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.
Figure
1: X-ray of lower limbs with lesions typical of
fibrous dysplasia
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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.
Comment
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
References
1.
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Rockwood
CA, Wilkins KE, Beaty JH. Fractures in children.
4th edition, Lippincott-Raven Publishers
1996:205-6
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2.
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Cabral
CE, Guedes P, Fonseca T. Polyostotic fibrous
dysplasia associated with intramuscular myxomas:
Mazabraud's syndrome. Skeletal Radiology
1998;27:278-82
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3.
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Weinstein
LS, Shenker A, Gejman PV et al. Activating
mutations of the stimulatory G protein in the
McCune-Albright syndrome. N Eng J Med
1991;325:1688-95.
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4.
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Schwindinger
WF, Francomano CA, Levine MA. Identification of a
mutation in the gene encoding the alpha subunit of
the stimulatory G-protein of adenylyl cyclase in
McCune-Albright syndrome. Proc Nat Acad Sc
1992;89:5152-6.
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5.
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Olsen
B. A rare disorder, yes; an unimportant one, never.
J Clin Invest 1998;101:1545-6.
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6.
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Alvarez-Arratia
MC, Rivas F, Avila-Abundis A et al. A probable
monogenic form of polyostotic fibrous dysplasia.
Clin Genet 1983;24:132-9.
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Liens
D, Delmas PD, Meunier PJ. Long-term effects of
intravenous pamidronate in fibrous dysplasia of
bone. Lancet 1994;343:953-4.
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