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Journal: 12663 Article: 196
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CASE REPORT1
2 Osteomyelitis of the Mandible in a Patient with Osteopetrosis.3 Case Report and Review of the Literature
4 Carlos Moreno Garcıa • Marıa Asuncion Pons Garcıa •
5 Raul Gonzalez Garcıa • Florencio Monje Gil
6 Received: 6 December 2009 / Accepted: 3 March 20117 ! Association of Oral and Maxillofacial Surgeons of India 2011
8 Abstract Osteopetrosis is a rare hereditary bone disorder
9 presenting with variable clinical features and is character-
10 ized by an increase in bone density and reduction of mar-
11 row spaces that result from a defect in the function of
12 osteoclasts and, consequently, a decrease in bone turnover.
13 This disease is generally divided into three types: severe
14 infantile malignant autosomal recessive, intermediate mild
15 autosomal recessive, and benign autosomal dominant. The
16 prognosis of the first two types is very poor and is char-
17 acterized by an early onset, usually within the first decade
18 of life, and early death. The benign-type is characterized by
19 a later onset and a longer life span. Ten percent of osteo-
20 petrosis cases develop osteomyelitis that usually involves
21 the mandible. The osteomyelitis is generally caused by
22 tooth extraction or pulpal necrosis. The leading cause of
23 the increased rate of infection is thought to be a lack of
24 adequate bone vasculature. Treatment of osteomyelitis
25 secondary to osteopetrosis is controversial. Treatment
26 regimens include high-dose systemic antibiotics coupled
27 with thorough debridement of necrotic bone and primary
28 closure of soft tissues, if possible. Hyperbaric oxygen has
29 been used for the treatment of chronic osteomyelitis.
30
31Introduction
32Osteopetrosis, also known as Albers-Schonberg disease,
33osteopetrosis generalisata [1] and marble bone disease
34[2, 3] was first described in 1904 by the German radiologist
35Albers-Schonberg [1, 4–6] as a bone disease with an
36increase in cortical bone mass at the expense of the med-
37ullary bone. In 1926, Karshner [7] introduced the term
38osteopetrosis to describe this disease [8]. It is a rare
39hereditary bone disorder [1, 6] presenting with variable
40clinical features and is characterized by an increase in bone
41density and reduction of marrow spaces that result from a
42defect in the function of osteoclasts [1, 4], and conse-
43quently, a decrease in bone turnover [6, 9]. It has been
44shown that the normal amount of osteoclasts are present,
45but that the cells are inactive or incompetent [8, 10].
46The disease represents a spectrum of clinical variants
47due to the heterogeneity of genetic defects resulting in
48osteoclast dysfunction. Classic osteopetrosis occurs in two
49varieties described as malignant and benign diseases [11].
50Malignant osteopetrosis is transmitted as a mendelian-
51recessive trait and is diagnosed at birth or during early
52childhood. They had a generalized increase in bone density
53and myelofibrosis suffering from hepatosplenomegaly,
54anemia, thrombocytopenia, and neurologic manifestations
55like optic atrophy [12]. They usually die during the first
56years of age because of anemia or secondary infection [13].
57At the moment, allogenic hemopoietic stem cell trans-
58plantation is the only curative treatment of autosomal
59recessive osteopetrosis and should be offered as early as
60possible [12, 14].
61The benign variety of osteopetrosis is transmitted as a
62mendelian-dominant trait, develops later, and is diagnosed
63at third or fourth decade of life by means of a routine
64roentgenograms. There are two forms differentiated by
A1 C. M. Garcıa (&) ! R. G. Garcıa ! F. M. GilA2 Department of Oral and Maxillofacial Surgery-Head and NeckA3 Surgery, University Hospital Infanta Cristina, Badajoz, SpainA4 e-mail: [email protected]
A5 M. A. P. GarcıaA6 Department of Neurology, University Hospital Infanta Cristina,A7 Badajoz, Spain
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65 clinical and radiological signs. Autosomal dominant oste-
66 opetrosis (ADO) type I is characterized by a pronounced
67 and symmetrical osteosclerosis of the skull and an enlarged
68 thickness of the cranial vault [15]. Clinically, ADO type I
69 is the only type of osteopetrosis not associated with
70 increased fracture rate [16, 17]. Less sclerosis of the skull
71 was found in type II (Albers-Schoberg disease) and it was
72 more pronounced in the base. Clinical manifestations of
73 ADO type II are dominated by long-bone fractures, which
74 occur, with or without trauma, in 78% of the patients [18].
75 Other classic manifestations of ADO type II include hip
76 osteoarthritis, facial nerve palsy, and mandibular osteo-
77 myelitis [2, 12, 18].
78 An intermediate type described by Beighton et al. [19] is
79 more prevalent in practice. Tips and Lynch [20] reported
80 no racial or sexual predisposition. Malfunction of osteo-
81 clastic activity results in excessive formation of immature
82 bone, thickening of the cortical bones, and narrowing or
83 obliteration of the medullary cavities. It is believed that
84 osteoclasts fail to release the necessary lysosomal enzymes
85 for bone resorption into the extracellular space [21, 22].
86 Defects in different genes have been described that lead to
87 a phenotype with osteopetrosis. These defects include
88 mutations in the gene encoding carbonic anhydrase II, the
89 proton pump gene and the chloride channel gene. Recently,
90 the immune response has been incriminated in the patho-
91 genesis of various metabolic bone diseases, including
92 osteopetrosis.
93 Both cytotoxic T lymphocyte-associated antigen 4 and
94 programmed death-1, a newly identified immunoregulatory
95 receptor, have been shown to negatively regulate immune
96 responses, and to affect osteoclastogenesis and bone
97 remodelling [23, 24]. The clinical presentation and radio-
98 logical picture may vary according to the severity of the
99 disease.
100 Case Report
101 A 26 years old white male was referred to the Department
102 of Oral and Maxillofacial Surgery, University Hospital
103 Infanta Cristina of Badajoz, Spain for evaluation and
104 treatment of chronic abscess in the right side of the face.
105 The patient explained that the process started 6 months ago
106 after the extraction a molar of the mandible. Facial
107 examination revealed a infection of the mandible and a
108 wide abscess in the submandibular region of the right side
109 of the face with draining fistula. Intraoral examination
110 revealed extensively exposed necrotic bone with seques-
111 trum in the right mandibular molar area. Past medical
112 history revealed the diagnosis of ADO, with numerous
113 bone fractures. The patient was bearer of a hip joint
114 prosthesis (Figs. 1, 2).
115A radiolucent, poorly demarcated image demonstrating
116evidence of sequestrum in the posterior right side of the
117mandible suggestive of a chronic osteomyelitis was
118observed in the panoramic radiograph (Fig. 3). An increase
119in bone density, with obliteration of the medullar spaces
120and loss of distinction between the cortex and medulla was
121present in the CT-scan. A hypodense image was observed
122in the posterior region of the right side of the mandible,
123showing destruction of the vestibular cortical suggestive of
124chronic osteomyelitis (Fig. 4).
125A biopsy was performed. The histopathology was
126reported as consistent with osteomyelitis. The treatment
Fig. 1 Past medical history revealed numerous bone fractures
Fig. 2 The patient was bearer of a hip joint prosthesis
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127 consisting in intravenous antibiotic therapy (clindamicyn),
128 debridement of the necrotic bone and sequestrum and
129 drainage of the abscess. He was submitted to a systemic
130 antibiotic regimen and daily irrigation of the osteomyelitis
131 region with iodine. Subsequently the patient maintained the
132 same antibiotic by oral administration for 10 days.
133 The chronic osteomyelitis remained unresolved for the
134 past 3 months and acute episodes are managed with anti-
135 biotic therapy (Co-amoxiclav, Metronidazole…). Hyper-
136 baric oxygen was used, with poor results. The condition
137 has maintained a chronic course for the last 12 months.
138 Discussion
139 The osteopetrosis are caused by a diminished activity of
140 osteoclasts, which results in defective remodelling of bone
141and increased bone density [12]. Osteopetrosis is generally
142divided into three types: severe infantile malignant auto-
143somal recessive, intermediate mild autosomal recessive,
144and benign autosomal dominant [3, 25]. The prognosis of
145the first two types is very poor and is characterized by an
146early onset, usually within the first decade of life, and early
147death. The benign-type is characterized by a later onset and
148a longer life span [3, 6].
149Dominant forms are more common [26]. Two subtypes
150of ADO are reported based on radiographical features [27].
151In type I (ADO I), there are generalized, diffuse osteo-
152sclerosis affecting mainly the cranial vault [27], due to
153mutation in the gene located in chromosome 11q12–13,
154precisely in the region where a high-bone-mass syndrome
155has been localised [28]. Type II (ADO II), the form orig-
156inally described in 1904 by Albers-Schonberg [29], is the
157most common form with an estimated prevalence of up to
1585.5/100,000. A gene residing in chromosome 16p13.3
159encoding the ClCN7 chloride channel [11], essential for the
160acidification of the extracellular resorption lacuna of
161osteoclast [30], is mainly defective in ADO II [31].
162There are three clinically distinct forms of autosomal
163recessive osteopetrosis (ARO) [32]. The most common
164ARO (also called the malignant type) [33], has severe
165manifestations, and presents in the infantile age group,
166presumably due to mutations either in the TCIRG1 gene
167which encode for the a3 subunit of the vacuolar H(?)-
168ATPase or in the ClCN7 gene encoding an osteoclast-
169specific chloride channel [34]. These patients have bone
170marrow compromise as a result of bone overgrowth in the
171marrow space. They usually die from anemia with con-
172gestive heart failure, or sepsis in their infancy or childhood.
173The increased susceptibility to severe infection is pre-
174sumably related to pancytopenia secondary to marrow
175space obliteration. The second ARO type with carbonic
176anhydrase II deficiency is associated with renal tubular
177acidosis and cerebral calcification, extramedullary hae-
178matopoiesis, hepatosplenomegaly and pancytopenia. The
179third recessive type is milder, presenting in childhood with
180variable orthopaedic and dental symptoms. They tend to
181have radiographical evidence of the disease, short stature,
182macrocephaly, increased upper segment/lower segment
183ratio, decreased arm span, mandibular prognathism, nerve
184compression, and a tendency for developing fractures and
185osteomyelitis. Of the 18 affected family members in 11
186families with this form reported so far, many children were
187asymptomatic with only radiographical disease. In many of
188these cases, there was parental consanguinity [31, 32].
189In osteopetrosis, the determining factor for healing is the
190vascularity of the bone. Consequently, in such patients the
191healing process is slow, the outcome often unfavorable, and
192the bone becomes susceptible to infection [35]. Osteomy-
193elitis is a well-recognized complication of osteopetrosis
Fig. 3 Panoramic radiograph showing sclerosis of the jaws, greatdistortion in permanent teeth, hypercementosis and evidence of bonesequestrum on the posterior right side of the mandible
Fig. 4 CT showed a generalized increase in bone density and in theposterior region of the right side of the mandible was seen ahypodense image suggestive of abscess
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194 [2, 3, 36, 38, 39], and the general dental practitioner should
195 be aware that the reduced vascularity of bone and impaired
196 white cell function might lead to the development of oste-
197 omyelitis in patients with osteopetrosis. The most common
198 site of involvement is the mandible, and it is associated with
199 dental extractions or surgical exposure of the pathologic
200 bone [1, 6].
201 Patients with osteopetrosis frequently visit the dentists
202 for several complications like dental caries, delayed erup-
203 tion and early loss of teeth, enamel hypoplasia, malformed
204 roots and crowns, and thickening of the lamina dura; with
205 the most common problem being caries. Constriction of the
206 canals housing neurovascular bundles supplying the teeth
207 and jaws as well as obliteration of the marrow cavities and
208 dental pulp chambers, lead to bone necrosis and dental
209 caries [31], and ultimately develop osteomyelitis in 10% of
210 cases. Osteomyelitis may be potentially severe with a
211 protracted course due to the accompanying anemia and
212 neutropenia [31].
213 The change in bone structure is accompanied by a
214 marked tendency toward fragility, and fractures may be
215 sustained even in trivial accidents [35]. The pathologic
216 fractures in patients with osteopetrosis are likely the result
217 of structural weakness associated with poorly organized
218 bone and persistent accumulations of immature bone and
219 calcified cartilage. With progression of the disease, the
220 bones become increasingly sclerotic and opaque on radio-
221 graphs, the latter feature giving rise to the term ‘‘marble
222 bone’’ [4, 35]. The frontal and nasal bones may be dense
223 and somewhat enlarged, and the air sinuses may be
224 obscured [1, 35]. According to Bakeman et al. [3], osteo-
225 petrosis radiographically appears as an increased density of
226 the entire skeleton (e.g., ribs, pelvis, clavicle, femur, skull
227 base, and jaws). The long bones show increased cortical
228 thickening and decreased marrow space, and become club-
229 shaped. The pelvis and the scapula may show endobone
230 formations [3]. The presence of hypercementosis, involv-
231 ing different teeth, was also mentioned, was reported in the
232 literature only by Smith [6, 35].
233 The malignant form presents with devastating symptoms
234 early in childhood and rapid worsening of the condition,
235 resulting in a short lifespan, whereas the benign formmay be
236 diagnosed late in childhood with a variety of prominent
237 clinical features, such as frontal bossing, leonine facies,
238 malocclusion of teeth and hepatosplenomegaly [39]. Atyp-
239 ical features may include microcephaly and a normal upper
240 segment to lower segment ratio. A radiological skeletal
241 survey usually reveals increased bone density with poor
242 differentiation between the cortex and the medulla. The
243 defective remodelling process characteristic of osteopetrosis
244 has many clinical implications in the head and face regions.
245 Cranial imaging of autosomal recessive osteopetrosis shows
246 small optic canals, orbits and nasoethmoid complex. The
247paranasal sinuses are either poorly pneumatized, like the
248mastoid air cells, or show bud formation [40] Areas of
249condylar cartilage calcification may be seen [1]. These
250radiological characteristics of underdevelopment may sup-
251port the theory that delayed maturation is the primary mor-
252phological abnormality in osteopetrosis and that bone
253thickening is a secondary manifestation to reduced bone
254turnover. Of importance in the head and neck region is the
255stenosis and compression of the cranial foramina, resulting
256in multiple cranial palsies. The optic, olfactory, trigeminal,
257facial and cochlear nerves are most commonly affected.
258Cummings et al. [41] reported the case of a six-month-old
259infant who was diagnosed with malignant autosomal
260recessive osteopetrosis and was found to have optic nerve
261pallor secondary to orbital fissure narrowing (seen on
262computed tomography of the brain) [24].
263Batra and Shah [54] reported a case of osteomyelitis of
264the mandible following tooth extraction in a 19-year-old
265woman with malignant osteopetrosis. This result was
266attributed to the poor bone vascularization and reduced local
267defences. Most teeth were unerupted and the paranasal
268sinuses were not aerated (as seen on computed tomographic
269evaluation of the facial bones). The initial clinical diagnosis
270was a draining gingivobuccal fistula; however, failure to
271respond to broad-spectrum antibiotics and the pathological
272description of the debrided bony fragments of the right
273maxilla shifted the diagnosis to chronic osteomyelitis. The
274chronicity of this infection has necessitated repeated surgi-
275cal intervention for further debridement of the necrotic tis-
276sues and infected bone [24].
277Ten percent of osteopetrosis cases develop osteomyelitis
278that usually involves the mandible. The osteomyelitis is
279generally caused by tooth extraction or pulpal necrosis. The
280leading cause of the increased rate of infection is thought to
281be a lack of adequate bone vasculature. Treatment of the
282infection is difficult because of the large amounts of poorly
283vascularized bone with gradual obliteration of the marrow
284space in the affected regions. Multiple draining fistulae and
285bony sequestrum are common clinical finding [8].
286Osteomyelitis of the maxilla is very rare, probably because
287of the thin cortical bone and rich collateral blood supply
288[12].
289Radiographically, the typical brugger jersey spineQ and
290endobones (bbone within a boneQ) were seen in the pelvis of
291the patients with ADO type II. These alterations are not
292present in ADO type I patients. On the other hand, radio-
293graphs in patients with ADO type I showed a pronounced
294sclerosis of the skull with an enlarged thickness of the cra-
295nial and facial walls positively correlated to age. The scle-
296rosis of the skull in type II was most striking at the base.
297Laboratory findings in ADO usually show the characteristic
298of a myelophthisic anemia due to the obliteration of hemo-
299poietic marrow cavities [2, 5, 24, 55].
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300 Important differential diagnoses considered are pykno-
301 dysostosis, metaphyseal dysplasia, diaphyseal sclerosis,
302 melorheostosis, osteopetrosis striata, osteopoikilosis,
303 Engelmann’s disease and infantile cortical sclerosis [31].
304 Treatment of osteomyelitis secondary to osteopetrosis is
305 controversial. Treatment regimens include high-dose sys-
306 temic antibiotics coupled with thorough debridement of
307 necrotic bone and primary closure of soft tissues, if possible
308 [2–4]. Hyperbaric oxygen (HBO) has been used for the
309 treatment of chronic osteomyelitis [3, 4]. Mechanisms of
310 HBO action in osteomyelitis include enhanced leucocytic
311 killing, osteoclastic resorption of the dead osteomyelitic
312 tissue, fibroblastic division, collagen production, neovas-
313 cularisation, and enhanced permeation of certain antibiotics
314 (aminoglycosides) across bacterial cell walls within the
315 necrotic tissue. As osteoclasts are 100 times more meta-
316 bolically active than osteocytes, its function is highly oxy-
317 gen dependant [31]. There are few reports demonstrating the
318 success of treatment; in many cases, the osteomyelitis
319 remains unresolved indefinitely [2, 12]. In a review of 57
320 cases of osteomyelitis resulting from osteopetrosis, most
321 cases were found to be chronic and resistant to treatment [2].
322 Unfortunately, there seems to be no definitive treatment for
323 osteopetrosis of the maxilla or mandible without complete
324 removal of the affected bone. In order to minimize such
325 problems, patients with osteopetrosis should be encouraged
326 to maintain good dental care and oral hygiene, because there
327 is a potential risk of promoting osteomyelitis if surgical
328 procedures are performed [6].
329 Management of osteopetrosis has to be individualised
330 because of the wide spectrum of clinical symptoms and
331 complications. Medical management of osteopetrosis
332 revolves around modulation of the osteoclasts, either to
333 stimulate the remaining host osteoclasts or to provide an
334 alternative source of the same. Restriction of calcium
335 intake [56], high-dose calcitriol therapy, steroids, para-
336 thyroid hormone and recombinant human interferon
337 gamma-1b, have all been attempted to stimulate the host
338 osteoclasts with variable success rate.
339 Use of a microvascularized osseous free flap may be
340 favorable but may be precluded because of absence of a
341 suitable donor site in these patients [12].
342 Palliative treatment, including nerve decompression and
343 debridement, seems to be the best course of action. The
344 best treatment appears to be preventive management with
345 routine dental care. Teeth should be endodontically treated,
346 if possible, rather than extracted, because periosteal strip-
347 ping of bone may predispose asymptomatic bone to
348 become necrotic and to sequester. Any debridement should
349 be as conservative as possible, removing only grossly
350 necrotic bone through limited flap dissections. Because the
351 disease process is systemic, there is often no clear delin-
352 eation between affected and unaffected bone [9].
353Recently, bone marrow transplantation has been suc-
354cessfully used in the treatment of malignant osteopetrosis,
355offering hope to those so afflicted; [6, 57] it has been
356curative in a significant percentage of patients but an
357acceptable donor can be found in only about 40% [31].
358
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