by molecular genetic testing (Table 1).

Radiographic findings

  • Hyperostosis of one or more of the long bones:
    • Begins with the diaphyses of the long bones
    • Can progress to the metaphyses and (in rare cases) epiphyses
  • Periosteal involvement with uneven cortical thickening and increased diameter
  • Endosteal bony sclerosis that can lead to narrowed medullary canal
  • Hyperostosis usually symmetric in the appendicular skeleton but in some cases asymmetric
    Note: Hyperostosis does not affect the spine.
  • Other radiologic findings variably seen:
    • 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

Molecular genetic testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing.

  • Single-gene testing. Sequence analysis of TGFB1 is performed.
    Note: CED is postulated to occur through a gain-of-function mechanism. Large intragenic deletions or duplications have not been reported in individuals with CED; testing for intragenic deletions or duplication is not indicated.
  • A multigene panel that includes TGFB1 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene varies by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Camurati-Engelmann Disease

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
TGFB1Sequence analysis 3>90% 4
Gene-targeted deletion/duplication analysis 5Unknown 6
Unknown 7NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

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; deletion/duplication analysis was not done on these individuals [Hecht et al 2001]. Several additional individuals with CED have not had TGFB1 pathogenic variants identified, implying genetic locus heterogeneity [Author, personal observation].

Clinical Characteristics

Clinical Description

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 306 reported individuals is 13.4 years [Carlson et al 2010] with a range from birth to age 76 years [Wallace et al 2004].

Musculoskeletal. 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 48%-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]. Musculoskeletal involvement can lead to varying degrees of lumbar lordosis, kyphosis, scoliosis, coxae valga, radial head dislocation, genua valga, hallux valgus, flat feet, and frontal bossing [Yuldashev et al 2017].

Bone pain is reported in 68%-90% of affected individuals [Wallace et al 2004, Janssens et al 2006]. The reported severity of bone pain ranged from mild (not requiring any treatment) to severe (requiring narcotic analgesics) [Yuldashev et al 2017]. 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. Bone pain has resulted in limited ambulation in some individuals. 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.

Although bone mineral density measured at the hip and femoral neck are increased in individuals with CED, bone strength measured by bone impact microindentation in three sibs with CED was below normal. Because of the small sample size, the difference in bone strength was not statistically significant. [Herrera et al 2017]. Increased susceptibility to fracture has not been reported. 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 19% of individuals with CED have conductive and/or sensorineural hearing loss [Carlson et al 2010]. 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 hearing loss can also occur with attempted decompression of the facial nerves.

Involvement of the orbit has led to blurred vision, proptosis, papilledema, epiphora, glaucoma, and subluxation of the globe [Carlson et al 2010, Popiela & Austin 2015].

Rarely, clonus [Neuhauser et al 1948], sensory loss, slurred speech, dysphagia, cerebellar ataxia, and bowel and bladder incontinence are reported [Carlson et al 2010]. Calvarial hyperostosis can lead to increased intracranial pressure and headaches.

Recurrent cranial hyperostosis following surgical decompression can occur [Wong et al 2017].

Facial features. Children with CED do not typically have recognizable changes to their facial features. In older individuals who are severely affected, osteosclerosis of the skull can lead to macrocephaly, frontal bossing, enlargement of the mandible, proptosis, and cranial nerve impingement resulting in facial palsy.

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 pathogenic variants in TGFB1 [Janssens et al 2006]. Thus, CED and Ribbing disease represent phenotypic variations of the same disorder.

Other. Rare manifestations include anemia (hypothesized to be caused by a narrowed medullary cavity), anorexia, low body mass index, hepatosplenomegaly, decreased subcutaneous tissue, atrophic skin, hyperhidrosis of the hands and feet, delayed dentition, extensive caries, delayed puberty, and hypogonadism [Gupta & Cheikh 2005, Yuldashev et al 2017].

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 methylene diphosphate (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 pathogenic variants and the severity of the clinical or radiographic manifestations [Campos-Xavier et al 2001].

Penetrance

Some obligate heterozygotes with an identified TGFB1 pathogenic variant 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 pathogenic variant in exon 1, the pathogenic variant 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. More than 300 affected individuals have been reported.

The disorder is pan ethnic.

Differential Diagnosis

Few disorders share the clinical and radiographic findings of Camurati-Engelmann disease (CED). The correct diagnosis is made by physical examination and skeletal survey.

Table 2.

Disorders to Consider in the Differential Diagnosis of CED

DisorderGeneMOIClinical Features of This Disorder
Overlapping w/CEDDistinguishing from CED
Craniodiaphyseal dysplasia (CDD) (OMIM 218300)UnknownAR (suggested)Diaphyseal sclerosis, cranial hyperostosis
  • Cranial involvement in CED is milder & rarely results in frontal bossing & proptosis.
  • The sclerosis of the long bones in CDD is restricted to the diaphyses; in CED metaphyses can also be affected.
Kenny-Caffey syndrome type 2 (OMIM 127000)FAM111AADSclerosis of long bones, cortical thickening, medullary stenosisHypocalcemia, hypoparathyroidism, delayed fontanel closure
Juvenile Paget disease (OMIM 239000)TNFRSF11BARCranial hyperostosis, sensorineural hearing loss, sclerosis of long bonesPredisposition to fractures, bowing of the long bones
Ghosal hematodiaphyseal dysplasia (OMIM 231095)TBXAS1ARDiaphyseal sclerosisSevere anemia; leukopenia & thrombocytopenia
Endosteal hyperostosis, AD (OMIM 144750)LRP5ADDiaphyseal sclerosis (endosteal), cranial nerve involvement in someWide deep mandible w/increased gonial angle, which is distinct from the enlarged mandible found only occasionally in CED
SOST-related sclerosing bone dysplasias incl sclerosteosis & van Buchem diseaseSOSTARCranial hyperostosis, cranial nerve involvement, diaphyseal sclerosisSyndactyly, dysplastic or absent nails

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Camurati-Engelmann disease (CED), the initial evaluation should include the following if they have not already been completed:

  • Complete skeletal survey
  • Assessment for cranial nerve deficits, including neurologic examination, audiology evaluation, and ophthalmologic evaluation
  • Baseline blood pressure if considering treatment with losartan
  • CBC to evaluate for anemia in individuals with significant endosteal involvement
  • If acute bone pain is present, consideration of serum ESR and bone scan examination as baseline measures of disease activity
  • In individuals with radiographic evidence of skull base sclerosis and neurologic symptoms, consideration of baseline CT examination of the head and neck to determine the extent of disease and allow consideration of surgical treatment options
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No consensus management guidelines have been developed to date.

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, Baş 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.

Note: Steroids may delay bone hyperostosis and prevent or delay the onset of skull involvement. Although histologic studies following steroid therapy showed increased bone resorption and secondary remodeling with increased osteoblast activity and decreased lamellar bone deposition, several authors reported no regression of sclerosis on radiographic evaluation [Verbruggen et al 1985] or on scintigraphic evaluation [Baş et al 1999]. Lindstrom [1974] and Baş 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.

Calcitonin. Pain relief from intranasal calcitonin was reported in one individual [Trombetti et al 2012].

Losartan. Reduced bone pain and increased physical activity were reported in two individuals treated with losartan [Ayyavoo et al 2014, Simsek-Kiper et al 2014]. Losartan has an anti-TGFβ effect and is being tested in individuals with Marfan syndrome. Treatment with losartan has not improved bone pain in some individuals [Yuldashev et al 2017]

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

Surgical treatment for persistent bone pain by intramedullary reaming was reported in a woman age 22 years diagnosed with Ribbing disease [Oztürkmen & Karamehmetoğlu 2011]. Pain in the tibia resolved completely following the surgery; the individual remained pain free at five-year follow up.

Craniectomy has relieved increased intracranial pressure and headaches in affected individuals [Carlson et al 2010]. Recurrent cranial hyperostosis with resultant increased intracranial pressure has been managed by radical craniectomy with titanium mesh cranioplasties [Wong et al 2017].

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 woman age 30 years 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 woman age 71 years 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.

Carlson et al [2010] reported six individuals with CED and bilateral sensorineural hearing loss. Three underwent internal auditory canal decompression with mixed results. Conservative management was used in the other three individuals with no worsening of symptoms (see also Hereditary Deafness and Hearing Loss Overview).

Prevention of Primary Manifestations

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.

Prevention of Secondary Complications

Monitor blood pressure in individuals treated with corticosteroids and treat hypertension if necessary.

Individuals taking losartan also need regular blood pressure monitoring due to the increased risk for hypotension.

Taper corticosteroid dose as tolerated to reduce the risk of osteoporosis and compression fractures of the spine.

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, ongoing evaluations should include the following:

  • Annual:
    • Complete neurologic examination
    • CBC
    • Measurement of blood pressure
    • Audiology evaluation
    • Ophthalmology evaluation
    • Evaluation of bone mineral density
      Note: CED does not appear to cause an increase in spine density; therefore, steroid therapy could lead to osteoporosis of the spine [Author, personal observation].
  • Routine monitoring of linear growth in children due to the possible side effect of delayed or stunted growth
  • Individuals with cranial hyperostosis (including those treated surgically) should continue to be monitored for signs and symptoms of increased intracranial pressure, as cranial hyperostosis can recur.

The authors are aware of one affected teenage individual who died of a dilated ascending aorta dissection. Whether this is related to CED is unknown. Because the mechanism of CED involves increased TGFB1 signaling, also found in Marfan syndrome and Loeys-Dietz syndrome, this death is of some concern. The authors are unaware of any other similar cases. Note: No recommendations for routine evaluation of the aorta can be made at this time.

Agents/Circumstances to Avoid

Bisphosphonates. Pamidronate did not improve symptoms in four individuals [Inaoka et al 2001, Janssens et al 2006]. 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.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify the diagnosis as early as possible, avoid potential misdiagnosis, and provide appropriate treatment for extremity pain.

Evaluations can include:

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

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.
  • Some individuals diagnosed with CED may have the disorder as the result of a de novo TGFB1 pathogenic variant. The proportion of cases caused by de novo pathogenic variants is unknown.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
    If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Though theoretically possible, no instances of germline mosaicism have been reported.
  • The family history of some individuals diagnosed with CED may appear to be negative because of failure to recognize the disorder in family members, early death of a parent before the onset of symptoms, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations (i.e., molecular genetic testing or radiographs) have been performed on the parents of the proband.
  • Note: Though not reported, if the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

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, the risk to the sibs of inheriting the pathogenic variant is 50%. However, the risk that sibs would be affected is less than 50% because of reduced penetrance. Severity is impossible to predict, as there is significant phenotypic variability within families.
  • If the parents have been tested for the TGFB1 pathogenic variant identified in the proband and:
    • A parent of the proband has the TGFB1 pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Because of reduced penetrance, some individuals who inherit TGFB1 pathogenic variants will not have manifestations. The exact penetrance is unknown.
    • The TGFB1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism.
  • If the parents have not been tested for the TGFB1 pathogenic variant and are clinically unaffected, the risk to the sibs of a proband appears to be low. The sibs of a proband with clinically unaffected parents are still at increased risk for CED because of the possibility of reduced penetrance in a parent or the theoretic possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with CED has a 50% chance of inheriting the TGFB1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TGFB1 pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with CED has the TGFB1 pathogenic variant or clinical evidence of the disorder, the TGFB1 variant is likely de novo. 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the TGFB1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CED are possible.

Because of reduced penetrance, results of prenatal testing may not be useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • AboutFace International
    123 Edward Street
    Suite 1003
    Toronto Ontario M5G 1E2
    Canada
    Phone: 800-665-3223 (toll-free); 416-597-2229
    Fax: 416-597-8494
    Email: info@aboutfaceinternational.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Camurati-Engelmann Disease: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Camurati-Engelmann Disease (View All in OMIM)

131300CAMURATI-ENGELMANN DISEASE; CAEND
190180TRANSFORMING GROWTH FACTOR, BETA-1; TGFB1
601477RIBBING DISEASE

Gene structure. TGFB1 has seven exons. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Three pathogenic variants in exon 4 of TGFB1 account for approximately 80% of the pathogenic variants observed in CED [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]:

  • c.652C>T is found in about 40% of individuals.
  • c.653G>A or c.673T>C is found in an additional 35% of individuals.
  • Other selected pathogenic variants are listed in Table 3.

For more information, see Table A.

Table 3.

TGFB1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.30_38dupp.Leu11_Leu13dupNM_000660​.4
NP_000651​.3
c.241T>Cp.Tyr81His
c.652C>Tp.Arg218Cys
c.653G>Ap.Arg218His
c.664C>Gp.His222Asp
c.673T>Cp.Cys225Arg

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Transforming growth factor beta-1 (TGF-β1) is synthesized as a large precursor molecule. TGF-β1 preprotein contains a signal peptide of 29 amino acids that is proteolytically cleaved. TGF-β1 is further cleaved after amino acid 278 to form latency-associated peptide (LAP) and active TGF-β1. LAP dimerizes with interchain disulfide links at Cys223 and Cys225. TGF-β1 can be secreted as an inactive small latent complex that consists of a mature TGF-β1 homodimer non-covalently associated with an LAP homodimer at LAP residues Ile53-Leu59. LAP shields the type II receptor binding sites in the mature TGF-β1. Most cells secrete TGF-β1 as a large latent complex (LLC) of TGF-β1/LAP covalently bound between Cys33 in the LAP chains and latent TGFB-binding protein (LTBP). LTBPs facilitate TGF-β1 folding, secretion, and possibly targeting to the extracellular matrix. Activation of the LLC occurs via the N-terminal domain of LTBP binding to the extracellular matrix.

Abnormal gene product. The majority of pathogenic variants in individuals with CED result in single amino-acid substitutions in the carboxy terminus of TGF-β1 latency-associated peptide (LAP). The substitutions are near the site of interchain disulfide bonds between the LAP homodimers. These pathogenic variants disrupt dimerization of LAP and binding to active TGF-β1 [Walton et al 2010], leading to increased active TGF-β1 release from the cell. p.Arg218His mutated fibroblasts from individuals with CED showed increased active TGF-β1 in the cell media compared to normal fibroblasts [Saito & Kinoshita 2001]. In vitro analysis of p.Arg218Cys, p.His222Asp, and p.Cys225Arg mutated constructs also showed increased active TGF-β1 in the medium of transfected cells. In contrast, the p.Leu11_Leu13dup and p.Tyr81His pathogenic variants caused a decrease in the amount of TGF-β1 secreted. However, in a luciferase reporter assay specific for TGF-β1-induced transcriptional response, the mutated cells showed increased luciferase activity, suggesting intracellular activation of the receptor [Janssens et al 2003].

References

Literature Cited

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Chapter Notes

Revision History

  • 12 October 2017 (ha) Comprehensive update posted live
  • 5 March 2015 (me) Comprehensive update posted live
  • 6 December 2012 (me) Comprehensive update posted live
  • 1 June 2010 (me) Comprehensive update posted live
  • 16 August 2006 (me) Comprehensive update posted live
  • 25 June 2004 (me) Review posted live
  • 18 march 2004 (sw) Original submission
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