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At a glance

A musculoskeletal syndrome with progressive hyperostosis of the diaphyses of the long bones and the skull base, clinically manifesting as often severe limb pain, muscle weakness and wasting, a waddling gait, and joint contractures.

Synonyms

Progressive Diaphyseal Dysplasia; Engelmann Disease; Osteopathia Hyperostotica Scleroticans Multiplex Infantilis.

History

The syndrome bears the names of the Italian physician Mario Camurati (1896-1948), who in 1922 described four generations of an affected family, and of the Czechoslovakian orthopedic surgeon Guido Engelmann (1876-1959), who described another case in 1929. However, the British physician Edward A. Cockayne (1880-1956) may have been the first to describe the disease in 1920.

Incidence

The exact incidence is unknown. To date, more than 300 cases have been described. No racial predilection.

Genetic inheritance

Autosomal dominant. CED is caused by mutations in the β1 transforming growth factor (TGFβ1) gene located on chromosome 19q13.2. TGFβ1 activity is increased in CED patients. A rare CED variant exists in which TGFβ1 is not altered. There is a wide inter- and even intrafamilial variability in the phenotypical expression (eg, age at disease onset, speed of progression, and severity of the disease). A tendency of anticipation has been suggested in some families, ie, the course of the disease exhibits a more severe phenotype with an earlier age of onset in successive generations.

Pathophysiology

Under normal circumstances, TGFβ1 stimulates bone formation and suppresses bone resorption. Growth suppression of fibroblasts and proliferation of osteoblasts lead to the characteristic thickening of bony cortices on periosteal surfaces and in the medullary canal. Initially, the disorder occurs in femur and tibia, but will then progressively spread to other bones. TGFβ1 is also a known inhibitor of adipogenesis and myogenesis (with impaired fusion of myoblasts into multinucleated myotubes), thus due to the increased TGFβ1 activity in CED this explains, at least in part, cachexia, muscle weakness, and wasting.

Diagnosis

Based on the clinical findings and confirmed by radiographs (radiological anomalies are present in 94% of patients, with cortical thickening of the diaphyses of the long bones being the first manifestation). Bone scintigraphy may reveal increased osteoblastic activity (in 74% of patients) in limbs, pelvis, skull, and spine, sometimes even before sclerotic changes become detectable on radiographs. Electron microscopic examination of muscle biopsies may reveal selective atrophy of type II fibers and/or thickening of the capillary basement membrane.

Clinical aspects

The disease typically presents with severe bone pain (in 68% of patients; especially in the legs), gait anomalies (in 48%; waddling and broad-based), difficulties in running, easy fatigability (in 44%), and reduced muscle mass with proximal muscle weakness (in 39%) in childhood or adolescence, but onset as late as well beyond the seventh decade ...

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