Osteopetrosis

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

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 the following:

Stunted growth, deformity, and increased likelihood of fractures
Patients experience anemia, 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 nerves by the extra bone
Abnormal cortical bone morphology
Abnormal form of the vertebral bodies
Abnormality of temperature regulation
Abnormality of the ribs
Abnormality of vertebral epiphysis morphology
Bone pain
Cranial nerve paralysis
Craniosynostosis
Hearing impairment
Hypocalcemia
Malignant infantile osteopetrosis

Autosomal recessive osteopetrosis, also known as malignant infantile osteopetrosis or infantile malignant 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 the absence of normal diaphyseal 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-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 and multiple bone fractures. There are two types of adult osteopetrosis based on the basis of radiographic, biochemical, and clinical features.

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.

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.
Normally, bone growth is a balance between osteoblasts and osteoclasts. This process is necessary to keep bones strong and healthy. Those with osteopetrosis have a deficiency of osteoclasts, meaning too little bone is being resorbed, resulting in too much bone being created. 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. 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.
Three different types of inheritance-autosomal dominant, autosomal recessive and X-linked recessive have been observed.

Mutations in the CLCN7 gene cause most cases of autosomal dominant osteopetrosis, 10-15% of cases of autosomal recessive osteopetrosis, and all known cases of intermediate autosomal osteopetrosis.
Mutations in the TCIRG1 gene cause about 50% of cases of AR osteopetrosis.
Mutations in the IKBKG gene cause X-linked osteopetrosis.
Mutations in the CA-II gene can be an extremely rare cause of AR osteopetrosis in the setting of renal defects.
Mutations in the RANKL gene cause AR osteoclast-poor osteopetrosis.
Mutations in other genes are less common causes of osteopetrosis.
In about 30% of affected people, the cause is unknown.
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 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.

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 first genetic disease treated with hematopoietic stem cell transplantation. 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. 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:

Vitamin D appears to stimulate dormant osteoclasts, which stimulates bone resorption
Gamma interferon can have long-term benefits. It improves white blood cell function, decreases bone volume, and increases bone marrow volume.
Erythropoietin can be used for anemia, and corticosteroids can be used for anemia and to stimulate bone resorption.

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.