Osteopetrosis is a very rare heredity disorder in children caused by a defect in bone resorption. The osteoclast plays a big role in the human body in remodeling the bone. The malfunctioning of the osteoclast result in the thickening of the bone, but the bone becomes more fragile and brittle. The osteopetrosis is being specialized into three types; type 1 is the autosomal dominant osteopetrosis (ADO), type 2 is the intermediate autosomal recessive and the type 3 is autosomal recessive. The type 1 occurred most frequent where approximately 5:100,000 births were reported 6. Then, the autosomal recessive or also known as the Malignant Infantile Osteopetrosis (MIOP) is the least common and most severe where approximately 1:250,000 births has been reported 6.
The autosomal dominant osteopetrosis (ADO) was divided into two subtypes that are ADO-I and ADO-II 9. The ADO-I is the least severe form where it results in subtle bone thickening and frequently asymptomatic 9. The ADO-II is more severe and asymptomatic to 10-20% sufferers that do not show any symptoms until they reach their twenties. The autosomal recessive is the most severe type that could cause death if early treatment not being given.
The normal healthy bone associated with 80% of cortical bone and 20% of trabecular bone. The porosity of healthy bone is usually lower than 5% and the percentage would increase with the age. However, this condition does not occur in osteopetrotic sufferers.
The word osteopetrosis origin from the Greek word where ‘osteo’ meaning bone and ‘petrosis’ meaning stone. Osteopetrosis is caused by the event of malfunctioning or missing of the osteoclast. The osteoclast is important in remodeling the bone, the differentiation and function of the osteoclast would cause an increase in the bone density. The bone would decrease in porosity and would increase the bone thickness on the inside of the bone and would make the bone to be unstable and become brittle.
This disease that associated with an increased skeletal mass due to the abnormally dense bone can be generalized its appearance radiographically with “bone within a bone” appearance tolar. The transverse radiolucent bands may be visualized and the marrow cavity may be hard to be recognized. The change in activity and function of osteoclast cause the medullary cavity to be filled with endochondral new bone, with little space remaining for hematopoietic cells.
The bone density is dependent on the function of osteoblasts and osteoclasts. Osteoblasts are of mesenchymal origin to synthesize bone matrix while osteoclasts are multinucleated cells of hematopoietic lineage and function in resorbing and remodeling the bone. The osteoblasts secrete colony-stimulating factor (M-CSF), granulocyte-macrophage-colony-stimulating factor (GM-CSF), interleukin-1, and interleukin-6, 5 which would facilitate the function of osteoclasts.
The genetic etiologies such as the mutations in the gene ATP6i (TCIRG1)coding for an osteoclast-specific a3 subunit V-ATPase vascular pump is a type of protein that responsible in creating a highly acidic microenvironment underneath the osteoclast-resorbing lacuna required for the solubilization of the hydroxyapatite crystals of bone 8. Another genetic etiologies has been discovered recently in the infantile recessive osteopetrosis that is the mutations in the CIC7 (CIcn7) chloride channel uk. The ATP6i and C1C7 are both proven to affect the osteoclasts resorption.
Children who had been affected usually showing the symptoms on the first year of their life and usually on the first three months 8. The most reported concern by the parents is regarding the child’s vision. The complications that affect the vision are such as failure to achieve normal visual milestones, roving eye movements, and/or squint are often reported 8. The failure to thrive and recurrent infection, both secondary to the underlying anemia and bone marrow involvement are other symptoms that could occur. However, there are also less common symptoms being a complaint, that are hypocalcemic seizures, excessive bruising, fractures, nasal congestion, and an abnormal craniofacial appearance 8. The symptoms are not specific and invariably present at an early age that may be missed and the rarity of the disease causes the initial correct clinical diagnosis cannot be made. Frequently it is the distinctive sclerotic bony changes on a radiograph that alerts the clinician. The diagnosis would be confirmed if the child has features of anemia with compensatory erythropoietic hepatosplenomegaly and/or visual impairment.
The PU. 1 is the important factor for early production of osteoclasts. The defect would affect the other hematopoietic cells including the myeloid cells and B cells. The PU. 1 are observed to interact with microphthalmia transcription factor (Mitf) but the differentiation take place later and the osteoclasts are observed to be abnormal in appearance 5. In normal activities, the differentiation occurs when the receptor activator of nuclear factor-(kappa)B (RANK) ligand produced by osteoblasts binds to RANK on osteoclast precursors 5. However, the differentiation could not occur with osteoclasts with defects in genes 5. The signaling for the interaction is mediated by tumor necrosis factor receptor-associated factor 6 (TRAF-6), nuclear factor-(kappa)B (NF-(kappa)B), and c-fos 5. In disorder of acidification that results in lower defects in differentiation, the defects are included in carbonic anhydrase II (CAII), the osteoclast-specific proton pump, and the gene encoding a chloride channel (CLCN7) 5.
Figure 1: Molecules Affecting Osteoclast Differentiation and Function 5.
The activation of the receptor activator of nuclear factor-(kappa)B (RANK) would be by the cytokine RANK ligand (RANKL). The interleukin-1, interleukin-6, and interleukin-11 would enhance the expression of RANKL. The osteoprotegerin (OPG) that also produced by osteoclasts are functioned in osteoclasts differentiation and activation by blocking the interaction of RANK and RANKL 5. The signaling would influence the differentiation in several ways associated with the RANK and RANKL that through the tumor necrosis factor receptor-associated factor 6 (TRAF-6) and nuclear factor (kappa)B (NF_(kappa)B). the TRAF-6 also effects on the mitogen-activated protein (MAP) kinases and the MAP kinases would target the AP-1 transcription factor, c-fos and c-jun. The differentiation of the osteoclasts is influenced by these pathways 5.
Figure 2: The model of roles of RANK and RANKL5.
The diagnosis of the osteopetrosis in clinical are after the history and physical examination and the appearance can be visualized greatly through radiography. The examination can be either confirmed by using the plain radiography, Dual-energy X-ray Absorptiometry, radiotracers, Compute Tomography scan (CT scan) and also the Magnetic Resonance Imaging (MRI).
Figure 3: The Erlenmeyer flask deformity of the distal femur (arrows) and generalized increased bone density 6.
Figure 4: The “bone-in-bone” appearance of phalanges 6
Figure 5: (a) Sclerosis of vertebral endplates giving rise to “sandwich” vertebrae (arrows) 6. (b) The ‘rugger jersey’ appearance 7.
Figure 6: (a) Loss of mandibular angle (arrow) and increased thickness of vault 6. (b) Sclerosis and thickening of orbital rims 7.
Figure 7: The increase of bone mineral density (BMD) using Dual-energy X-ray Absorptiometry 2.
Figure 8: The appearance of ‘sandwich’ vertebrae using the computed tomography scan (CT scan), 2.
Figure 9; MRI showing compressed optic nerve sheath 3