Osteopetrosis
Encyclopedia
Osteopetrosis, literally "stone bone", also known as marble bone disease and Albers-Schonberg disease is an extremely rare inherited disorder
whereby the bone
s harden, becoming denser, in contrast to more prevalent conditions like osteoporosis
, in which the bones become less dense and more brittle, or osteomalacia
, in which the bones soften.
It can cause osteosclerosis
.
The exact mechanism is unknown. However, deficiency of carbonic anhydrase
in osteoclasts is noted. The absence of this enzyme causes defective hydrogen ion pumping by osteoclasts and this in turn causes defective bone resorption by osteoclasts, as an acidic environment is needed for dissociation of calcium hydroxyapatite from bone matrix. Hence, bone resorption fails while its formation persists. Excessive bone is formed.
, recurrent infections and hepatosplenomegaly
due to bone expansion leading to bone marrow
narrowing and extramedullary hematopoiesis
. It can also result in blindness
, facial paralysis
, and deafness, due to the increased pressure put on the nerve
s by the extra bone.
include other disorders which can cause diffuse osteosclerosis, such as hypervitaminosis D
, and hypoparathyroidism
, Paget's disease
, diffuse bone metastasis of breast
or prostate cancer
(which tend to be osteoblastic while most metastases are osteolytic
), intoxication with fluoride
, lead
or beryllium
, and hematological disorders such as myelofibrosis
, sickle cell disease and leukemia
.
If complications occur in children, patients can be treated with vitamin D
. Gamma interferon has also been shown to be effective, and it can be associated to vitamin D. Erythropoetin has been used to treat any associated anemia
. Corticosteroids may alleviate both the anemia and stimulate bone resorption. Fractures and osteomyelitis
can be treated as usual.
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
whereby the bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
s harden, becoming denser, in contrast to more prevalent conditions like osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
, in which the bones become less dense and more brittle, or osteomalacia
Osteomalacia
Osteomalacia is the softening of the bones caused by defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium, or because of overactive resorption of calcium from the bone as a result of hyperparathyroidism...
, in which the bones soften.
It can cause osteosclerosis
Osteosclerosis
Osteosclerosis, an elevation in bone density, is normally detected on an X-ray as an area of whiteness, and is where the bone density has significantly increased...
.
Pathogenesis
Normal bone growth is achieved by a balance between bone formation by osteoblasts and bone resorption (break down of bone matrix) by osteoclasts. In osteopetrosis, the number of osteoclasts may be reduced, normal, or increased. Most importantly, osteoclast dysfunction mediates the pathogenesis of this disease.The exact mechanism is unknown. However, deficiency of carbonic anhydrase
Carbonic anhydrase
The carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...
in osteoclasts is noted. The absence of this enzyme causes defective hydrogen ion pumping by osteoclasts and this in turn causes defective bone resorption by osteoclasts, as an acidic environment is needed for dissociation of calcium hydroxyapatite from bone matrix. Hence, bone resorption fails while its formation persists. Excessive bone is formed.
Symptoms
Despite this excess bone formation, people with osteopetrosis tend to have bones that are more brittle than normal. Mild osteopetrosis may cause no symptoms, and present no problems. However, serious forms can result in stunted growth, deformity, increased likelihood of fractures, also patients suffers anemiaAnemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, recurrent infections and hepatosplenomegaly
Hepatosplenomegaly
Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...
due to bone expansion leading to bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
narrowing and extramedullary hematopoiesis
Extramedullary hematopoiesis
Extramedullary hematopoiesis refers to hematopoiesis occurring outside of the medulla of the bone.In some cases, it may be physiologic. For example, during fetal development, hematopoiesis occurs at many different locations, such as the liver and spleen....
. It can also result in blindness
Blindness
Blindness is the condition of lacking visual perception due to physiological or neurological factors.Various scales have been developed to describe the extent of vision loss and define blindness...
, facial paralysis
Paralysis
Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...
, and deafness, due to the increased pressure put on the nerve
Nerve
A peripheral nerve, or simply nerve, is an enclosed, cable-like bundle of peripheral axons . A nerve provides a common pathway for the electrochemical nerve impulses that are transmitted along each of the axons. Nerves are found only in the peripheral nervous system...
s by the extra bone.
Variations
There are several forms:| Name | OMIM | Gene |
|---|---|---|
| OPTA1 | LRP5 LRP5 Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the LRP5 gene.- Function :LRP5 is a transmembrane low-density lipoprotein receptor that binds and internalizes ligands in the process of receptor-mediated endocytosis... |
|
| OPTA2 | CLCN7 CLCN7 Chloride channel 7, also known as CLCN7, is a human gene. In melanocytic cells this gene is regulated by the Microphthalmia-associated transcription factor.-External Links:*... |
|
| OPTB1 | TCIRG1 TCIRG1 V-type proton ATPase 116 kDa subunit a isoform 3 is an enzyme that in humans is encoded by the TCIRG1 gene.- Function :Through alternate splicing, this gene encodes two protein isoforms with similarity to subunits of the vacuolar ATPase but the encoded proteins seem to have different functions... |
|
| OPTB2 | TNFSF11 | |
| OPTB3 | CA2 Carbonic anhydrase II Carbonic anhydrase II , is one of fourteen forms of human α carbonic anhydrases. Carbonic anhydrase catalyzes reversible hydration of carbon dioxide... (renal tubular acidosis Renal tubular acidosis Renal tubular acidosis is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine. When blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for exchange of salts, acid... ) |
|
| OPTB4 | CLCN7 CLCN7 Chloride channel 7, also known as CLCN7, is a human gene. In melanocytic cells this gene is regulated by the Microphthalmia-associated transcription factor.-External Links:*... |
|
| OPTB5 | OSTM1 OSTM1 Osteopetrosis-associated transmembrane protein 1 is a protein that in humans is encoded by the OSTM1 gene.-Further reading:... |
|
| OPTB6 | PLEKHM1 PLEKHM1 Pleckstrin homology domain-containing family M member 1 also known as PLEKHM1 is a protein that in humans is encoded by the PLEKHM1 gene.- Function :PLEKHM1 may have critical function in vesicular transport in osteoclasts.... |
|
| OPTB7 | TNFRSF11A |
Differential diagnosis
The differential diagnosesDifferential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
include other disorders which can cause diffuse osteosclerosis, such as hypervitaminosis D
Hypervitaminosis D
Hypervitaminosis D is a state of vitamin D toxicity.The recommended daily allowance is 400 IU per day. Overdose has been observed at 1925 µg/d...
, and hypoparathyroidism
Hypoparathyroidism
Hypoparathyroidism is decreased function of the parathyroid glands with under production of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany , and several other symptoms...
, Paget's disease
Paget's disease
Sir James Paget, a surgeon and pathologist, described several diseases, including:* Paget's disease of bone * Paget's disease of the breast* Paget-Schroetter disease* Extramammary Paget's disease...
, diffuse bone metastasis of breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
or prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
(which tend to be osteoblastic while most metastases are osteolytic
Osteolysis
Osteolysis refers to an active resorption of bone matrix by osteoclasts as part of an ongoing disease process.-Osteolysis in joint replacement:...
), intoxication with fluoride
Fluoride
Fluoride is the anion F−, the reduced form of fluorine when as an ion and when bonded to another element. Both organofluorine compounds and inorganic fluorine containing compounds are called fluorides. Fluoride, like other halides, is a monovalent ion . Its compounds often have properties that are...
, lead
Lead poisoning
Lead poisoning is a medical condition caused by increased levels of the heavy metal lead in the body. Lead interferes with a variety of body processes and is toxic to many organs and tissues including the heart, bones, intestines, kidneys, and reproductive and nervous systems...
or beryllium
Beryllium
Beryllium is the chemical element with the symbol Be and atomic number 4. It is a divalent element which occurs naturally only in combination with other elements in minerals. Notable gemstones which contain beryllium include beryl and chrysoberyl...
, and hematological disorders such as myelofibrosis
Myelofibrosis
Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow...
, sickle cell disease and leukemia
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
.
Treatment
The only durable cure for osteopetrosis types affecting the osteoclasts (most types) is bone marrow transplant.If complications occur in children, patients can be treated with vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
. Gamma interferon has also been shown to be effective, and it can be associated to vitamin D. Erythropoetin has been used to treat any associated anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. Corticosteroids may alleviate both the anemia and stimulate bone resorption. Fractures and osteomyelitis
Osteomyelitis
Osteomyelitis simply means an infection of the bone or bone marrow...
can be treated as usual.
External links
- International Osteopetrosis Association
- GeneReviews/NCBI/NIH/UW entry on CLCN7-Related Osteopetrosis
- http://www.rarediseases.org/search/rdbdetail_abstract.html?disname=Osteopetrosis