Polyostotic fibrous dysplasia: a rare cause of pain in the leg

N. Soonawala1, A.M.J.B. Smets2, A.S.P. van Trotsenburg1

1Emma Kinderziekenhuis AMC, Amsterdam
2Department of radiology, AMC, Amsterdam


Case report
A 16-month-old boy was seen at the emergency department because of pain in his right upper leg after a minor injury from a fall. He is the second son of non-consanguineous Dutch parents and was born after an uncomplicated pregnancy. His growth and development had been normal. The family history was negative for bone diseases. Both parents were healthy. The mother had a large café-au-lait spot with an irregular border on her right upper arm. On physical examination, he was a healthy looking boy without any signs of precocious puberty. Physical examination of the right leg showed no abnormalities and further pediatric and orthopedic examinations were also normal. In view of a possible inflammation of the bone a full blood count was carried out that was normal.
 table 1
Figure 1: X-ray of lower limbs with lesions typical of fibrous dysplasia
Radiographic studies were performed revealing expansile, osteolytic lesions with a sharp border and ground-glass appearance in the proximal and distal parts of the right femur. The lesions were also seen in the left femur, left and right tibia, fibula, humerus, ulna and radius as well as in the ninth rib on the left side. The lesions were strikingly symmetrical and were typical of polyostotic fibrous dysplasia. Fractures were not observed. (see Fig.1) Since fibrous dysplasia may be associated with endocrine dysfunction, including precocious puberty, hyperthyroidism, hyperparathyroidism, growth hormone and cortisol overproduction, laboratory studies of plasma LH, FSH, testosterone, sex hormone-binding globulin, TSH, free T4, thyroxin, calcium, phosphate, insulin-like growth factor-1, ACTH and cortisol were performed and were all found to be normal. Only serum alkaline phosphatase levels were elevated (914 U/L) indicating high bone turnover. To exclude the McCune-Albright syndrome, DNA-analysis was performed in leucocytes. Both mother and son were tested for the known mutations in the GNAS 1-gene which were, however, not found. Four months after the diagnosis of polyostotic fibrous dysplasia, the boy developed a pathologic fracture of his right femur, two months later followed by a pathologic fracture of his left femur. Both fractures were successfully treated conservatively.

Fibrous dysplasia (FD) is a developmental abnormality of bone mesenchyma presenting as expansile fibrous lesions of the skeleton that may result in pathologic fracture. The X-ray appearance is that of expansile lesions with erosion and thinning of the cortex and a ground-glass appearance caused by metaplastic woven bone.1 Although the lesions are benign, sarcomatous degeneration has been described in approximately 0.5 per cent of the patients. The pathogenesis of FD remains obscure.
FD can be divided into monostotic and polyostotic forms. In monostotic FD only one bone is affected. Its peak incidence is found between ten and fifteen years of age with boys and girls equally affected. Polyostotic FD usually presents before the age of ten years with bone pain, a limp, deformity of the extremity and pathologic fractures. It is more common in females, the female to male incidence ratio being 3:1. Bones most commonly affected are the facial bones, ribs, phalanges, humerus, radius, femur, tibia, and pelvis. A tendency towards segmental distribution in the bones of one limb is observed, usually the lower one; this segmental distribution pattern is a hallmark of FD.1 The symmetrical arrangement of the bone lesions in this case is inconsistent with this finding. Often serum alkaline phosphatase levels are increased, reflecting a high bone turnover.
Polyostotic FD may occur solely with bony lesions, the so-called Jaffé-Lichtenstein type, but may be associated with other disorders such as hypophosphataemia, hyperparathyroidism, neurofibromatosis, Mazabraud's syndrome and McCune-Albright syndrome. In this patient the normal laboratory findings excluded hypophosphataemia and hyperparathyroidism. Physical examination showed no signs of neurofibromatosis or of Mazabraud's syndrome in which FD is accompanied by intramuscular myxomas and which occurs mainly in adults.2 McCune-Albright syndrome is usually caused by mozaicism for a mutation in the GNAS1- gene (20q13.2). The GNAS1-gene encodes a G-protein that stimulates the production of cAMP. The mutation results in a continuous activation of the G-protein leading to overproduction of cAMP in affected tissues.3,4 This results in a hyperfunction of affected endocrine organs, frequently giving rise to precocious puberty, hyperthyroidism, growth hormone and cortisol overproduction. Secondly, there is an increased proliferation of melanocytes resulting in large café-au-lait spots with irregular margins as opposed to the regular outlined café-au-lait spots in neurofibromatosis. Thirdly, cAMP is thought to have an effect on the differentation of osteoblasts leading to FD.5
This patient did not have café-au-lait spots and laboratory and DNA analysis were normal. DNA analysis was, however, performed on his peripheral leucocytes, while the mutation is predominantly expected in affected tissues. If this patient would ever have to undergo surgery in the future, a bone biopsy for further DNA analysis could be considered in the same surgical session, as this would spare the child from an additional invasive procedure. It is remarkable that mother has a large café-au-lait spot with irregular margins, typical for McCune-Albright syndrome. This probably is a coincidental finding since a postzygotic mutation is most likely in McCune-Albright syndrome. However, a few familial cases have been described.6
There is no known treatment for FD. Several trials with calcitonin have been carried out but without any clinical or radiological change. Intravenous bisphosphonates have also been tried and have led to clinical and radiological improvement via reduced bone remodelling. However, in young patients the potential influence of bisphosphonates on growth plate mineralisation has to be taken into account.7



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