Osteopetrosis, literally , also known as marble bone disease or Albers-Schönberg disease, is an extremely rare inherited disorder whereby the bones 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. Osteopetrosis can cause bones to dissolve and break.
It is one of the hereditary causes of osteosclerosis. It is considered to be the prototype of osteosclerosing dysplasias. The cause of the disease is understood to be malfunctioning osteoclasts and their inability to resorb bone. Although human osteopetrosis is a heterogeneous disorder encompassing different molecular lesions and a range of clinical features, all forms share a single pathogenic nexus in the osteoclast. The exact molecular defects or location of the mutations taking place are unknown. Osteopetrosis was first described in 1903 by German radiologist Albers-Schönberg.
Signs and symptoms
thumb|A 17-year-old male with osteopetrosis: Typical cranial deformity and thoracic scoliosis
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.
thumb|The metabolism of calcium, phosphate, hormones, and Vitamin D
However, serious forms can result in the following:
The precise and early diagnosis of infantile osteopetrosis is important for management of complications, genetic counselling, and timely institution of appropriate treatment, namely hematopoietic stem cell transplantation (HSCT), which offers a satisfactory treatment modality for a considerable percentage of infantile osteopetrosis. Amelioration of radiographic bone lesions after HSCT in infantile osteopetrosis has been proposed as an important indicator of success of the therapy. A few publications with limited study participants have demonstrated the resolution of skeletal radiographic pathology following HSCT.
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Adult osteopetrosis
Autosomal dominant osteopetrosis (ADO) is also known as Albers-Schönberg disease. Most do not know they have this disorder because most individuals do not show any symptoms. However, those who do show symptoms will typically have a curvature of the spine (scoliosis) and multiple bone fractures. There are two types of adult osteopetrosis based on the basis of radiographic, biochemical, and clinical features.
{| class="wikitable"
!Characteristic
!Type I
!Type II
|-
|Skull sclerosis
|Marked sclerosis mainly of the vault
|Sclerosis mainly of the base
|-
|Spine
|Does not show signs of sclerosis
|Shows the sandwich appearance
|-
|Pelvis
|No endobones
|Shows endobones in the pelvis
|-
|Risk of fracture
|Low
|High
|-
|Serum acid phosphate
|Normal
|Very high
|}
Many patients will have bone pains. The defects are very common and include neuropathies due to cranial nerve entrapment, osteoarthritis, and carpal tunnel syndrome. About 40% of patients will experience recurrent fractures of their bones. 10% of patients will have osteomyelitis of the mandible. If this happens, old bone cannot be broken down as new bone is formed, so bones become too dense and prone to breaking.
Gene variation
{| class="wikitable"
|-
! Name
! OMIM
! Gene
|-
| OPTA1
|
| LRP5 receptor
|-
| OPTA2
|
| CLCN7 chloride channel
|-
| OPTB1
|
| TCIRG1 ATPase
|-
| OPTB2
|
| RANKL
|-
| OPTB3
|
| CA2 (renal tubular acidosis)
|-
| OPTB4
|
| CLCN7 chloride channel
|-
| OPTB5
|
| OSTM1 ubiquitin ligase
|-
| OPTB6
|
| PLEKHM1 adapter protein
|-
| OPTB7
|
| TNFRSF11A (RANK receptor)
|}
Mechanisms
Normal bone growth is achieved by a balance between bone formation by osteoblasts and bone resorption (breakdown 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.
Osteopetrosis can be caused by underlying mutations that interfere with the acidification of the osteoclast resorption pit, for example due to a deficiency of the carbonic anhydrase enzyme encoded by the CA2 gene. Carbonic anhydrase is required by osteoclasts for proton production. Without this enzyme hydrogen ion pumping is inhibited and bone resorption by osteoclasts is defective, as an acidic environment is needed to dissociate calcium hydroxyapatite from the bone matrix. As bone resorption fails while bone formation continues, excessive bone is formed.
Mutations in any of the genes associated with osteopetrosis lead to abnormal or missing osteoclasts. Without functional osteoclasts, old bone is not broken down as new bone is formed. As a result, bones throughout the skeleton become unusually dense. The bones are also structurally abnormal, making them prone to fracture. These problems with bone remodeling underlie all of the major features of osteopetrosis.thumb|Protein TNFSF 11(RANKL)
Diagnosis
The differential diagnosis of osteopetrosis includes other disorders that produce osteosclerosis. They constitute a wide array of disorders with clinically and radiologically diverse manifestations. Among the differential diagnosis are hereditary ostoesclerosing dysplasias such as; neuropathic infantile osteopetrosis, infantile osteopetrosis with renal tubular acidosis, infantile osteopetrosis with immunodeficiency, infantile osteopetrosis with leukocyte adhesion deficiency syndrome (LAD-III), pyknodysostosis (osteopetrosis acro-osteolytica), osteopoikilosis (Buschke–Ollendorff syndrome), osteopathia striata with cranial sclerosis, mixed sclerosing skeletal dysplasias, progressive diaphyseal dysplasia (Camurati–Engelmann disease), SOST-related sclerosing skeletal dysplasias.
Treatment
It was the first genetic disease treated with hematopoietic stem cell transplantation (osteoclasts are derived from hematopoietic precursors). There is no cure, although curative therapy with bone marrow transplantation is being investigated in clinical trials. It is believed the healthy marrow will provide cells from which osteoclasts will develop.
Prevalence
Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. One in every 100,000 to 500,000 individuals is born with this form of osteopetrosis. Higher rates have been found in Denmark and Costa Rica. Males and females are affected in equal numbers.
The adult type of osteopetrosis affects about 1,250 individuals in the United States. One in every 200,000 individuals is affected by the adult type of osteopetrosis. Higher rates have been found in Brazil. Males and females are affected in equal numbers. worldwide, but the odds are much higher in the Russian region of Chuvashia (1 of every 3,500–4,000 newborns) due to genetic traits of the Chuvash people.
Recent research
Recent research demonstrated that the systematic administration of RANKL for one month to Rankl(-/-) mice, which closely resemble the human disease, significantly improved the bone phenotype and has beneficial effects on bone marrow, spleen and thymus; major adverse effects arise only when mice are clearly overtreated. Overall, it provided evidence that the pharmacological administration of RANKL represents the appropriate treatment option for RANKL-deficient ARO patients, to be validated in a pilot clinical trial.
Interferon gamma-1b is FDA-approved to delay the time to disease progression in patients with severe, malignant osteopetrosis.
Notable cases
- Laurel Burch
- Henri de Toulouse-Lautrec (osteopetrosis was at one time thought to be what he suffered from, but it was later discovered to be pycnodysostosis)
References
Bibliography
- GeneReviews/NCBI/NIH/UW entry on CLCN7-Related Osteopetrosis