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Camurati-Engelmann Disease

Synonym: Progressive Diaphyseal Dysplasia. Includes: Ribbing Disease

, MD and , MD, PhD.

Author Information
, MD
Division of Genetic Medicine, University of Washington
Seattle Children’s Hospital
Seattle, Washington
, MD, PhD
Medical Genetics
Cedars-Sinai Medical Center
Los Angeles, California

Initial Posting: ; Last Update: December 6, 2012.

Summary

Disease 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 molecular genetic testing. Bone and muscle histology are nonspecific. TGFB1 is the only gene in which mutations are known to cause CED. Sequence analysis identifies mutations in TGFB1 in approximately 90% of affected individuals.

Management. Treatment of manifestations: Treatment includes use of corticosteroids. 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 count, blood pressure, and hearing screen.

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

Diagnosis

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 in which mutations are known to cause CED.

Evidence for locus heterogeneity. 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

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

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
TGFB1Sequence analysisSequence variants 2, 3>90%
Sequence analysis of select exonsSequence variants in select exons 4Unknown
Deletion / duplication analysis 5None reportedUnknown, none reported

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

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. 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].

4. Exons sequenced vary by laboratory.

5. Testing that identifies deletions/duplications not readily 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.

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

Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).

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.
  • No deletions/duplications involving TGFB1 have been reported as causative for CED. The clinical utility of such testing is unknown.

Predictive testing for 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.

Clinical Description

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

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 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].

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. 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] has 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.
  • 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 occur in CED.
  • 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.
  • Diaphyseal dysplasia with anemia [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 present in CED help distinguish it from the endosteal hyperostoses as well.
  • Hyperostosis corticalis generalisata, Worth type [OMIM 144750] has 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.
  • 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

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.

Individuals with radiographic evidence of skull base sclerosis and neurologic symptoms may benefit from a baseline computed tomography of the head and neck to determine the extent of disease and allow consideration of surgical treatment options.

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.

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

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.

Surgical treatment for persistent bone pain by intramedullary reaming was reported in a 22-year-old female diagnosed with Ribbing disease [Öztürkmen & Karamehmetoğlu 2011]. Pain in the tibia resolved completely following the surgery; at five-year follow-up, the patient remains pain free.

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.

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 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. Bone mineral density should be followed annually in affected individuals on corticosteroids. CED does not appear to cause an increase in spine density. Therefore steroid therapy could lead to osteoporosis of the spine [Author, personal observation]. Linear growth should be monitored in children on corticosteroids 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 and Loeys-Dietz syndromes, this death is of some concern. The authors are unaware of any other similar cases. Recommendations for routine evaluation of the aorta cannot be made at this time.

Agents/Circumstances to Avoid

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

Evaluation 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
  • Bisphosphonates. 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.

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 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.

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

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 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.

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 approximately 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 be 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 an option for some families in which the disease-causing mutation 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
    #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
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528

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

Normal allelic variants. TGFB1 has seven exons. Several normal allelic 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 normal 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 normal allelic variants have 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 normal allelic variants, four in intron 1 (c.355+1156C>T, c.355+1191A>G, c.355+1709T>G, c.355+3080C>T), three in intron 2 (c.517-1490A>G, c.85145T>C, c.85358G>T), and two in intron 5 (c.96298C>G, c.97236A>G).

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

Pathologic allelic variants. Three pathologic variants in exon 4 of the TGFB1 gene account for approximately 80% of the mutations 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 transition causing a p.Arg218Cys substitution is found in about 40% of individuals.
  • c.653G>A transition causing a p.Arg218His substitution or a c.673T>C transition causing a p.Cys225Arg substitution is found in an additional 35% of individuals.
  • Other mutations are listed in Table 2.

For more information, see Table A.

Table 2. Selected TGFB1 Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change Reference Sequences
Normalg.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
c.355+1156C>T
(1511C>T)
--
c.355+1191A>G
(1546A>G)
--
c.355+1709T>G
(2064T>G)
--
c.355+3080C>T
(3435C>T)
--
c.517-1490A>G
(2085A>G)
--NM_000660​.4
rs2014015
85145T>C
(2484T>C)
--AC011462​.4
85358G>T
(2691G>T)
--
96298C>G
(7219C>G)
--
97236A>G
(8157A>G
--
Pathologicc.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 author(s). 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 mutations in individuals with CED lead to 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 mutations 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]. 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 mutations 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

Literature Cited

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Chapter Notes

Revision History

  • 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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