Year : 2008 | Volume
: 20 | Issue : 4 | Page : 151--156
Infantile malignant osteopetrosis: A case report with review of literature
Sunil Chaudhary1, Arun Sharma2,
1 Department of Oral Medicine and Radiology, I.T.S. Centre for Dental Studies and Research, Delhi-Meerut Road, Murad Nagar, Ghaziabad-201 206, Uttar Pradesh, India
2 Department of Pedodontics and Preventive Dentistry, I.T.S. Centre for Dental Studies and Research, Delhi-Meerut Road, Murad Nagar, Ghaziabad-201 206, Uttar Pradesh, India
Sector-14, House No. 166, Vasundhara, Ghaziabad-201 012, Uttar Pradesh
Osteopetrosis is a rare hereditary, generalized disorder of bone characterized by a significant increase in the density of the skeletal tissues usually manifesting in two basic forms: an autosomal dominant benign form (osteopetrosis tarda) and an autosomal recessive malignant form (osteopetrosis congenita). The present article documents an incidentally diagnosed case of malignant osteopetrosis in a 4-year-old child with periapical abscess. It is our belief that given the nature of this disease, its nosological confusion and lack of definitive treatment modalities, as oral physicians we can still manage such cases merely by timely preventive measures, early intervention and by avoiding complications. This was just a single case which was incidentally diagnosed; our focus must shift to the many cases which otherwise go unnoticed to ensure that timely intervention can be lifesaving.
|How to cite this article:|
Chaudhary S, Sharma A. Infantile malignant osteopetrosis: A case report with review of literature.J Indian Acad Oral Med Radiol 2008;20:151-156
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Chaudhary S, Sharma A. Infantile malignant osteopetrosis: A case report with review of literature. J Indian Acad Oral Med Radiol [serial online] 2008 [cited 2022 Jul 4 ];20:151-156
Available from: https://www.jiaomr.in/text.asp?2008/20/4/151/52828
Osteopetrosis is a rare hereditary, generalized disorder of bone characterized by a significant increase in the density of the skeletal tissues usually manifesting in two basic forms: an autosomal dominant benign form (osteopetrosis tarda) and an autosomal recessive malignant form (osteopetrosis congenita). A third form, the intermediate recessive type, has also been reported in literature associated with carbonic anhydrase II deficiency, renal tubular acidosis and cerebral calcification. In all three forms, pathologic alteration of osteoclastic bone resorption, thickening of cortical and lamellar bones are the main features. Hence osteopetrosis is basically a group of uncommon genetic disorders characterized by increased skeletal density and abnormal bone remodeling. ,
Patients with infantile malignant osteopetrosis are the most severely affected and even though more common than the intermediate recessive form, they are still rarely seen in the general population.  Carious exposure of dental pulps leading to osteomyelitis is a recognized complication and may contribute to the early death of the patient. Thus preventive measures directed at aborting caries and its sequelae, or the need for extraction is recommended because they can be lifesaving for these patients.  The present article documents an incidentally diagnosed case of malignant osteopetrosis in a 4-year-old child with periapical abscess. The importance of routine radiography is highlighted with a need for prompt care emphasized to avoid complications that might result in significant mortality in such patients.
A four-year-old male patient accompanied his parents to the Out-Patient Department of Oral Medicine and Radiology, Kothiwal Dental College and Research Centre, Moradabad, India, with the chief complaint of pain in lower right back tooth region for the past few days. Pain was mild, intermittent, throbbing, aggravated while eating and relieved by itself.
On general examination, the patient was thin built, short statured with physical milestones seemingly delayed. He had a typical big head, frontal bossing, exophthalmus and hypertelorism [Figure 1]. Extra-oral examination revealed cervicofacial lymphadenopathy with localized tenderness in right submandibular lymph nodes. Family history revealed he was the only child, there was no significant past history. Intra-oral examination revealed presence of full complement of deciduous teeth and caries in all the deciduous 2 nd molars. Clinical pulp exposure was present in 55, 74 and 85 with tenderness in 85. Based on the findings of pulpal exposure and tender lymphadenopathy, a diagnosis of periapical abscess with 85 was made. An intra-oral periapical radiograph was taken for confirmation of the clinical diagnosis. To our surprise we noted a non-specific opacification of image. A scout panoramic radiograph was taken for generalized examination of both the arches. The panoramic image also showed an overall increase in bone density, including the mandible, with full complement of teeth in mixed dentition along with features of periapical abscess [Figure 2]. Based on the clinical appearance of the patient and panoramic findings, a series of radiographs were then advised to rule out any associated syndrome or underlying systemic disease. These included a lateral cephalogram, posterior-anterior skull view, hand, wrist and radiographs of lower extremities.
A lateral cephalogram analysis revealed a characteristic increase in bone density, faint sutural and vascular markings and obliteration of all the paranasal sinuses. Whole skull showed homogenous opacification involving the cranial vault with indistinct inner and outer cortical table and absence of diploic space. Increased radiopacity made the whole image distorted with complete homogenization of the roof of skull with absence of distinction between inner and outer cortical table. Mastoid air cells, paranasal sinuses, orbits were also involved. The pituitary fossa appeared small because of a thickened anterior and posterior clinoid process. Appearance of the teeth in the maxillary and mandibular arch was non-specific because of increased radiopacity. Cervical vertebrae also showed an increase in overall radiodensity. A postero-anterior skull radiograph also revealed opacification similar to those of the lateral cephalogram [Figure 3].
Hand radiograph showed a characteristic diffuse homogenous sclerosis of all the bones with clubbing and transverse striation at the ends of the long bones. Increased cortical density with transverse striations and a relative radiolucent centre gave a bone within bone appearance in the wrist and as well in the radius and ulna [Figure 4a] and [Figure 4b]. The ends of the long bones appeared flared with widening of the shafts [Figure 5]. Chest radiograph was also planned but could not be taken because the patient reported with the complaint of headache and lethargy during the radiographic series. Considering the overall clinical picture a differential diagnosis of sclerosing bone disease was formulated.
Routine blood examination including peripheral smear and serum biochemistry revealed moderate to severe pancytopenia with low red blood count (3 million/cu ml), low hemoglobin percentage (7.1 gm %) and platelet count (1.08 lacs/cu ml). WBC count was also low (8700 /cu ml) with overall decrease in neutrophils (26%) and lymphocytes (76%). Blood smear indicated normoblastic hypochromic (myelophthistic) anemia. Blood chemistry revealed normal serum calcium, phosphorus and alkaline phosphatase levels except the acid phosphatase level which was above normal (1.1 U/L). A general physician confirmed hepatosplenomegaly and ascites [Figure 6] with a positive history of recurrent upper respiratory infection which was not disclosed earlier by the patient in history taking. Based on history (age), clinical examination with findings of generalized homogenous bones opacification and blood picture, a diagnosis of periapical abscess with 85 in malignant osteopetrotic patient was made. Empirical antibiotic therapy (Tab Amoxicillin 125 mg thrice daily) was prescribed and pulpectomy of abscessed 85 was done along with exposed 55, 74. Subsequently the patient was referred to a tertiary health care centre where the systemic symptoms could be taken care of.
Alber-Schonberg first reported osteopetrosis in 1904. In 1921, Schulze described it as marmorknochen / marble bone disease after observing this peculiar appearance in six cases from German literature. In 1926, Karshner termed this disease entity 'osteopetrosis' ( stone-like or petrified bone ) and noted that the increased hardness more closely resembled limestone than that of marble. Subsequently, many surgical reports described the consistency of osteopetrotic bone as chalklike.  The actual incidence of osteopetrosis is unknown; however it is thought to be 1 in 1,00,000 to 1 in 5,00,000. Clinical features of osteopetrosis depend remarkably on its severity and speed of onset. Malignant osteopetrosis generally begins in utero, often resulting in stillbirth or sometimes appears very early, progresses rapidly with the patient failing to survive even infancy. At the other extreme, the disease is diagnosed incidentally from routine radiography. All the other degrees of severity seem to exist between these two forms. ,,
The infantile malignant form is marked by widespread osteopetrosis, a characteristic heavy head with frontal bossing, hypertelorism, and blindness. The principal manifestations are anemia, infections, sensory disorders and fractures, due to generalized bone condensation. Moreover, 75% of the patients with infantile osteopetrosis die before the age of six, many of recurrent infections, especially pneumonia, or osteomyelitis complicated by septicemia. , Retarded growth, exophthalmus, flattened nose, mandibular prognathism, and cranial nerves palsies are seen. Severe hematological malformation with bone marrow failure and hepatosplenomegaly lead to an intractable myelophthis anemia causing severe constitutional symptoms.  All these hallmark features, except palsies, were also present in our patient.
In the second benign form, the disease is milder, benign; not incompatible with life and symptoms might be entirely absent. Anemia and hepatosplenomegaly are rare. Neurologic disturbances may result from narrowing of cranial nerve exit foramina and pressure on nerve trunks. Pathologic fractures are a problem; however healing is normal. Infections are also prone to occur; however, the prognosis is better than that of the malignant form because these patients usually are not anemic.  Presence of anemia, hepatosplenomegaly with absence of any neurological symptoms distinguish the present case from benign form.
As normal bone develops, precursor elements lay down woven bone that is replaced by lamellar bone occurring through a resorptive and remodeling process, whereby bone trabeculae are added and aligned to support function, while maintaining spaces for the marrow elements between the trabeculae. In osteopetrosis, the primary spongiosum or initial bone does not remodel because of defective function of osteoclast. The resulting bone is dense but weak and susceptible to fracture. Healing occurs because osteoclastic function is impaired. In addition, bone continues to be laid down because of normal osteoblastic function; ultimately, the marrow spaces are obliterated because of the defective osteoclastic functions. Hyperplasia of the extra-osseous blood-forming elements develops, resulting in hepatomegaly, splenomegaly and enlarged lymph nodes, thus infection is a very serious complication in osteopetrosis. 
Histologic features of malignant osteopetrosis include a production of endosteal bone without any physiologic resorption. Significant numbers of osteoblasts with few or no osteoclasts and a persistence of cartilaginous core of trabecular bone in endochondral bone even after its ossification are seen. Trabecular pattern is usually disorganized and marrow tissue, fibrous. Evidence of bone remodeling with deficit collagen matrix in the benign form differentiate it from the malignant form. [11-13] Serum calcium, phosphorus and alkaline phosphatase levels are usually in normal limits. However, acid phosphatase level may be increased because of an increase in the number of non-functioning osteoclasts.  In the present case only acid phosphatase level (1.1 U/L) was increased.
Other sclerotic bone diseases sharing common features with osteopetrosis include pyknodysostosis, fluorosis, diffuse cementosis, Engelmann's disease, melorheostosis and endosteal hyperostosis. Pyknodysostosis, "a condition of abnormally dense bone" is an autosomal recessive disorder characterized by benign osteopetrosis, dwarfism, shortened terminal phalanges, delayed closure of the fontanels and occasionally, open cranial sutures. Underdeveloped paranasal sinus is frequently seen. Other features like brachycephalic skull, obtuse mandibular angle, micrognathia, exophthalmia, parrot beak nose may be present. Pectus excavatum, hypoplastic clavicle, kyphosis, scoliosis, genu valgu and bowing of long bones can be been seen with absence of severe anemia and hepatosplenomegaly. Healing of pathologic fractures occurs well in these patients. 
Hyperostosis generalisata is characterized by a thickening of subcutaneous tissues with subsequent deformities of extremities (multiple joint ankylosis) and scalp. Absence of bone fragility differentiates fluorosis and cementosis from osteopetrosis. Engelmann's disease is characterized by symmetric spindle shaped sclerotic thickening of corticated bones with narrowing of medullary cavities in long bones leading to pain and weakness especially in legs. 
Endosteal can be further categorized into different subtypes that include endosteal hypostasis, sclerosteosis, diaphyseal dysplasia, osteoclasia with hyperphosphatemia, infantile cortical hyperostosis, pyknodysostosis, craniometaphyseal dysplasia and osteitis deformans. ,,,,, Cotton wool appearance with an increased level of alkaline phosphatase values differentiates Paget's disease from osteopetrosis. Melorheostosis greatly resembles osteopetrosis however, and can be differentiated because of involvement of only a single extremity. Other endosteal are usually associated with increase bone deposition in selected sites. Abnormal serum values like elevated serum alkaline phosphatase are usually helpful in differentiating these diseases with that of osteopetrosis. 
Radiographically, osteopetrosis is usually generalized, affecting many bones of the skeleton. The characteristic appearance is an amorphous, structureless, overall increase in density involving the entire bone; however, trabeculation still can be seen with diminished marrow spaces. The maxilla and face are more commonly affected with least changes in mandible. Within the jaws, the alveolar bone is the least likely to be affected. There can also be a thickening of the inferior border of the mandible and cortical outlines of the inferior alveolar canal. The thickening is more evident in the anterior body of the mandible with a diminishing involvement towards the angle. Loss of lamina dura and root outline is usually obscured due to opacification. In osteopetrosis, the mandibular angle becomes much more obtuse leading to angle class III malocclusion. In most instances periapical infection is not usually identified in the image. However, minor infection is unlikely to cause major changes in a normal person but may cause intractable osteomyelitis. ,
In the skull, the cartilaginous base is more likely to be involved than the calvaria. It appears densely sclerotic with clubbing and thickening of the posterior clinoid process; the pituitary fossa may appear small. The frontal and nasal bones may be dense and the paranasal sinuses obliterated. When calvaria are affected, the entire cranial vault may appear uniformly thickened, with a loss of diploic space. The cranial foramina may appear diminished in size. The various sutural and vascular markings may be lost, and the cranium may have a homogenous amorphous density resembling "a bladder of lard". , These features as well as the skeletal changes were consistent with the present case report.
Reported dental changes in osteopetrosis include delayed eruption, early loss of teeth, missing teeth, malformed roots and crown, teeth that are poorly calcified, prone to caries, and thickened lamina dura. ,,, The roots are often deformed and stunted and may be irregularly covered by cementum. Osteomyelitis secondary to odontogenic infection is a common complication in these patients.,, The disease can be severe and difficult to treat in these patients with resultant gross disfigurement due to surgical removal of the affected facial and skeletal bones. Fortunately, the advent of antibiotics has greatly reduced the prevalence of osteomyelitis in the maxillofacial skeletal. Thus, any preventive measures directing at aborting caries and its sequelae or the need for extraction are recommended because they can be lifesaving for these patients. Endodontic procedures are preferred over extraction to avoid post-operative infection or pathologic fractures and even the simplest procedures should be performed with antibiotic coverage. [23-26] Treatment in severe cases includes incision and drainage, antibiotics, sequestrectomy, extraction of teeth, saucerization, decortications, resection of the jaw and hyperbaric oxygen, singularly or in combination.  Though periapical abscess was also diagnosed in the present case, timely antibiotic and nonsurgical intervention of causative tooth helped the patient avoid any untoward complication.
Various therapeutic strategies have been tried like corticosteroids, limitation of calcium, calcitrol, parathormone, erythropoietin and interferon gamma (IFNγ) to reverse the phenotype or slow the progression of the disease, but with minimal success. ,, Prednisolone given in these patients is believed to inhibit bone and cartilage mineralization thereby reducing bone mass. Treatment with IFNγ has been shown to generate some improvement of osteopetrosis but not in all patients probably due to heterogeneous nature of the disease. IFNg decreases the number of severe infections and to a small extent increases bone resorption due to its ability to induce superoxide production. Superoxide is thought to be directly involved in the breakdown of bone matrix proteins, indicating that in those cases where bone matrix degrading enzymes are affected, IFNg might have an effect. It is less likely that osteopetrosis caused by defects in the demineralization process of bone is ameliorated, but as the effects of IFNg have not been correlated to the type of mutation in the patients, this possibility cannot be excluded. 
At present, the only curative therapy for infantile malignant osteopetrosis is human stem cell transplant therapy with the success rate varying greatly depending on the type of donor.  Patients receiving grafts from HLA-identical siblings have a five-year disease free survival of 73-79% while transplantation with unrelated or mismatched donors only gives disease free survival of approximately 13-45%. Follow-up of treated children with osteopetrosis indicates that the age of the patient is important for the outcome. Hypercalcemia, one of the early and severe side effects, markedly increased when patients older than 2 years were given transplants. Besides, to stop the progressive vision impairment resulting from compression of the optic nerve, transplantation of younger patient is preferred. Even when patients are given transplants within the first months of life, these children may still suffer from growth retardation, vision impairment and damage to permanent teeth indicating a need for the indicating a need for the functional osteoclast transplanted prenatally. One approach that holds the potential to avoid these effects of osteopetrosis is in utero human stem cell transplantation. Since this route of administration requires a prenatal diagnosis of osteopetrosis and as osteopetrosis is very rare, this therapy is more useful in patients with a positive family history of infantile malignant osteopetrosis. ,
Osteopetrosis until recently wass thought to be caused only by functional abnormalities of osteoclast. The reason for this is not known but it is likely that the majority of mutations affecting osteoclastic formation are embryonic lethal in humans. , Most osteopetrotic mutations are found within genes encoding protein in the acidification pathway of the resorption lacuna between the osteoclast and bone surface. However, very recent findings add an osteoclast-poor form of osteopetrosis because of mutations in the gene encoding the osteoclast growth factor, receptor activator of nuclear factor kappa B (RANK)-ligand (TNFSF11) to the group of autosomal recessive variants. , Recent developments of gene therapies are promising in the near future for these rare sufferings in humans.
"The eye ultimately sees what the brain knows". And for this hard-core evidence must be presented in the form of clinical findings backed by strong radiologic substantiation. Since osteopetrosis shares many of its features with other diseases in this group of diseases, diagnostic accuracy is a must. It is our belief that given the nature of this disease, its nosological confusion and lack of definitive treatment modalities, as oral physicians we can still manage such cases by merely timely preventive measures, early intervention and by avoiding complications. This was just a single case which was incidentally diagnosed; our focus must shift to the many cases which otherwise go unnoticed to ensure that timely intervention can be lifesaving.
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