Camurati-Engelmann disease is a rare autosomal dominant type of bone bone dysplasia. The hallmark of the disorder is the cortical thickening of the diaphyses of the long bones. Hyperostosis is bilateral and symmetrical and usually starts at the ... Camurati-Engelmann disease is a rare autosomal dominant type of bone bone dysplasia. The hallmark of the disorder is the cortical thickening of the diaphyses of the long bones. Hyperostosis is bilateral and symmetrical and usually starts at the diaphyses of the femora and tibiae, expanding to the fibulae, humeri, ulnae, and radii. As the disease progresses, the metaphyses may be affected as well, but the epiphyses are spared. Sclerotic changes at the skull base may be present. The onset of the disease is usually during childhood and almost always before the age of 30. Most patients present with limb pain, muscular weakness, a waddling gait, and easy fatigability. Systemic manifestations such as anemia, leukopenia, and hepatosplenomegaly occur occasionally (summary by Janssens et al., 2006).
Camurati (1922) of Bologna described a rare type of 'symmetrical hereditary osteitis' involving the lower limbs in a father and son and several others in a total of 4 generations. Pain in the legs and fusiform swelling of ... Camurati (1922) of Bologna described a rare type of 'symmetrical hereditary osteitis' involving the lower limbs in a father and son and several others in a total of 4 generations. Pain in the legs and fusiform swelling of the legs below the knees were noted. Engelmann (1929) of Vienna reported an isolated case of 'osteopathica hyperostotica (sclerotisans) multiplex infantilis.' The disorder is sometimes called Camurati-Engelmann disease in recognition of the earlier description. Cockayne (1920) described a probable case before the publications of Camurati and Engelmann. The nature of the condition and the possibility that it represented syphilitic osteitis were discussed. Lennon et al. (1961) described a case of Engelmann disease and reviewed the literature. Gross thickening of the cortex of bones, both on the periosteal surface and in the medullary canal, is characteristic. The process usually begins in the shaft of the femur or tibia but spreads to involve all bones. Onset is usually before age 30 years, often before age 10. All races and both sexes are affected. Nine examples of familial occurrence in 1 or 2 generations were mentioned. Severe bone pains, especially in the legs, and muscular hypoplasia are the distinctive features of this form of sclerotic bone disease. The bones of the base of the skull and rarely the mandible may be affected. The skeletal disorder is often associated with muscular weakness, peculiar gait, pains in the legs, fatigability, and apparent undernutrition. The muscular weakness is not necessarily progressive and typical bone changes may be found in asymptomatic persons. Because of the associated features, muscular dystrophy or poliomyelitis is sometimes diagnosed in these patients. The condition described by Ribbing and in the past sometimes referred to as Ribbing disease (601477) has been considered by some to be Engelmann disease. Ribbing (1949) described a family in which 4 of 6 sibs were affected. The diaphyseal osteosclerosis and hyperostosis were limited to one or more (up to 4) of the long bones, the tibia being affected in all. The father, who was dead, had complained for many years of pains in the legs. Thus, the condition may be dominant; no x-ray studies of the father were available and Ribbing (1949) noted that the body had been cremated. Paul (1953) reported the same entity in 2 of 4 sibs, one of whom also had otosclerosis, which was present in several other members of the kindred. In an addendum, Paul noted that the infant son of one of his patients had difficulty walking and was found to have multiple sclerosing lesions of long bones. Again dominant inheritance was suggested. Ribbing (1949) referred to the condition described as hereditary multiple diaphyseal sclerosis (rather than dysplasia), and the same term was used by Paul (1953) and Furia and Schwartz (1990). Seeger et al. (1996) insisted that Ribbing disease is a disorder separate from Engelmann disease. Although it may appear to be identical radiographically, many clinical differences exist. Camurati-Engelmann disease presents during childhood, whereas Ribbing disease was thought by Seeger et al. (1996) to present in middle age. (They wrote: 'patients contract Ribbing disease after puberty.') The disease is confined to the diaphyses of long bones, especially the tibia and the femur. Whereas Engelmann disease is bilateral and symmetric, Ribbing disease is either unilateral or asymmetric and asynchronously bilateral. In Engelmann disease, the skull is involved as well as the long bones. The gait and neurologic abnormalities and anemia with extramedullary hematopoiesis occurs only in Engelmann disease. Makita et al. (2000) reported a 3-generation Japanese family with Engelmann disease with a wide variation in phenotype among the affected family members. Of the 12 patients, 7 had full manifestations of Engelmann disease, while the other 5 exhibited only segmental (rhizomelic and/or mesomelic) involvement and asymmetric diaphyseal sclerosis without any clinical symptoms, resembling Ribbing disease. The authors proposed that Engelmann disease and Ribbing disease represent phenotypic variation of the same disorder. Crisp and Brenton (1982) emphasized systemic manifestations in Engelmann disease: anemia, leukopenia, hepatosplenomegaly, and raised erythrocyte sedimentation rate. Their patient also had the Raynaud phenomenon and multiple nail-fold infarcts. Clybouw et al. (1994) reported a 10-year-old girl with characteristic clinical and roentgenologic manifestations of Camurati-Engelmann disease. Scintigraphy with 99mTc showed increased osteoblastic activity in the diaphyseal portions of almost all long bones. Clinical and roentgenologic investigations of her parents produced normal results, but a clear focus of osteoblastic hyperactivity was demonstrated scintigraphically at the base of the skull of the proband's mother. Some persons with Camurati-Engelmann disease may have subclinical manifestations. According to Clybouw et al. (1994), a detailed study including x-ray examination and scintigraphy is necessary for genetic counseling in apparently sporadic cases. Grey et al. (1996) provided a 45-year follow-up on a patient with Engelmann disease initially described by Stronge and McDowell (1950) when he was 28 years of age. The disease had shown progression over the subsequent 45 years, characterized by the unique involvement of the femoral capital epiphyses. The patient had changed little in physical appearance, apart from aging. He was thin and tall with generalized underdevelopment and weakness of the muscles, particularly around the pelvic girdle and thighs. The legs were bowed and the lumbar lordosis had increased. Serum alkaline phosphatase levels had remained normal. In 1950 the disease involved only the diaphyses of the affected limbs. By 45 years later it had affected the metaphyses of all limbs, the epiphyses, and the articular surfaces of the femoral heads and acetabula, as well as the right tibial epiphysis. The spine and hands, unaffected in 1950, showed changes and there was some progression of the disease in the skull. Saraiva (2000) described anticipation as judged by age of onset of symptoms in successive generations of a large family with 15 affected members in 3 generations. Wallace et al. (2004) reported a 4-generation pedigree with 7 individuals affected by CED. The pedigree demonstrated autosomal dominant inheritance but with remarkable variation in expressivity and reduced penetrance. The most severely affected individual had progression of mild skull hyperostosis to severe skull thickening and cranial nerve compression over 30 years. His carrier father, on the other hand, remained asymptomatic into his ninth decade and had no radiographic hyperostosis or sclerosis of the bones. Symptomatic relatives presented with lower limb pain and weakness. They were initially diagnosed with a variety of other conditions. Two of the symptomatic individuals were treated successfully with prednisone. Linkage to 19q13.1-q13.3 was confirmed. The arg218-to-his mutation in the TGFB1 gene (R218H; 190180.0003) was identified in the affected individuals, the asymptomatic obligate carrier, and in another unaffected relative. Janssens et al. (2006) reported 41 individuals with CED confirmed by genetic analysis from 14 families and provided a detailed review of the disorder.
Because the transforming growth factor-beta-1 gene (TGFB1; 190180) maps to the same region of chromosome 19, Kinoshita et al. (2000) screened it for mutations in Camurati-Engelmann disease in 7 unrelated Japanese families and 2 families of European descent. ... Because the transforming growth factor-beta-1 gene (TGFB1; 190180) maps to the same region of chromosome 19, Kinoshita et al. (2000) screened it for mutations in Camurati-Engelmann disease in 7 unrelated Japanese families and 2 families of European descent. They detected 3 different heterozygous missense mutations in exon 4, near the carboxy terminus of the latency-associated peptide (LAP), in all 9 families examined.
Campos-Xavier et al. (2001) stated that 5 mutations in the TGFB1 gene had been identified in 21 families with CED. In 1 Australian family and 6 European families with CED, they found 3 of these mutations, R218H (190180.0002) ... Campos-Xavier et al. (2001) stated that 5 mutations in the TGFB1 gene had been identified in 21 families with CED. In 1 Australian family and 6 European families with CED, they found 3 of these mutations, R218H (190180.0002) in 1 family, R218C (190180.0003) in 3 families, and C225R (190180.0001) in 3 families, which had previously been observed in families of Japanese and Israeli origin. The R218C mutation appeared to be the most prevalent worldwide, having been found in 17 of 28 reported families.
Features essential to the diagnosis of Camurati-Engelmann disease (CED) in a proband include the following:...
DiagnosisClinical DiagnosisFeatures essential to the diagnosis of Camurati-Engelmann disease (CED) in a proband include the following:Proximal muscle weaknessRadiographic 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.TestingChanges in bone and muscle histology are nonspecific.Molecular Genetic TestingGene. 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 DiseaseView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTGFB1Sequence analysisSequence variants 2, 3>90%Clinical Sequence analysis of select exonsSequence variants in select exons 4UnknownDeletion / duplication analysis 5None reportedUnknown, none reported1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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 probandMolecular 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.Genetically Related (Allelic) DisordersCED and Ribbing disease, representing phenotypic variations of the same disorder, are the only phenotypes currently known to be associated with mutations in TGFB1.
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]. ...
Natural HistoryIndividuals 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.
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]. ...
Genotype-Phenotype CorrelationsNo known correlation exists between the nature of the TGFB1 mutations and the severity of the clinical or radiographic manifestations [Campos-Xavier et al 2001].
Few disorders share the clinical and radiographic findings of Camurati-Engelmann disease (CED). The correct diagnosis is made by physical examination and skeletal survey....
Differential DiagnosisFew 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
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....
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsCorticosteroids 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 ComplicationsSteroids 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. SurveillanceAfter 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 RiskTesting 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 InvestigationSearch 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.OtherThe 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTGFB119q13.2Transforming growth factor beta-1TGFB1 homepage - Mendelian genesTGFB1Data 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) View in own window 131300CAMURATI-ENGELMANN DISEASE; CAEND 190180TRANSFORMING GROWTH FACTOR, BETA-1; TGFB1Normal 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 View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid Change Reference SequencesNormalg.14128514A>G (-1347C>T)--NT_011109.15 rs1800469c.29C>Tp.Leu10ProNM_000660.4 NP_000651.3c.-171delC (11007delC)--c.74G>C (75G>C)p.Arg25Proc.788C>T (11935C>T)p.Thr263Ilec.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 rs201401585145T>C (2484T>C)--AC011462.485358G>T (2691G>T)--96298C>G (7219C>G)--97236A>G (8157A>G--Pathologicc.30_38dupp.Leu11_Leu13dupNM_000660.4 NP_000651.3c.241T>Cp.Tyr81Hisc.466C>Tp.Arg156Cysc.505G>Ap.Glu169Lysc.652C>Tp.Arg218Cysc.653G>Ap.Arg218Hisc.664C>Gp.His222Aspc.667T>Ap.Cys223Serc.667T>Cp.Cys223Argc.667T>Gp.Cys223Glyc.673T>Cp.Cys225ArgSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal 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].