Clinical characteristics.

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

Diagnosis/testing.

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

Management.

Targeted therapy: Corticosteroid therapy as needed to control symptoms; losartan may be a helpful adjuvant therapy to minimize the need for steroids to control pain.

Supportive care: Management of muscle weakness and gait issues per physical medicine and rehabilitation specialists and physical therapist. Treatment of joint contractures and other musculoskeletal manifestations per orthopedist with experience in skeletal dysplasias; pain is also managed with analgesics, non-pharmacologic methods, and on occasion surgical treatment. Management of hearing loss per otolaryngologist; bilateral myringotomy can improve conductive hearing loss resulting from serous otitis. Treatment of ocular manifestations per ophthalmic subspecialist with low vision services as needed; craniectomy may be needed to reduce intracranial pressure and relieve symptoms in individuals with several cranial sclerosis. Adjustment of corticosteroids or losartan as needed for hyper- or hypotension; treatment with antihypertensives as needed; mobility assessment with adaptive devices and fall precautions.

Surveillance: Assess development of gross motor skills throughout childhood; assess for mobility issues, weakness, contractures, bone pain, and other musculoskeletal manifestations at each visit; serum ESR and bone scan as needed in those with acute bone pain to assess disease activity; evaluation of bone mineral density annually in those treated with corticosteroids; annual neurologic examination to assess for cranial nerve deficits and headaches; monitor for signs and symptoms of increased intracranial pressure at each visit; head and neck CT as needed in those with sclerosis of the skull base and neurologic symptoms to determine extent of disease and allow consideration of surgical treatment options; annual audiology evaluation with BAER and inner ear CT as needed; monitor linear growth and pubertal development at each visit throughout childhood; assess blood pressure at each visit; annual CBC.

Agents/circumstances to avoid: Excess phosphate.

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.

Genetic counseling.

CED is inherited in an autosomal dominant manner. Many individuals diagnosed with CED have an affected parent; some individuals diagnosed with CED may have the disorder as the result of a de novo TGFB1 pathogenic variant. Each child of an individual with CED has a 50% chance of inheriting the TGFB1 pathogenic variant. Once the TGFB1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CED are possible.

Suggestive Findings

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

• Proximal muscle weakness
• Easy fatigability
• Bone pain primarily affecting the lower extremities
• Waddling gait

Establishing the Diagnosis

The clinical diagnosis of CED can be established in a proband with the characteristic radiographic findings or, if radiographic findings are inconclusive, a heterozygous pathogenic (or likely pathogenic) variant in TGFB1 identified by molecular genetic testing (see Table 1).

Clinical Description

Individuals with Camurati-Engelmann disease (CED) present with proximal muscle weakness, poor muscular development, a wide-based, waddling gait, easy fatigability, bone pain, 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 onset from birth to age 76 years [Wallace et al 2004].

Musculoskeletal. Decreased muscle mass and weakness are most apparent in the proximal lower limbs, resulting in difficulty when rising from a sitting position. A wide-based, waddling gait is common. Delayed onset of walking has been reported [Kim et al 2018, Mwasamwaja et al 2018]. Joint contractures occur in 43% of individuals. Marfanoid body habitus is described in some affected individuals, with reduction of muscle mass and subcutaneous tissue resulting in low body mass index in some individuals [Wallace et al 2004, Janssens et al 2006, Van Hul et al 2019]. Musculoskeletal involvement can lead to varying degrees of lumbar lordosis, kyphosis, scoliosis, coxa valga, radial head dislocation, genu valgum, hallux valgus, and flat feet [Yuldashev et al 2017].

Bone pain is reported in the majority of affected individuals [Wallace et al 2004, Janssens et al 2006, Liang et al 2022]. The reported severity of bone pain ranged from mild (not requiring any treatment) to severe (requiring narcotic analgesics) [Yuldashev et al 2017]. The pain is described as constant, aching, and most intense in the lower limbs. Pain often increases with activity, stress, and cold weather. Many individuals have intermittent episodes of severe pain and incapacitation. Bone pain has resulted in limited ambulation in some individuals. The enlarged bone shafts can also be palpable and tender on examination; 52% of affected individuals report bone tenderness with palpation [Wallace et al 2004]. Intermittent limb swelling, erythema, and warmth also occur. Corticosteroid treatment has been reported to reduce pain and weakness and improve gait, exercise tolerance, and flexion contractures in several individuals [Lindstrom 1974, Baş et al 1999, Wallace et al 2004, Mwasamwaja et al 2018, Liang et al 2022]. Losartan alone or in combination with corticosteroids was reported to reduce bone pain and increase physical activity [Ayyavoo et al 2014, Simsek-Kiper et al 2014, Kim et al 2018, Abdulla 2019, Cui et al 2022]. The severity of bone pain may decrease in adulthood [Hughes et al 2019].

Although bone mineral density measured at the hip and femoral neck are increased in individuals with CED, bone strength measured by bone impact microindentation in three sibs with CED was below normal. Because of the small sample size, the difference in bone strength was not statistically significant [Herrera et al 2017]. Increased susceptibility to fracture has not been reported. Healing of fractures, when they occur, may be delayed [Wallace et al 2004].

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

Approximately 19%-54% of individuals with CED have conductive and/or sensorineural hearing loss [Carlson et al 2010, Liang et al 2022]. Conductive loss can be caused by narrowing of the external auditory meatus, bony encroachment of the ossicles, or narrowing of the oval and round windows. Sensorineural hearing loss is caused by narrowing of the internal auditory canal and compression of the cochlear nerve and/or vasculature. Sensorineural hearing loss can also occur with attempted decompression of the facial nerves.

Vestibulopathy including tinnitus and vertigo have also been reported in several individuals [Carlson et al 2010, Kim et al 2018].

Involvement of the orbit has led to blurred vision, proptosis, papilledema, epiphora, glaucoma, subluxation of the globe, and retinal detachment [Carlson et al 2010, Popiela & Austin 2015, Kim et al 2018].

Facial paralysis has been successfully treated by surgical decompression of the facial nerve in one affected individual [Achahbar et al 2021].

Calvarial hyperostosis can lead to increased intracranial pressure, chronic headaches that can be severe, and frontal bossing. Chronic intracranial hypertension led to a bone defect and meningoencephalocele in one individual at age 57 years [Yanagihara et al 2022]. Recurrent cranial hyperostosis following surgical decompression can occur [Wong et al 2017].

Rarely, clonus [Neuhauser et al 1948], sensory loss, slurred speech, dysphagia, cerebellar ataxia, and bowel and bladder incontinence are reported [Carlson et al 2010].

Corticosteroids may delay bone hyperostosis and prevent or delay the onset of skull involvement. Although histologic studies following steroid therapy showed increased bone resorption and secondary remodeling with increased osteoblast activity and decreased lamellar bone deposition, several authors reported no regression of sclerosis on radiographic evaluation [Verbruggen et al 1985] or on scintigraphic evaluation [Baş et al 1999]. Lindstrom [1974] and Baş et al [1999] reported diminished sclerosis on radiographs following steroid therapy. Verbruggen et al [1985] and Inaoka et al [2001] reported reduced radioactivity on bone scintigraphy.

Endocrine manifestations. Hypopituitarism has been described in several individuals, resulting in short stature, delayed pubertal development, and hypocortisolism [Yuldashev et al 2017, Li et al 2022]. Hypopituitarism has been attributed to skull base osteosclerosis resulting in a small sella and/or pituitary compression due to intracranial hypertension [Das et al 2021]. In addition, hypopituitarism may be secondary to direct effects of TGFB1 on the pituitary gland. Hypogonadism and lack of pubertal development has also been attributed to reduced adipose tissue and/or direct effects of TGFB1 on the gonads [Das et al 2021]. Combination corticosteroid therapy and losartan led to initiation of pubertal development in a female age 18 years [Cui et al 2022]. Hypothyroidism is also rarely described as a result of pituitary effects or autoimmune hypothyroidism [Das et al 2021].

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

Less common manifestations in individuals with CED include anemia (hypothesized to be caused by a narrowed medullary cavity), hepatosplenomegaly, atrophic skin, hyperhidrosis of the hands and feet, delayed dental eruption, and extensive dental caries.

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. Osteoblastoma of the distal radius and enchondroma of the fifth finger have each been reported in one individual with clinical and radiographic diagnosis of CED and no TGFB1 pathogenic variant identified [Nagasawa et al 2010, Yonezawa et al 2021].

The authors are aware of one teenager with CED who died following dissection of a dilated ascending aorta [Authors, personal communication]. To date, it is unknown if dilatation of the aorta is a rare manifestation of CED. The authors are unaware of any additional individuals with aortic disease. Because the mechanism of CED involves increased TGFB1 signaling, also found in Marfan syndrome and Loeys-Dietz syndrome, incidence of aortic disease in those with CED should continue to be reassessed. At this time no recommendations for routine evaluation of the aorta can be made.

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

Genotype-Phenotype Correlations

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

Penetrance

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

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.

CED is referred to as "TGFB1-related diaphyseal dysplasia Camurati-Engelmann" in the 2023 revision of the Nosology and Classification of Genetic Skeletal Disorders [Unger et al 2023].

Prevalence

The prevalence is unknown. More than 300 affected individuals have been reported.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CED, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for CED.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 6 are recommended.

Agents/Circumstances to Avoid

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

Evaluation of Relatives at Risk

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

• Molecular genetic testing if the pathogenic variant in the family is known;
• Radiographic evaluation for hyperostosis if the pathogenic variant in the family is not known.

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Many individuals diagnosed with CED have an affected parent.
• Some individuals diagnosed with CED may have the disorder as the result of a de novo TGFB1 pathogenic variant. The proportion of individuals with CED caused by a de novo pathogenic variant is unknown.
• If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• 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 without appropriate clinical evaluation (radiographs) of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents.

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because of reduced penetrance, some individuals who inherit a TGFB1 pathogenic variant will not have manifestations. The exact penetrance is unknown.
• CED is associated with significant intrafamilial phenotypic variability; the severity of disease manifestations in affected sibs is impossible to predict [Hughes et al 2019].
• If the proband has a known TGFB1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism.

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

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

Related Genetic Counseling Issues

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

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the TGFB1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for CED are possible. Because of reduced penetrance, results of prenatal testing may not be useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

TGFB1 encodes transforming growth factor beta-1 (TGFB1), which is synthesized as a large precursor molecule. TGFB1 preprotein contains a signal peptide of 29 amino acids that is proteolytically cleaved. TGFB1 is further cleaved after amino acid 278 to form latency-associated peptide (LAP) and active TGFB1. LAP dimerizes with interchain disulfide links at Cys223 and Cys225. TGFB1 can be secreted as an inactive small latent complex that consists of a mature TGFB1 homodimer non-covalently associated with an LAP homodimer at LAP residues Ile⁵³-Leu⁵⁹. LAP shields the type II receptor binding sites in the mature TGFB1. Most cells secrete TGFB1 as a large latent complex (LLC) of TGFB1/LAP covalently bound between Cys³³ in the LAP chains and latent TGFB1-binding protein (LTBP). LTBPs facilitate TGFB1 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.

The majority of pathogenic variants in individuals with Camurati-Engelmann disease (CED) result in single amino acid substitutions in the carboxy terminus of 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 TGFB1 [Walton et al 2010], leading to increased active TGFB1 release from the cell. p.Arg218His mutated fibroblasts from individuals with CED showed increased active TGFB1 in the cell media compared to normal fibroblasts [Saito & Kinoshita 2001]. In vitro analysis of p.Arg218Cys, p.His222Asp, and p.Cys225Arg mutated constructs also showed increased active TGFB1 in the medium of transfected cells. In contrast, the p.Leu11_Leu13dup and p.Tyr81His pathogenic variants caused a decrease in the amount of TGFB1 secreted. However, in a luciferase reporter assay specific for TGFB1-induced transcriptional response, the mutated cells showed increased luciferase activity, suggesting intracellular activation of the receptor [Janssens et al 2003]. TGFB1 pathogenic variants may alter bone remodeling processes in part by aberrant activation of Rho GTPases [Chen et al 2022].

Mechanism of disease causation. Gain of function

Acknowledgments

The authors would like to thank all of the individuals with Camurati-Engelmann disease and their families for contributing to the understanding of this disorder.

Revision History

• 31 August 2023 (sw) Comprehensive updated posted live
• 12 October 2017 (ha) Comprehensive update posted live
• 5 March 2015 (me) Comprehensive update posted live
• 6 December 2012 (me) Comprehensive update posted live
• 1 June 2010 (me) Comprehensive update posted live
• 16 August 2006 (me) Comprehensive update posted live
• 25 June 2004 (me) Review posted live
• 18 March 2004 (sw) Original submission

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