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Camurati-Engelmann Disease

Synonym: Progressive Diaphyseal Dysplasia

, MD and , MD, PhD.

Author Information
, MD
Division of Genetic Medicine
University of Washington
Seattle Children’s Hospital
Seattle, Washington
, MD, PhD
Department of Human Genetics
Emory University School of Medicine
Atlanta, Georgia

Initial Posting: ; Last Update: March 5, 2015.

Summary

Clinical characteristics.

Camurati-Engelmann disease (CED) is characterized by hyperostosis of the long bones and the skull, proximal muscle weakness, severe limb pain, a wide-based, waddling gait, and joint contractures. Facial features such as 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.

Diagnosis of CED is based on physical examination and radiographic findings and can be confirmed by identification of a heterozygous pathogenic variant in TGFB1 on molecular genetic testing.

Management.

Treatment of manifestations: Treatment includes use of corticosteroids to control pain. 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. Bilateral myringotomy can improve conductive hearing loss resulting from serous otitis.

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, hearing screen, and bone density scan.

Genetic counseling.

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

GeneReview Scope

Camurati-Engelmann Disease: Included Disorders
  • 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For synonyms and outdated names see Nomenclature.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 by molecular genetic testing (Table 1) if radiographic findings are inconclusive.

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 rarely epiphyses
  • Periosteal involvement with uneven cortical thickening and increased diameter
  • Endosteal bony sclerosis that can lead to narrowed medullary canal
  • Usually symmetric in the appendicular skeleton but may be 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:

  • Sequence analysis of TGFB1. Deletion/duplication analysis is available. However, no deletions or duplications have been reported thus far.
  • Use of a multi-gene panel that includes TGFB1 and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1.

Summary of Molecular Genetic Testing Used in Camurati-Engelmann Disease

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
TGFB1Sequence analysis 2 >90% 3
Deletion/duplication analysis 4Unknown, none reported
Unknown 5NA

NA = not applicable

1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

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

3.

The majority are missense mutations in exon 4 leading to single amino acid substitutions in the encoded protein [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].

4.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

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]. 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 of 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 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, genua valga, flat feet, and frontal bossing.

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 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 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].

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.

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

Penetrance

Some obligate heterozygotes with an identified TGFB1 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.

  • Craniodiaphyseal dysplasia (OMIM 218300) is characterized by progressive and marked enlargement of the midline cranial bones causing a distinct facial deformity including nasal bridge widening and ocular hypertelorism. Cranial involvement in CED is milder and only on occasion results in frontal bossing and proptosis. The sclerosis of the long bones in craniodiaphyseal dysplasia is restricted to the diaphyses, which helps differentiate it from CED, in which the metaphyses can be affected as well. The gene(s) in which pathogenic variants occur have not been identified. Autosomal recessive inheritance is suggested.
  • Kenny-Caffey syndrome type 2 (OMIM 127000) is characterized by dwarfism, cortical thickening of the long bones, delayed fontanel closure, craniofacial anomalies, hypocalcemia, and hypoparathyroidism. Neither laboratory abnormalities nor delayed fontanel closure occurs in CED. Heterozygous FAM111A pathogenic variants are causative. Inheritance is autosomal dominant.
  • Juvenile Paget disease (OMIM 239000) is characterized by a predisposition to fractures, coarse trabeculations, and bowing of the long bones. There is no predisposition to fractures or bowing of the long bones in CED. Biallelic TNFRSF11B pathogenic variants are causative. Inheritance is autosomal recessive.
  • Ghosal hematodiaphyseal dysplasia (OMIM 231095) results in severe anemia and an increased susceptibility to infections. Diaphyseal dysplasia with anemia comprises endosteal bone formation with no evidence of subperiosteal bone formation. The presence of endosteal and subperiosteal bone deposition in CED helps distinguish it from the endosteal hyperostoses as well. Biallelic TBXAS1 pathogenic variants are causative. Inheritance is autosomal recessive.
  • Endosteal hyperostosis, autosomal dominant (OMIM 144750) is characterized by endosteal thickening without widening of the diaphyseal shaft. There is also a characteristic wide deep mandible with an increased gonial angle, which is distinct from the enlarged mandible found only occasionally in CED. Heterozygous LRP5 pathogenic variants are causative.
  • SOST-related sclerosing bone dysplasias include sclerosteosis (SCL) and van Buchem disease. A distinguishing clinical feature of SCL is variable syndactyly, usually of the second (index) and third (middle) fingers. The manifestations of van Buchem disease are generally milder than SCL, and syndactyly is absent. The SOST-related sclerosing bone dysplasias are inherited in an autosomal recessive manner, while CED is inherited in an autosomal dominant manner. Individuals with SCL and van Buchem disease have endosteal hyperostosis with smooth periosteal surfaces, whereas individuals with CED have periosteal thickening and an uneven, rough cortex.

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:

  • Complete skeletal survey (if not performed as part of the diagnostic work up)
  • Assessment for cranial nerve deficits, including neurologic examination, hearing screen, 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 ESR and bone scan as baseline measures of disease activity
  • In individuals with radiographic evidence of skull base sclerosis and neurologic symptoms, consideration of baseline CT of the head and neck to determine the extent of disease and allow consideration of surgical treatment options
  • Medical genetics consultation

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 osteoblastic 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 is reported in one patient [Trombetti et al 2012].

Losartan. Reduced bone pain and increased physical activity are reported in two patients 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.

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; at five-year follow-up, the individual remained pain free.

Craniectomy relieved increased intracranial pressure and headaches in two patients [Author, personal observation].

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] report 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
    • Hearing screen
    • 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

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. Bone pain and uptake of 99mTc methylene diphosphonate by scintigraphy increased with pamidronate in a woman age 27 years 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.

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.

  • If the TGFB1 pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, radiographic evaluation for hyperostosis can be used to clarify the disease status of at-risk relatives.

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.

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.
  • A proband with CED may have the disorder as the result of de novo mutation of TGFB1. The proportion of cases caused by de novo mutation is unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include (a) molecular genetic testing if a TGFB1 pathogenic variant has been identified in the proband or (b) a complete skeletal survey or AP radiographs of the extremities and a lateral skull film if the TGFB1 pathogenic variant has not been identified in the proband.
  • 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 or has an identified pathogenic variant in TGFB1, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • Because of reduced penetrance, some individuals who inherit TGFB1 pathogenic variants will not have manifestations. The exact penetrance is unknown.
  • When the parents are clinically unaffected, molecular genetic testing can be used to identify individuals who have a TGFB1 pathogenic variant but no clinical manifestations. 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.
  • If the TGFB1 pathogenic variant 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 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 TGFB1 pathogenic variant.

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 pathogenic variant in TGFB1, his or her family members are 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 mutation. When neither parent of a proband with CED has the TGFB1 pathogenic variant or clinical evidence of the disorder, the TGFB1 mutation 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

If the TGFB1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing. 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.

Requests for prenatal testing for conditions which (like CED) do not affect intellect and have some treatment available are not common. 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the TGFB1 pathogenic variant has been identified.

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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) 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 Symbol.

Benign allelic variants. Several benign variants in TGFB1 have been investigated for their effect on plasma TGFB1 levels and bone mineral density. These include a 5’UTR in a consensus CREB halfsite [Grainger et al 1999], g.14128514A>G, c.29T>C in the signaling peptide resulting in a p.Leu10Pro amino acid substitution, c.-171delC, and an intron 5 variant [Keen et al 2001]. Several other benign allelic variants have been identified [Beránek et al 2002] including c.74G>C in exon 1, resulting in a p.Arg25Pro substitution and c.788C>T in exon 5, resulting in a p.Thr263Ile substitution [Langdahl et al 1997, Grainger et al 1999, Hinke et al 2001, Keen et al 2001, Yamada et al 2001, Ziv et al 2003]. None of these benign allelic variants has been found to be associated with disease severity in families with Camurati-Engelmann disease (CED) [Campos-Xavier et al 2001, Wallace et al 2004].

Watanabe et al [2002] catalogued nine additional single-base substitution benign variants in introns.

Shah et al [2006] identified a distal promoter segment and ten novel normal allelic variants.

Pathogenic allelic 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 2.

For more information, see Table A.

Table 2.

Selected TGFB1 Allelic Variants

Variant ClassificationDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
Benigng.14128514A>G
(-1347C>T)
--NT_011109​.15
rs1800469
c.29C>Tp.Leu10ProNM_000660​.4
NP_000651​.3
c.-171delC
(11007delC)
--
c.74G>C
(75G>C)
p.Arg25Pro
c.788C>T
(11935C>T)
p.Thr263Ile
Pathogenicc.30_38dupp.Leu11_Leu13dupNM_000660​.4
NP_000651​.3
c.241T>Cp.Tyr81His
c.466C>Tp.Arg156Cys
c.505G>Ap.Glu169Lys
c.652C>Tp.Arg218Cys
c.653G>Ap.Arg218His
c.664C>Gp.His222Asp
c.667T>Ap.Cys223Ser
c.667T>Cp.Cys223Arg
c.667T>Gp.Cys223Gly
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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

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 mutant 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 mutant 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 mutant cells showed increased luciferase activity, suggesting intracellular activation of the receptor [Janssens et al 2003].

References

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Chapter Notes

Revision History

  • 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 to live Web site
  • 25 June 2004 (me) Review posted to live Web site
  • 18 march 2004 (sw) Original submission
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