To the Editor:
Camurati-Engelmann disease (CED) is an autosomal-dominant condition, initially described by Cockayne in 19201. Camurati was the first to suggest the hereditary component in 1922, when he reported a rare symmetrical osteitis of lower limbs in a father and son and several others in a total of 4 generations2. Later, Engelmann reported a case with muscular wasting and important bone involvement3. The disease begins in an age span between 3 months and 50 years old, with higher prevalence in males. It is characterized by progressive cortical expansion, sclerosis, and symmetrical hyperostosis affecting the diaphyses of the long bones4,5. We describe a case of CED in a female patient with lower limb pain with progressive worsening and difficult diagnosis.
A 37-year-old woman from Manaus, Brazil, was referred for investigation of a 5-year history of fatigue, headache, and pain in both legs, worsening over the preceding year, that had not responded to a variety of analgesics. The initial investigation included the following: normal blood count, erythrocyte sedimentation rate 15 mm/h (ESR; normal 0 to 20); rheumatoid factor 47 II/ml (normal 10 IU/ml), C-reactive protein 10.3 mg/dl (normal < 8 mg/dl), a negative antinuclear factor, alkaline phosphatase 111 U/l (normal 38–126 U/l); serum calcium was 8.7 mg/dl (normal 8.4–10.6), ionized calcium 1.42 (normal 1.2–1.6), urinary calcium 421 mg/24 h (normal 200), inorganic phosphorus 2.8 mg/dl (normal 2.5–4.5), parathyroid hormone 62 pg/ml (normal 7–53); and negative Bence-Jones proteins and normal urinary sediment.
Radiographs of both lower limbs showed cortical thickening at the diaphyses, the medium third of the tibias, and distal third of the right and left middle femur causing obliteration of the medullary cavity (Figure 1); these alterations were confirmed by computed tomography (CT; Figure 2). Radiographs of the forearms were normal. Bone scintigraphy revealed asymmetrical increased uptake in the tibias, femurs, and humerals (Figure 3A, 3B). Biopsy of the tibias and right femur revealed typical osteoclasts, and osteoblasts distributed in a circle, compatible with hyperostosis and absence of malignancy. Examination revealed proximal muscle weakness in her lower limbs, with absence of muscular atrophy. Her gait was normal. The neurological and systemic examinations were normal and musculoskeletal examination confirmed pain at legs and knees, without arthritis. She had used nonsteroidal antiinflammatory drugs (NSAID), with improvement of clinical symptoms. Repeated laboratory tests were normal. Ophthalmological examination and audiometry were normal. Chest radiograph, head CT, and abdominal ultrasound scans were unremarkable. The clinical findings and characteristic radiological appearance led to the diagnosis of CED. It was decided to initiate prednisone 40 mg/day and maintain symptomatic medications. The molecular genetic investigation showed G653A; R218H mutations in exon-4 of the ß-TGF1 gene, located in chromosome 19q13, confirmed the diagnosis of CED. The symptoms improved over the next few months with the use prednisone.
CED, or progressive diaphyseal dysplasia, is a rare autosomal-dominant inherited bone disease (prevalence 1/1,000,000) with variable penetrance, typically presenting in childhood6; however, cases in adults have been described7. All races and both sexes are affected8. Hyperostosis is bilateral and symmetrical, usually at the diaphyses of long bones, especially the tibia, femur, fibula, humerus, radius, and ulna8.
The pathogenic mechanism underlying the sclerosing bone phenotype in patients with CED is increased transforming growth factor-ß1 (TGF-ß1) signaling as a result of disturbed activation or secretion of the mutant protein9,10. The responsible gene has been identified on chromosome 19q1311–13. Experimental results suggest the existence of 2 mechanisms of increased TGF-ß1 activity in CED, depending on the underlying mutation. In the first, illustrated by the R218C, H222D, and C225R mutations in exon 4 of TGF-ß1, secretion is normal, but the percentage of active TGF-ß1 is elevated9. In the second mechanism, illustrated by the LLL12-13ins and Y81H mutations, secretion is disturbed, leading to intracellular accumulation of TGF-ß19. In our patient we found G653A and R218H mutations in exon 4 of TGF-ß1 gene, located in chromosome 19q13. However, absence of mutations in the coding region of TGF-ß1 was described, indicating the existence of at least one other form14. Based on the existence of mutation in the TGF-ß1 or exclusion of the TGF-ß1 gene as the site of mutation, CED is classified as type I15 or type II14, respectively.
Bone pain in the extremities was reported to be the most common clinical symptom (68%); other important features were waddling gait (48%), easy fatigability (44%), and generalized muscle weakness (39%), or an asymptomatic presentation5,6. Campos-Xavier, et al10 found no obvious correlation between the manifestation of TGF-ß1 mutations and the severity of the clinical manifestations of CED. Laboratory findings (anemia, leukopenia, and elevated ESR) are not specific and occur occasionally16. Abnormal values for markers of bone resorption have been reported17.
The radiological changes include symmetrical endosteal and subperiosteal cortical thickening, and involve primarily the diaphyses, and may extend to the metaphysis but spare the epiphyses5,6. Typically the long bones, especially the femur and tibia, are affected, but skull, mandible, pelvis, and vertebral involvement is recognized5,6. Scintigraphy examination exposed increased osteoblastic activity in the affected regions (limbs, pelvis, skull)6.
As clinical and radiological variability is extensive, molecular analysis can provide an additional resource for a correct diagnosis6. Molecular genetic study was done through polymerase chain reaction and direct sequencing of the coding exons of the TGF-ß1 gene located in chromosome 19q13.
The differential diagnosis includes consideration of hereditary multiple diaphyseal sclerosis (Ribbing disease) and the group of the endosteal hyperostoses (Van Buchen, Worth, Nakamura, and Truswell-Hansen diseases)4. Other cranial-facial conditions resulting from osteodysplasias include Paget disease, fibrous dysplasia, especially in its pagetoid or sclerotic forms (in dysplasia there is expansion to the medullary cavity), osteogenesis imperfecta (van der Hoeve syndrome)18, and exostosis and exuberant osteoma, among others.
There is no specific treatment for CED. NSAID such as aspirin can alleviate pain, but are ineffective at improving bone changes6. Corticosteroids have been reported to provide effective symptomatic improvement16,19. Corticosteroids are antiinflammatory and immunosuppressive agents in bone, but decrease density (1) by increasing the apoptosis rate of osteoblasts and osteocytes while suppressing osteoblast proliferation, differentiation, and bone matrix synthesis; (2) by enhancing proliferation and differentiation of osteoclast precursors; and (3) by decreasing intestinal calcium absorption. Moreover, they change the activation/expression in TGF-ß1 receptors, inhibiting the induced transcription of the gene6. The initial dose of prednisone is 1 mg/kg/day, with progressive tapering and maintenance at 5 to 10 mg/day. Longterm steroid therapy is not recommended due to the secondary effects, including osteoporosis. Deflazacort, a steroid with an antiinflammatory effect similar to prednisolone but with fewer adverse effects, was started in a dose of 1.2 mg/kg/day and resulted in clinical and radiological improvement within 12 months with no side effects. Deflazacort may be a safe alternative steroid therapy20.
Biphosphonate reduced bone reabsorption, but its value in treatment of CED is disputed6. The use of pamidronate in CED has been reported, some reports describing worsening of bone pain19, others describing improvement in clinical symptoms of bone pain21.
Surgery is an alternative to drug therapy, with reaming of the medullary canal22 or osteotomy6. Physiotherapy is important for increasing motor amplitudes and muscle strength23.
In summary, CED should be considered in the differential diagnosis of nonspecific limb pain along with other musculoskeletal diseases.
Footnotes
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