Osteopetrosis


Osteopetrosis, literally "stone bone", 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.

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...
Autosomal recessive osteopetrosis, also known as malignant infantile osteopetrosis, is a rare type of skeletal dysplasia characterized by a distinct radiographic pattern of overall increased density of the bones with fundamental involvement of the medullary portion. Infantile osteopetrosis typically manifests in infancy. Diagnosis is principally based on clinical and radiographic evaluation, confirmed by gene analysis where applicable. As a result of medullary canal obliteration and bony expansion, grave pancytopenia, cranial nerve compression, and pathologic fractures may ensue. The prognosis is poor if untreated. The classic radiographic features include, endobone or "bone-within-bone" appearance in the spine, pelvis and proximal femora, upper limbs, and short tubular bones of the hand. Additionally, there is the Erlenmeyer flask deformity type 2 which is characterized by absence of normal diaphysial metaphysical modeling of the distal femora with abnormal radiographic appearance of trabecular bone and alternating radiolucent metaphyseal bands.
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, 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.

Adult osteopetrosis

Autosomal dominant osteopetrosis is also known as Albers-Schonberg disease. Most do not know they have this disorder because most individuals do not show any symptoms. However, the ones that do show symptoms will typically have a curvature of the spine, and multiple bone fractures. There are two types of adult osteopetrosis based on the basis of radiographic, biochemical, and clinical features.
CharacteristicType IType II
Skull SclerosisMarked sclerosis mainly of the vaultSclerosis mainly of the base
SpineDoes not show signs of sclerosisShows the rugger-jersey appearance
PelvisNo endobonesShows endobones in the pelvis
Risk of FractureLowHigh
Serum Acid PhosphateNormalVery 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.

Causes

The various types of osteopetrosis are caused by genetic changes in one of at least ten genes. There is nothing a parent can do before, during or after a pregnancy to cause osteopetrosis in a child.
The genes associated with osteopetrosis are involved in the development and/or function of osteoclasts, cells that break down bone tissue when old bone is being replaced by new bone. This process is necessary to keep bones strong and healthy. Mutations in these genes can lead to abnormal osteoclasts, or having too few osteoclasts. If this happens, old bone cannot be broken down as new bone is formed, so bones become too dense and prone to breaking.
Normally, bone growth is a balance between osteoblasts and osteoclasts. Sufferers of osteopetrosis have a deficiency of osteoclasts, meaning too little bone is being resorbed, resulting in too much bone being created.

Gene variation

Mechanisms

Normal bone growth is achieved by a balance between bone formation by osteoblasts and bone resorption 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 is 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 at least nine genes cause the various types of osteopetrosis. Mutations in the CLCN7 gene are responsible for about 75 percent of cases of autosomal dominant osteopetrosis, 10 to 15 percent of cases of autosomal recessive osteopetrosis, and all known cases of intermediate autosomal osteopetrosis. TCIRG1 gene mutations cause about 50 percent of cases of autosomal recessive osteopetrosis. Mutations in other genes are less common causes of autosomal dominant and autosomal recessive forms of the disorder. The X-linked type of osteopetrosis, OL-EDA-ID, results from mutations in the IKBKG gene. In about 30 percent of all cases of osteopetrosis, the cause of the condition is unknown.
The genes associated with osteopetrosis are involved in the formation, development, and function of specialized cells called osteoclasts. These cells break down bone tissue during bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. Bones are constantly being remodeled, and the process is carefully controlled to ensure that bones stay strong and healthy.
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.

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, pyknodysostosis, osteopoikilosis, osteopathia striata with cranial sclerosis, mixed sclerosing skeletal dysplasias, progressive diaphyseal dysplasia, SOST-related sclerosing skeletal dysplasias. Besides, the differential diagnosis includes acquired conditions that induce osteosclerosis such as osteosclerotic metastasis notably carcinomas of the prostate gland and breast, Paget's disease of bone, myelofibrosis, Erdheim-Chester disease, osteosclerosing types of osteomyelitis, sickle cell disease, hypervitaminosis D, and hypoparathyroidism.

Treatment

It was the 1st genetic disease treated with hematopoietic stem cell transplantation. There is no cure, although curative therapy with bone marrow transplantion is being investigated in clinical trials. It is believed the healthy marrow will provide the sufferer with cells from which osteoclasts will develop. 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. Treatment for osteopetrosis depends on the specific symptoms present and the severity in each person. Therefore, treatment options must be evaluated on an individual basis. Nutritional support is important to improve growth and it also enhances responsiveness to other treatment options. A calcium-deficient diet has been beneficial for some affected people.
Treatment is necessary for the infantile form:
Bone marrow transplantation improves some cases of severe, infantile osteopetrosis associated with bone marrow failure, and offers the best chance of longer-term survival for individuals with this type.
In pediatric osteopetrosis, surgery is sometimes needed because of fractures. Adult osteopetrosis typically does not require treatment, but complications of the condition may require intervention. Surgery may be needed for aesthetic or functional reasons, or for severe degenerative joint disease.

Prognosis

The long-term-outlook for people with osteopetrosis depends on the subtype and the severity of the condition in each person. The severe infantile forms of osteopetrosis are associated with shortened life expectancy, with most untreated children not surviving past their first decade. Bone marrow transplantation seems to have cured some infants with early-onset disease. However, the long-term prognosis after transplantation is unknown. For those with onset in childhood or adolescence, the effect of the condition depends on the specific symptoms. Life expectancy in the adult-onset forms is normal.

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.
Osteopetrosis affects 1 newborn out of every 20,000 to 250,000 worldwide, but the odds are much higher in the Russian region of Chuvashia due to genetic traits of the Chuvash people.

Recent research

The medication listed below have been approved by the Food and Drug Administration as orphan products for treatment of this condition.